|
1
|
Osterlund E, Hammarström K, Nunes L, Mathot L, Mezheyeuski A, Sjöblom T, Glimelius B. Primary tumour location, molecular alterations, treatments, and outcome in a population-based metastatic colorectal cancer cohort. BJC REPORTS 2025; 3:38. [PMID: 40437037 PMCID: PMC12120107 DOI: 10.1038/s44276-025-00156-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 05/04/2025] [Accepted: 05/13/2025] [Indexed: 06/01/2025]
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) patients in trials are selected. The aim was to study mCRC features population-based. METHODS All 765 mCRC patients in the Uppsala region, Sweden, 2010-2020 were identified and analysed for RAS (n = 356/708) and BRAF-V600E (n = 123/708) mutations (mt) and deficient mismatch repair (dMMR, n = 58/643). RESULTS Right colon primary tumours were associated with BRAF-V600Emt and dMMR and had worse median overall survival (mOS) than left colon or rectal mCRC. RAS&BRAF wildtype (wt) and proficient MMR were seen in 22%, 45%, and 31% of right colon, left colon, and rectum, respectively. Patients with right colon primaries received best supportive care only more often (34% vs 25% vs 24%) and metastasectomy less often (21% vs 31% vs 33%) than left colon and rectal primaries. In molecularly homogeneous subgroups (RAS&BRAFwt/RASmt/BRAF-V600Emt/dMMR) no difference in mOS were seen between right and left colon primaries, whereas rectal primaries had better mOS (26/15/8/9 vs 24/21/8/8 vs 32/23/6/NA months, respectively). This was also the case in homogenous treatment groups. Primary tumour location turned non-significant in multivariable OS analyses. CONCLUSIONS The high variation of BRAF-V600Emt, RASmt, dMMR, and treatment allocation population-based per primary tumour location explain the poor outcome in right-sided cancers.
Collapse
Affiliation(s)
- Emerik Osterlund
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Klara Hammarström
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Luís Nunes
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Lucy Mathot
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Artur Mezheyeuski
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Tobias Sjöblom
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
2
|
Lanzloth R, Harris NL, Cannon AM, Kaplan MH, O’Hagan HM. Mast cells interact directly with colorectal cancer cells to promote epithelial-to-mesenchymal transition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.19.644113. [PMID: 40166179 PMCID: PMC11957126 DOI: 10.1101/2025.03.19.644113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Mast cells (MCs), a type of granulocytic immune cell, can be both pro- and anti-tumorigenic in colorectal cancer (CRC). We hypothesized that these contrasting findings may be in part due to differential interactions of MCs with CRC subtypes. BRAF mutant CRC uniquely contains intestinal secretory cell types. In this study, we demonstrated that MCs are enriched in BRAF mutant CRC, likely because they are recruited by factors released from cancer secretory cells. To investigate the functional consequences of MC-CRC cell interactions, we performed direct coculture experiments. We demonstrated that MCs promote epithelial-to-mesenchymal transition (EMT) in CRC cells in a calcium- and contact-dependent fashion. Furthermore, inhibiting LFA-1 and ICAM1 integrin binding reduced the coculture-induced EMT-related marker expression in CRC cells. The MC-CRC cell interaction facilitates the transfer of biological materials, including mRNA molecules, from MCs to CRC cells. This study is the first to report a contact-dependent, pro-tumorigenic role of MCs in CRC, as well as the transfer of molecules encoded by MCs to CRC cells. These findings enhance our comprehension of cell-cell communication between immune and cancer cells. Furthermore, this work suggests that targeting MC-CRC interactions, particularly through modulating integrin pathways, could offer new therapeutic strategies for aggressive CRC subtypes.
Collapse
Affiliation(s)
- Rosie Lanzloth
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, IN, 47405, USA
| | - Nicole L. Harris
- Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, IN 47405, USA
| | - Anthony M. Cannon
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
| | - Mark H. Kaplan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
| | - Heather M. O’Hagan
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, 47405, USA
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, 46202, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| |
Collapse
|
|
3
|
Yohanathan L, Chopra A, Simo K, Clancy TE, Khithani A, Anaya DA, Maegawa FA, Sheikh M, Raoof M, Jacobs M, Aleassa E, Boff M, Ferguson B, Tan-Tam C, Winslow E, Qadan M, D’Angelica MI. Assessment and treatment considerations for patients with colorectal liver metastases: AHPBA consensus guideline and update for surgeons. HPB (Oxford) 2025; 27:263-278. [PMID: 39828468 DOI: 10.1016/j.hpb.2024.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/20/2024] [Accepted: 12/09/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Colorectal cancer most commonly metastasizes to the liver. While various treatment strategies have been developed, surgical management of these patients has vital implications on the prognosis and survival of this group of patients. There remains a need for a consensus guideline regarding the surgical evaluation and management of patients with colorectal liver metastases (CRLM). METHODS This review article is a consensus guideline established by the members of the AHPBA Professional Standards Committee, as an amalgamation of existent literature and a guide to surgeons managing this complex disease. RESULTS These guidelines reports the benefits and shortcomings of various diagnostic modalities including imaging and next-generation sequencing in the management of patients with CRLM. While surgery has established survival benefits in patients with resectable disease, this report notes the importance of treatment sequencing with non-surgical modalities as well as between colon and liver resection. Finally, the guidelines address the various treatment modalities for patients with unresectable disease, that may have significant impact on survival. CONCLUSION CRLM is a complex diagnosis which warrants multidisciplinary approach with early surgical involvement in both assessment and management of the disease, to optimize patient outcomes and survival.
Collapse
|
|
4
|
Tatsuta K, Sakata M, Kojima T, Booka E, Kurachi K, Takeuchi H. Updated insights into the impact of adjuvant chemotherapy on recurrence and survival after curative resection of liver or lung metastases in colorectal cancer: a rapid review and meta-analysis. World J Surg Oncol 2025; 23:56. [PMID: 39966950 PMCID: PMC11834510 DOI: 10.1186/s12957-025-03714-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/11/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) frequently metastasizes to the liver and lungs, leading to poor prognosis. Advances in chemotherapy, minimally invasive surgery, and perioperative care have expanded adjuvant chemotherapy (AC) regimens and eligibility for AC. However, the impact of AC after curative resection of distant metastases on recurrence and prognosis remains uncertain. This study evaluated the role of AC in CRC liver and lung metastases, focusing on cases with curative resection based on the latest studies published in the past five years. METHODS This systematic review followed PRISMA guidelines. Literature searches of Medline and Cochrane Library (2019-2023) identified studies on AC or observation after curative resection of CRC metastases, reporting outcomes such as overall survival (OS) and disease-free survival (DFS). Data analysis was performed using Review Manager and R software, with results expressed as hazard ratios (HR) and 95% confidence intervals (CI). RESULTS Seven studies met the eligibility criteria, including one randomized controlled trial and six retrospective studies, encompassing 1580 patients who underwent curative resection (R0) for CRC metastases. This meta-analysis showed a positive trend in OS for the AC group compared to that for the surgery-alone group (HR 0.86, 95% CI: 0.73-1.01; p = 0.06), but the difference was insignificant. AC significantly improved DFS (HR 0.81, 95% CI: 0.66-0.99; p = 0.04). Subgroup analysis indicated that AC significantly improved DFS and tended to improve OS for liver metastasis. In contrast, AC did not improve OS in cases of lung metastasis. CONCLUSIONS This meta-analysis suggests that AC demonstrated significant positive effects on DFS. Moreover, AC could contribute to improvements in OS. These findings, supported by the latest research, reinforce the recommendation of AC as a valuable strategy for improving both recurrence and survival outcomes in patients with curatively resected distant CRC metastases.
Collapse
Affiliation(s)
- Kyota Tatsuta
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Mayu Sakata
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan.
| | - Tadahiro Kojima
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Eisuke Booka
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Kiyotaka Kurachi
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Chuo-ku, Hamamatsu, Shizuoka, 431-3192, Japan
| |
Collapse
|
|
5
|
Gu T, Qi H, Wang J, Sun L, Su Y, Hu H. Identification of T cell dysfunction molecular subtypes and exploration of potential immunotherapy targets in BRAF V600E-mutant colorectal cancer. Discov Oncol 2025; 16:163. [PMID: 39934467 DOI: 10.1007/s12672-025-01930-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/04/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Immunotherapy is an effective treatment for BRAF V600E-mutant colorectal cancer, but currently, only a few benefit from it. Therefore, exploring new immunotherapy strategies is essential. METHODS We obtained RNA sequencing data and clinical information of colorectal cancer patients from the TCGA and GEO databases. The impact of the BRAF V600E mutation on tumor microenvironment characteristics, gene expression, and signaling pathways was evaluated using bioinformatics approaches. Weighted gene co-expression network analysis (WGCNA) were used to identify core genes associated with T cell dysfunction. Consensus clustering was applied for subtype construction. Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF) algorithms were employed to filter potential immunotherapy targets. RESULTS We found that BRAF V600E mutation has a complex impact on the immune profile of colorectal cancer. It increases immune cell infiltration and activates immune-related signaling pathways, yet it also severely restricts T cell function. We subsequently identified 39 core genes associated with T cell dysfunction and constructed subtypes of BRAF V600E colorectal cancer based on their expression profiles. Significant heterogeneity was observed between these subtypes in immune signaling pathway activity, immune infiltration patterns, immune phenotype scores, and mechanisms of resistance to immunotherapy. Ultimately, using machine learning algorithms and bioinformatics validation, we identified IDO1 as a potential immunotherapy targets for BRAF V600E-mutant colorectal cancer. CONCLUSION This study constructed novel T cell dysfunction molecular subtypes for BRAF V600E-mutant colorectal cancer and identified IDO1 as a potential immunotherapy target, providing a new strategy for immunotherapy.
Collapse
Affiliation(s)
- Tiefeng Gu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China
| | - Haonan Qi
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China
| | - Jiaqi Wang
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China
| | - Liangwei Sun
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China
| | - Yongqi Su
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China
| | - Hanqing Hu
- Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, China.
| |
Collapse
|
|
6
|
Piercey O, Chantrill L, Hsu H, Ma B, Price T, Tan IB, Teng H, Tie J, Desai J. Expert consensus on the optimal management of BRAF V600E-mutant metastatic colorectal cancer in the Asia-Pacific region. Asia Pac J Clin Oncol 2025; 21:31-45. [PMID: 39456063 PMCID: PMC11733838 DOI: 10.1111/ajco.14132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 09/14/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024]
Abstract
The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.
Collapse
Affiliation(s)
| | - Lorraine Chantrill
- Illawarra Shoalhaven Local Health DistrictIllawarraNew South WalesAustralia
- Faculty of Science, Medicine and HealthUniversity of WollongongWollongongNew South WalesAustralia
| | - Hung‐Chih Hsu
- Division of Hematology OncologyChang Gung Memorial HospitalNew TaipeiTaiwan
- College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Brigette Ma
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, Hong Kong Cancer InstituteThe Chinese University of Hong KongHong Kong SARChina
| | - Timothy Price
- The Queen Elizabeth HospitalAdelaideSouth AustraliaAustralia
| | - Iain Beehuat Tan
- Division of Medical OncologyNational Cancer Centre SingaporeSingaporeSingapore
| | - Hao‐Wei Teng
- Department of OncologyTaipei Veterans General HospitalTaipeiTaiwan
| | - Jeanne Tie
- Peter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVictoriaAustralia
| | - Jayesh Desai
- Peter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneVictoriaAustralia
| |
Collapse
|
|
7
|
Wei GX, Zhou YW, Dong C, Zhang T, Cao P, Xie L, Qiu M. Clinicopathologic features and treatment efficacy of patients with BRAF V600E-mutated metastatic colorectal cancer: a multi-center real-world propensity score matching study. BMC Cancer 2024; 24:1395. [PMID: 39538135 PMCID: PMC11558966 DOI: 10.1186/s12885-024-13171-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Patients with BRAF 600E mutated mCRC are associated with specific clinicopathological features and poor prognosis. The relative efficacy of first-line FOLFOXIRI triplet chemotherapy or doublet chemotherapy combined with bevacizumab in patients with BRAF 600E mutated mCRC remains controversial. METHODS BRAF V600E-mutated mCRC patients from 3 institutions were included. The clinicopathological characteristics of the enrolled patients were analyzed. Overall survival (OS) of patients was divided into 4 fractions, including 0-25%, 25-50%, 50-75%,75-100% by quartile method. Patients with OS ranging from 0 to 25% were defined as the poor prognosis group, and patients with OS ranging from 75 to 100% were defined as the good prognosis group. A propensity score matching (PSM) analysis was performed to balance the baseline characteristics of patients treated with doublet chemotherapy and triplet chemotherapy combined with bevacizumab. Survival and tumor response of the two regimens were evaluated. RESULTS A total of 125 patients with BRAF V600E-mutated mCRC were enrolled. The median OS of BRAF V600E-mutated mCRC was 14.9 months and the median PFS of first-line therapy was 6.1 months. According to the multivariate analysis and the difference in baseline characteristics between the poor prognosis group and the good prognosis group, poor differentiation and liver metastasis were negative independent prognostic factors for OS in patientsx with BRAF V600E-mutated mCRC. Patients treated with first-line triplets had a longer OS than those treated with doublets both before PSM (17.4 months vs. 13.4 months, p = 0.022) and after PSM (17.4 months vs. 10.4 months, p = 0.004). There was no significant benefit between triplet-drug group and doublet-drug group for PFS, ORR and DCR. Subgroup analysis showed that patients in the triplet-drug group had a better prognosis with the following favorable factors: age ≤ 60 years old, PS score of 0-1, liver metastases and multiple organ metastases. CONCLUSION The overall prognosis of BRAF V600E mutant mCRC patients is poor. Poor differentiation and liver metastases were negative independent prognostic factors for OS. First-line triplet-drug therapy was associated with better OS, especially in patients with good physical condition and high tumor burden.
