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1
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Beech C, Hechtman JF. Molecular Approach to Colorectal Carcinoma: Current Evidence and Clinical Application. Clin Lab Med 2024; 44:221-238. [PMID: 38821642 DOI: 10.1016/j.cll.2023.08.011] [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] [Indexed: 06/02/2024]
Abstract
Colorectal carcinoma is one of the most common cancer types in men and women, responsible for both the third highest incidence of new cancer cases and the third highest cause of cancer deaths. In the last several decades, the molecular mechanisms surrounding colorectal carcinoma's tumorigenesis have become clearer through research, providing new avenues for diagnostic testing and novel approaches to therapeutics. Laboratories are tasked with providing the most current information to help guide clinical decisions. In this review, we summarize the current knowledge surrounding colorectal carcinoma tumorigenesis and highlight clinically relevant molecular testing.
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Affiliation(s)
- Cameron Beech
- Department of Pathology, Yale New Haven Hospital, New Haven, CT, USA
| | - Jaclyn F Hechtman
- Molecular and GI Pathologist, NeoGenomics Laboratories, Fort Myers, FL, USA.
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2
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Liao PF, Wu TW, Peng TR. Monoclonal Antibodies for First-Line Treatment of Metastatic Colorectal Cancer. Am J Ther 2024; 31:e286-e297. [PMID: 35972911 DOI: 10.1097/mjt.0000000000001547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND In addition to discontinuing treatment at disease progression, cumulative toxicity limitations and genetic mutations play important roles in chemotherapy choice in metastatic colorectal cancer (mCRC). However, in recent years, targeted therapies, such as immune checkpoint inhibitors or monoclonal antibodies (MoAbs), have been used with chemotherapy to improve clinical outcomes in patients with mCRC. AREAS OF UNCERTAINTY Approximately 15% of patients with CRC would be eligible for further targeted therapy with immune checkpoint inhibitors based on genetic testing, but most patients with CRC would not qualify, especially Kirsten rat sarcoma wild-type. Therefore, adding MoAb is only an option for most patients until disease progression or unacceptable toxicity occurs. However, the results are not consistent with the combination of MoAb and different chemotherapy bases. In addition, most results from combining MoAb with different chemotherapy bases are not consistent. DATA SOURCES This meta-analysis includes published of the PubMed and Embase databases, limited to English literature, and patients were treated with MoAb combination. Randomized control trials conducted published up to May 2021 were considered for inclusion. THERAPEUTIC ADVANCES Fluoropyrimidine-based chemotherapy has been the backbone of palliative therapy for mCRC, with demonstrated benefits. This article will review the efficacy and safety of randomized control trials comparing different MoAb with fluoropyrimidine-based chemotherapy as first-line therapy for patients with mCRC, particularly in Kirsten rat sarcoma wild-type. CONCLUSION This meta-analysis revealed that MoAb plus chemotherapy has better progression-free survival and objective response rate than chemotherapy alone. However, treatment-related serious adverse events (grade ≥ 3) should be considered, particularly severe rash, diarrhea, and hypertension.
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Affiliation(s)
- Pei-Fei Liao
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, Republic of China
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3
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Yang H, Yuan R, Alex D, Hughesman C, Liu S, Lee U, Zhou C, Wang G. Metastatic Small Bowel Adenocarcinoma Mimicking a Primary Ovarian Mucinous Tumour - Clinical, Radiologic, Pathologic and Molecular Correlation. Int J Surg Pathol 2023; 31:110-118. [PMID: 35477328 DOI: 10.1177/10668969221098083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We describe an interesting case of a patient who presented with a large adnexal mass, first favored to be mucinous carcinoma of the gynecologic origin. The primary tumour site was ascertained after the patient's small bowel was resected by identifying an adenomatous component evolving into an invasive adenocarcinoma identical in morphology and immunophenotype to the ovarian tumour. Notably, both tumours were found to harbor a BRAF K601E mutation, which is extremely rare for a primary of the ovary. BRAF mutations are present in a subset of large bowel and small bowel adenocarcinoma, but our case shows the first instance of a BRAF K601E mutation being present in a small bowel adenocarcinoma, to the best of our knowledge. This case serves as a great illustration of the pivotal role of molecular diagnostics in modern pathology in arriving at the correct diagnosis. Additionally, it is an excellent example of how clinical-radiologic-pathologic-molecular correlation plays into the landscape of molecular pathology to deliver optimal care for the patient.
