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García-Alfonso P, Valladares-Ayerbes M, Muñoz Martín AJ, Morales Herrero R, Galvez Muñoz E, Prat-Llorens G. State of the art of the molecular hyperselection to guide treatment with anti-EGFR antibodies in RAS WT mCRC: implications for clinical practice and future perspectives. Expert Opin Biol Ther 2025; 25:413-423. [PMID: 40066702 DOI: 10.1080/14712598.2025.2477192] [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: 12/04/2024] [Accepted: 03/04/2025] [Indexed: 03/14/2025]
Abstract
INTRODUCTION Adding monoclonal antibodies to chemotherapy drastically changed the landscape of advanced colorectal cancer. The prediction of benefit from anti-EGFR therapies is mainly based on the absence of mutations in RAS and BRAF genes, the primary tumor sidedness and microsatellite MSS/MSI status. Molecular hyperselection may optimize the outcome of patients receiving anti-EGFR while detecting additional resistance alterations, both in chemo-naïve and in chemo-refractory settings. AREAS COVERED Our review focuses on negative molecular hyperselection, both on tissue samples and ctDNA, and the impact of this further patient selection on response rate and survival outcomes. We searched electronic database, selecting relevant English-language publications from 2017 to 2024. EXPERT OPINION Negative hyperselection beyond RAS and BRAF in advanced colorectal cancer appears to be a powerful tool for predicting outcomes to anti-EGFR therapy and spare patients from unnecessary treatment. This improvement appears in both naïve and pre-treated patients. However, data come mainly from retrospective studies. Therefore, to validate and integrate these findings in the clinical practice, prospective studies should be conducted. It will be interesting to elucidate the role of ctDNA in this setting and the choice of molecular techniques, considering costs and accessibility, to guarantee its implementation in the clinic.
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Affiliation(s)
- Pilar García-Alfonso
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain
| | - Manuel Valladares-Ayerbes
- Medical Oncology Department, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain
| | - Andrés J Muñoz Martín
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain
| | - Rocío Morales Herrero
- Medical Oncology Department, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain
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Dey S, Ghosh M, Dev A. Signalling and molecular pathways, overexpressed receptors of colorectal cancer and effective therapeutic targeting using biogenic silver nanoparticles. Gene 2025; 936:149099. [PMID: 39557372 DOI: 10.1016/j.gene.2024.149099] [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: 08/15/2024] [Revised: 10/18/2024] [Accepted: 11/13/2024] [Indexed: 11/20/2024]
Abstract
Increasing morbidity and mortality in CRC is a potential threat to human health. The major challenges for better treatment outcomes are the heterogeneity of CRC cases, complicated molecular pathway cross-talks, the influence of gut dysbiosis in CRC, and the lack of multimodal target-specific drug delivery. The overexpression of many receptors in CRC cells may pave the path for targeting them with multiple ligands. The design of a more target-specific drug-delivery device with multiple ligand-functionalized, green-synthesized silver nanoparticles is highly promising and may also deliver other approved chemotherapeutic agents. This review presents the various aspects of colorectal cancer and over-expressed receptors that can be targeted with appropriate ligands to enhance the specific drug delivery potency of green synthesised silver nanoparticles. This review aims to broaden further research into this multi-ligand functionalised, safer and effective silver nano drug delivery system.
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Affiliation(s)
- Sandip Dey
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Manik Ghosh
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India
| | - Abhimanyu Dev
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Jharkhand, India.
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Radić J, Nikolić I, Kolarov-Bjelobrk I, Vasiljević T, Djurić A, Vidović V, Kožik B. Prognostic and Predictive Significance of Primary Tumor Localization and HER2 Expression in the Treatment of Patients with KRAS Wild-Type Metastatic Colorectal Cancer: Single-Centre Experience from Serbia. J Pers Med 2024; 14:879. [PMID: 39202071 PMCID: PMC11355236 DOI: 10.3390/jpm14080879] [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: 07/03/2024] [Revised: 08/02/2024] [Accepted: 08/15/2024] [Indexed: 09/03/2024] Open
Abstract
The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.
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Affiliation(s)
- Jelena Radić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivan Nikolić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivana Kolarov-Bjelobrk
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Tijana Vasiljević
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Pathology and Laboratory Diagnostic, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Aleksandar Djurić
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Vladimir Vidović
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Bojana Kožik
- Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
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Lawler T, Parlato L, Warren Andersen S. The histological and molecular characteristics of early-onset colorectal cancer: a systematic review and meta-analysis. Front Oncol 2024; 14:1349572. [PMID: 38737895 PMCID: PMC11082351 DOI: 10.3389/fonc.2024.1349572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/16/2024] [Indexed: 05/14/2024] Open
Abstract
Background Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes. Methods We systematically searched PubMed for original research articles published between April 2013-January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC. Results In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in KRAS (OR, 95% CI: 0.91, 0.85-0.98), BRAF (0.63, 0.51-0.78), APC (0.70, 0.58-0.84), and NRAS (0.88, 0.78-1.00) but more likely to include mutations in PTEN (1.68, 1.04-2.73) and TP53 (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and BRAF (0.77, 0.64-0.92) and APC mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with PIK3CA mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent. Discussion A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.
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Affiliation(s)
- Thomas Lawler
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Shaneda Warren Andersen
- School of Medicine and Public Health, Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, United States
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, United States
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Lawler T, Parlato L, Warren Andersen S. Racial disparities in colorectal cancer clinicopathological and molecular tumor characteristics: a systematic review. Cancer Causes Control 2024; 35:223-239. [PMID: 37688643 PMCID: PMC11090693 DOI: 10.1007/s10552-023-01783-y] [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: 03/21/2023] [Accepted: 08/21/2023] [Indexed: 09/11/2023]
Abstract
PURPOSE African Americans have the highest colorectal cancer (CRC) mortality of all racial groups in the USA, which may relate to differences in healthcare access or advanced stage at diagnosis. Recent evidence indicates that differences in tumor characteristics may also underlie disparities in mortality. To highlight recent findings and areas for investigation, we completed the first systematic review of racial disparities in CRC tumor prognostic markers, including clinicopathological markers, microsatellite instability (MSI), oncogene mutations, and novel markers, including cancer stem cells and immune markers. METHODS Relevant studies were identified via PubMed, limited to original research published within the last 10 years. Ninety-six articles were identified that compared the prevalence of mortality-related CRC tumor characteristics in African Americans (or other African ancestry populations) to White cases. RESULTS Tumors from African ancestry cases are approximately 10% more likely to contain mutations in KRAS, which confer elevated mortality and resistance to epidermal growth factor receptor inhibition. Conversely, African Americans have approximately 50% lower odds for BRAF-mutant tumors, which occur less frequently but have similar effects on mortality and therapeutic resistance. There is less consistent evidence supporting disparities in mutations for other oncogenes, including PIK3CA, TP53, APC, NRAS, HER2, and PTEN, although higher rates of PIK3CA mutations and lower prevalence of MSI status for African ancestry cases are supported by recent evidence. Although emerging evidence suggests that immune markers reflecting anti-tumor immunity in the tumor microenvironment may be lower for African American cases, there is insufficient evidence to evaluate disparities in other novel markers, cancer stem cells, microRNAs, and the consensus molecular subtypes. CONCLUSION Higher rates of KRAS-mutant tumors in in African Americans may contribute to disparities in CRC mortality. Additional work is required to understand whether emerging markers, including immune cells, underlie the elevated CRC mortality observed for African Americans.
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Affiliation(s)
- Thomas Lawler
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Shaneda Warren Andersen
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA.
- University of Wisconsin-Madison, Suite 1007B, WARF, 610 Walnut Street, Madison, WI, 53726, USA.
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Singh H, Kang A, Bloudek L, Hsu LI, Corinna Palanca-Wessels M, Stecher M, Siadak M, Ng K. Systematic literature review and meta-analysis of HER2 amplification, overexpression, and positivity in colorectal cancer. JNCI Cancer Spectr 2024; 8:pkad082. [PMID: 37815820 PMCID: PMC10868379 DOI: 10.1093/jncics/pkad082] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/25/2023] [Accepted: 09/21/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second most common cause of cancer death globally. Recent clinical trials suggest an emerging role for HER2 as a potential clinically relevant biomarker in CRC. Testing for HER2 in CRC is not standard practice; consequently, the prevalence of HER2 positivity (HER2+) in patients with CRC remains uncertain. METHODS A systematic literature review and meta-analysis were conducted to generate estimates of proportions of patients with CRC with HER2 overexpression or HER2 amplification and HER2+ (either overexpression or amplification), overall and in patients with rat sarcoma virus (RAS) wild-type cancer. HER2+ was defined as 1) immunohistochemistry with a score of 3+, 2) immunohistochemistry with a score of 2+ and in situ hybridization+, or 3) next-generation sequencing positive. RESULTS Of 224 studies identified with information on HER2 in CRC, 52 studies used a US Food and Drug Administration-approved assay and were selected for further analysis. Estimated HER2+ rate was 4.1% (95% confidence interval [CI] = 3.4% to 5.0%) overall (n = 17 589). HER2+ rates were statistically higher in RAS wild-type (6.1%, 95% CI = 5.4% to 6.9%) vs RAS mutant CRC (1.1%, 95% CI = 0.3% to 4.4%; P < .0001). Despite limited clinical information, we confirmed enrichment of HER2+ CRC in patients with microsatellite stable and left-sided CRC. CONCLUSION This meta-analysis provides an estimate of HER2+ CRC and confirms enrichment of HER2 in microsatellite stable, left-sided, RAS wild-type CRC tumors. Our work is important given the recently described clinical efficacy of HER2-targeted therapies in HER2+ CRC and informs strategies for incorporation of HER2 testing into standard of care.