Collapse
Affiliation(s)
- Gui-Xia Wei
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
- The Clinical Medical College of Sichuan University, Chengdu, China
| | - Yu-Wen Zhou
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
| | - Chao Dong
- Department of Oncology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Tao Zhang
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Cao
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China
| | - Lin Xie
- Department of Oncology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China.
| | - Meng Qiu
- Department of Colorectal Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu, 610041, Sichuan Province, China.
| |
Collapse
|
|
8
|
Gao Z, Qi X, Wang R, Wen Z, Qi H, Ju M, Liu X, Wang J, Zhou H, Zhu Z, Liu X, Li K. Effect of RAS and BRAF mutations on peritoneal metastasis risk and cytoreductive surgery/hyperthermic intraperitoneal chemotherapy efficacy in colorectal cancer: A systematic review and meta-analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108474. [PMID: 38870874 DOI: 10.1016/j.ejso.2024.108474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 05/13/2024] [Accepted: 06/04/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) patients with peritoneal metastasis (CRC-PM) have a worse prognosis than those with liver and lung metastases. Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective locoregional treatment for CRC-PM. To date, the prognostic analysis of CRS/HIPEC mostly focuses on clinical and pathological characteristics; however, genetic characteristics, such as RAS/BRAF mutation status, are not sufficient. This study aimed to systematically assess the correlation between RAS/BRAF status and PM risk, as well as the prognostic efficacy of CRS/HIPEC for CRC. METHOD This study was written in accordance with the 2020 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We searched PubMed, EMBASE, and the Cochrane library with the following keywords: "Peritoneal Neoplasms," "raf Kinases" and "ras Proteins". The fixed-effects model and inverse variance method were used for analysis. Odds ratios (OR) and 95 % confidence intervals (CI) were used to reflect the risk of PM associated with RAS/BRAF mutations. Hazard ratios (HR) and 95 % CI were used to evaluate the effects of RAS/BRAF mutations on the prognosis of CRS/HIPEC. RESULT Eighteen articles included 5567 patients. In the risk analysis of PM, patients with BRAF mutation were more likely to have PM than those with wild-type BRAF (OR = 2.28, 95 % CI = 1.73-3.01, P < 0.001, I2 = 0 %). In contrast, there was no significant difference in the effect of RAS mutation and wild-type on PM of CRC (OR = 1.28, 95 % CI = 0.99-1.66, P = .06, I2 = 0 %). In a prognostic analysis of CRS/HIPEC, RAS mutation predicted poor overall survival (HR = 1.68, 95 % CI = 1.39-2.02, P < 0.001, I2 = 1 %) and disease-free survival (HR = 1.61, 95 % CI = 1.34-1.94, P < 0.001, I2 = 42 %). The results for BRAF mutation was consistent with the prognostic impact of RAS mutation's overall survival (HR = 2.57, 95 % CI = 1.93-3.44, P < 0.001, I2 = 0 %) and disease-free survival (HR = 1.90, 95 % CI = 1.40-2.56, P < 0.001, I2 = 82 %). CONCLUSION BRAF mutation, rather than RAS mutation, was a high-risk factor for CRC-PM. And both BRAF and RAS mutations negatively affected the prognosis of CRS/HIPEC in CRC-PM patients. Our results could provide suggestions for the selection of comprehensive treatment for CRC-PM with RAS/BRAF mutations.
Collapse
Affiliation(s)
- Ziming Gao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Xiang Qi
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Ruiying Wang
- Department of Ultrasound, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Zhitong Wen
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Hao Qi
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Mingguang Ju
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Xiaoxu Liu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Junye Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Heng Zhou
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China; Department of Anesthesiology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Zhi Zhu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Xiaofang Liu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China; Department of Anorectal Surgery, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| | - Kai Li
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
| |
Collapse
|
|
9
|
Margonis GA, Wang J, Papakonstantinou D, Beyer K, Kreis ME, D’Angelica M. A critical appraisal of the current landscape of resectable BRAF mutated colorectal liver metastases: a systematic review. Chin Clin Oncol 2024; 13:51. [PMID: 38859602 PMCID: PMC11752564 DOI: 10.21037/cco-23-128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 04/03/2024] [Indexed: 06/12/2024]
Abstract
BACKGROUND Patients with surgically resectable BRAF-mutated colorectal liver metastases (CRLM) or limited extrahepatic disease constitute a highly selective subgroup among BRAF-mutated patients, characterized by a more indolent disease biology. This is evident in their suitability for surgical resection. However, initial studies from a decade ago presented a discouraging outlook for these patients, citing early, frequent, multifocal recurrences and a very limited median overall survival (OS) of less than two years. Our objective was to provide an updated, comprehensive, and critically assessed review of the current literature on the prognostic impact of BRAF variants in CRLM, as well as to explore optimal treatment strategies for these patients through a systematic search. METHODS A systematic literature search of the Medline, Scopus, and CENTRAL databases for studies reporting long-term outcomes of patients with a known BRAF status was performed. RESULTS A total of 386 unique studies were screened during the study selection process. After applying the exclusion criteria, a total of 18 studies published between 2012 and 2023 were deemed eligible for inclusion. CONCLUSIONS In contrast to older studies, more recent studies, with larger sample sizes, have revealed that the rate of extrahepatic recurrence is comparable between BRAF-mutated and wild-type patients. Furthermore, they have reported significantly improved survival outcomes, with OS extending up to 52 months. Notably, patients with non-V600E BRAF mutations may even achieve outcomes comparable to those with wild-type BRAF CRLM. Additionally, a few recent studies have compared surgery and systemic therapies, indicating that surgery is associated with improved survival rates, even for patients with the V600E mutation. This challenges the previous belief that BRAF mutations are absolute contraindications to surgical treatment. Surgical denial for technically resectable patients may now be reserved for specific clinical scenarios, such as the presence of a BRAF V600E mutation and concurrent extrahepatic disease.
Collapse
Affiliation(s)
| | - Jaeyun Wang
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Dimitris Papakonstantinou
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Katharina Beyer
- Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Martin E. Kreis
- Department of General and Visceral Surgery, Charité Campus Benjamin Franklin, Berlin, Germany
| | - Michael D’Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, NYC, NY, USA
| |
Collapse
|
|
10
|
50th Anniversary Presidential Edition - Graeme Poston. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108454. [PMID: 39550133 DOI: 10.1016/j.ejso.2024.108454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2024]
|
|
11
|
Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
Collapse
Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
| |
Collapse
|
|
12
|
Petrelli F, Arru M, Colombo S, Cavallone M, Cribiu' FM, Villardita V, Floris P, Digiesi L, Severgnini G, Moraes MT, Conti B, Celotti A, Viti M, Sozzi A. BRAF mutations and survival with surgery for colorectal liver metastases: A systematic review and meta-analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108306. [PMID: 38603866 DOI: 10.1016/j.ejso.2024.108306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 03/13/2024] [Accepted: 03/23/2024] [Indexed: 04/13/2024]
Abstract
INTRODUCTION Mutations in the BRAF gene (BRAFmut) are associated with an unfavorable prognosis in patients with metastatic colorectal cancer (CRC). The aim of this meta-analysis was to evaluate the prognosis of colorectal cancer (CRC) patients with liver metastases and the potential benefits of liver resection in patients with BRAFmut CRC. MATERIAL AND METHODS A systematic search of PubMed, Cochrane Central Controlled Trials, and Embase databases was conducted on May 31, 2023. The inclusion criteria were as follows:1) reporting of outcomes in patients with BRAFmut CRC who underwent surgery for liver metastases and/or comparison of outcomes between those who underwent and those who did not undergo resection; 2) reporting of survival information as hazard ratios (HR); and 3) publication in English. RESULTS 34 studies were included. Median follow up was 48 months for prognostic BRAF status meta-analysis. BRAFmut status showed a significantly increased risk of mortality (hazard ratio [HR] = 2.56, 95% confidence interval [CI] 2.04-3.22; P < 0.01) and relapse (HR = 1.97, 95% CI 1.44-2.71; P < 0.01). Resection of liver metastases was associated with a survival benefit (median follow up 46 months). The HR for survival was 0.44 (95% confidence interval [CI] 0.33-0.59; P < 0.01) in favor of surgery. CONCLUSIONS and Relevance: Our analysis indeed confirms that BRAF mutation is associated with poor survival outcomes after liver resection of CRC metastases. However, upon quantitatively assessing the survival benefit of surgical intervention in patients with BRAF-mutated CRC liver metastases, we identified a significant 56% reduction in the risk of death.
Collapse
Affiliation(s)
| | - Marcella Arru
- Surgery Unit, ASST Bergamo Ovest, Treviglio, BG, Italy
| | - Silvia Colombo
- Hepatology Unit, ASST Bergamo Ovest, Treviglio, BG, Italy
| | | | | | | | - Paola Floris
- Surgery Unit, ASST Bergamo Ovest, Treviglio, BG, Italy
| | | | | | | | - Barbara Conti
- Surgery Unit, ASST Bergamo Ovest, Treviglio, BG, Italy
| | | | - Matteo Viti
- Surgery Unit, ASST Bergamo Ovest, Treviglio, BG, Italy
| | - Andrea Sozzi
- Surgery Unit, ASST Bergamo Ovest, Treviglio, BG, Italy
| |
Collapse
|
|
13
|
Deng W, Liu X, Huang S, Wu Z, Alessandro F, Lin Q, Cai Z, Zhang Z, Huang Y, Wang H, Yuan Z. CXCL16 promotes tumor metastasis by regulating angiogenesis in the tumor micro-environment of BRAF V600E mutant colorectal cancer. Transl Oncol 2024; 41:101854. [PMID: 38232513 PMCID: PMC10827530 DOI: 10.1016/j.tranon.2023.101854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/24/2023] [Accepted: 11/30/2023] [Indexed: 01/19/2024] Open
Abstract
Patients of colorectal cancer (CRC) with BRAF V600E mutation obtain poor prognosis. This study aimed to explore the role and mechanism of BRAF V600E mutation in angiogenesis of tumor micro-environment (TME). It has been reported that CXCL16 expression in TME is closely related to BRAF mutation. Clinicopathological features of CRC with BRAF V600E mutant or wild type were collected in this study. Immunohistochemistry (IHC) assays were conducted to test the expressions of vascular endothelial growth factor (VEGF), CD31 and CXCL16. ROC curve was used to determine the optimal cut off values of CXCL16. A total of 680 patients including 141 BRAF V600E type and 679 wild type were included. BRAF V600E mutant tumors were presented with significant worse clinicopathological features and a shorter overall survival (OS) than wild-type. Besides, chemokines CXCL16 was up-regulated in BRAF V600E mutant tissues and was associated with poorer prognosis. In addition, VEGF levels and vascular endothelial cell density was significantly increased in BRAF mutation. At last, CXCL16 was positively correlated with VEGF expression and vascular endothelial cell density. In conclusion, BRAF V600E mutations may promote metastasis of CRC by regulating CXCL16 expression and promoting angiogenesis in the TME.