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Affiliation(s)
- Hang Yang
- Department of Pathology and Laboratory Medicine, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
| | - Ren Yuan
- Department of Radiology, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
| | - Deepu Alex
- Department of Pathology and Laboratory Medicine, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
| | - Curtis Hughesman
- Department of Pathology and Laboratory Medicine, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
| | - Shiru Liu
- Department of Oncology, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
| | - Ursula Lee
- Department of Oncology, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
| | - Chen Zhou
- Department of Pathology and Laboratory Medicine, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
| | - Gang Wang
- Department of Pathology and Laboratory Medicine, BC Cancer, 8144University of British Columbia, Vancouver, V6 T 2B5, Canada
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4
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Vaquero J, Pavy A, Gonzalez-Sanchez E, Meredith M, Arbelaiz A, Fouassier L. Genetic alterations shaping tumor response to anti-EGFR therapies. Drug Resist Updat 2022; 64:100863. [DOI: 10.1016/j.drup.2022.100863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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Catalano F, Borea R, Puglisi S, Boutros A, Gandini A, Cremante M, Martelli V, Sciallero S, Puccini A. Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14061388. [PMID: 35326540 PMCID: PMC8946235 DOI: 10.3390/cancers14061388] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/03/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability. Up to 15–20% of colorectal cancers carry alterations in DDR. However, the role of DDR alterations as a prognostic factor and as a therapeutic target must be elucidated. To date, disappointing results have been obtained in different clinical trials mainly due to poor molecular selection of patients. Several challenges must be overcome before these compounds may have an impact on colorectal cancer. For instance, although some preclinical evidence showed the vulnerability of a subset of CRCs to PARP inhibitors, no specific clinical or molecular biomarkers have been validated to select patients. Moreover, different DDR alterations may not equally confer platinum sensitivity in CRC patients. Further efforts are needed in both preclinical and clinical settings to exploit DDR alterations as therapeutic targets and to eventually discover PARP or other DDR inhibitors (e.g., Wee1) with clinical benefit on colorectal cancer patients. Abstract Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.
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Affiliation(s)
- Fabio Catalano
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
| | - Roberto Borea
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
| | - Silvia Puglisi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
| | - Andrea Boutros
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
| | - Annalice Gandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
| | - Malvina Cremante
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
| | - Valentino Martelli
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
| | - Stefania Sciallero
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
| | - Alberto Puccini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy; (F.C.); (R.B.); (S.P.); (A.B.); (A.G.); (M.C.); (V.M.); (S.S.)
- Department of Internal Medicine and Medical Specialties (DIMI), School of Medicine, University of Genoa, 16132 Genoa, Italy
- Correspondence: ; Tel.: +39-0105553301 (ext.3302); Fax: +39-0105555141
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Gaggianesi M, Mangiapane LR, Modica C, Pantina VD, Porcelli G, Di Franco S, Lo Iacono M, D’Accardo C, Verona F, Pillitteri I, Turdo A, Veschi V, Brancato OR, Muratore G, Pistone G, Bongiorno MR, Todaro M, De Maria R, Stassi G. Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells. Cancers (Basel) 2022; 14:cancers14030673. [PMID: 35158939 PMCID: PMC8833549 DOI: 10.3390/cancers14030673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/16/2021] [Accepted: 01/25/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Compelling evidence has shown that cancer stem cells (CSCs) are responsible for high resistance to conventional anti-cancer therapies. Here, we demonstrate that the tumor microenvironment protects CR-CSCs from EGFR/HER2, BRAF and PI3K targeting, promoting CD44v6 and Myc expression. Alternatively, as a substitution for HER2 and BRAF, the Myc transcription inhibitor can overcome the protective effects of microenvironmental cytokines, impairing the survival of CR-CSCs. These data highlight the targeting of Myc and PI3K activity as a novel therapeutic strategy against advanced colorectal cancer. Abstract Despite advances in the curative approach, the survival rate of advanced colorectal cancer (CRC) patients is still poor, which is likely due to the emergence of cancer cell clones resistant to the available therapeutic options. We have already shown that CD44v6-positive CRC stem cells (CR-CSCs) are refractory toward standard anti-tumor therapeutic agents due to the activation of the PI3K pathway together with high HER2 expression levels. Tumor microenvironmental cytokines confer resistance to CR-CSCs against HER2/PI3K targeting by enhancing activation of the MAPK pathway. Here, we show that the CSC compartment, spared by BRAF inhibitor-based targeted therapy, is associated with increased expression levels of CD44v6 and Myc and retains boosted clonogenic activity along with residual tumorigenic potential. Inhibition of Myc transcription, downstream of the MAPK cascade components, and PI3K pathway activity was able to overcome the protective effects of microenvironmental cytokines, affecting the survival and the clonogenic activity of CR-CSCs, regardless of their mutational background. Likewise, the double targeting induced stabilization of mouse tumor avatars. Altogether, these data outline the rationale for dual kinase targeting of CR-CSCs to prevent their adaptive response, which would lead to disease progression.