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Affiliation(s)
- Harshabad Singh
- Division of Gastrointestinal Cancers, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | | | | | | | - Kimmie Ng
- Division of Gastrointestinal Cancers, Dana-Farber Cancer Institute, Boston, MA, USA
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Edjtemaei R, Nili F, Jahanzad I, Ameli F, Ghasemi D. HER-2 overexpression in female genital tract clear cell carcinomas: Evaluation of different scoring guidelines, clinicopathological features and prognostic impact. Ann Diagn Pathol 2023; 66:152184. [PMID: 37543027 DOI: 10.1016/j.anndiagpath.2023.152184] [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: 06/30/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/07/2023]
Abstract
BACKGROUND Clear cell carcinoma (CCC) is a rare high-grade adenocarcinoma associated with poor response to platinum-based chemotherapy agents in the female genital tract. Human epidermal growth factor receptor 2 (HER2) overexpression is routinely used as a biomarker for targeted therapy in breast and gastric carcinomas, but its role in CCC remains unclear. METHODS In this study, HER2 overexpression was evaluated by immunohistochemistry (IHC) using College of American Pathologists (CAP) HER2 scoring guidelines for breast and endometrial serous carcinoma (ESC) on tissue microarray blocks. In equivocal and positive cases, fluorescence in situ hybridization (FISH) was performed. IHC score 3, and all amplified cases on FISH test were considered positive. RESULTS Thirty-six cases of ovarian (OCCC), 36 endometrial (ECCC), and 2 cervical CCC were included. According to ESC and breast scoring guidelines, 20 % and 15.1 % of ECCC and 14.7 % and 6 % of OCCC were HER2 positive, respectively. Both cases of cervical CCC were negative. Scoring based on breast carcinoma guideline showed higher concordance (100 %) with gene amplification results, in comparison with ESC guideline (82.7 %). On multivariate survival analysis, HER2 positive ECCC and OCCC (based on ESC scoring methods) had significantly lower overall and disease-free survivals (OS, DFS) (P < 0.05). CONCLUSION HER2 immunoscoring based on ESC guideline can yield a higher sensitivity with relevant clinical and prognostic features in OCCC and ECCC. HER2 can be considered a potential biomarker for targeted therapy and future clinical trials.
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Affiliation(s)
- Ramtin Edjtemaei
- Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Nili
- Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
| | - Issa Jahanzad
- Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Ameli
- Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Dorsa Ghasemi
- Department of Pathology, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
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Wu Z, Cheng Y, Wang H, Liu D, Qi X, Wang C, Zhang Y, Zhang Y, Cai R, Huo H, Zhang J, Cai Y, Li W, Hu H, Deng Y. Distinct Clinicopathological Features and Prognostic Values of High-, Low-, or Non-Expressing HER2 Status in Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15020554. [PMID: 36672503 PMCID: PMC9856362 DOI: 10.3390/cancers15020554] [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: 11/23/2022] [Revised: 01/05/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
The encouraging effects of HER2-ADC in patients with HER2-low expression cancers indicated the classical classifications based on positive and negative HER2 might no longer be suitable. However, the biology and prognosis of colorectal cancer patients with different HER2 expression status were still not clear. This is a multi-center retrospective study that included patients with histologically confirmed colorectal cancer and determined HER2 status who received radical surgical resection. HER2 immunohistochemistry (IHC) 1+ and IHC 2+ groups were combined and defined as a HER2-low group because of the concordance of clinicopathological characteristics. As compared with the HER2-high group, both the HER2-zero and the HER2-low group had less tumor with perineural invasion (14.3%, 13.1% vs. 31.6%, p = 0.001 and p < 0.001), less stage III disease (41.8%, 39.9% vs. 56.1%, p = 0.044 and p = 0.022), more RAS/BRAF mutation (52.1%, 49.9% vs. 19.5%, p < 0.001 and p < 0.001) and better disease-free survival (DFS) (3y-DFS rate of 78.7%, 82.4% vs. 59.3%, p < 0.001 and p < 0.001). Multivariate analysis and propensity score matching also revealed that HER2-high expression was an independent prognostic factor of DFS. In conclusion, our study revealed that HER2-low colorectal cancer tumors are close to HER2-zero tumors, but different from HER2-high tumors. The routine examination of HER2 IHC is needed in early-stage colorectal cancer.
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Affiliation(s)
- Zehua Wu
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yi Cheng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Huaiming Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515000, China
| | - Dian Liu
- Department of Lymphoma and Abdominal Radiotherapy, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China
| | - Xiaoxing Qi
- Department of Medical Oncology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453002, China
| | - Chao Wang
- Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yuanzhe Zhang
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yuting Zhang
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Runkai Cai
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Hong Huo
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Jianwei Zhang
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yue Cai
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Weiwei Li
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Huabin Hu
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yanhong Deng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
- Correspondence: ; Tel.: +86-13925106525
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The Impact of Molecular Biology in the Seeding, Treatment Choices and Follow-Up of Colorectal Cancer Liver Metastases-A Narrative Review. Int J Mol Sci 2023; 24:ijms24021127. [PMID: 36674640 PMCID: PMC9863977 DOI: 10.3390/ijms24021127] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 12/27/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
There is a clear association between the molecular profile of colorectal cancer liver metastases (CRCLM) and the degree to which aggressive progression of the disease impacts patient survival. However, much of our knowledge of the molecular behaviour of colorectal cancer cells comes from experimental studies with, as yet, limited application in clinical practice. In this article, we review the current advances in the understanding of the molecular behaviour of CRCLM and present possible future therapeutic applications. This review focuses on three important steps in CRCLM development, progression and treatment: (1) the dissemination of malignant cells from primary tumours and the seeding to metastatic sites; (2) the response to modern regimens of chemotherapy; and (3) the possibility of predicting early progression and recurrence patterns by molecular analysis in liquid biopsy.
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Karan C, Tan E, Sarfraz H, Knepper TC, Walko CM, Felder S, Kim R, Sahin IH. Human Epidermal Growth Factor Receptor 2-Targeting Approaches for Colorectal Cancer: Clinical Implications of Novel Treatments and Future Therapeutic Avenues. JCO Oncol Pract 2022; 18:545-554. [PMID: 35613416 DOI: 10.1200/op.21.00904] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The treatment paradigm for colorectal cancer (CRC) has changed significantly over the past decade with targeted therapeutics. Human epidermal growth factor receptor 2 (HER2) amplification is seen among 3%-4% of patients with metastatic CRC (mCRC). The biological discovery of HER2 amplification in cancer cells has led to practice-changing drug development for several solid tumors, including breast, gastric, and esophageal cancers. HER2 amplification is now highly actionable in CRC with distinct therapeutic combinations, including the combination of monoclonal antibodies and HER2 receptor-specific tyrosine kinase inhibitors, as well as antibody-drug conjugates, that delivers targeted cytotoxic agents. However, it is essential to define the therapeutic role and sequence of these different combinations, some of which are already part of standard clinical practice. In this review article, we discuss recent clinical studies demonstrating the clinical benefits of each distinct therapeutic approach and their impacts on the current management of HER2-amplified mCRC. We also review ongoing clinical trials targeting the HER2 pathway in mCRC and elaborate on novel therapeutic opportunities in this space that may further define the changing paradigm of HER2-targeted therapy for CRC.
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Affiliation(s)
- Canan Karan
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Elaine Tan
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Humaira Sarfraz
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Todd C Knepper
- Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Christine M Walko
- Department of Individualized Cancer Management, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Seth Felder
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Ibrahim Halil Sahin
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
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Ahcene Djaballah S, Daniel F, Milani A, Ricagno G, Lonardi S. HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target. Am Soc Clin Oncol Educ Book 2022; 42:1-14. [PMID: 35580290 DOI: 10.1200/edbk_351354] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Human epidermal growth factor receptor 2 (HER2) is a well-known oncogenic driver in different tumors and an approved therapeutic target in breast and gastroesophageal cancer. In metastatic colorectal cancer, only 3% to 5% of patients present with HER2 alterations: somatic mutations and amplifications. HER2 was first assessed as a biomarker of resistance to anti-EGFR therapy; however, in more recent years, its role as a potential actionable target has emerged. In this article, we discuss the predictive and prognostic value of HER2 in metastatic colorectal cancer, its emerging role as an actionable therapeutic target, and its possible future developments.
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Affiliation(s)
| | - Francesca Daniel
- Medical Oncology Unit 1, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - Anna Milani
- Medical Oncology Unit 3, Veneto Institute of Oncology IRCCS, Padua, Italy.,Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy
| | - Gianmarco Ricagno
- Medical Oncology Unit 3, Veneto Institute of Oncology IRCCS, Padua, Italy.,Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy
| | - Sara Lonardi
- Medical Oncology Unit 3, Veneto Institute of Oncology IRCCS, Padua, Italy
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12
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Schröder C, Gower-Page C, Reyes-Rivera I, Patel A, Price R, Sen S, Davies J, Castellanos E, Snider J, Bai X, Fisher V, Mhatre SK. Natural History of Human Epidermal Growth Factor Receptor 2-Amplified and Human Epidermal Growth Factor Receptor 2 Wild-Type Refractory Metastatic Colorectal Cancer in US Clinical Practice. JCO Clin Cancer Inform 2022; 6:e2100133. [PMID: 35297649 PMCID: PMC8955081 DOI: 10.1200/cci.21.00133] [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] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The molecular heterogeneity of metastatic colorectal cancer (mCRC) presents a therapeutic challenge, with few trials focused on patients with human epidermal growth factor receptor 2 amplification (HER2-Amp). Our limited understanding of real-world patterns and outcomes by HER2 status of treatment-refractory patients leaves treatment decisions with little contextual information. We conducted a retrospective cohort study to describe the natural disease history of patients with refractory mCRC using an electronic health record-derived database with oncogenomic information. METHODS We included patients with stage IV or recurrent mCRC diagnosed from January 2011 through December 2019 from a deidentified clinicogenomic database. Patients with ≥ 2 documented clinic visits, ≥ 2 lines of therapy (LOT) after mCRC diagnosis, and comprehensive genomic profiling were eligible. Patient records defined by treatment-refractory LOT were allocated to the HER2-Amp or HER2 wild-type (WT) cohort on the basis of comprehensive genomic profiling. Index date was defined as the start of any treatment-refractory LOT (≥ 2 LOT; patients could contribute multiple records). Descriptive statistics included demographic and clinical characteristics, treatments, laboratory values, and biomarkers. Overall survival (OS) was calculated as time (in months) from the index date until death from any cause and analyzed using Kaplan-Meier methodology. Sensitivity analyses were conducted to test the robustness of the primary findings. RESULTS A total of 576 patients were included (1,339 records); 63 (158 records) were HER2-Amp, and 513 (1,181 records) were HER2-WT. Demographics, clinical characteristics, biomarkers, and laboratory values were comparable between HER2 cohorts. OS was similar, with an unadjusted median OS of 11.2 months (95% CI, 8.6 to 15.1) and 9.9 months (95% CI, 8.3 to 10.9) across LOT for HER2-Amp and HER2-WT cohorts, respectively. CONCLUSION This study showed considerable treatment heterogeneity and poor outcomes among patients with treatment-refractory mCRC, emphasizing a substantial unmet therapeutic need.