Collapse
Affiliation(s)
- Weihao Deng
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China
| | - Xiaoxia Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Department of General Surgery, Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, China
| | - Shuhui Huang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China
| | - Zhijie Wu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Department of General Surgery, Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, China
| | - Fichera Alessandro
- Colon and Rectal Surgery, Baylor University Medical Center, TX, United States of America
| | - Qingfeng Lin
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Department of General Surgery, Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, China
| | - Zonglu Cai
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Department of General Surgery, Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, China
| | - Zitong Zhang
- Department of General Surgery, Houjie Hospital, Dongguan, Guangdong, China.
| | - Yan Huang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China.
| | - Hui Wang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Department of General Surgery, Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, China.
| | - Zixu Yuan
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, China; Department of General Surgery, Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, China.
| |
Collapse
|
|
14
|
Tsai HL, Huang CW, Chen YC, Su WC, Chang TK, Chen PJ, Li CC, Chang YT, Wang JY. Real-World Outcomes of First-Line FOLFIRI Plus Bevacizumab with Irinotecan Dose Escalation versus FOLFOXIRI Plus Bevacizumab in BRAFV600E-Mutant Metastatic Colorectal Cancer: The Preliminary Data from a Single-Center Observational Study. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2108. [PMID: 38138211 PMCID: PMC10745094 DOI: 10.3390/medicina59122108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 12/24/2023]
Abstract
Background and Objectives: Approximately 5-10% of all patients with metastatic colorectal cancer (mCRC) harbor a BRAFV600E mutation. These patients exhibit distinct metastatic patterns, poor prognosis, and heterogenous survival outcomes. The findings from the TRIBE study indicated that the administration of FOLFOXIRI plus bevacizumab as first-line treatment extended the median duration of overall survival (OS). In this study, we explored the effects of UGT1A1 polymorphism on the outcomes of irinotecan dose escalation versus FOLFOXIRI plus bevacizumab in patients with BRAFV600E-mutant mCRC. Materials and Methods: We retrospectively reviewed the medical records of 25 patients who had received a diagnosis of BRAFV600E-mutant mCRC between October 2015 and August 2022. All patients underwent UGT1A1 genotyping before receiving bevacizumab plus FOLFIRI. The primary end point was progression-free survival (PFS), and secondary endpoints were OS and adverse events (AEs). The two treatment arms were compared in terms of 6-month PFS and 12-month OS. Results: Over a median follow-up duration of 15.0 (interquartile range, 10.0-30.5) months, no significant differences were noted between the treatment arms in severe AEs (SAEs), 6-month PFS, or 12-month OS (all p < 0.05). Regarding AEs, the FOLFIRI plus bevacizumab regimen was associated with a lower incidence of anorexia than was the FOLFOXIRI plus bevacizumab regimen (p = 0.042). Conclusions: Our findings indicate that FOLFIRI plus bevacizumab with irinotecan dose escalation is an effective first-line treatment regimen for patients with BRAFV600E-mutant mCRC. This regimen leads to acceptable clinical outcomes with manageable AEs. However, the effects on survival and safety outcomes could only be speculated, and further studies are needed because of the sample size, the follow-up for the OS evaluation, and the non-uniformity in all the variables considered in the two groups.
Collapse
Affiliation(s)
- Hsiang-Lin Tsai
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-Wen Huang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yen-Cheng Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Wei-Chih Su
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Tsung-Kun Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Surgery, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Po-Jung Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-Chun Li
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
| | - Yu-Tang Chang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Division of Pediatric Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jaw-Yuan Wang
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (H.-L.T.); (C.-W.H.); (Y.-C.C.); (W.-C.S.); (T.-K.C.); (P.-J.C.); (C.-C.L.); (Y.-T.C.)
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| |
Collapse
|
|
15
|
Kunitomo A, Ouchi A, Komori K, Kinoshita T, Sato Y, Abe T, Ito S, Sano T, Shimizu Y. Clinical Impact of Radical Resection of Synchronous and Metachronous Peritoneal Metastases from Colorectal Cancer. Ann Surg Oncol 2023; 30:8501-8508. [PMID: 37658266 DOI: 10.1245/s10434-023-14191-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 08/07/2023] [Indexed: 09/03/2023]
Abstract
BACKGROUND According to some case series, patients with colorectal cancer (CRC) who underwent radical resection of synchronous peritoneal metastases (PM) with the primary tumor had better survival than patients who underwent non-surgical treatment. However, little evidence exists regarding the significance of radical resection for metachronous PM. OBJECTIVE This study aimed to evaluate the clinical significance of surgical intervention for isolated PM from CRC, with a particular focus on time to PM. METHODS A total of 74 consecutive patients with isolated PM from CRC, including 40 and 34 patients with synchronous and metachronous PM, respectively, treated between 2007 and 2018 were retrospectively analyzed. The primary outcome measure was overall survival (OS) from diagnosis, and the OS was compared between radical resection and palliative chemotherapy. RESULTS Five-year OS was 39.7% for all patients. Patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy (62.8% vs. 11.0%; p < 0.0001). According to time to PM, patients with radical resection had significantly better 5-year OS compared with those with palliative chemotherapy for both synchronous PM (47.6% vs. 0%; p = 0.019) and metachronous PM (77.2% vs. 15.2%; p < 0.0001). Multivariable analysis stratified by time to PM revealed that surgical intervention is a significant favorable prognostic factor only in patients with metachronous PM (hazard ratio 0.117, 95% confidence interval 0.020-0.678; p = 0.017). CONCLUSIONS Patients with radical resection of PM had good survival compared with those with chemotherapy alone, especially for metachronous PM. Surgical intervention should be considered for isolated metachronous PM when radical resection is feasible.
Collapse
Affiliation(s)
- Aina Kunitomo
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
- Department of Gastroenterological Surgery, Aichi Medical University Hospital, Nagakute, Aichi, Japan
| | - Akira Ouchi
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.
| | - Koji Komori
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Takashi Kinoshita
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Yusuke Sato
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Tetsuya Abe
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Tsuyoshi Sano
- Department of Gastroenterological Surgery, Aichi Medical University Hospital, Nagakute, Aichi, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| |
Collapse
|
|
16
|
Pranteda A, Piastra V, Serra M, Bernardini R, Lo Sardo F, Carpano S, Diodoro MG, Bartolazzi A, Milella M, Blandino G, Bossi G. Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance. Biomed Pharmacother 2023; 167:115480. [PMID: 37713993 DOI: 10.1016/j.biopha.2023.115480] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/17/2023] Open
Abstract
Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF inhibitor resistance is critical for the development of novel therapeutic opportunities for this subtype of CRC patients. CRC cells bearing BRAF mutations are mostly sensitive to the abrogation of Mitogen-Activated Protein Kinase Kinase 3 (MKK3), a specific activator of p38MAPKs signaling, suggesting that BRAF alterations might addict CRC cells to the MKK3/p38MAPK signaling. Interestingly, publicly available gene expression profiling data show significantly higher MKK3 transcript levels in CRC lines with acquired resistance to BRAF inhibitors. Herein, we investigated the roles of MKK3 in the response to BRAF targeting (dabrafenib) with COLO205 and HT29 BRAFV600E CRC lines and derived dabrafenib-resistant (DABR) sublines. Dabrafenib treatments reduce MKK3 activation by inducing autophagy in parental but not DABR cells. The MKK3 knockdown induces cell death in DABR cells, whereas ectopic MKK3 expression reduces dabrafenib sensitivity in parental cells. Mechanistically, activated MKK3 interacts and co-localizes with c-Myc oncoprotein (MYC), sustaining MYC protein stability and thus preventing the dabrafenib induced effects in CRC DABR cells both in vitro and in vivo. Overall, we identify a novel molecular mechanism beyond the dabrafenib resistance, shedding light on an uncovered vulnerability for the development of novel therapeutic opportunities in BRAFV600E CRC.
Collapse
Affiliation(s)
- Angelina Pranteda
- Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy; Department of Science, University Roma TRE, Viale G. Marconi, 446 I, 00146 Rome, Italy
| | - Valentina Piastra
- Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy; Department of Science, University Roma TRE, Viale G. Marconi, 446 I, 00146 Rome, Italy
| | - Martina Serra
- Interdepartmental Centre for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome "Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy
| | - Roberta Bernardini
- Interdepartmental Centre for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome "Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy; Center for Research and Services "Preclinical Experimentation and Animal Welfare" (SPBA), University of Rome "La Sapienza", Piazzale Aldo Moro, 5, 00185 Rome, Italy
| | - Federica Lo Sardo
- Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy
| | - Silvia Carpano
- Second Division of Medical Oncology, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy
| | - Maria Grazia Diodoro
- Department of Pathology, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy
| | - Armando Bartolazzi
- Pathology Research Laboratory, Sant'Andrea University Hospital, Via di Grottarossa, 1035, 00189 Rome, Italy
| | - Michele Milella
- UOC of Oncology, Verona University and Hospital Trust (Azienda Ospedaliera Universitaria Integrata-AOUI-Verona), Piazzale Aristide Stefani, 1, 37126 Verona, Italy
| | - Giovanni Blandino
- Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy
| | - Gianluca Bossi
- Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy.
| |
Collapse
|
|
17
|
Wang YY, Xin ZC, Wang K. Impact of Molecular Status on Metastasectomy of Colorectal Cancer Liver Metastases. Clin Colon Rectal Surg 2023; 36:423-429. [PMID: 37795466 PMCID: PMC10547543 DOI: 10.1055/s-0043-1767700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2023]
Abstract
Although surgical resection could provide better survival for patients with colorectal cancer liver metastases (CRLM), the recurrence rate after resection of CRLM remains high. The progress of genome sequencing technologies has greatly improved the molecular understanding of colorectal cancer. In the era of genomics and targeted therapy, genetic mutation analysis is of great significance to guide systemic treatment and identify patients who can benefit from resection of CRLM. RAS and BRAF mutations and microsatellite instability/deficient deoxyribonucleic acid (DNA) mismatch repair status have been incorporated into current clinical practice. Other promising molecular biomarkers such as coexisting gene mutations and circulating tumor DNA are under active investigation. This study aimed to review the prognostic significance of molecular biomarkers in patients with CRLM undergoing metastasectomy based on the current evidence.
Collapse
Affiliation(s)
- Yan-Yan Wang
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China
| | - Ze-Chang Xin
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China
| | - Kun Wang
- Hepatopancreatobiliary Surgery Department I, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China
| |
Collapse
|
|
18
|
Zeng J, Fan W, Li J, Wu G, Wu H. KRAS/NRAS Mutations Associated with Distant Metastasis and BRAF/PIK3CA Mutations Associated with Poor Tumor Differentiation in Colorectal Cancer. Int J Gen Med 2023; 16:4109-4120. [PMID: 37720173 PMCID: PMC10503567 DOI: 10.2147/ijgm.s428580] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 08/30/2023] [Indexed: 09/19/2023] Open
Abstract
Background The occurrence, progression, and prognosis of colorectal cancer (CRC) are regulated by EGFR-mediated signaling pathways. However, the relationship between the core genes (KRAS/NRAS/BRAF/PIK3CA) status in the signaling pathways and clinicopathological characteristics of CRC patients in Hakka population remains controversial. Methods Patients were genotyped for KRAS (codons 12, 13, 61, 117, and 146), NRAS (codons 12, 61, 117, and 146), BRAF (codons 600), and PIK3CA (codons 542, 545 and 1047) mutations. Clinical records were collected, and clinicopathological characteristic associations were analyzed together with mutations of studied genes. Results Four hundred and eight patients (256 men and 152 women) were included in the analysis. At least one mutation in the four genes was detected in 216 (52.9%) patients, while none was detected in 192 (47.1%) patients. KRAS, NRAS, BRAF, and PIK3CA mutation status were detected in 190 (46.6%), 11 (2.7%), 10 (2.5%), 34 (8.3%) samples, respectively. KRAS exon 2 had the highest proportion (62.5%). Age, tumor site, tumor size, lymphovascular invasion, and perineural invasion were not associated with gene mutations. KRAS mutations (adjusted OR 1.675, 95% CI 1.017-2.760, P=0.043) and NRAS mutations (adjusted OR 5.183, 95% CI 1.239-21.687, P=0.024) appeared more frequently in patients with distant metastasis. BRAF mutations (adjusted OR 7.224, 95% CI 1.356-38.488, P=0.021) and PIK3CA mutations (adjusted OR 3.811, 95% CI 1.268-11.455, P=0.017) associated with poorly differentiated tumor. Conclusion KRAS/NRAS mutations are associated with distant metastasis and BRAF/PIK3CA mutations are associated with poor tumor differentiation in CRC. And the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients.
Collapse
Affiliation(s)
- Juanzi Zeng
- Department of Medical Oncology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
- Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Wenwei Fan
- Department of Gastroenterology, Dongguan Eighth People’s Hospital, Dongguan, People’s Republic of China
| | - Jiaquan Li
- Department of Medical Oncology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
- Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Guowu Wu
- Department of Medical Oncology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
- Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| | - Heming Wu
- Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China
| |
Collapse
|
|
19
|
Mahamid A, Abu-Zaydeh O, Kazlow E, Froylich D, Sawaied M, Goldberg N, Berger Y, Khoury W, Sadot E, Haddad R. The Effects of Primary Tumor Location on Survival after Liver Resection for Colorectal Liver Metastasis in the Mediterranean Population. J Clin Med 2023; 12:5242. [PMID: 37629285 PMCID: PMC10455848 DOI: 10.3390/jcm12165242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/26/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
(1) Background: There is an abundance of literature available on predictors of survival for patients with colorectal liver metastases (CRLM) but minimal information available on the relationship between the primary tumor location and CRLM survival. The studies that focus on the primary tumor location and CRLM survival exhibit a great deal of controversy and inconsistency with regard to their results (some studies show statistically significant connections between the primary tumor location and prognosis versus other studies that find no significant relationship between these two factors). Furthermore, the majority of these studies have been conducted in the West and have studied more diverse and heterogenous populations, which may be a contributing factor to the conflicting results. (2) Methods: We included patients who underwent liver resection for CRLM between December 2004 and January 2019 at two university-affiliated medical centers in Israel: Carmel Medical Center (Haifa) and Rabin Medical Center (Petach Tikvah). Primary tumors located from the cecum up to and including the splenic flexure were labeled as right-sided primary tumors, whereas tumors located from the splenic flexure down to the anal verge were labeled as left-sided primary tumors. (3) Results: We identified a total of 501 patients. Of these patients, 225 had right-sided primary tumors and 276 had left-sided primary tumors. Patients with right-sided tumors were significantly older at the time of liver surgery compared to those with left-sided tumors (66.1 + 12.7 vs. 62 + 13.1, p = 0.002). Patients with left-sided tumors had slightly better overall survival rates than those with right-sided tumors. However, the differences were not statistically significant (57 vs. 50 months, p = 0.37 after liver surgery). (4) Conclusions: The primary tumor location does not significantly affect patient survival after liver resection for colorectal liver metastasis in the Mediterranean population.