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Affiliation(s)
- Miriam Gaggianesi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Laura Rosa Mangiapane
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Chiara Modica
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Vincenzo Davide Pantina
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Gaetana Porcelli
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Melania Lo Iacono
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Caterina D’Accardo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Francesco Verona
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Irene Pillitteri
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Alice Turdo
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Veronica Veschi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Ornella Roberta Brancato
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Giampaolo Muratore
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
| | - Giuseppe Pistone
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Maria Rita Bongiorno
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Matilde Todaro
- Department of Health Promotion Sciences, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (L.R.M.); (G.P.); (C.D.); (F.V.); (A.T.); (G.P.); (M.R.B.); (M.T.)
| | - Ruggero De Maria
- Dipartimento di Medicina e Chirurgia Traslazionale, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
- Fondazione Policlinico A Gemelli IRCCS, 00168 Roma, Italy
- Correspondence: (R.D.M.); (G.S.); Tel.: +39-06-3015-4914 (R.D.M.); +39-091-2389-0813 (G.S.)
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (M.G.); (C.M.); (V.D.P.); (S.D.F.); (M.L.I.); (I.P.); (V.V.); (O.R.B.); (G.M.)
- Correspondence: (R.D.M.); (G.S.); Tel.: +39-06-3015-4914 (R.D.M.); +39-091-2389-0813 (G.S.)
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Beech C, Hechtman JF. Molecular Approach to Colorectal Carcinoma: Current Evidence and Clinical Application. Surg Pathol Clin 2021; 14:429-441. [PMID: 34373094 DOI: 10.1016/j.path.2021.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Colorectal carcinoma is one of the most common cancer types in men and women, responsible for both the third highest incidence of new cancer cases and the third highest cause of cancer deaths. In the last several decades, the molecular mechanisms surrounding colorectal carcinoma's tumorigenesis have become clearer through research, providing new avenues for diagnostic testing and novel approaches to therapeutics. Laboratories are tasked with providing the most current information to help guide clinical decisions. In this review, we summarize the current knowledge surrounding colorectal carcinoma tumorigenesis and highlight clinically relevant molecular testing.
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Affiliation(s)
- Cameron Beech
- Department of Pathology, Yale New Haven Hospital, New Haven, CT, USA
| | - Jaclyn F Hechtman
- Molecular and GI Pathologist, NeoGenomics Laboratories, Fort Myers, FL, USA.
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8
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Moradi-Marjaneh R, Asgharzadeh F, Khordad E, Marjaneh MM. The Clinical Impact of Quantitative Cell-free DNA, KRAS, and BRAF Mutations on Response to Anti-EGFR Treatment in Patients with Metastatic Colorectal Cancer. Curr Pharm Des 2021; 27:942-952. [PMID: 33030125 DOI: 10.2174/1381612826666201007163116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 08/31/2020] [Indexed: 11/22/2022]
Abstract
Colorectal cancer (CRC) is one of the most common leading causes of cancer death in the world. Although EGFR inhibitors have established efficacy in metastatic colorectal cancer (mCRC), some patients do not respond to this treatment. The EGFR inhibitors' failure and acquired resistance are partly due to KRAS and BRAF mutations. Thus, prognostic biomarkers that help to select eligible patients are highly in demand. To improve patient selection, assessment of mutational status in circulating cell free DNA (cfDNA), which possibly represents the dynamicity of tumor genetic status better than tumor tissue, could be advantageous. This review summarizes the current knowledge of the prognostic value of cfDNA in patients with mCRC treated with EGFR inhibitors with emphasis on the clinical importance of identification of KRAS and BRAF mutations.
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Affiliation(s)
- Reyhaneh Moradi-Marjaneh
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fereshteh Asgharzadeh
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elnaz Khordad
- Department of Physiology, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
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Gmeiner WH. Recent Advances in Our Knowledge of mCRC Tumor Biology and Genetics: A Focus on Targeted Therapy Development. Onco Targets Ther 2021; 14:2121-2130. [PMID: 33790575 PMCID: PMC8007558 DOI: 10.2147/ott.s242224] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/11/2021] [Indexed: 12/20/2022] Open
Abstract
Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy although considerable progress has resulted from characterizing molecular alterations such as RAS mutation status and extent of microsatellite instability (MSI) to guide optimal use of available therapies. The availability of gene expression profiling, next generation sequencing technologies, proteomics analysis and other technologies provides high resolution information on individual tumors, including metastatic lesions to better define intra-tumor and inter-tumor heterogeneity. Recent literature applying this information to further customize personalized therapies is reviewed. Current biomarker-based stratification used to select optimal therapy that is personalized to the mutation profile of individual tumors is described. Recent literature using whole exome sequencing of metastatic lesions and primary CRC tumors and other advanced technologies to more fully elucidate the tumor biology specific to mCRC sub-types and to develop more precise therapies that improve outcomes is also reviewed.