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Affiliation(s)
| | | | | | | | | | - Shiraj Sen
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
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13
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Siemińska I, Węglarczyk K, Walczak M, Czerwińska A, Pach R, Rubinkiewicz M, Szczepanik A, Siedlar M, Baran J. Mo-MDSCs are pivotal players in colorectal cancer and may be associated with tumor recurrence after surgery. Transl Oncol 2022; 17:101346. [PMID: 35074719 PMCID: PMC8789589 DOI: 10.1016/j.tranon.2022.101346] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/12/2021] [Accepted: 01/12/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy. Its development and progression is associated with natural immunosuppression related, among others, to myeloid derived suppressor cells (MDSCs). Overall, 54 patients in different stage of CRC, before any treatment were recruited into the study. The analysis included flow cytometry evaluation of blood MDSCs subsets, correlation their level with the tumor stage and T cell subsets. In the case of 11 patients, MDSCs level was evaluated before and 3 days after surgery, and these patients were monitored for cancer recurrence over 5 years. The results showed that frequency of circulating MDSCs subsets is increased significantly in CRC patients, with highest level detected in most advanced tumor stages. Moreover, only monocytic MDSCs (Mo-MDSCs) positively correlate with regulatory Treg, and negatively with tumor Her2/neu specific CD8+ T cells. Circulating MDSCs, in contrast to tumor resident (mostly Mo-MDSCs), are negative for PD-L1 expression. Additionally, after surgery the blood level of Mo-MDSCs increases significantly, and this is associated with tumor recurrence during a 5-year follow-up. In conclusion, Mo-MDSCs are pivotal players in CRC-related immunosuppression and may be associated with the risk of tumor recurrence after surgery.
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Affiliation(s)
- Izabela Siemińska
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka str. 265, Krakow 30-663, Poland
| | - Kazimierz Węglarczyk
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka str. 265, Krakow 30-663, Poland
| | - Marta Walczak
- First Department of General Surgery, Jagiellonian University Medical College, M. Jakubowskiego str. 2, Krakow 30-688, Poland
| | - Agata Czerwińska
- Second Department of General Surgery, Jagiellonian University Medical College, M. Jakubowskiego str. 2, Krakow 30-688, Poland
| | - Radosław Pach
- First Department of General Surgery, Jagiellonian University Medical College, M. Jakubowskiego str. 2, Krakow 30-688, Poland
| | - Mateusz Rubinkiewicz
- Second Department of General Surgery, Jagiellonian University Medical College, M. Jakubowskiego str. 2, Krakow 30-688, Poland
| | - Antoni Szczepanik
- First Department of General Surgery, Jagiellonian University Medical College, M. Jakubowskiego str. 2, Krakow 30-688, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka str. 265, Krakow 30-663, Poland
| | - Jarek Baran
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, Wielicka str. 265, Krakow 30-663, Poland.
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14
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Scripcariu V, Ciobanu Apostol DG, Dumitrescu GF, Turliuc MD, Sava A. Clinical, histopathological and immunohistochemical features of brain metastases originating in colorectal cancer: a series of 27 consecutive cases. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:81-93. [PMID: 32747898 PMCID: PMC7728123 DOI: 10.47162/rjme.61.1.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Introduction: Brain metastases (BMs) originating in colorectal cancer (CRC) have a significant importance for patients’ survival. Because in literature there are only isolated case reports and only few series published on this issue, we aimed to assess the incidence of BMs from CRC, to identify patient’s characteristics and BMs clinical, histopathological (HP) and immunohistochemical (IHC) features, and to compare the data we obtained with those from literature. Patients, Materials and Methods: We present a retrospective study of 27 histologically confirmed cases of BMs from CRC among all 1040 patients who received metastasectomy in the Department of Neurosurgery, Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iaşi, Romania, in an eight-year period (January 2011 to December 2018). Patients’ characteristics (gender, age), primary tumor location, time from primary tumor surgery to BMs surgery and BMs features (number, location and HP characteristics) were investigated. Histochemical [Alcian Blue (AB) and Periodic Acid–Schiff (PAS)] staining and IHC stainings for cytokeratin (CK) 7, CK20, caudal-type homeobox 2 (CDX2) and human epidermal growth factor receptor 2 (HER2)/neu were performed on all available BMs specimens. Results: There were 27 consecutive patients with BMs from CRC, corresponding to 2.59% of all patients with BMs during the eight-year period we have studied, most of them being diagnosed and treated in 2016. Male:female ratio was 1.45. The mean age for all patients at diagnosis of the BMs was 62.25 years (range: 40–79 years). The origin of the primary cancer was mainly the colon (62.96% of all cases). Of all 27 patients, only two (7.4%) presented neurological symptoms without a diagnosis of CRC. BMs were identified in a period ranging from six months to 70 months after the initial diagnosis. The average time between diagnosis of the primary tumor and of the BMs was 25.92 months. At the moment of the diagnosis of BMs, 17 (62.96%) patients also had other systemic metastases. Most of the cases (55.55%) were situated in the supratentorial compartment. IHC stainings were negative for CK7 and positive for CK20 and CDX2 in all BMs from colonic adenocarcinomas (ADCs), a profile consistent with a non-neuronal and gastric origin. AB and PAS stainings revealed pools of extracellular mucin, especially in cases of mucinous ADC. Ki67 labeling index ranged between 90% and 100%. IHC staining with anti-HER2/neu antibody showed in 25 (96.15%) cases a strong and diffuse aberrant nuclear staining. Conclusions: BMs originating in CRC represent a rare pathology and have particular clinical and IHC features that could vary from one series to another series. In a few cases, BMs may be diagnosed in the absence of a known CRC diagnosis and in these situations, the correct diagnosis is of interest. However, a panel of antibodies can help in establishing a correct diagnosis. Our study was among the first to analyze the HER2/neu expression pattern in BMs from CRC and we found a strong aberrant nuclear expression of this molecular marker on IHC investigation. Related to the data published so far in the literature, it is possible that HER2/neu aberrant expression in the tumor nuclei of the BMs from our series may express the metastatic tumor cell phenotype that was previously subjected to cytostatics and radiation therapies. As such, we suggest that HER2/neu aberrant expression in BMs originating in CRC could represent a proof for the worst prognosis of these patients.
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Affiliation(s)
- Viorel Scripcariu
- Department of Morpho-Functional Sciences I, Department of Surgery II, Grigore T. Popa University of Medicine and Pharmacy, Iaşi, Romania; ,
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15
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Klupp F, Sass M, Bergmann F, Khajeh E, Ghamarnejad O, Hassenpflug M, Mehrabi A, Kulu Y. Impact of EGFR and EGFR ligand expression on treatment response in patients with metastatic colorectal cancer. Oncol Lett 2021; 21:448. [PMID: 33868486 DOI: 10.3892/ol.2021.12709] [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] [Received: 01/01/2021] [Accepted: 03/16/2021] [Indexed: 12/20/2022] Open
Abstract
Up to 50% of patients with colorectal cancer (CRC) have either synchronous or metachronous hepatic metastases in the course of their disease. Patients with metastatic CRC (mCRC) whose tumors express wild-type KRAS benefit from treatment with monoclonal antibodies (such as cetuximab or panitumumab) that target the epidermal growth factor receptor (EGFR). However, the therapeutic response to these antibodies is variable, and further predictive models are required. The present study examined whether expression of different EGFRs or their ligands in tumors was associated with the response to cetuximab treatment. Tumor tissues, collected during liver resection in 28 patients with mCRC, were analyzed. The protein expression levels of EGFR/ErbB1, ErbB2, ErbB3 and the EGFR ligands heregulin and amphiregulin were determined using Luminex 200® and enzyme-linked immunosorbent assays. Computed tomography or magnetic resonance imaging was performed 4 weeks before and 6-8 weeks after treatment with cetuximab. Response to treatment was assessed using the response evaluation criteria for solid tumors (RECIST). The association between the protein expression levels of different EGFRs and their ligands with RECIST criteria was then analyzed to determine whether these protein levels could predict the treatment response to cetuximab. A total of 12 patients exhibited a partial response, 9 exhibited stable disease and 7 exhibited progressive disease after cetuximab therapy according to RECIST. The expression levels of EGFRs (EGFR/ErbB1, ErbB2 and ErbB3) and their ligands (heregulin and amphiregulin) were not significantly associated with the response to cetuximab therapy. Therefore, the present study indicated that EGFR or EGFR ligand expression did not predict treatment response in patients with CRC with liver metastases following cetuximab therapy.
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Affiliation(s)
- Fee Klupp
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Malte Sass
- Department of Otorhinolaryngology, Head and Neck Surgery, Asklepios Hospital, D-21075 Hamburg, Germany
| | - Frank Bergmann
- Institute of Pathology, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Elias Khajeh
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Matthias Hassenpflug
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany
| | - Yakup Kulu
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany
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16
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Moussa M, Badawy A, Helal N, Hegab F, Youssef M, Aboushousha T, Al Farouk L, Elwy D. Differential Expression of HER2 and SKP2 in Benign and Malignant Colorectal Lesions. Asian Pac J Cancer Prev 2020; 21:2357-2366. [PMID: 32856866 PMCID: PMC7771937 DOI: 10.31557/apjcp.2020.21.8.2357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 08/14/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the fourth most common cancer worldwide. Both HER2 and SKP2 have a carcinogenic role in CRC making them attractive targets for tailored treatment. This work aims to correlate HER2 and SKP2 protein expression as well as HER2 gene amplification with clinicopathological parameters aiming at identifying potential candidates for targeted therapy. METHODS This Study was conducted on 127 paraffin-embedded tissue samples of different colorectal lesions [controls, chronic colitis, ulcerative colitis (UC), hyperplastic polyps (HPs), adenomas and CRCs] to investigate HER2 and SKP2 expression by immunohistochemistry (IHC), Selected CRC cases [equivocal (2+) and positive (3+) by IHC] were further evaluated by ISH (CISH and SISH ) to assess HER2 gene amplification. RESULTS Chronic colitis, UC, HPs and adenomas were HER2-negative. HER2 positivity (scores 2+ and 3+) was found only in15% of CRCs. Both SISH and CISH showed the same results with high concordance as 66.7% of equivocal and 100% of positive cases showed amplification of HER2 gene. SKP2 positivity was detected in 26.7% and 45% of adenomas and CRCs respectively, while other studied groups were negative. A significant correlation was noted between HER2 and SKP2 expression. CONCLUSION A small percent of CRCs exhibited HER2 gene amplification, which would be potential candidates for anti HER2 therapy whereas IHC could be a primary screening test for patient selection. A potential carcinogenic role of SKP2 was suggested by the findings that SKP2 expression was undetectable in normal colonic mucosa but significantly increases from adenoma to carcinoma, hoping adenoma patients to get benefit from targeted therapy.