Collapse
Affiliation(s)
- Ahmad Mahamid
- Department of Surgery, Carmel Medical Center, Haifa 3436212, Israel; (A.M.); (O.A.-Z.); (E.K.); (D.F.); (M.S.); (W.K.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
| | - Omar Abu-Zaydeh
- Department of Surgery, Carmel Medical Center, Haifa 3436212, Israel; (A.M.); (O.A.-Z.); (E.K.); (D.F.); (M.S.); (W.K.)
| | - Esther Kazlow
- Department of Surgery, Carmel Medical Center, Haifa 3436212, Israel; (A.M.); (O.A.-Z.); (E.K.); (D.F.); (M.S.); (W.K.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
| | - Dvir Froylich
- Department of Surgery, Carmel Medical Center, Haifa 3436212, Israel; (A.M.); (O.A.-Z.); (E.K.); (D.F.); (M.S.); (W.K.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
| | - Muneer Sawaied
- Department of Surgery, Carmel Medical Center, Haifa 3436212, Israel; (A.M.); (O.A.-Z.); (E.K.); (D.F.); (M.S.); (W.K.)
| | - Natalia Goldberg
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
- Department of Radiology, Carmel Medical Center, Haifa 3436212, Israel
| | - Yael Berger
- Department of Surgery, Rabin Medical Center, Petch Tikvah 4941492, Israel; (Y.B.); (E.S.)
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 6139001, Israel
| | - Wissam Khoury
- Department of Surgery, Carmel Medical Center, Haifa 3436212, Israel; (A.M.); (O.A.-Z.); (E.K.); (D.F.); (M.S.); (W.K.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
| | - Eran Sadot
- Department of Surgery, Rabin Medical Center, Petch Tikvah 4941492, Israel; (Y.B.); (E.S.)
- Sackler School of Medicine, Tel Aviv University, Tel Aviv 6139001, Israel
| | - Riad Haddad
- Department of Surgery, Carmel Medical Center, Haifa 3436212, Israel; (A.M.); (O.A.-Z.); (E.K.); (D.F.); (M.S.); (W.K.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel;
| |
Collapse
|
|
20
|
Dao V, Heestand G. Beyond EGFR inhibitors in advanced colorectal cancer: Targeting BRAF and HER2. Curr Probl Cancer 2023; 47:100960. [PMID: 37285606 DOI: 10.1016/j.currproblcancer.2023.100960] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 06/09/2023]
Abstract
The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.
Collapse
Affiliation(s)
- Vinh Dao
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California
| | - Gregory Heestand
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
| |
Collapse
|
|
21
|
Heuvelings DJI, Wintjens AGWE, Luyten J, Wilmink GEWA, Moonen L, Speel EJM, de Hingh IHJT, Bouvy ND, Peeters A. DNA and RNA Alterations Associated with Colorectal Peritoneal Metastases: A Systematic Review. Cancers (Basel) 2023; 15:cancers15020549. [PMID: 36672497 PMCID: PMC9856984 DOI: 10.3390/cancers15020549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/04/2023] [Accepted: 01/08/2023] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND As colorectal cancer (CRC) patients with peritoneal metastases (PM) have a poor prognosis, new treatment options are currently being investigated for CRC patients. Specific biomarkers in the primary tumor could serve as a prediction tool to estimate the risk of distant metastatic spread. This would help identify patients eligible for early treatment. AIM To give an overview of previously studied DNA and RNA alterations in the primary tumor correlated to colorectal PM and investigate which gene mutations should be further studied. METHODS A systematic review of all published studies reporting genomic analyses on the primary tissue of CRC tumors in relation to PM was undertaken according to PRISMA guidelines. RESULTS Overall, 32 studies with 18,906 patients were included. BRAF mutations were analyzed in 17 articles, of which 10 found a significant association with PM. For all other reported genes, no association with PM was found. Two analyses with broader cancer panels did not reveal any new biomarkers. CONCLUSION An association of specific biomarkers in the primary tumors of CRC patients with metastatic spread into peritoneum could not be proven. The role of BRAF mutations should be further investigated. In addition, studies searching for potential novel biomarkers are still required.
Collapse
Affiliation(s)
- Danique J. I. Heuvelings
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 ER Maastricht, The Netherlands
- Correspondence:
| | - Anne G. W. E. Wintjens
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Julien Luyten
- Department of General Surgery, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands
| | - Guus E. W. A. Wilmink
- Department of General Surgery, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands
- Faculty of Science and Engineering, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Laura Moonen
- Department of Pathology, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands
- GROW–School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ernst-Jan M. Speel
- Department of Pathology, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands
- GROW–School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Ignace H. J. T. de Hingh
- GROW–School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
- Department of General Surgery, Catharina Ziekenhuis, 5623 EJ Eindhoven, The Netherlands
| | - Nicole D. Bouvy
- Department of General Surgery, Maastricht University Medical Center (MUMC+), 6202 AZ Maastricht, The Netherlands
- GROW–School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Andrea Peeters
- Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre (MUMC+), 6202 AZ Maastricht, The Netherlands
| |
Collapse
|
|
22
|
O'Riordan E, Bennett MW, Daly L, Power DG. The implication of BRAF mutation in advanced colorectal cancer. Ir J Med Sci 2022; 191:2467-2474. [PMID: 34877621 PMCID: PMC9672001 DOI: 10.1007/s11845-021-02689-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 06/09/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND Advanced colorectal cancer (CRC) is frequently a lethal disease. Mutations in the BRAF gene is a key driver in CRC pathogenesis and confers a poor prognosis. To date, Irish data on this molecular subtype of CRC is lacking. AIMS Our aim was to compare the natural history of Irish patients with BRAF (BRAFMUT) metastatic CRC with a control group of metastatic CRC patients without BRAF mutation (BRAFWT wild- type). METHOD A retrospective observational analysis of advanced CRC patients with known BRAFMUT was conducted by chart review. BRAFMUT patients were identified from the Cork University Hospital (CUH) histopathology database. Controls with known BRAFWT were randomly selected from the database. Demographic characteristics and clinicopathological data were recorded. Survival was assessed with Kaplan-Meier curve/Cox proportional hazard models. RESULTS Twenty patients with BRAFMUT and 36 with BRAFWT were studied. BRAFMUT were more likely female (75% vs 33%, p = 0.007) and right-sided (65% vs 31.4%, p = 0.033). Median overall survival was lower in BRAFMUT group (17.3 months (95% CI 0-40.8)) compared to patients with BRAFWT (median survival not reached, log rank p = 0.001). On multivariate analysis, BRAFMUT was independently associated with an increased risk of mortality (HR 12.76 (95% CI 3.15-51.7), p < 0.001). CONCLUSION BRAFMUT advanced colorectal cancer was associated with significantly reduced overall survival in this Irish CRC population. Knowledge of mutation status should now be considered standard of care and should dictate management. Surgeons should be aware of this genetic signature as the natural history of the disease may mitigate against an aggressive surgical strategy. A prospective study should be conducted to further corroborate these findings.
Collapse
Affiliation(s)
- Emma O'Riordan
- School of Medicine, University College Cork, Cork, Republic of Ireland.
| | | | - Louise Daly
- School of Food & Nutritional Sciences, University College Cork, Cork, Republic of Ireland
| | - Derek G Power
- Department of Medical Oncology, Mercy & Cork University Hospitals, Cork, Republic of Ireland
| |
Collapse
|
|
23
|
Kim CH. Molecular Analyses in Peritoneal Metastasis from Colorectal Cancer: A Review-An English Version. J Anus Rectum Colon 2022; 6:197-202. [PMID: 36348949 PMCID: PMC9613417 DOI: 10.23922/jarc.2022-045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 09/04/2022] [Indexed: 11/23/2022] Open
Abstract
Despite a trend showing continued improvement in survival by combing targeted agents in colorectal cancer, the improvement was limited, and clinically meaningful benefits were not achieved in peritoneal metastasis. The role of cytoreductive surgery (CRS) and proportion of the benefit from hyperthermic intraperitoneal chemotherapy (HIPEC) have been questioned. The PRODIGE 7 study aimed to assess the specific contribution of HIPEC to the survival benefit of peritoneal metastasis from colorectal cancer (CRC-PM) by grouping CRS alone versus CRS with oxaliplatin-based HIPEC, but failed to show any survival improvement. Of these criticisms, oxaliplatin resistance was suggested as the main cause of the negative result. In this regard, the relative resistance to oxaliplatin in consensus molecular subtype 4 colorectal cancer (CRC) is of great interest. Recent treatments for metastatic CRC have gradually moved to precision medicine based on individual biological information through high-throughput technology such as next generation sequencing. This review aimed to provide an overview of the current status of studies reporting the molecular knowledge of CRC-PM.
Collapse
Affiliation(s)
- Chang Hyun Kim
- Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea
| |
Collapse
|
|
24
|
Masri R, Al Housseiny A, Aftimos G, Bitar N. Incidence of BRAF V600E Gene Mutation Among Lebanese Population in Melanoma and Colorectal Cancer: A Retrospective Study Between 2010 and 2019. Cureus 2022; 14:e29315. [PMID: 36277559 PMCID: PMC9580600 DOI: 10.7759/cureus.29315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/18/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction: Cancers arise owing to the accumulation of mutations in critical genes that leads to uncontrolled cell division and the avoidance of apoptosis. Among these oncogenes, BRAF is a potent mitogen-activated protein kinase (MAPK) pathway activator known to be somatically mutated by a glutamic acid to valine substitution at codon 600 (V600E). It is a common finding in various types of human cancers, including malignant melanoma and colorectal cancer (CRC), and is considered a poor prognostic factor and a predictive biomarker. The study aims to determine the incidence of BRAF V600E gene mutation in Lebanese patients with melanoma and CRC and its correlation with gender and age. Methods: We conducted a retrospective cohort design study in which 210 and 132 patients diagnosed to have melanoma and CRC, respectively, were recruited from 2010 to 2019 from "L’Institut National de Pathologie," where a specific polymerase chain reaction is used to detect BRAF mutations. Data from digitized records were collected, including demographic characteristics (age and gender), cancer type, and BRAF mutation. The collected data were analyzed using SPSS Statistics version 20.0 (IBM Corp., Armonk, NY). A p-value < 0.05 was considered significant. Results: The incidence of BRAF mutation in melanoma is 88.10%. There is female predominance with a ratio of 2.6:1 (p = 0.240) and the majority of patients aged between 40 and 60 years (51.2%) with a mean age of 53.74 years. While in CRC, BRAF is mutated in 7.5% with a ratio of 1.2:1 of male predominance (p = 0.999). The majority of patients (54.8%) were between the ages of 60 and 80 years, with a mean age of 65.5 years. Conclusion: BRAF is a frequent oncogenic mutation that is found in lethal tumors. Targeted therapies for these cancers interfere with developing more effective therapeutic strategies, which affect the treatment response in BRAF mutants and improve the prognosis of the patients.
Collapse
|
|
25
|
Kim CH. Molecular analyses of peritoneal metastasis from colorectal cancer. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2022. [DOI: 10.5124/jkma.2022.65.9.586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Background: Despite a trend showing continued improvement in survival by combing targeted agents for colorectal cancer (CRC), the improvement observed is limited. Moreover, clinically relevant benefits were not achieved in peritoneal metastasis cases. The role of cytoreductive surgery (CRS) and the benefits of hyperthermic intraperitoneal chemotherapy (HIPEC) have been questioned. This review aimed to provide an overview of the current status of the studies reporting on the molecular knowledge of peritoneal metastasis from CRC (CRC-PM).Current Concepts: The PRODIGE 7 study was performed to assess the specific contributions of HIPEC to the survival benefit in CRC-PM cases by comparing CRS treatment alone and CRS with oxaliplatin-based HIPEC. However, this study did not reveal any survival improvement, and oxaliplatin resistance was suggested as the main cause of this negative outcome. Hence, the relative resistance to oxaliplatin in consensus molecular subtype (CMS) 4 CRC is of great interest.Discussion and Conclusion: Recent treatments for metastatic CRC have gradually moved to precision medicine based on individual biological information through high-throughput technology, such as next-generation sequencing. In the transcriptome study, CRC-PM was identified as an almost homogeneous CMS4 classification, which is known to have strong resistance to oxaliplatin-based chemotherapy. These results suggest the need to clarify complex sub-signal transmission pathways derived from transcriptome or proteome studies of CRC-PM. Finally, to compare two studies, it is necessary to establish a representative patient group and consider standardized sample collection, treatment, and analysis.