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Affiliation(s)
- Mona Moussa
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.
| | - Afkar Badawy
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.
| | - Noha Helal
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.
| | - Fatma Hegab
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.
| | - Magdy Youssef
- Department of Gastroenterology and Hepatology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.
| | - Tarek Aboushousha
- Department of Pathology, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.
| | - Lubna Al Farouk
- Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt.
| | - Dalal Elwy
- Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt.
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Wan ML, Wang Y, Zeng Z, Deng B, Zhu BS, Cao T, Li YK, Xiao J, Han Q, Wu Q. Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways. Biosci Rep 2020; 40:BSR20200265. [PMID: 32149326 PMCID: PMC7087324 DOI: 10.1042/bsr20200265] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 02/21/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and one of the leading causes of cancer-related death among men worldwide. CRC is a multifactor digestive pathology, which is a huge problem faced not only by clinicians but also by researchers. Importantly, a unique feature of CRC is the dysregulation of molecular signaling pathways. To date, a series of reviews have indicated that different signaling pathways are disordered and have potential as therapeutic targets in CRC. Nevertheless, an overview of the function and interaction of multiple signaling pathways in CRC is needed. Therefore, we summarized the pathways, biological functions and important interactions involved in CRC. First, we investigated the involvement of signaling pathways, including Wnt, PI3K/Akt, Hedgehog, ErbB, RHOA, Notch, BMP, Hippo, AMPK, NF-κB, MAPK and JNK. Subsequently, we discussed the biological function of these pathways in pathophysiological aspects of CRC, such as proliferation, apoptosis and metastasis. Finally, we summarized important interactions among these pathways in CRC. We believe that the interaction of these pathways could provide new strategies for the treatment of CRC.
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Affiliation(s)
- Mao-lin Wan
- Department of Hepatobiliary and Pancreatic Surgery, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Yu Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of University of South China, Hengyang, 421001, P.R. China
| | - Zhi Zeng
- Department of Pathology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Bo Deng
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Bi-sheng Zhu
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Ting Cao
- Department of Digestive Medical, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
| | - Yu-kun Li
- Key Laboratory of Tumor Cellular and Molecular Pathology, College of Hunan Province, Cancer Research Institute, University of South China, Hengyang, Hunan, 421001, P.R. China
| | - Jiao Xiao
- Department of Endocrinology, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
| | - Qi Han
- Department of Oncology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437000, P.R. China
| | - Qing Wu
- Department of Digestive Medical, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421002, P.R. China
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18
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Zhang X, Wu J, Wang L, Zhao H, Li H, Duan Y, Li Y, Xu P, Ran W, Xing X. HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China. PeerJ 2020; 8:e8602. [PMID: 32095377 PMCID: PMC7023828 DOI: 10.7717/peerj.8602] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 01/19/2020] [Indexed: 12/11/2022] Open
Abstract
Objective To investigate the frequency and prognostic role of the human epidermal growth factor receptor 2 gene (HER2) and BRAF V600E gene mutation in Chinese patients with colorectal cancer (CRC). Methods Clinicopathological and survival information from 480 patients with stage I–III CRC were reviewed and recorded. HER2 amplification was analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), BRAF V600E mutation was tested by IHC and Sanger sequencing. The relationship between HER2 and BRAF V600E mutation status and clinicopathological characteristics and outcomes were determined. Results The amplification of HER2 and BRAF V600E mutation were identified in 27 of 480 (5.63%) and 19 of 480 (3.96%) CRC patients, respectively. HER2 amplification significantly correlated with greater bowel wall invasion (P = 0.041) and more advanced TNM stage (I vs. II vs. III; 0 vs 5.78% vs. 7.41%, P = 0.013). Patients suffering from tumors with poor differentiation had a higher incidence rate of BRAF V600E mutation than those with moderate/well differentiation (7.77% vs 2.92%, P = 0.04). HER2 amplification was an independent prognostic factor for worse disease-free survival (DFS) (HR = 2.53, 95% CI: 1.21–5.30, P = 0.014). Conclusion The prevalence of HER2 amplification and BRAF V600E mutation in stage I–III CRC patients in Chinese was 6% and 4%, respectively, and HER2 amplification appeared to be associated with a worse DFS. More comprehensive molecular classification and survival analysis are needed to validate our findings.
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Affiliation(s)
- Xiangyan Zhang
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jie Wu
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lili Wang
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Han Zhao
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hong Li
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuhe Duan
- Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yujun Li
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ping Xu
- Department of Obstetrics, Laixi People's Hospital, Qingdao, China
| | - Wenwen Ran
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoming Xing
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
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19
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Somatic mutation profiling and HER2 status in KRAS-positive Chinese colorectal cancer patients. Sci Rep 2019; 9:16894. [PMID: 31729406 PMCID: PMC6858340 DOI: 10.1038/s41598-019-53039-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 10/21/2019] [Indexed: 12/24/2022] Open
Abstract
KRAS is an independent negative predictor for anti-epidermal growth factor receptor (anti-EGFR) treatment in colorectal cancers (CRCs). However, 30% to 50% of CRC patients are KRAS-positive and do not benefit from anti-EGFR therapy. In this study, we investigated the mutational features and clinical significance of KRAS-positive Chinese CRC patients. A total of 139 Chinese CRC patients who received clinical KRAS testing (Sanger sequencing) were examined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Fifty KRAS-positive specimens were further detected by next-generation sequencing (NGS). The most prevalent mutation in KRAS was G12D (46%), followed by G12V (20%), and G13D (18%). In addition to KRAS, 72 unique alterations in another 12 genes were also detected. The most common mutated genes were TP53 (62%), APC (46%), and PIK3CA (22%). The proportion of HER2 amplifications in KRAS-positive CRC patients was 4.4%, which was lower than that in KRAS -negative CRC patients (14.3%). No relationship was found between HER2 amplification and KRAS status (p = 0.052). However, the odds ratio is very low (0.279). In addition, these gene mutations were not significantly associated with age, sex, tumor size, lymph node metastasis, mismatch repair-deficient, or tumor differentiation. However, TP53 mutations were more prevalent in colon cancer with KRAS mutations than in rectal cancer (75.0% vs 28.6%, respectively, p = 0.004). The negative predictive value of the IHC analysis for predicting HER2 amplification reached to 98.39%, while the positive predictive value reached only 50%. Overall, the mutation profiling of Chinese CRC patients with KRAS mutations is different from that of Western CRC patients. Our results will help us to understand the molecular features of Chinese CRC patients.
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Fu C, Zhou N, Zhao Y, Duan J, Xu H, Wang Y. Dendritic cells loaded with CD44 + CT-26 colon cell lysate evoke potent antitumor immune responses. Oncol Lett 2019; 18:5897-5904. [PMID: 31788063 PMCID: PMC6865088 DOI: 10.3892/ol.2019.10952] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/11/2019] [Indexed: 02/07/2023] Open
Abstract
Increasing evidence supports the concept that cancer stem cells (CSCs) are responsible for cancer progression and metastasis, therapy resistance and relapse. In addition to conventional therapies for colon cancer, the development of immunotherapies targeting cancer stem cells appears to be a promising strategy to suppress tumor recurrence and metastasis. In the present study, dendritic cells (DCs) were pulsed with whole-tumor cell lysates or total RNA of CD44+ colon cancer stem cells (CCSCs) isolated from mouse colon adenocarcinoma CT-26 cell cultures and investigated for their antitumor immunity against CCSCs in vivo and in vitro. In a model of colon adenocarcinoma using BALB/c mice, a sequential reduction in tumor volume and weight was associated with an extended survival in tumor-bearing mice vaccinated with DCs pulsed with RNA or CCSC lysate. In addition, a lactate dehydrogenase assay indicated that cytotoxic T-cells derived from the treated mice exhibited strong cytotoxic activity. Additionally, an enzyme-linked immunosorbent assay revealed that the cytotoxic T-cells of the treated mice released higher levels of interferon-γ against CCSCs compared with those of the control group. In all experiments, the antitumor efficacy of the lysate-pulsed DC-treated and RNA-pulsed DC-treated groups were significantly higher compared with that of the DC-treated and control groups. The results of the present study indicated the potential use of DCs pulsed with cancer stem cell lysates as a potent therapeutic antigen to target CSCs in colon cancer. Additionally, the results provided a rationale for using lysate-pulsed DCs in vivo to eliminate residual tumor deposits in post-operative patients.
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Affiliation(s)
- Changhao Fu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Ning Zhou
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yuanyuan Zhao
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jinyue Duan
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hao Xu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
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RAS-expanded Mutations and HER2 Expression in Metastatic Colorectal Cancer: A New Step of Precision Medicine. Appl Immunohistochem Mol Morphol 2019; 26:539-544. [PMID: 30199395 PMCID: PMC6135466 DOI: 10.1097/pai.0000000000000475] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cetuximab and panitumumab monoclonal antibodies are a milestone in the history of treatment of metastatic colorectal cancer (mCRC) and point toward future directions for personalized treatment. Recent studies have shown that broader RAS testing is needed to select patients for targeted therapy. The objectives of our study were to identify the prevalence of RAS mutations and evaluate human epidermal growth factor receptor 2 (HER2) expression in KRAS exon 2 wild-type (WT) mCRC patients, correlating the findings with objective response rate, progression-free survival, and overall survival. In total, 29 mCRC patients undergoing treatment with cetuximab therapy were enrolled in this study. By pyrosequencing, mutations were found in 17% of nonresponder patients, in KRAS codon 146 and NRAS codon 12. HER2 positivity was limited to only 1 responder carcinoma specimen. There was no correlation between RAS mutation, HER2/neu expression, and clinicopathologic findings. We highlighted significantly the differences between objective response rate and RAS gene status. The overall survival and progression-free survival of RAS WT patients were higher compared with those with RAS-mutated disease. Clinical response to cetuximab therapy is impaired in the presence of RAS-expanded mutations. In fact, our finding of 5 mutations in RAS-expanded genes allowed us to understand the resistance to cetuximab in 33% of KRAS WT exon 2 nonresponder patients. HER2 does not seem to be a potential biomarker for cetuximab-targeted therapy. These analyses suggest that the assessment of other biomarkers is needed to determine the best treatment for patients with mCRC, to maximize benefit and minimize harm.
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22
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Wang XY, Zheng ZX, Sun Y, Bai YH, Shi YF, Zhou LX, Yao YF, Wu AW, Cao DF. Significance of HER2 protein expression and HER2 gene amplification in colorectal adenocarcinomas. World J Gastrointest Oncol 2019; 11:335-347. [PMID: 31040898 PMCID: PMC6475672 DOI: 10.4251/wjgo.v11.i4.335] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 02/13/2019] [Accepted: 03/16/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. While the role of HER2 as a prognostic biomarker in colorectal adenocarcinomas (CRCs) remains uncertain, its relevance as a therapeutic target has been established. We undertook the present study to evaluate the frequency of HER2 expression in CRC and to correlate it with various clinicopathological variables. AIM To correlate HER2 protein expression and HER2 gene amplification with clinicopathological features and survival in surgically resected CRC. METHODS About 1195 consecutive surgically resected CRCs were analyzed by immunohistochemical staining (IHC) to assess HER2 protein expression, and 141 selected tumors were further evaluated by fluorescence in situ hybridization (FISH) to assess HER2 gene amplification. Follow-up information was available for 1058 patients, and using this information we investigated the prevalence of HER2 protein overexpression and gene amplification in a large series of surgically resected CRCs, and evaluated the relationship between overexpression and clinicopathological parameters and prognosis. RESULTS HER2 IHC scores of 3+, 2+, 1+, and 0 were seen in 31 (2.6%), 105 (8.8%), 475 (39.7%), and 584 (48.9%) tumors, respectively. HER2 gene amplification was seen in 24/29 tumors with an IHC score of 3+ (82.8%; unreadable in 2/31), 12/102 tumors with an IHC score of 2+ (11.8%; unreadable in 2/104), and 0 tumors with IHC score of 1+ (0/10). HER2 gene amplification was seen in 36/1191 tumors (3.0%; unreadable in 4/1195). Among the tumors with HER2 IHC scores of 3+ and 2+, the mean percentage of tumor cells with positive IHC staining was 90% (median 100%, range 40%-100%) and 67% (median 75%, range 5%-95%), respectively (P < 0.05). Among tumors with IHC scores of 2+, those with HER2 gene amplification had a higher number of tumors cells with positive IHC staining (n = 12, mean 93%, median 95%, range 90%-95%) than those without (n = 90, mean 70%, median 50%, range 5%-95%) (P < 0.05). HER2 gene status was significantly associated with distant tumor metastasis and stage (P = 0.028 and 0.025). HER2 protein overexpression as measured by IHC or HER2 gene amplification as measured by FISH was not associated with overall survival (OS) or disease-specific survival for the overall group of 1058 patients. However, further stratification revealed that among patients with tubular adenocarcinomas who were 65 years old or younger (n = 601), those exhibiting HER2 gene amplification had a shorter OS than those without (mean: 47.9 mo vs 65.1 mo, P = 0.04). Among those patients with moderately to poorly differentiated tubular adenocarcinomas, those with positive HER2 tumor IHC scores (2+, 3+) had a shorter mean OS than those with negative HER2 IHC scores (0, 1+) (47.2 mo vs 64.8 mo, P = 0.033). Moreover, among patients with T2 to T4 stage tumors, those with positive HER2 IHC scores also had a shorter mean OS than those with negative HER2 IHC scores (47.1 mo vs 64.8 mo, P = 0.031). CONCLUSION HER2 protein levels are correlated with clinical outcomes, and positive HER2 expression as measured by IHC confers a worse prognosis in those patients 65 years old or younger with tubular adenocarcinomas.
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Affiliation(s)
- Xin-Yu Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhi-Xue Zheng
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
- Department of General Surgery, Beijing Jishuitan Hospital, Beijing 100035, China
| | - Yu Sun
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yan-Hua Bai
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yun-Fei Shi
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Li-Xin Zhou
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Yun-Feng Yao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Ai-Wen Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Deng-Feng Cao
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing 100142, China
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, United States
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Zangui M, Atkin SL, Majeed M, Sahebkar A. Current evidence and future perspectives for curcumin and its analogues as promising adjuncts to oxaliplatin: state-of-the-art. Pharmacol Res 2019; 141:343-356. [DOI: 10.1016/j.phrs.2019.01.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 01/11/2019] [Accepted: 01/11/2019] [Indexed: 02/06/2023]
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24
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Feng Y, Li Y, Huang D, Cai S, Peng J. HER2 as a potential biomarker guiding adjuvant chemotherapy in stage II colorectal cancer. Eur J Surg Oncol 2019; 45:167-173. [DOI: 10.1016/j.ejso.2018.10.059] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 09/19/2018] [Accepted: 10/17/2018] [Indexed: 02/08/2023] Open
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25
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Kwon MJ, Soh JS, Lim SW, Kang HS, Lim H. HER2 as a limited predictor of the therapeutic response to neoadjuvant therapy in locally advanced rectal cancer. Pathol Res Pract 2019; 215:910-917. [PMID: 30772061 DOI: 10.1016/j.prp.2019.01.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 01/02/2019] [Accepted: 01/25/2019] [Indexed: 12/23/2022]
Abstract
Human epidermal growth factor 2 (HER2) is a candidate therapeutic and prognostic marker for rectal cancer treated with neoadjuvant chemoradiotherapy. The specific frequency and prognostic role of HER2 protein expression and HER2 gene amplification in those rectal cancers has not been fully investigated. Pretreatment biopsied and surgically resected formalin-fixed paraffin-embedded tissues from 74 patients were retrospectively evaluated for HER2 protein expression and HER2 gene copy number using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. The tumor response to chemoradiation was evaluated with TNM staging and tumor regression grading (TRG) systems. Good response to chemoradiation therapy (TRG3), poor response (22 TRG1 and 19 TRG2), and TNM downstaging achieved in 33 (44.6%), 41 (55.4%), and 42 (56.8%) patients, respectively. The frequency of HER2 positivity is 17.6%, all of which were low-level HER2 gene amplification with 2.2 of median gene copy number ratio, detected in IHC0 (3/39), IHC1+ (2/18), IHC2+ (5/14) and IHC3+ (2/3). There was no association of HER2 positivity with clinicopathological parameters or survival. However, older age (≥61 years) and HER2 positivity were the independent predictive factors for non-down staging, while poorly differentiation and the papillary pattern were predictors for poor response. In multivariate analysis, good response proved as an only independent favorable prognostic factor affecting survivals. In conclusion, HER2 positivity may be predictive for a high-risk therapeutic resistance in rectal cancers. The discrepancy between IHC and gene amplification may result from the low-level amplification, which may explain lack of prognostic impact of HER2 positivity.
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Affiliation(s)
- Mi Jung Kwon
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
| | - Jae Seung Soh
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
| | - Sang-Woo Lim
- Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea.
| | - Ho Suk Kang
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
| | - Hyun Lim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
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26
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Hasan R, Bhatt D, Khan S, Khan V, Verma AK, Anees A, Dev K. Association of Her-2 Expression and Clinicopathological Parameters in Colorectal Carcinoma in Indian Population. Open Access Maced J Med Sci 2019; 7:6-11. [PMID: 30740151 PMCID: PMC6352485 DOI: 10.3889/oamjms.2019.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 10/28/2018] [Accepted: 10/30/2018] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND: Human epidermal growth factor receptor 2 (HER-2) is an oncogenic gene and a well-established therapeutic target in several cancers including breast and ovary. AIM: The present study aimed to compare HER-2 expression status with histological grades as well as Clinicopathological parameters including age, bleeding per rectum, pain/burning sensation in defecation and exercise. METHODS: Her-2 status was assessed by immunohistochemistry (IHC). RESULTS: Results of the study shows that 40.96% patients were Her-2 positive for expression and a statistically significant difference (p-value = 0.004) was observed in histological grades where most of the cases were of grade II. We also observed a significant difference in histological grades with gender (p-value = 0.04), as well as in both the age groups ≤ 55 years and > 55 years (p-value = < 0.0001). Patients with the bleeding rectum and pain/burning sensation in defecation had grade II/III tumours (93.4%, 88.7%) respectively. A significant association was observed between bleeding per rectum and pain/burning sensation in defecation. About 95% of patients with pain/burning sensation in defecation had bleeding per rectum. CONCLUSION: To conclude, Her-2 can be a potential prognostic marker in CRC. The role of age, tumour grade and bleeding per rectum/burning sensation in defecation are of significant worth. Thus, CRC cases of high grades can be screened for HER-2/neu positivity so that they can be subjected to mAb-based individualised therapy.
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Affiliation(s)
- Rameez Hasan
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India.,Department of Surgery, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh-202001, Uttar Pradesh, India
| | - Deepti Bhatt
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
| | - Shahbaz Khan
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
| | - Vasiuddin Khan
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
| | - Amit Kumar Verma
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
| | - Afzal Anees
- Department of Surgery, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh-202001, Uttar Pradesh, India
| | - Kapil Dev
- Department of Biotechnology, Jamia Millia Islamia, Jamia Nagar, New Delhi-110025, India
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27
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Greally M, Kelly CM, Cercek A. HER2: An emerging target in colorectal cancer. Curr Probl Cancer 2018; 42:560-571. [DOI: 10.1016/j.currproblcancer.2018.07.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 04/20/2018] [Accepted: 07/09/2018] [Indexed: 02/07/2023]
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28
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Pan G, Li D, Li X, Peng Y, Wang T, Zuo C. SPECT/CT imaging of HER2 expression in colon cancer-bearing nude mice using 125I-Herceptin. Biochem Biophys Res Commun 2018; 504:765-770. [PMID: 30217443 DOI: 10.1016/j.bbrc.2018.08.201] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 08/31/2018] [Indexed: 02/07/2023]
Abstract
An accurate assessment of HER2 status in patients with colorectal cancer is very important, because only the patients overexpressing HER2 can benefit most from the anti-HER2 targeted therapy. In this study, we investigated the feasibility of detecting HER2 expression in colon cancer by SPECT imaging using 125I-Herceptin, which showed high labeling rate, good in vitro stability and high binding specificity for HER2. HER2-positive mouse colon adenocarcinoma cell line (MC 38) was chosen as the colon caner cell model, and used for the establishment of colon cancer-bearing nude mice model. SPECT/CT imaging suggested that the tumors can be visualized at 12 h after the injection of 125I-Herceptin, and the uptake of tracer in tumors reached the peak at 24 h after injection, and can be attenuated significantly by pretreatment with an excess of nonlabeled Herceptin. These results indicates that 125I-Herceptin can be considered as an effective SPECT probe for the non-invasive detection of HER2 expression in colon cancer.
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Affiliation(s)
- Guixia Pan
- Department of Nuclear Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China
| | - Danni Li
- Department of Nuclear Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China
| | - Xiao Li
- Department of Nuclear Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China
| | - Ye Peng
- Department of Nuclear Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China
| | - Tao Wang
- Department of Nuclear Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China.
| | - Changjing Zuo
- Department of Nuclear Medicine, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, China.