Collapse
|
|
26
|
Adamina M, Warlaumont M, Berger MD, Däster S, Delaloye R, Digklia A, Gloor B, Fritsch R, Koeberle D, Koessler T, Lehmann K, Müller P, Peterli R, Ris F, Steffen T, Weisshaupt CS, Hübner M. Comprehensive Treatment Algorithms of the Swiss Peritoneal Cancer Group for Peritoneal Cancer of Gastrointestinal Origin. Cancers (Basel) 2022; 14:4275. [PMID: 36077810 PMCID: PMC9454505 DOI: 10.3390/cancers14174275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients.
Collapse
Affiliation(s)
- Michel Adamina
- Klinik für Viszeral- und Thoraxchirurgie, Kantonsspital Winterthur, 8401 Winterthur, Switzerland
- Faculty of Medicine, University of Basel, 4056 Basel, Switzerland
| | - Maxime Warlaumont
- Chirurgie Digestive et Cancérologique, CHU de Lille, CH de Cambrai, 59000 Lille, France
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne, 1011 Lausanne, Switzerland
| | - Martin D. Berger
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Silvio Däster
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Claraspital and University Hospital Basel, 4031 Basel, Switzerland
| | - Raphaël Delaloye
- Department of Medical Oncology, University Hospital Basel, 4031 Basel, Switzerland
| | - Antonia Digklia
- Department of Oncology, Lausanne University Hospital CHUV, University of Lausanne, 1011 Lausanne, Switzerland
| | - Beat Gloor
- Department of Visceral Surgery and Medicine, Inselspital, University Bern, 3010 Bern, Switzerland
| | - Ralph Fritsch
- Department of Medical Oncology and Hematology, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Dieter Koeberle
- Department of Medical Oncology and Hematology, St. Claraspital, 4002 Basel, Switzerland
- Faculty of Medicine, University of Bern, 3012 Bern, Switzerland
| | - Thibaud Koessler
- Department of Oncology, Geneva University Hospital, 1205 Geneva, Switzerland
| | - Kuno Lehmann
- Department of Surgery and Transplantation, University Hospital Zurich, 8091 Zurich, Switzerland
| | - Phaedra Müller
- Klinik für Viszeral- und Thoraxchirurgie, Kantonsspital Winterthur, 8401 Winterthur, Switzerland
| | - Ralph Peterli
- Clarunis, Department of Visceral Surgery, University Centre for Gastrointestinal and Liver Diseases, St. Claraspital and University Hospital Basel, 4031 Basel, Switzerland
| | - Frédéric Ris
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland
| | - Thomas Steffen
- Klinik für Allgemein-, Viszeral-, Endokrine und Transplantationschirurgie, Kantonsspital St. Gallen, 9000 St. Gallen, Switzerland
| | | | - Martin Hübner
- Department of Visceral Surgery, Lausanne University Hospital CHUV, University of Lausanne, 1011 Lausanne, Switzerland
| |
Collapse
|
|
27
|
Wang PP, Lin C, Wang J, Margonis GA, Wu B. BRAF Mutations in Colorectal Liver Metastases: Prognostic Implications and Potential Therapeutic Strategies. Cancers (Basel) 2022; 14:cancers14174067. [PMID: 36077604 PMCID: PMC9454989 DOI: 10.3390/cancers14174067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary In this literature review, we investigated the relationship between BRAF mutation and prognosis in patients with colorectal cancer liver metastases. We also investigated factors affecting the prognosis of patients with BRAF mutations and summarized the latest research on targeted therapies. Abstract Surgery combined with chemotherapy and precision medicine is the only potential treatment for patients with colorectal cancer liver metastases (CRLM). The use of modern molecular biotechnology to identify suitable biomarkers is of great significance for predicting prognosis and formulating individualized treatment plans for these patients. BRAF mutations, particularly V600E, are widely believed to be associated with poor prognosis in patients with metastatic CRC (mCRC). However, it is unclear which specific factors affect the prognosis of CRLM patients with BRAF mutations. It is also unknown whether patients with resectable CRLM and BRAF mutations should undergo surgical treatment since there is an increased recurrence rate after surgery in these patients. In this review, we combined the molecular mechanism and clinical characteristics of BRAF mutations to explore the prognostic significance and potential targeted therapy strategies for patients with BRAF-mutated CRLM.
Collapse
Affiliation(s)
- Pei-Pei Wang
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Chen Lin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
| | - Jane Wang
- Department of Surgery, University of California San Francisco, San Francisco, CA 94158, USA
| | | | - Bin Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China
- Correspondence:
| |
Collapse
|
|
28
|
Ciombor KK, Strickler JH, Bekaii-Saab TS, Yaeger R. BRAF-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape. J Clin Oncol 2022; 40:2706-2715. [PMID: 35649231 PMCID: PMC9390817 DOI: 10.1200/jco.21.02541] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/07/2022] [Accepted: 03/07/2022] [Indexed: 12/13/2022] Open
Abstract
BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAFV600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAFV600E-mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAFV600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.
Collapse
Affiliation(s)
- Kristen K. Ciombor
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - John H. Strickler
- Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, Durham, NC
| | | | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| |
Collapse
|
|
29
|
Mjahed RB, Astaras C, Roth A, Koessler T. Where Are We Now and Where Might We Be Headed in Understanding and Managing Brain Metastases in Colorectal Cancer Patients? Curr Treat Options Oncol 2022; 23:980-1000. [PMID: 35482170 PMCID: PMC9174111 DOI: 10.1007/s11864-022-00982-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2022] [Indexed: 02/01/2023]
Abstract
OPINION STATEMENT Compared to liver and lung metastases, brain metastases (BMs) from colorectal cancer (CRC) are rare and remain poorly investigated despite the anticipated rise in their incidence. CRC patients bearing BM have a dismal prognosis with a median survival of 3-6 months, significantly lower than that of patients with BM from other primary tumors, and of those with metastatic CRC manifesting extracranially. While liver and lung metastases from CRC have more codified treatment strategies, there is no consensus regarding the treatment of BM in CRC, and their management follows the approaches of BM from other solid tumors. Therapeutic strategies are driven by the number and localisation of the lesion, consisting in local treatments such as surgery, stereotactic radiosurgery, or whole-brain radiotherapy. Novel treatment modalities are slowly finding their way into this shy unconsented armatorium including immunotherapy, monoclonal antibodies, tyrosine kinase inhibitors, or a combination of those, among others.This article reviews the pioneering strategies aiming at understanding, diagnosing, and managing this disease, and discusses future directions, challenges, and potential innovations in each of these domains. HIGHLIGHTS • With the increasing survival in CRC, brain and other rare/late-onset metastases are rising. • Distal colon/rectal primary location, long-standing progressive lung metastases, and longer survival are risk factors for BM development in CRC. • Late diagnosis and lack of consensus treatment strategies make BM-CRC diagnosis very dismal. • Liquid biopsies using circulating tumor cells might offer excellent opportunities in the early diagnosis of BM-CRC and the search for therapeutic options. • Multi-modality treatment including surgical metastatic resection, postoperative SRS with/without WBRT, and chemotherapy is the best current treatment option. • Recent mid-sized clinical trials, case reports, and preclinical models show the potential of unconventional therapeutic approaches as monoclonal antibodies, targeted therapies, and immunotherapy. Graphical abstract.
Collapse
Affiliation(s)
- Ribal Bou Mjahed
- Department of Oncology, University hospital of Geneva (HUG), Geneva, Switzerland.
- Département de médecine interne - CHUV, Rue du Bugnon 21, CH-1011, Lausanne, Switzerland.
| | - Christoforos Astaras
- Department of Oncology, University hospital of Geneva (HUG), Geneva, Switzerland
| | - Arnaud Roth
- Department of Oncology, University hospital of Geneva (HUG), Geneva, Switzerland
| | - Thibaud Koessler
- Department of Oncology, University hospital of Geneva (HUG), Geneva, Switzerland
| |
Collapse
|
|
30
|
Tang W, Liu Y, Ji M, Liu T, Chen Y, Zhuang A, Mao Y, Chang W, Wei Y, Ren L, Xu J. Association of RAS/BRAF Status and Prognosis of Metastatic Colorectal Cancer: Analysis of 1002 Consecutive Cases. Ann Surg Oncol 2022; 29:3593-3603. [PMID: 35301609 DOI: 10.1245/s10434-021-11302-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND This study aimed to analyze the association of RAS/BRAF status and the prognosis of patients with metastatic colorectal cancer (mCRC) based on multi-disciplinary team (MDT) treatment mode. METHODS The study retrospectively analyzed 1002 consecutive mCRC patients with different tumor RAS/BRAF status at Zhongshan Hospital Fudan University from April 2012 to December 2018. The association of RAS/BRAF status with clinicopathologic features and prognosis was analyzed. RESULTS The mutation rate was 42.3% (424/1002) for RAS and 5.0% (50/1002) for BRAF. The RAS and BRAF mutations were mutually exclusive of each other. An association of RAS/BRAF status with sex (P < 0.001), age (P = 0.021), primary tumor location (P < 0.001), pathologic type (P < 0.001), differentiation (P < 0.001), metastatic organ (P < 0.001), carcinoembryonic antigen (CEA) (P < 0.001), and cancer antigen (CA)19-9 (P < 0.001) was observed. Overall survival (OS) was better for the RAS/BRAF wild-type patients than for the RAS-mutant patients, whereas the BRAF-mutant patients had the worst OS (51.0 vs 34.9 vs 18.9 months; P < 0.001). Regardless of RAS/BRAF status, metastases resection significantly improved OS (64.0 vs. 21.3 months; P < 0.001). Among the initially unresectable patients, the RAS/BRAF wild-type patients had a better conversional resection rate (32.9% vs 19.1% vs 0; P < 0.001) and a better OS (33.8 vs 23.3 vs 13.2 months; P = 0.005) than the RAS- and BRAF-mutant patients. Similarly, among the initially resectable patients, the RAS/BRAF wild-type patients had a better OS than the RAS- or BRAF- mutant patients (not assessable vs 51.7 vs 35.4 months; P = 0.005). CONCLUSIONS This large-sample study showed that regardless of metastases resection or no resection, RAS and BRAF mutations were associated with a poor prognosis. Resection of metastases could bring survival benefits for patients regardless of RAS/BRAF status.
Collapse
Affiliation(s)
- Wentao Tang
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Centre of Colorectal Cancer Minimally Invasive Technology, Shanghai, China
| | - Yu Liu
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Meiling Ji
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Centre of Colorectal Cancer Minimally Invasive Technology, Shanghai, China
| | - Tianyu Liu
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Centre of Colorectal Cancer Minimally Invasive Technology, Shanghai, China
| | - Yijiao Chen
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Aobo Zhuang
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yihao Mao
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wenju Chang
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Centre of Colorectal Cancer Minimally Invasive Technology, Shanghai, China
| | - Ye Wei
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Engineering Research Centre of Colorectal Cancer Minimally Invasive Technology, Shanghai, China
| | - Li Ren
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China.
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
- Shanghai Engineering Research Centre of Colorectal Cancer Minimally Invasive Technology, Shanghai, China.
| | - Jianmin Xu
- Colorectal Cancer Centre, Zhongshan Hospital, Fudan University, Shanghai, China.
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
- Shanghai Engineering Research Centre of Colorectal Cancer Minimally Invasive Technology, Shanghai, China.
| |
Collapse
|
|
31
|
De Baere T, Tselikas L, Delpla A, Roux C, Varin E, Kobe A, Yevich S, Deschamps F. Thermal ablation in the management of oligometastatic colorectal cancer. Int J Hyperthermia 2022; 39:627-632. [PMID: 35477367 DOI: 10.1080/02656736.2021.1941311] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
PURPOSE To review available evidence on thermal ablation of oligometastatic colorectal cancer. METHODS Technical and cancer specific considerations for percutaneous image-guided thermal ablation of oligometastatic colorectal metastases in the liver and lung were reviewed. Ablation outcomes are compared to surgical and radiation therapy literature. RESULTS The application of thermal ablation varies widely based on tumor burden, technical expertise, and local cancer triage algorithms. Ablation can be performed in combination or in lieu of other cancer treatments. For surgically non-resectable liver metastases, a randomized trial has demonstrated the superiority of thermal ablation combined with chemotherapy compared to systemic chemotherapy alone in term of progression-free survival and overall survival (OS), with 5-, and 8-year OS of 43.1% and 35.9% in the combined arm vs. 30.3% and 8.9% in the chemotherapy alone arm. As ablation techniques and technology improve, the role of percutaneous thermal ablation may expand even into surgically resectable disease. Many of the prognostic factors for better OS after local treatment of lung metastases are the same for surgery and thermal ablation, including size and number of metastases, disease-free interval, complete resection/ablation, negative carcinoembryonic antigen, neoadjuvant chemotherapy, and controlled extra-pulmonary metastases. When matched for these factors, thermal ablation for lung and liver metastases appears to provide equivalent overall survival as surgery, in the range of 50% at 5 years. Thermal ablation has limitations that should be respected to optimize patient outcomes and minimize complications including targets that are well-visualized by image guidance, measure <3cm in diameter, and be located at least 3mm distance from prominent vasculature or major bronchi. CONCLUSIONS The routine incorporation of image-guided thermal ablation into the therapeutic armamentarium for the treatment of oligometastatic colorectal cancer can provide long survival and even cure.