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29
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El Dika I, Ilson DH. Current and future therapies for targeting HER2 mutations in gastrointestinal cancer. Expert Rev Anticancer Ther 2018; 18:1085-1092. [PMID: 30092682 DOI: 10.1080/14737140.2018.1510324] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Gastrointestinal (GI) cancers altogether represent the most common cancer type. HER2 is found to be present in nearly all histologic types of GI cancers in variable degrees of expression. Over the last decade, substantial advances have been made in targeting HER2-positive cancers. Areas covered: The present review summarizes the current progress and future directions for HER2 targeted therapies in GI cancers, including esophagogastric, pancreaticobiliary, and colon cancers. To date trastuzumab is the only anti-HER2 therapy approved for metastatic esophagogastric adenocarcinoma. Efforts are ongoing to expand the therapeutic role of HER2 to other GI cancers and overcome mechanisms of drug resistance. Novel agents and combinations are being tested in most HER2 positive GI cancers including early stage disease. These are of recent interest in colorectal cancer with studies indicating that HER2 overexpression might increase resistance to anti-EGFR therapy and may be potentially targeted. Expert commentary: With the current ability to sequence tumors and detect genetic alterations, emphasis should be put on genomically-selected pan-tumor targeted therapies. HER2 is a perfect example of a promising drug target in GI cancers.
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Affiliation(s)
- Imane El Dika
- a Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA
| | - David H Ilson
- a Department of Medicine , Memorial Sloan Kettering Cancer Center , New York , NY , USA.,b Weill Cornell Medical College , New York , NY , USA
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30
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Schirripa M, Cohen SA, Battaglin F, Lenz HJ. Biomarker-driven and molecular targeted therapies for colorectal cancers. Semin Oncol 2018; 45:124-132. [PMID: 30262397 PMCID: PMC7496213 DOI: 10.1053/j.seminoncol.2017.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 06/27/2017] [Indexed: 12/23/2022]
Abstract
Improved clinical selection and identification of new molecules and innovative strategies have widened treatment options and increased overall survival in metastatic colorectal cancer patients in recent years. Biomarker-driven therapies represent an emerging issue in this field and new targeted treatments are under investigation and probably will be soon adopted into daily clinical practice. In the present review, the role RAS, BRAF mutations, Her2 amplification, microsatellite instability, and CpG island methylator phenotype are discussed according to their possible roles as prognostic, predictive markers, as well as possible biomarker-driven treatment options.
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Affiliation(s)
- Marta Schirripa
- Division of Medical Oncology 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Stacey A Cohen
- Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Francesca Battaglin
- Division of Medical Oncology 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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31
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Buhmeida A, Assidi M, Al-Maghrabi J, Dallol A, Sibiany A, Al-Ahwal M, Chaudhary A, Abuzenadah A, Al-Qahtani M. Membranous or Cytoplasmic HER2 Expression in Colorectal Carcinoma: Evaluation of Prognostic Value Using Both IHC & BDISH. Cancer Invest 2018; 36:129-140. [PMID: 29504811 DOI: 10.1080/07357907.2018.1439054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Human epidermal growth factor recptor-2 (HER2) was identified as a driver gene in several types of cancers with both prognostic and predictive value. However, the molecular association of HER2 gene mutation with HER2 gene amplification and/or protein expression in cancer tissues has not been clearly defined. Moreover, there is little information available on HER2 status role in tumor progression and metastasis in colorectal carcinoma (CRC) compared to other solid tumors. The aim of this study was to evaluate both HER2 amplification and protein expression profiles using immunohistochemistry (IHC) and bright-field dual in situ hybridization (BDISH) techniques, respectively. PATIENTS AND METHODS Tissue microarray (TMA) was constructed to accommodate a total of 243 CRC formalin-fixed paraffin embedded (FFPE) samples of consent patients and stained by IHC and BDISH methods. The expression patterns of HER2 protein status were evaluated and correlated to HER2 gene amplification status and then assessed for its prognostic value. RESULTS The expression profile of 58% samples showed cytoplasmic expression patterns of different categories. Interestingly, only 1% showed strong (+3) membranous expression pattern of HER2 with perfect match with their corresponding gene amplification status (>2). However, the cytoplasmic HER2 protein status did not show significant correlation with most clinicopathological features and survival outcomes except with age (p = 0.04) and tumor size (p = 0.03). CONCLUSION We demonstrated that the membranous HER2 gene/protein status is infrequent, while the main fraction of HER2 overexpression was cytoplasmic and lacking prognostic value. This cytoplasmic HER2 overexpression was induced through a gene-amplification independent pathway, making the HER2 gene status evaluation approach in those cases not worthy. Further investigations about the molecular pathways of the cytoplasmic HER2 protein in CRC and its associations with survival outcomes are required to allow either a breakthrough in CRC management; or to confirm the hypothesis of a marginal role in CRC onset and progression.
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Affiliation(s)
- Abdelbaset Buhmeida
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mourad Assidi
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Jaudah Al-Maghrabi
- c Department of Pathology, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Ashraf Dallol
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Abdulrahman Sibiany
- d Department of Surgery, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mahmoud Al-Ahwal
- e Department of Internal Medicine, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Adeel Chaudhary
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Adel Abuzenadah
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mohammed Al-Qahtani
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
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32
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Auclin E, Zaanan A, Vernerey D, Douard R, Gallois C, Laurent-Puig P, Bonnetain F, Taieb J. Subgroups and prognostication in stage III colon cancer: future perspectives for adjuvant therapy. Ann Oncol 2018; 28:958-968. [PMID: 28453690 DOI: 10.1093/annonc/mdx030] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Since the MOSAIC study, oxaliplatin-based adjuvant chemotherapy has been the standard treatment of stage III colon cancer. Combination therapy with fluoropyrimidines and oxaliplatin has improved overall survival (OS) and reduced the risk of recurrence in patients with resected stage III colon cancer. However, only 20% of patients really benefit from adjuvant chemotherapy, exposing 80% of patients to unnecessary toxicity. Recent analyses of large multicenter adjuvant studies have focused on the prognostication of OS and disease-free survival in stage III colon cancer in order to reduce over-treatment and to find more accurate prognostic tools than those used for adjuvant treatment decision-making in stage II disease. Indeed, clinical and pathological prognostic factors, although important, are not sufficient to decide which stage III patients will benefit from adjuvant therapy, and biomarkers will help select patient that need adjuvant treatment. Molecular markers such as microsatellite status and BRAF and KRAS mutations have recently been explored, and molecular signatures have been identified as promising prognostic factor for OS. Furthermore, recent studies have highlighted the prognostic value of immune infiltration. This review focuses on pathologic, immunologic and molecular prognostic markers for stage III colon cancer that could help clinicians tailor adjuvant treatment in a comprehensive transversal approach.
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Affiliation(s)
- E Auclin
- Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.,Methodological and Quality of Life in Oncology Unit, Besançon, France
| | - A Zaanan
- Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.,Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - D Vernerey
- Methodological and Quality of Life in Oncology Unit, Besançon, France
| | - R Douard
- Department of Digestive Surgery, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France
| | - C Gallois
- Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France
| | - P Laurent-Puig
- Paris Descartes University, Sorbonne Paris Cité, Paris, France.,Department of Biology, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, INSERM-UMR-S1147, Paris, France
| | - F Bonnetain
- Methodological and Quality of Life in Oncology Unit, Besançon, France
| | - J Taieb
- Department of Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France.,Paris Descartes University, Sorbonne Paris Cité, Paris, France
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33
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Takegawa N, Yonesaka K. HER2 as an Emerging Oncotarget for Colorectal Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy. Clin Colorectal Cancer 2017; 16:247-251. [DOI: 10.1016/j.clcc.2017.03.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/10/2017] [Accepted: 03/01/2017] [Indexed: 12/15/2022]
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34
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Immunohistochemical Study of HER2/neu Expression in Colorectal Cancer and its Relation to other Clinicopathological Criteria and Prognostic Factors. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcm.5700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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35
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Pan HD, Peng YF, Xiao G, Gu J. High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis. World J Gastroenterol 2017; 23:1233-1240. [PMID: 28275303 PMCID: PMC5323448 DOI: 10.3748/wjg.v23.i7.1233] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/13/2016] [Accepted: 01/03/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To develop predictive markers in blood for colorectal cancer liver metastasis.
METHODS Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was IIIC (T3-4N2M0), while another 10 patients with synchronous liver metastasis (TNM stage IV) were recruited for group B. During the surgical procedure, a 10-mL drainage vein (DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-mL peripheral vein (PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology.
RESULTS Univariate analysis revealed that platelet-derived growth factor AA (PDGFAA) in DV blood (dPDGFAA) (P = 0.001), PDGFAA in PV blood (pPDGFAA) (P = 0.007), and human epidermal growth factor receptor-2 in PV blood (pHER2) (P = 0.001), pMMP7 (P = 0.028), pRANTES (P = 0.013), and pEGF (P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified dPDGFAA (HR = 1.001, P = 0.033) and pHER2 (HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance (P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA (r = 0.794, P < 0.001), but not for HER2 (r = 0.189, P = 0.424).
CONCLUSION PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.
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Plasticity of Resistance and Sensitivity to Anti-Epidermal Growth Factor Receptor Inhibitors in Metastatic Colorectal Cancer. Handb Exp Pharmacol 2017; 249:145-159. [PMID: 28382467 DOI: 10.1007/164_2017_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer mortality worldwide. Survival in the metastatic setting has been gradually improved by the addition to cytotoxic chemotherapy of agents targeting the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Considerable heterogeneity exists within CRC due to the varied genetic and epigenetic mechanisms involved in differing pathways of carcinogenesis. The knowledge of molecular abnormalities underlying colorectal tumourigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced in recent years by comprehensive sequencing studies. From these genome-scale analyses, we know that a handful of genes are commonly affected by somatic mutations, whereas recurrent copy-number alterations and chromosomal translocations are rarer in this disease. Even though some of these molecular abnormalities make genes acting as drivers of cancer progression, translation of this recognition for therapeutic purposes is still limited, encompassing only as standard of care the exclusion of RAS-mutated cancers for better selecting patients to candidate to EGFR-targeted therapy with monoclonal antibodies. However, the effort of ameliorating molecular selection should not be considered exhausted by demonstration of RAS and BRAF-induced resistance, as the genomic landscape of response to EGFR blockade has been demonstrated to be wider and dynamically multifaceted. In this chapter we will review main molecular biomarkers of de novo (primary) and acquired (secondary) resistance to EGFR-targeted monoclonal antibodies in metastatic CRC and discuss therapeutic implications.