Collapse
Affiliation(s)
- Thierry De Baere
- Departement d'anesthésie, de chirurgie, et de radiologie interventionnelle, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin Bicêtre, France
| | - Lambros Tselikas
- Departement d'anesthésie, de chirurgie, et de radiologie interventionnelle, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin Bicêtre, France
| | - Alexandre Delpla
- Departement d'anesthésie, de chirurgie, et de radiologie interventionnelle, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin Bicêtre, France
| | - Charles Roux
- Departement d'anesthésie, de chirurgie, et de radiologie interventionnelle, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin Bicêtre, France
| | - Eloi Varin
- Departement d'anesthésie, de chirurgie, et de radiologie interventionnelle, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin Bicêtre, France
| | - Adrian Kobe
- Departement d'anesthésie, de chirurgie, et de radiologie interventionnelle, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin Bicêtre, France
| | - Steven Yevich
- Interventional Radiology Department, MD Anderson Cancer Center, Houston, TX, USA
| | - Frederic Deschamps
- Departement d'anesthésie, de chirurgie, et de radiologie interventionnelle, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UFR Médecine Le Kremlin-Bicêtre, Le Kremlin Bicêtre, France
| |
Collapse
|
|
32
|
Newhook TE, Vauthey JN. Colorectal liver metastases: state-of-the-art management and surgical approaches. Langenbecks Arch Surg 2022; 407:1765-1778. [DOI: 10.1007/s00423-022-02496-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023]
|
|
33
|
Larsen SG, Goscinski MA, Dueland S, Steigen SE, Hofsli E, Torgunrud A, Lund-Iversen M, Dagenborg VJ, Flatmark K, Sorbye H. Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients. Br J Cancer 2022; 126:726-735. [PMID: 34887523 PMCID: PMC8888568 DOI: 10.1038/s41416-021-01620-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. METHODS In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. RESULTS In total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis. CONCLUSIONS PM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.
Collapse
Affiliation(s)
- S. G. Larsen
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - M. A. Goscinski
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - S. Dueland
- grid.55325.340000 0004 0389 8485Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - S. E. Steigen
- grid.412244.50000 0004 4689 5540Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway
| | - E. Hofsli
- grid.52522.320000 0004 0627 3560The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway ,grid.5947.f0000 0001 1516 2393Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - A. Torgunrud
- grid.5947.f0000 0001 1516 2393Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - M. Lund-Iversen
- grid.5510.10000 0004 1936 8921Department of Clinical Pathology, University of Oslo, Oslo, Norway
| | - V. J. Dagenborg
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - K. Flatmark
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway ,grid.55325.340000 0004 0389 8485Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - H. Sorbye
- grid.7914.b0000 0004 1936 7443Department of Oncology, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
| |
Collapse
|
|
34
|
Adjuvant intra-arterial chemotherapy for patients with resected colorectal liver metastases: a systematic review and meta-analysis. HPB (Oxford) 2022; 24:299-308. [PMID: 34895829 DOI: 10.1016/j.hpb.2021.10.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/18/2021] [Accepted: 10/27/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The practice of adjuvant hepatic arterial infusion chemotherapy (HAIC) for colorectal liver metastasis (CRLM) varies widely. This meta-analysis investigates the effectiveness of adjuvant HAIC and the influence of variations in HAIC treatment in patients with resected CRLM. METHODS PRISMA guidelines were followed for this study. The search was limited to comparative studies (HAIC vs non-HAIC) for overall survival. Subgroup meta-analyses using random-effects were performed for type of intra-arterial drug, method of catheter insertion, use of concomitant adjuvant systemic chemotherapy, and study design. RESULTS Eighteen eligible studies were identified. After excluding overlapping cohorts, fifteen studies were included in the quantitative analysis, corresponding to 3584 patients. HAIC was associated with an improved overall survival (pooled hazard ratio (HR) 0.77; 95%CI 0.64-0.93). Survival benefit of HAIC was most pronounced in studies using floxuridine (HR 0.76; 95%CI: 0.62-0.94), surgical catheter insertion with subcutaneous pump (HR 0.71; 95%CI: 0.61-0.84), and concomitant adjuvant systemic chemotherapy (HR 0.75; 95%CI: 0.59-0.96). The pooled HR of RCTs was 0.91 (95%CI 0.72-1.14), of which only 3 used floxuridine. CONCLUSION Adjuvant HAIC is a promising treatment for patients with resectable CRLM, in particular HAIC with floxuridine using a surgically placed catheter and a subcutaneous pump, and concomitant systemic chemotherapy.
Collapse
|
|
35
|
Ecker BL, Shin P, Saadat LV, Court CM, Balachandran VP, Chandwani R, Drebin JA, Jarnagin WR, Kingham TP, Soares KC, Vakiani E, Wei AC, Kemeny NE, Smith JJ, Gonen M, D’Angelica MI. Genomic Stratification of Resectable Colorectal Liver Metastasis Patients and Implications for Adjuvant Therapy and Survival. Ann Surg 2022; 275:371-381. [PMID: 34793355 PMCID: PMC8754193 DOI: 10.1097/sla.0000000000005315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To determine whether genomic risk groups identified by somatic mutation testing of colorectal liver metastasis (CRLM) can be used for "molecularly-guided" selection for adjuvant systemic chemotherapy and hepatic artery infusion of FUDR (SYS+HAI-FUDR). BACKGROUND Several genomic biomarkers have been associated with clinical phenotype and survival for patients with resectable CRLM. It is unknown whether prognostication afforded by genomic stratification translates into enhanced patient selection for adjuvant hepatic artery infusion therapy. METHODS Consecutive patients with resected CRLM and available mutational characterization via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets were reviewed from a prospective institutional database. Patients were stratified into three genomic risk groups based on previously defined alterations in SMAD4, EGFR and the RAS/RAF pathway. The association between SYS+HAI-FUDR and overall survival, relative to adjuvant chemotherapy alone (SYS), was evaluated in each genomic risk group by Cox proportional hazard regression and propensity score matched analyses. RESULTS A total of 334 patients (SYS+HAI-FUDR 204; SYS 130) were identified; the rates of RAS/RAF alterations and SMAD4 inactivation were 47.4% and 11.7%, respectively. After a median follow-up of 58 months, adjuvant SYS+HAI-FUDR was independently associated with a reduced risk of death (HR 0.50, 95%CI 0.26-0.98, P = 0.045) in the low-risk genomic group, but not in the moderate-risk (HR 1.07, 95%CI 0.5-2.07, P = 0.749) or high-risk (HR 1.62, 95%CI 0.29-9.12, P = 0.537) cohorts. Following propensity score matching, adjuvant SYS+HAI-FUDR remained associated with significant improvements in long-term survival selectively in the low-risk genomic cohort (5-year actuarial survival: 89% vs. 68%, P = 0.019). CONCLUSIONS Genomic alterations in RAS/RAF, SMAD4, and EGFR may be useful to guide treatment selection in resectable CRLM patients and warrant external validation and integration in future clinical trial design.
Collapse
Affiliation(s)
- Brett L. Ecker
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Paul Shin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lily V. Saadat
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Colin M. Court
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Vinod P. Balachandran
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Immuno-oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center New York, NY
| | - Rohit Chandwani
- Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Jeffrey A. Drebin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - William R. Jarnagin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - T. Peter Kingham
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Kevin C. Soares
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Efsevia Vakiani
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alice C Wei
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nancy E. Kemeny
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - J. Joshua Smith
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mithat Gonen
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael I. D’Angelica
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| |
Collapse
|
|
36
|
España MS. Treatment of advanced BRAF-mutated colorectal cancer: where we are and where we are going. Clin Colorectal Cancer 2022; 21:71-79. [DOI: 10.1016/j.clcc.2022.01.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 01/16/2022] [Accepted: 01/24/2022] [Indexed: 11/03/2022]
|
|
37
|
Chong CY, Jalali A, Wong HL, Loft M, Wong R, Lee M, Gately L, Hong W, Shapiro J, Kosmider S, Tie J, Ananda S, Yeung JM, Ma B, Burge M, Jennens R, Tran B, Lee B, Lim L, Dean A, Nott L, Gibbs P. Impact of the evolution in RAS mutation analysis in Australian patients with metastatic colorectal cancer. Asia Pac J Clin Oncol 2022; 18:e363-e368. [DOI: 10.1111/ajco.13728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/25/2021] [Indexed: 11/27/2022]
|
|
38
|
Riedesser JE, Ebert MP, Betge J. Precision medicine for metastatic colorectal cancer in clinical practice. Ther Adv Med Oncol 2022; 14:17588359211072703. [PMID: 35237350 PMCID: PMC8882813 DOI: 10.1177/17588359211072703] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/17/2021] [Indexed: 12/22/2022] Open
Abstract
Globally, metastatic colorectal cancer is one of the leading causes for cancer-related death. Treatment limited to conventional chemotherapeutics extended life for only a few months. However, advances in surgical approaches and medical treatment regimens have greatly increased survival, even leading to long-term remission in selected patients. Advances in multiomics analysis of tumors have built a foundation for molecular-targeted therapies. Furthermore, immunotherapies are on the edge of revolutionizing oncological practice. This review summarizes recent advances in the growing toolbox of personalized treatment for patients with metastatic colorectal cancer. We provide an overview of current multimodal therapy and explain novel immunotherapy and targeted therapy approaches in detail. We emphasize clinically relevant therapies, such as inhibitors of MAPK signaling, and give recommendations for clinical practice. Finally, we describe the potential predictive impact of molecular subtypes and provide an outlook on novel concepts, such as functional precision medicine.
Collapse
Affiliation(s)
- Julian E. Riedesser
- Junior Clinical Cooperation Unit Translational
Gastrointestinal Oncology and Preclinical Models, German Cancer Research
Center (DKFZ), Heidelberg, Germany
| | - Matthias P. Ebert
- Department of Medicine II, University Medical
Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim,
GermanyMannheim Cancer Center, University Medical Center Mannheim, Medical
Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Betge
- Junior Clinical Cooperation Unit Translational
Gastrointestinal Oncology and Preclinical Models, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg 69120, GermanyDKFZ-Hector
Cancer Institute at University Medical Center Mannheim, Mannheim,
Germany.Department of Medicine II, University Medical Center Mannheim,
Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyMannheim
Cancer Center, University Medical Center Mannheim, Medical Faculty Mannheim,
Heidelberg University, Mannheim, Germany
| |
Collapse
|
|
39
|
Hatthakarnkul P, Quinn JA, Matly AAM, Ammar A, van Wyk HC, McMillan DC, Edwards J. Systematic review of tumour budding and association with common mutations in patients with colorectal cancer. Crit Rev Oncol Hematol 2021; 167:103490. [PMID: 34619332 DOI: 10.1016/j.critrevonc.2021.103490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Despite a well-known prognostic role in colorectal cancer, the genomic profiling of tumour budding remains to be elucidated. We aim to review the association of common mutations with tumour budding. METHODS A systematic review of studies relating to tumour budding and genetic mutation in CRC was performed. The relationship between mutational status and tumour budding was evaluated using meta-analysis. RESULTS A total of 6153 patients from 17 articles were included. According to the meta-analysis, high-grade tumour budding was significantly associated with KRAS mutation (OR = 1.52, 95 %CI: 1.13-2.02, P = 0.005) and MSS/pMMR (OR = 2.06, 95 %CI: 1.42-2.97, P = 0.0001). CONCLUSION The significant association between high-grade tumour budding and mutated KRAS or MSS/pMMR may suggest a role of these mutations in the development of the tumour budding phenotype and be useful for stratifying patient outcome in CRC.