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Parikh A, Atreya C, Korn WM, Venook AP. Prolonged Response to HER2-Directed Therapy in a Patient With HER2-Amplified, Rapidly Progressive Metastatic Colorectal Cancer. J Natl Compr Canc Netw 2017; 15:3-8. [PMID: 28040715 PMCID: PMC5564419 DOI: 10.6004/jnccn.2017.0002] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 09/13/2016] [Indexed: 12/21/2022]
Abstract
HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor-based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient's disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient's functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.
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Affiliation(s)
- Aparna Parikh
- From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Chloe Atreya
- From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - W Michael Korn
- From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Alan P Venook
- From University of California San Francisco, Hellen Diller Family Comprehensive Cancer Center, San Francisco, California
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Sartore-Bianchi A, Loupakis F, Argilés G, Prager G. Challenging chemoresistant metastatic colorectal cancer: therapeutic strategies from the clinic and from the laboratory. Ann Oncol 2016; 27:1456-66. [DOI: 10.1093/annonc/mdw191] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 04/27/2016] [Indexed: 12/22/2022] Open
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Karaca H, Deniz K, Berk V, Inanc M, Ozkan M. Association of human epidermal growth factor receptor-2 expression and clinicopathological findings in patients with colorectal cancer. Asian Pac J Cancer Prev 2016; 13:6221-5. [PMID: 23464435 DOI: 10.7314/apjcp.2012.13.12.6221] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To determine the frequency of HER-2 overexpression in colorectal cancer (CRC) patients, and to explore the relationship between clinicopathological prognostic factors and their effects on survival, based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) analysis. MATERIALS AND METHODS The study included 80 patients with a histologically proven diagnosis of CRC that received adjuvant FOLFOX-4 chemotherapy at our department between March 2006 and September 2010. Patient data were analyzed retrospectively. RESULTS The median follow-up period and age of the patients were 24 months and 59 years, respectively. In immunohistochemical staining, 3+ staining was found in 2 patients (2.5%) while 2+ was in 13 (16%) . FISH for HER-2 was performed for all of these 15 patients; samples which were 3+ showed positivity but the ones with 2+ were negative. There was no significant correlation between HER-2 expression and age, gender, tumor localization, histological subtype, grade, lymphovascular and perineural invasion, or pTN stage (P>0.05), even when the patients with HER-2 overexpression were analyzed separately. There was also no significant relationship between progression-free survival (PFS) and overall survival (OS), and HER-2 expression, gender, tumor localization, obstruction-perforation, bleeding, histological type, grade, lymphovascular and perineural invasion, or pT staging (P>0.05); however, there was a significant relationship between lymph node involvement, and PFS and OS (P<0.05). CONCLUSIONS Evaluation of HER-2 overexpression in a more comprehensive, multi-center, prospective trial with standardized methods will be an appropriate approach.
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Affiliation(s)
- Halit Karaca
- Deparment of Medical Oncology, Erciyes University Medical Faculty, Kayseri, Turkey.
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Takahashi N, Iwasa S, Taniguchi H, Sasaki Y, Shoji H, Honma Y, Takashima A, Okita N, Kato K, Hamaguchi T, Shimada Y, Yamada Y. Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies. Br J Cancer 2016; 114:1003-11. [PMID: 27002940 PMCID: PMC4984915 DOI: 10.1038/bjc.2016.74] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/06/2016] [Accepted: 02/17/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND High amplification of epiregulin (EREG) and amphireglin (AREG) in tumour tissues has been previously reported to be associated with better outcome in metastatic colorectal cancer (mCRC) patients who were treated with anti-EGFR antibodies. Here we investigated associations between the expression of other candidate prognostic biomarkers and outcome in mCRC patients receiving similar treatment. METHODS The relative mRNA levels of seven genes including ERBB2, MET, VEGFA, EREG, AREG, PTEN and ERCC1 between tumour (T) and non-tumour (NT) tissue sections were analysed by quantitative real-time PCR. Relative mRNA values, that is, T/NT ratios, of target genes were calculated and hazard ratios (HRs) for each gene of interest were adjusted for age, gender, performance status, minor RAS mutations and other clinicopathological variables which exhibited P-values<0.1 on the basis of univariate analysis. RESULTS Among 108 cases who received anti-EGFR antibodies, there were 96 cases of KRAS exon2 wild-type patients enroled in this study. When the cutoff values for relative mRNA levels were set to the upper 25th percentile of all patients, there were statistically significant differences in overall survival (OS) between the patients with high and low levels of EREG (HR: 0.326, 95% CI: 0.136-0.772, P=0.011), ERBB2 (HR: 1.31, 95% CI: 1.084-1.652, P=0.040), MET (HR: 2.48, 95% CI: 1.356-5.463, P=0.026), and VEGF-A (HR: 1.29, 95% CI: 1.036-1.606, P=0.046). In addition, patients with high ERBB2 had shorter progression-free survival (PFS) compared with low ERBB2 (HR: 1.98, 95% CI: 1.062-3.850). There were no significant differences in PFS and OS with respect to relative expression levels of PTEN and ERCC1. The prognostic role of AREG was evaluated in only T sections, as the mRNA expression level of this gene was mostly (91% cases) undetectable in NT sections. Patients with high AREG had longer OS compared with low AREG (HR: 0.227, 95% CI: 0.095-0.808). CONCLUSIONS Our study has shown that higher T/NT ratios of ERBB2, MET and VEGFA mRNA were associated with worse OS in mCRC patients treated with anti-EGFR antibodies, with higher EREG and AREG were associated with better prognosis in the same setting. These findings will contribute the further understanding and management of anti-EGFR antibody treatment in mCRC patients.
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Affiliation(s)
- Naoki Takahashi
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Satoru Iwasa
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hirokazu Taniguchi
- Pathology and Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yusuke Sasaki
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hirokazu Shoji
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yoshitaka Honma
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Atsuo Takashima
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Natsuko Okita
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Ken Kato
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tetsuya Hamaguchi
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yasuhiro Shimada
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yasuhide Yamada
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
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Assessment of a HER2 scoring system for colorectal cancer: results from a validation study. Mod Pathol 2015; 28:1481-91. [PMID: 26449765 DOI: 10.1038/modpathol.2015.98] [Citation(s) in RCA: 219] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/13/2015] [Accepted: 07/13/2015] [Indexed: 12/22/2022]
Abstract
We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrollment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.
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Meng X, Huang Z, Di J, Mu D, Wang Y, Zhao X, Zhao H, Zhu W, Li X, Kong L, Xing L. Expression of Human Epidermal Growth Factor Receptor-2 in Resected Rectal Cancer. Medicine (Baltimore) 2015; 94:e2106. [PMID: 26632727 PMCID: PMC5058996 DOI: 10.1097/md.0000000000002106] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The addition of trastuzumab to chemotherapy was demonstrated to be beneficial for advanced human epidermal growth factor receptor-2 (HER-2) positive gastric cancer. However, the HER-2 status of rectal cancer remains uncertain. This study aimed to determine the HER-2 expression in a large multicenter cohort of rectal cancer patients. The clinical and pathological features of 717 patients were retrospectively reviewed. All the patients were diagnosed with primary rectal adenocarcinoma without distant metastasis and took surgery directly without any preoperative anticancer treatment. HER-2 status was assessed on resected samples. A total of 99 cases with IHC3+ and 16 cases with IHC 2+ plus gene amplification were determined as HER-2 positive. 22.6% of HER-2 positive patients had local recurrence, whereas 16.9% of HER-2 negative patients did (P = 0.146). HER-2 positive tumors were more likely to have distant metastasis (P = 0.007). Univariate analysis revealed that pathological tumor stage, pathological node stage, positive margin, and lymphovascular invasion were significantly correlated with 5-year disease-free survival (DFS) and 5-year overall survival (OS). The patients with >10 dissected lymph nodes showed significantly longer OS (P = 0.045) but not DFS (P = 0.054). HER-2 negative patients had significantly better 5-year DFS (P < 0.001) and 5-year OS (P = 0.013) than those of the HER-2 positive patients. In the subgroup analysis for the early rectal cancer and locally advanced rectal cancer, HER-2 was also a poor predictor for survival. Multivariate analysis revealed that HER-2 was an independent prognostic factor for 5-year DFS (hazard ratio [HR] = 1.919, 95% confidence interval [CI] 1.415-2.605, P < 0.001) and for 5-year OS (HR = 1.549, 95% CI 1.097-2.186, P = 0.013). When the treatment was included in the analysis for locally advanced patients, HER-2 was a prognostic factor for 5-year DFS (P = 0.001) but not for 5-year OS (P = 0.106). This study confirmed that HER-2 was expressed in a part of patients with rectal cancers and might be used as a negative predictor. The results may support the trials to assess the efficacy of trastuzumab in treating HER-2 positive rectal cancer patients.
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Affiliation(s)
- Xiangjiao Meng
- From the Department of Radiation Oncology (XM, JD, XZ, HZ, WZ, XL, LK, LX), Shandong Cancer Hospital and Institute; Department of Radiology (ZH), Provincial Hospital Affiliated to Shandong University; Department of Pathology (DM), Shandong Cancer Hospital and Institute; and Department of Chemotherapy (YW), Qilu Hospital, Shandong University, Jinan, Shandong Province, China
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Wu SW, Ma CC, Li WH. Does overexpression of HER-2 correlate with clinicopathological characteristics and prognosis in colorectal cancer? Evidence from a meta-analysis. Diagn Pathol 2015; 10:144. [PMID: 26276145 PMCID: PMC4537540 DOI: 10.1186/s13000-015-0380-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 07/28/2015] [Indexed: 12/11/2022] Open
Abstract
Background Previous studies have been inconsistent with respect to the reported associations between human epidermal growth factor receptor (HER-2/neu) overexpression in colorectal cancer. The aims of this meta-analysis are to assess its correlation with clinicopathological characteristics and prognostic significance in colorectal cancer. Methods Eligible studies were searched in Pubmed, Embase and Web of Science databases. The inclusion criteria were studies that assessed the relationship between HER-2 expression detected by immunohistochemistry (IHC) and the prognosis or clinicopathological features in patients with colorectal cancer (CRC). Subgroup analysis according to sex, tumor location, TNM stage, grade of differentiation and lymph node metastasis were produced. Odds ratio (OR) or hazard ratio (HR) with 95 % confidence interval (CI) were calculated to examine the risk or hazard association, and heterogeneity and publication bias analyses were also performed. Results A total of 18 studies comprising 2867 colorectal cancer patients were included to assess the association between HER-2 immunohistochemical expression and clinicopathological characteristics and survival. The overall analysis showed that there was no detectable relation between HER-2 expression and prognosis in colorectal cancer patients with the pooled HR of 1.08 (95 % CI: 0.96–1.21, P = 0.21). With respect to clinicopathological features, there was also no detectable relation between HER-2 expression and sex (OR = 0.91, 95 % CI: 0.72–1.15, P = 0.42), tumor location (OR = 1.21, 95 % CI = 0.88–1.65, P = 0.24), grade of differentiation (OR = 1.03, 95 % CI = 0.72–1.47, P = 0.86), TNM stages (OR = 0.72, 95 % CI = 0.31–1.66, P = 0.44), or lymph node metastasis (OR = 1.90, 95 % CI = 0.90–4.02, P = 0.09) in CRC. Conclusions The finding from this present meta-analysis suggested that HER-2 overexpression was not related to clinicopathological characteristics and poor prognostic of colorectal cancer patients.
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Affiliation(s)
- Sheng-wen Wu
- Department of General Surgery, The Affiliated Jianhu Hospital of Nantong University, Jianhu People's Hospital, Jianhu, 224700, Jiangsu Province, China
| | - Cong-chao Ma
- Department of General Surgery, The Affiliated Jianhu Hospital of Nantong University, Jianhu People's Hospital, Jianhu, 224700, Jiangsu Province, China
| | - Wen-hui Li
- Department of Interventional Radiology, The Affiliated Yancheng Hospital of Southeast University Medical College, Yancheng Third People's Hospital, Yancheng, 224001, Jiangsu Province, China.
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Omar N, Yan B, Salto-Tellez M. HER2: An emerging biomarker in non-breast and non-gastric cancers. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.pathog.2015.05.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Han J, Meng QY, Liu X, Xi QL, Zhuang QL, Wu GH. Lack of effects of HER-2/neu on prognosis in colorectal cancer: a meta-analysis. Asian Pac J Cancer Prev 2015; 15:5551-6. [PMID: 25081663 DOI: 10.7314/apjcp.2014.15.14.5551] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The prognostic value of human epidermal growth factor receptor-2 (HER-2/neu) for survival of patients with colorectal cancer (CRC) is still ambiguous. We therefore performed a meta-analysis to evaluate its prognostic significance. MATERIALS AND METHODS We searched the MEDLINE and EMBASE databases for published literature investigating associations between HER-2/neu status and overall survival of patients with CRC. A meta-analysis was performed using a DerSimonian-Laird model and publication bias was investigated by Begg's and Egger's tests. Subgroup analysis was also conducted according to the study design type, study quality score, cut-off value for HER-2/neu overexpression, publication region, patient number and publication year. RESULTS A total of 17 eligible studies involving 2,347 patients were identified for this meta-analysis. The combined hazard ratio (HR) was 1.31 (95% confidence interval (CI): 0.96-1.79), suggesting that HER-2/neu overexpression was not significantly associated with overall survival of patients with CRC. However, subgroup analysis revealed that HER-2/neu overexpression had an unfavorable impact on survival when the analysis was restricted to subgroups of study quality score ≤ 5 (HR=1.56, 95%CI: 1.17-2.10), Asian patients (HR=1.74, 95%CI: 1.22-2.49), patient number ≤ 106 (HR=1.57, 95%CI: 1.01-2.44), publication year before 2003 (HR=1.59, 95%CI: 1.02-2.49), and prospectively designed study (HR=3.62, 95%CI: 1.42-9.24). The effect disappeared in subgroups of study quality scores > 5 (HR=0.69, 95%CI: 0.33-1.44), non Asian patients (HR=1.14, 95%CI: 0.77-1.70), patients' number > 106 (HR=1.07, 95%CI: 0.67-1.72), publication year after 2003 (HR=1.13, 95%CI: 0.76-1.69), and retrospectively designed study (HR=1.22, 95%CI: 0.89-1.67). CONCLUSIONS Our meta-analysis suggests that HER-2/neu overexpression might not be a significantly prognostic indicator for patients with CRC. Further studies are required to confirm these results.
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Affiliation(s)
- Jun Han
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China E-mail :
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Li C, Liu DR, Ye LY, Huang LN, Jaiswal S, Li XW, Wang HH, Chen L. HER-2 overexpression and survival in colorectal cancer: a meta-analysis. J Zhejiang Univ Sci B 2015; 15:582-9. [PMID: 24903996 DOI: 10.1631/jzus.b1300258] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Numerous studies examining the relationship between human epidermal growth factor receptor 2 (HER-2) overexpression and survival in patients with colorectal cancer (CRC) have yielded controversial results. We therefore performed a meta-analysis more precisely to estimate its prognostic value. METHODS Published studies investigating the effect of HER-2 overexpression on CRC survival were identified; the hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were pooled in terms of disease-specific or overall survival. RESULTS Eleven studies were included in the meta-analysis. The pooled data showed that HER-2 overexpression was negatively related to CRC survival (HR=1.10, 95% CI: 0.77-1.44). Subgroup analyses regarding test method and study quality also demonstrated little association between HER-2 overexpression and CRC survival (HR=0.89, 95% CI: 0.50-1.29; HR=0.90, 95% CI: 0.43-1.37, respectively). CONCLUSIONS Regardless of several limitations, our study suggested that HER-2 overexpression probably had little impact on CRC survival.
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Affiliation(s)
- Chao Li
- Department of Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310021, China
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Tu J, Yu Y, Liu W, Chen S. Significance of human epidermal growth factor receptor 2 expression in colorectal cancer. Exp Ther Med 2014; 9:17-24. [PMID: 25452770 PMCID: PMC4247305 DOI: 10.3892/etm.2014.2063] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Accepted: 06/20/2014] [Indexed: 12/18/2022] Open
Abstract
The aim of the present study was to evaluate the protein expression level of human epidermal growth factor receptor 2 (HER-2) using immunohistochemistry (IHC), and assess the association with clinicopathological parameters and the prognosis of patients with colorectal cancer (CRC). In addition, the current study observed the consistency between the levels of HER-2 protein expression determined by IHC and HER-2 gene amplification determined by fluorescence in situ hybridization (FISH) in the CRC samples. Overexpression of HER-2 and gene amplification were examined with semiquantitative standardized IHC in 878 formalin-fixed paraffin-embedded CRC samples, while 102 of these cases were analyzed with FISH. A total of 102 cases (11.6%), out of the 878 cases, were determined by IHC to overexpress HER-2. Of these, 25 cases were strongly positive (IHC3+), while 77 cases revealed moderate staining (IHC2+). HER-2 overexpression was more frequent in early-stage cases compared with advanced-stage cases of CRC (P<0.001). However, there was no association observed between HER-2 overexpression and clinicopathological parameters. FISH analysis revealed that 64% (16/25) of the IHC3+ cases had HER-2 gene amplification. By contrast, only 6.5% (5/77) of the IHC2+ cases, and none of the 20 randomly selected IHC0 or 1+ cases, demonstrated HER-2 gene amplification. Furthermore, no associations were observed between HER-2 overexpression or gene amplification with the survival time. Thus, the present study observed that HER-2 overexpression does not correlate with other clinicopathological data or the survival rate, with the exception of clinical stages. However, IHC3+ and 2+ cases should be further analyzed by FISH to assess the status of the HER-2 gene in CRC. Patients with HER-2 gene amplification may constitute as potential candidates for targeted therapy with trastuzumab.
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Affiliation(s)
- Jinhua Tu
- Department of Pathology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361004, P.R. China ; Department of Pathology, Dongfang Hospital, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Yinghao Yu
- Department of Pathology, Dongfang Hospital, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Wei Liu
- Department of Pathology, Dongfang Hospital, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Shunping Chen
- Department of Pathology, Dongfang Hospital, Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
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Ingold Heppner B, Behrens HM, Balschun K, Haag J, Krüger S, Becker T, Röcken C. HER2/neu testing in primary colorectal carcinoma. Br J Cancer 2014; 111:1977-84. [PMID: 25211663 PMCID: PMC4229629 DOI: 10.1038/bjc.2014.483] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Revised: 08/04/2014] [Accepted: 08/07/2014] [Indexed: 02/06/2023] Open
Abstract
Background: Anti-HER2/neu therapy is well-established in breast and gastric carcinoma. The increased understanding of this pathway led to the identification of new promising drugs in addition to trastuzumab, offering further perspectives. The role of HER2/neu in colorectal carcinoma is controversially discussed, as discrepant data has been reported. Methods: Here, we retrospectively assessed the prevalence of HER2/neu positivity in a large series of colorectal carcinoma, testing HER2/neu status according to current recommendations. We correlated the results to clinico-pathological data and patient survival. Results: Overall, in 1645 primary colorectal carcinoma cases, 1.6% of the cases were HER2/neu positive. HER2/neu positivity significantly correlated with higher UICC stages (P=0.017) and lymph node metastases (P=0.029). In the subgroup of sigmoideal and rectal carcinomas, positive HER2/neu status was associated with T-category (P=0.041) and higher UICC stages (P=0.022). Although statistically not significant, HER2/neu-positive colorectal carcinomas displayed a tendency to poorer overall survival. Conclusions: These results illustrate the importance of testing HER2/neu by approved diagnostic techniques and scoring systems. We assume that although the prevalence of HER2/neu positivity in colorectal carcinoma is low, HER2/neu testing in advanced, nodal-positive colorectal carcinoma is reasonable, offering a potential target in high risk colorectal carcinoma.
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Affiliation(s)
- B Ingold Heppner
- Department of Pathology, Campus Mitte, Charité University Hospital, 10117 Berlin, Germany
| | - H-M Behrens
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - K Balschun
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - J Haag
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - S Krüger
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany
| | - T Becker
- Department of General Surgery and Thoracic Surgery, Christian-Albrechts-University, 24105 Kiel, Germany
| | - C Röcken
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany
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Wu SW, Ma CC, Yang Y. The prognostic value of HER-2/neu overexpression in colorectal cancer: evidence from 16 studies. Tumour Biol 2014; 35:10799-804. [DOI: 10.1007/s13277-014-2376-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 07/17/2014] [Indexed: 12/22/2022] Open
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50
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Guan SS, Chang J, Cheng CC, Luo TY, Ho AS, Wang CC, Wu CT, Liu SH. Afatinib and its encapsulated polymeric micelles inhibits HER2-overexpressed colorectal tumor cell growth in vitro and in vivo. Oncotarget 2014; 5:4868-80. [PMID: 24947902 PMCID: PMC4148106 DOI: 10.18632/oncotarget.2050] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 05/30/2014] [Indexed: 12/31/2022] Open
Abstract
Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo. The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo.
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Affiliation(s)
- Siao-Syun Guan
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Jungshan Chang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chun-Chia Cheng
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tsai-Yueh Luo
- Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
| | - Ai-Sheng Ho
- Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Chia-Chi Wang
- Division of Hepatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Cheng-Tien Wu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
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