Collapse
Affiliation(s)
- Phimmada Hatthakarnkul
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Jean A Quinn
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Amna Ahmed Mohemmd Matly
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Aula Ammar
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| | - Hester C van Wyk
- School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Alexandria Parade, Glasgow, G31 2ER, United Kingdom.
| | - Donald C McMillan
- School of Medicine, University of Glasgow, Glasgow Royal Infirmary, Alexandria Parade, Glasgow, G31 2ER, United Kingdom.
| | - Joanne Edwards
- Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Estate, Glasgow, G61 1QH, United Kingdom.
| |
Collapse
|
|
40
|
Saravani K, Salarzaei M, Parooie F. Effect of KRAS and BRAF mutations in metastatic colorectal cancer patients: A systematic review and meta-analysis based on tumor sidedness and KRAS subtypes. Hum Antibodies 2021; 29:275-284. [PMID: 34334388 DOI: 10.3233/hab-210451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Metastatic or recurrent colorectal cancer (MRCRC) has a poor prognosis. The aim of the present meta-analysis was to assess the prevalence of different subtypes of KRAS mutation and BRAF mutation in metastatic CRC patients, and evaluate the relationship between the tumor sidedness and prevalence of KRAS and BRAF mutation. METHODS We searched MEDLINE/PubMed, the Cochrane Library, and ClinicalTrials.gov from January 2010 to July 2020. The data were extracted independently according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The statistical analysis was done using STATA and Meta-Disk 1.4 applications. RESULTS Overall, 6699 colorectal cancer patients were included. KRAS and BRAF mutation was reported in 28% and 6% of patients, respectively. The overall prevalence of right primary and left primary metastatic CRC patients with mutated KRAS was 40% and 60%. However, the prevalence BRAF mutated right primary and left primary metastatic CRC patients was 37% and 63%. The overall HR was 2.38 for patients with metastatic CRC who had a mutated type of KRAS. Our study showed a mean overall survival of 35.4 month for KRAS mutant and a 10.12 month survival for BRAF mutant patients with metastatic colorectal cancer patients. CONCLUSION The prevalence of KRAS and BRAF mutations varied significantly according to the location of the tumor. BRAF mutations are more commonly found in metastatic colorectal cancers on the right side. Liver was the most common site of metastases in patients with mutant KRAS and the mortality of patients with mutant KRAS was 2.3 times higher than the patients with wild types. These results help to better describe the population of mCRC patients and can have implications for improving and organizing anti-EGFR therapies. Further research is needed to assess differences in survival through mutation status and primary tumor location.
Collapse
|
|
41
|
Diehl TM, Abbott DE. Molecular Determinants and Other Factors to Guide Selection of Patients for Hepatic Resection of Metastatic Colorectal Cancer. Curr Treat Options Oncol 2021; 22:82. [PMID: 34224023 DOI: 10.1007/s11864-021-00878-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2021] [Indexed: 01/10/2023]
Abstract
OPINION STATEMENT Treatment for metastatic colorectal cancer (CRC) has changed significantly over the last few decades as cytotoxic and targeted chemotherapies have evolved and resection of (technically feasible) colorectal liver metastases (CRLM) has become standard of care for eligible patients. Overall, survival for metastatic CRC has considerably improved, but recurrences are common. Numerous clinical risk scores have been suggested to guide patient selection for CRLM resection, but none perfectly predict outcomes; therefore, a personalized approach to metastatic CRC treatment using genetic profiles for risk stratification and prognostication is a critically important advancement. All patients with suspected metastatic CRC should undergo genetic testing for common oncogene mutations (e.g., KRAS, BRAF, and NRAS) in addition to a triphasic CT scan of the chest, abdomen, and pelvis; if hepatectomy may be entertained and there is concern about the future liver remnant (FLR), liver volumetrics should also be performed. MRI and PET are useful adjuncts for cases in which diagnosis or extent of disease is unclear. The decision to operate should be individualized and based on each patient's condition, tumor biology, and technical resectability. Genetic profiles should be used to inform multidisciplinary meetings surrounding topics of chemotherapy and surgical resection, as well as patient discussions concerning the risks and benefits of surgery. In the end, most patients with technically resectable colorectal cancers and adequate cardiopulmonary fitness benefit from surgical resection, as it remains the only chance of long-term survival.
Collapse
Affiliation(s)
- Thomas M Diehl
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, USA
| | - Daniel E Abbott
- Department of Surgery, Division of Surgical Oncology, University of Wisconsin, Madison, Wisconsin, USA.
| |
Collapse
|
|
42
|
Shimada Y, Okuda S, Watanabe Y, Tajima Y, Nagahashi M, Ichikawa H, Nakano M, Sakata J, Takii Y, Kawasaki T, Homma KI, Kamori T, Oki E, Ling Y, Takeuchi S, Wakai T. Histopathological characteristics and artificial intelligence for predicting tumor mutational burden-high colorectal cancer. J Gastroenterol 2021; 56:547-559. [PMID: 33909150 DOI: 10.1007/s00535-021-01789-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 04/15/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tumor mutational burden-high (TMB-H), which is detected with gene panel testing, is a promising biomarker for immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC). However, in clinical practice, not every patient is tested for TMB-H using gene panel testing. We aimed to identify the histopathological characteristics of TMB-H CRC for efficient selection of patients who should undergo gene panel testing. Moreover, we attempted to develop a convolutional neural network (CNN)-based algorithm to predict TMB-H CRC directly from hematoxylin and eosin (H&E) slides. METHODS We used two CRC cohorts tested for TMB-H, and whole-slide H&E digital images were obtained from the cohorts. The Japanese CRC (JP-CRC) cohort (N = 201) was evaluated to detect the histopathological characteristics of TMB-H using H&E slides. The JP-CRC cohort and The Cancer Genome Atlas (TCGA) CRC cohort (N = 77) were used to develop a CNN-based TMB-H prediction model from the H&E digital images. RESULTS Tumor-infiltrating lymphocytes (TILs) were significantly associated with TMB-H CRC (P < 0.001). The area under the curve (AUC) for predicting TMB-H CRC was 0.910. We developed a CNN-based TMB-H prediction model. Validation tests were conducted 10 times using randomly selected slides, and the average AUC for predicting TMB-H slides was 0.934. CONCLUSIONS TILs, a histopathological characteristic detected with H&E slides, are associated with TMB-H CRC. Our CNN-based model has the potential to predict TMB-H CRC directly from H&E slides, thereby reducing the burden on pathologists. These approaches will provide clinicians with important information about the applications of ICIs at low cost.
Collapse
Affiliation(s)
- Yoshifumi Shimada
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.,Medical Genome Center, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Shujiro Okuda
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. .,Medical Genome Center, Niigata University Medical and Dental Hospital, Niigata, Japan.
| | - Yu Watanabe
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.,Division of Cancer Genome Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yosuke Tajima
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Hiroshi Ichikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Masato Nakano
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Jun Sakata
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Yasumasa Takii
- Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Takashi Kawasaki
- Department of Pathology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Kei-Ichi Homma
- Department of Pathology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Tomohiro Kamori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yiwei Ling
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Shiho Takeuchi
- Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.,Division of Cancer Genome Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan. .,Medical Genome Center, Niigata University Medical and Dental Hospital, Niigata, Japan.
| |
Collapse
|
|
43
|
Impact of BRAF mutations on clinical outcomes following liver surgery for colorectal liver metastases: An updated meta-analysis. Eur J Surg Oncol 2021; 47:2722-2733. [PMID: 34099355 DOI: 10.1016/j.ejso.2021.05.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 05/25/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Data regarding clinical outcomes of patients undergoing hepatic resection for BRAF-mutated colorectal liver metastases (CRLM) are scarce. Most of the studies report an impaired median overall survival (OS) in BRAF-mutated patients, but controversial Results regarding both recurrence-free survival (RFS) and recurrence patterns. The purpose of this updated meta-analysis was to better precise the impact of BRAF mutations on clinical outcomes following liver surgery for CRLM study, especially on recurrence. METHODS A systematic literature review was performed to identify articles reporting clinical outcomes including both OS and RFS, recurrence patterns, and clinicopathological details of patients who underwent complete liver resection for CRLM, stratified according to BRAF mutational status. RESULTS Thirteen retrospective studies, including 5192 patients, met the inclusion criteria. The analysis revealed that both OS (OR = 1.981; 95% CI = [1.613-2.432]) and RFS (OR = 1.49; 95% CI [1.01-2.21]) were impaired following liver surgery for CRLM in BRAF-mutated patients. Risks of both hepatic (OR = 0.42; 95% CI [0.18-0.98]) and extrahepatic recurrences (OR = 0.53; 95% CI [0.33-0.83] were significantly higher in BRAF-mutated patients. These patients tended to have higher rates of right-sided colon primary tumors, primary positive lymph nodes, and multiple CRLM. CONCLUSIONS This meta-analysis confirms that BRAF mutations impair both OS and RFS following liver surgery. Therefore, BRAF mutational status should probably be included in further prognostic scores for the assessment of the expected clinical outcomes following surgery for CRLM.
Collapse
|
|
44
|
Mauri G, Monfardini L, Garnero A, Zampino MG, Orsi F, Della Vigna P, Bonomo G, Varano GM, Busso M, Gazzera C, Fonio P, Veltri A, Calandri M. Optimizing Loco Regional Management of Oligometastatic Colorectal Cancer: Technical Aspects and Biomarkers, Two Sides of the Same Coin. Cancers (Basel) 2021; 13:2617. [PMID: 34073585 PMCID: PMC8198296 DOI: 10.3390/cancers13112617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/21/2021] [Accepted: 05/22/2021] [Indexed: 11/23/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and has a high rate of metastatic disease which is the main cause of CRC-related death. Oligometastatic disease is a clinical condition recently included in ESMO guidelines that can benefit from a more aggressive locoregional approach. This review focuses the attention on colorectal liver metastases (CRLM) and highlights recommendations and therapeutic locoregional strategies drawn from the current literature and consensus conferences. The different percutaneous therapies (radiofrequency ablation, microwave ablation, irreversible electroporation) as well as trans-arterial approaches (chemoembolization and radioembolization) are discussed. Ablation margins, the choice of the imaging guidance as well as characteristics of the different ablation techniques and other technical aspects are analyzed. A specific attention is then paid to the increasing role of biomarkers (in particular molecular profiling) and their role in the selection of the proper treatment for the right patient. In conclusion, in this review an up-to-date state of the art of the application of locoregional treatments on CRLM is provided, highlighting both technical aspects and the role of biomarkers, two sides of the same coin.
Collapse
Affiliation(s)
- Giovanni Mauri
- Divisione di Radiologia Interventistica, Istituto Europeo di Oncologia, IRCCS, 20141 Milan, Italy; (G.M.); (F.O.); (P.D.V.); (G.B.); (G.M.V.)
- Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, 20122 Milan, Italy
| | | | - Andrea Garnero
- Radiodiagnostica 1 U. A.O.U., San Luigi Gonzaga di Orbassano, Regione Gonzole 10, 10043 Orbassano, Torino, Italy; (A.G.); (M.B.); (A.V.); (M.C.)
- Department of Surgical Sciences, University of Turin, 10124 Torino, Italy;
| | - Maria Giulia Zampino
- Divisione di Oncologia Medica Gastrointestinale e Tumori Neuroendocrini, Istituto Europeo di Oncologia, IRCCS, 20141 Milan, Italy;
| | - Franco Orsi
- Divisione di Radiologia Interventistica, Istituto Europeo di Oncologia, IRCCS, 20141 Milan, Italy; (G.M.); (F.O.); (P.D.V.); (G.B.); (G.M.V.)
| | - Paolo Della Vigna
- Divisione di Radiologia Interventistica, Istituto Europeo di Oncologia, IRCCS, 20141 Milan, Italy; (G.M.); (F.O.); (P.D.V.); (G.B.); (G.M.V.)
| | - Guido Bonomo
- Divisione di Radiologia Interventistica, Istituto Europeo di Oncologia, IRCCS, 20141 Milan, Italy; (G.M.); (F.O.); (P.D.V.); (G.B.); (G.M.V.)
| | - Gianluca Maria Varano
- Divisione di Radiologia Interventistica, Istituto Europeo di Oncologia, IRCCS, 20141 Milan, Italy; (G.M.); (F.O.); (P.D.V.); (G.B.); (G.M.V.)
| | - Marco Busso
- Radiodiagnostica 1 U. A.O.U., San Luigi Gonzaga di Orbassano, Regione Gonzole 10, 10043 Orbassano, Torino, Italy; (A.G.); (M.B.); (A.V.); (M.C.)
| | - Carlo Gazzera
- Radiodiagnostica 1 U, A.O.U. Città della Scienza e della Salute, 10126 Torino, Italy;
| | - Paolo Fonio
- Department of Surgical Sciences, University of Turin, 10124 Torino, Italy;
- Radiodiagnostica 1 U, A.O.U. Città della Scienza e della Salute, 10126 Torino, Italy;
| | - Andrea Veltri
- Radiodiagnostica 1 U. A.O.U., San Luigi Gonzaga di Orbassano, Regione Gonzole 10, 10043 Orbassano, Torino, Italy; (A.G.); (M.B.); (A.V.); (M.C.)
- Department of Oncology, University of Turin, 10124 Torino, Italy
| | - Marco Calandri
- Radiodiagnostica 1 U. A.O.U., San Luigi Gonzaga di Orbassano, Regione Gonzole 10, 10043 Orbassano, Torino, Italy; (A.G.); (M.B.); (A.V.); (M.C.)
- Department of Oncology, University of Turin, 10124 Torino, Italy
| |
Collapse
|
|
45
|
Miller SA, Policastro RA, Sriramkumar S, Lai T, Huntington TD, Ladaika CA, Kim D, Hao C, Zentner GE, O'Hagan HM. LSD1 and Aberrant DNA Methylation Mediate Persistence of Enteroendocrine Progenitors That Support BRAF-Mutant Colorectal Cancer. Cancer Res 2021; 81:3791-3805. [PMID: 34035083 DOI: 10.1158/0008-5472.can-20-3562] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/23/2021] [Accepted: 05/05/2021] [Indexed: 11/16/2022]
Abstract
Despite the connection of secretory cells, including goblet and enteroendocrine (EEC) cells, to distinct mucus-containing colorectal cancer histologic subtypes, their role in colorectal cancer progression has been underexplored. Here, our analysis of The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data demonstrates that EEC progenitor cells are enriched in BRAF-mutant colorectal cancer patient tumors, cell lines, and patient-derived organoids. In BRAF-mutant colorectal cancer, EEC progenitors were blocked from differentiating further by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of intermediate EECs. Mechanistically, secretory cells and the factors they secrete, such as trefoil factor 3, promoted colony formation and activation of cell survival pathways in the entire cell population. Lysine-specific demethylase 1 (LSD1) was identified as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss blocks formation of EEC progenitors and reduces tumor growth and metastasis. These findings reveal an important role for EEC progenitors in supporting colorectal cancer. SIGNIFICANCE: This study establishes enteroendocrine progenitors as a targetable population that promotes BRAF-mutant colorectal cancer and can be blocked by LSD1 inhibition to suppress tumor growth.
Collapse
Affiliation(s)
- Samuel A Miller
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana.,Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Robert A Policastro
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana
| | - Shruthi Sriramkumar
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.,Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Tim Lai
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana.,Luddy School of Informatics, Computing, and Engineering, Indiana University, Bloomington, Indiana.,Department of Mathematics, Indiana University, Bloomington, Indiana
| | - Thomas D Huntington
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Christopher A Ladaika
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana.,Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana
| | - Daeho Kim
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Chunhai Hao
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
| | - Gabriel E Zentner
- Genome, Cell, and Developmental Biology, Department of Biology, Indiana University Bloomington, Bloomington, Indiana.,Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, Indiana.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
| | - Heather M O'Hagan
- Medical Sciences Program, Indiana University School of Medicine, Bloomington, Indiana. .,Cell, Molecular and Cancer Biology Graduate Program, Indiana University School of Medicine, Bloomington, Indiana.,Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana.,Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| |
Collapse
|
|
46
|
Wang N, Liu F, Xi W, Jiang J, Xu Y, Guan B, Wu J, Zhou C, Shi M, Zhu Z, Xu Y, Liu J, Zhang J. Development and validation of risk and prognostic nomograms for bone metastases in Chinese advanced colorectal cancer patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:875. [PMID: 34164509 PMCID: PMC8184451 DOI: 10.21037/atm-21-2550] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Bone metastases (BM) from colorectal cancer (CRC) are often accompanied by extraosseous metastases, resulting in a dismal prognosis. The present study aimed to determine the risk factors for BM in metastatic CRC (mCRC) and the prognostic factors for CRC patients with BM. Methods The study was based on a training cohort of 214 mCRC patients (of which, 101 patients had BM) from our center, and a validation cohort of 511 mCRC patients (of which, 173 patients had BM) from another institute. Risk and prognostic nomograms for BM were developed using univariate and multivariate analyses. The goodness of fit, discrimination, and calibration performance of the nomograms were assessed by R2, concordance statistics (C-statistics), and the calibration curve. The results were internally validated using bootstrap resampling in the training cohort, and externally validated in the validation cohort. Results The novel BM risk nomogram comprised seven variables [degree of tumor differentiation, N-stage, serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), liver metastasis, and lung metastasis]. It showed good performance, with an R2 of 0.447 and a C-statistic of 0.846 [95% confidence interval (CI), 0.793 to 0.898] in the training cohort, and an R2 of 0.325 and a C-statistic of 0.792 (95% CI, 0.750 to 0.834) in the validation cohort. The optimal cutoff value to identify individuals at low or high risk was 56% probability, with a sensitivity of 71.3% and a specificity of 89.4%. The prognostic nomogram included five factors (tumor differentiation, number of extra-BM organs, number of BM lesions, ALP, and LDH), and had an R2 of 0.284 and a C-statistic of 0.723 (95% CI, 0.657 to 0.789) in the training set. This nomogram was externally validated in the validation cohort, with an R2 of 0.182 and a C-statistic of 0.682 (95% CI, 0.638 to 0.726). Conclusions The developed and validated risk and prognostic nomograms showed good performance for predicting the occurrence of BM in mCRC as well as the prognosis of CRC patients with BM. The risk nomogram can be used as a cost-effective preliminary screening tool prior to bone scanning.
Collapse
Affiliation(s)
- Nan Wang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fangqi Liu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wenqi Xi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinling Jiang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Bingjie Guan
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junwei Wu
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenfei Zhou
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Shi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenggang Zhu
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jing Liu
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
47
|
Vega EA, Salehi O, Nicolaescu D, Dussom EM, Alarcon SV, Kozyreva O, Simonds J, Schnipper D, Conrad C. Failure to Cure Patients with Colorectal Liver Metastases: The Impact of the Liver Surgeon. Ann Surg Oncol 2021; 28:7698-7706. [PMID: 33939045 DOI: 10.1245/s10434-021-10030-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 03/27/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Lack of a liver surgeon (LS) may lead to failure to cure in patients with possibly resectable colorectal liver metastases (CRLM). This study aims to quantify the failure-to-cure rate due to noninclusion of an LS. PATIENTS AND METHODS All patients who underwent chemotherapy with palliative intent for CRLM at a community oncology network between 2010 and 2018 were identified from a prospectively maintained cancer registry. Two LS blinded to patient management and outcome reviewed pretreatment imaging and assigned each scan a newly developed resectability score. Nominal group technique and independent scores were combined to determine probability of curative-intent resection. Interobserver agreement was calculated using κ testing. RESULTS This study included 72 palliative CRLM patients. Demographic factors were: 44 (59%) male, median age 68 years (range 36-94 years), 23 (32%) rectal primary, 24 (33%) receiving oxaliplatin-based chemotherapy. Of the 72 patients with CRLM, 6 had left-sided metastases only. The median number of CRLM was 6 (1-8). Agreement on resectability was achieved in 32 (44%) patients for the entire cohort and 17 (54%) in patients without extrahepatic disease. A lower median number of CRLM was found in the group considered to be resectable by the two LS (2 versus 8; p = 0.001). Substantial agreement was found between liver surgeons in the group of patients without extrahepatic disease (κ = 0.9043). CONCLUSIONS Over 44% of patients who were assigned palliative chemotherapy at tumor boards without an LS were considered potentially resectable upon independent LS review.
Collapse
Affiliation(s)
- Eduardo A Vega
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Omid Salehi
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Diana Nicolaescu
- IOSUD Titu Maiorescu University of Bucharest, Medical Doctoral School, Tulcea Emergency Hospital, Bucharest, Romania
| | - Edward-Michael Dussom
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Sylvia V Alarcon
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Olga Kozyreva
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jana Simonds
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Deborah Schnipper
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Claudius Conrad
- Department of Surgery, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
| |
Collapse
|
|
48
|
Lund-Andersen C, Torgunrud A, Fleten KG, Flatmark K. Omics analyses in peritoneal metastasis-utility in the management of peritoneal metastases from colorectal cancer and pseudomyxoma peritonei: a narrative review. J Gastrointest Oncol 2021; 12:S191-S203. [PMID: 33968437 DOI: 10.21037/jgo-20-136] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
High-throughput "-omics" analysis may provide a broader and deeper understanding of cancer biology to define prognostic and predictive biomarkers and identify novel therapy targets. In this review we provide an overview of studies where the peritoneal tumor component of peritoneal metastases from colorectal cancer (PM-CRC) and pseudomyxoma peritonei (PMP) were analyzed. Most of the available data was derived from DNA mutation analysis, but a brief review of findings from transcriptomic and protein expression analysis was also performed. Studies reporting genomic analysis of peritoneal tumor samples from 1,779 PM-CRC and 623 PMP cases were identified. The most frequently mutated genes in PM-CRC were KRAS, APC, SMAD4, BRAF, and PIK3CA, while in PMP KRAS, GNAS, FAT4, TGFBR1, TP53 and SMAD3/4 mutations were most commonly identified. Analyses were performed by single-gene analyses and to some extent targeted next-generation sequencing, and a very limited amount of broad explorative data exists. The investigated cohorts were typically small and heterogeneous with respect to the methods used and to the reporting of clinical data. This was even more apparent regarding transcriptomic and protein data, as the low number of cases examined and quality of clinical data would not support firm conclusions. Even for the most frequently mutated genes, the results varied greatly; for instance, KRAS mutations were reported at frequencies between 20-57% in PM-CRC and 38-100% in PMP. Such variation could be caused by random effects in small cohorts, heterogeneity in patient selection, or sensitivity of applied technology. Although a large number of samples have been subjected to analysis, cross-study comparisons are difficult to perform, and combined with small cohorts and varying quality and detail of clinical information, the observed variation precludes useful interpretation in a clinical context. Although omics data in theory could answer questions to aid management decisions in PM-CRC and PMP, the existing data does not presently support clinical implementation. With the necessary technologies being generally available, the main challenge will be to obtain sufficiently large, representative cohorts with adequate clinical data and standardized reporting of results. Importantly, studies where the focus is specifically on peritoneal disease are needed, where the study designs are aligned with clearly defined research questions to allow robust conclusions. Such studies are highly warranted if patients with PM-CRC and PMP are to derive benefit from recent advances in precision cancer medicine.
Collapse
Affiliation(s)
- Christin Lund-Andersen
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Annette Torgunrud
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Karianne Giller Fleten
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| |
Collapse
|
|
49
|
Vemala RNG, Katti SV, Sirohi B, Manikandan D, Nandakumar G. Molecular Oncology in Management of Colorectal Cancer. Indian J Surg Oncol 2021; 12:169-180. [PMID: 33994743 PMCID: PMC8119525 DOI: 10.1007/s13193-021-01289-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 02/10/2021] [Indexed: 11/28/2022] Open
Abstract
Colorectal cancers are the third most common cancers in the world. Management of both primary and metastatic colorectal cancers has evolved over the last couple of decades. Extensive research in molecular oncology has helped us understand and identify these complex intricacies in colorectal cancer biology and disease progression. These advances coupled with improved knowledge on various mutations have helped develop targeted chemotherapeutics and has allowed planning an effective treatment regimen in this era of immunotherapy with precision. The diverse chemotherapeutic and biological agents at our disposal can make decision making a very complex process. Molecular profile, including CIN, RAS, BRAF mutations, microsatellite instability, ctDNA, and consensus molecular subtypes, are some of the important factors which are to be considered while planning an individualized treatment regimen. This article summarizes the current status of molecular oncology in the management of colorectal cancer and should serve as a practical guide for the clinical team.
Collapse
Affiliation(s)
| | | | | | | | - Govind Nandakumar
- Columbia Asia Hospitals, Bengaluru, India
- Weill Cornell Medical College, New York, USA
| |
Collapse
|
|
50
|
Shah S, Qin S, Luo Y, Huang Y, Jing R, Shah JN, Chen J, Chen H, Zhong M. AIM2 Inhibits BRAF-Mutant Colorectal Cancer Growth in a Caspase-1-Dependent Manner. Front Cell Dev Biol 2021; 9:588278. [PMID: 33842454 PMCID: PMC8027362 DOI: 10.3389/fcell.2021.588278] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 02/01/2021] [Indexed: 12/09/2022] Open
Abstract
Absent in melanoma 2 (AIM2), a DNA sensor that plays an important role in natural immunity system, has been reported to participate in colorectal cancer (CRC) development. However, the functional role of AIM2 in BRAF-mutant CRC remains unclear. In this study, we first investigated AIM2 expression level in BRAF-mutant CRC tumor tissues. Overexpression of AIM2 in CRC cells was performed to investigate the effect of AIM2 on CRC cell viability, and cell death detection and caspase activity assay were performed to explore the mechanism that AIM2 impacts the growth of BRAF-mutant CRC cells. Moreover, we confirmed the antitumor effect of AIM2 in BRAF-mutant CRC cell-derived tumor xenograft (CDX) models as well as patient-derived organoids (PDOs). Herein, we reported that AIM2 expression was lower in BRAF-mutant than that in BRAF wild-type CRC tumor tissues. Restoring the expression of AIM2 in BRAF-mutant CRC cells greatly inhibits the tumor cell growth by inducing necrotic cell death. Mechanism studies revealed that AIM2-induced cell death is in a caspase-1-dependent manner. Additionally, overexpression of AIM2 significantly inhibits tumor growth and metastasis in BRAF-mutant CRC in vivo, which was further confirmed in BRAF-mutant CRC PDOs. Taken together, our data suggested that AIM2 inhibits BRAF-mutant colon cancer growth in a caspase-1-dependent manner, which may provide evidence to understand the pathogenesis of CRC with BRAF-mutant, as well as new strategies for manipulation of CRC.
Collapse
Affiliation(s)
- Shailendra Shah
- Department of Surgery, Patan Hospital, Patan Academy of Health Sciences, Lalitpur, Nepal
| | - Shaolan Qin
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Luo
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yizhou Huang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ran Jing
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jay N Shah
- Department of Surgery, Patan Hospital, Patan Academy of Health Sciences, Kathmandu, Nepal
| | - Jianjun Chen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huimin Chen
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhong
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|