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Affiliation(s)
- William H Gmeiner
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
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10
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Wong V, Lee M, Wong R, Tie J, Shapiro J, Desai J, Nott L, Steel S, Burge M, Ma B, Khattak A, Hong W, Gibbs P. BRAFV600E Mutations Arising from a Left-Side Primary in Metastatic Colorectal Cancer: Are They a Distinct Subset? Target Oncol 2021; 16:227-236. [PMID: 33599905 DOI: 10.1007/s11523-021-00793-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND B-Raf proto-oncogene (BRAF)-V600E mutations (BRAFmt) in colorectal cancer (CRC) predominantly occur in right-side (RS) primaries. In metastatic CRC (mCRC), there is substantial overlap between the reported features of BRAFmt and of an RS primary. OBJECTIVES To explore the significance of BRAFmt in a left-side (LS) primary, we analysed data from a multi-site mCRC registry. Tumours distal to the splenic flexure were considered LS. RESULTS Of 3380 patients enrolled from June 2009 to June 2020, 214 (13%) of 1657 with known status were BRAFmt: 127 (24%) of 524 RS and 87 (8%) of 1133 LS. LS versus RS BRAFmt were younger (mean 59.5 vs. 65.1 years; p = 0.01), whereas sex (48 vs. 59% female; p = 0.13), mismatch repair-deficiency (dMMR) (16 vs. 21%; p = 0.47), and overall survival (OS) (median 15.1 vs. 17.7 months; p = 0.98) were similar. LS BRAFmt versus LS BRAF wildtype (wt) were of similar age (59.5 vs. 61.3 years; p = 0.28) with more females (48 vs. 37%; p = 0.04), more dMMR (16 vs. 1%; p < 0.0001), and inferior OS (median 15.1 vs. 36.6 months; p < 0.0001). Initial treatment with chemotherapy plus an epidermal growth factor receptor inhibitor produced median progression-free survival (PFS) of 4.3 versus 12.3 months (p = 0.20) for LS BRAFmt (n = 9) versus LS BRAFwt (n = 104). Initial chemotherapy and bevacizumab produced a median PFS of 7.6 versus 11.6 months (p = 0.02) for LS BRAFmt (n = 36) versus LS BRAFwt (n = 438), respectively. CONCLUSION LS BRAFmt cancers share many features with RS BRAFmt cancers, including poor survival outcomes. Mature data on the activity of BRAF-targeted therapies in the first-line setting are eagerly awaited.
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Affiliation(s)
- Vanessa Wong
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
| | - Margaret Lee
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Western Health, St Albans, VIC, Australia.,Eastern Health, Box Hill, VIC, Australia
| | - Rachel Wong
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Eastern Health, Box Hill, VIC, Australia.,Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia
| | - Jeanne Tie
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Western Health, St Albans, VIC, Australia.,Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | | | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Louise Nott
- Royal Hobart Hospital, Hobart, TAS, Australia
| | - Simone Steel
- Peninsula Private Hospital, Frankston, VIC, Australia
| | - Matthew Burge
- Royal Brisbane and Women's Hospital, Herston, QLD, Australia
| | - Brigette Ma
- Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | | | - Wei Hong
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | - Peter Gibbs
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Western Health, St Albans, VIC, Australia
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11
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Shuford RA, Cairns AL, Moaven O. Precision Approaches in the Management of Colorectal Cancer: Current Evidence and Latest Advancements Towards Individualizing the Treatment. Cancers (Basel) 2020; 12:E3481. [PMID: 33238500 PMCID: PMC7700522 DOI: 10.3390/cancers12113481] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/11/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
The genetic and molecular underpinnings of metastatic colorectal cancer have been studied for decades, and the applicability of these findings in clinical decision making continues to evolve. Advancements in translating molecular studies have provided a basis for tailoring chemotherapeutic regimens in metastatic colorectal cancer (mCRC) treatment, which have informed multiple practice guidelines. Various genetic and molecular pathways have been identified as clinically significant in the pathogenesis of metastatic colorectal cancer. These include rat sarcoma (RAS), epithelial growth factor receptor (EGFR), vascular endothelial growth factor VEGF, microsatellite instability, mismatch repair, and v-raf murine sarcoma viral oncogene homolog b1 (BRAF) with established clinical implications. RAS mutations and deficiencies in the mismatch repair pathway guide decisions regarding the administration of anti-EGFR-based therapies and immunotherapy, respectively. Furthermore, there are several emerging pathways and therapeutic modalities that have not entered mainstream use in mCRC treatment and are ripe for further investigation. The well-established data in the arena of targeted therapies provide evidence-based support for the use or avoidance of various therapeutic regimens in mCRC treatment, while the emerging pathways and platforms offer a glimpse into the future of transforming a precision approach into a personalized treatment.
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Affiliation(s)
- Rebecca A. Shuford
- Department of Surgery, Wake Forest University, Winston-Salem, NC 27157, USA; (R.A.S.); (A.L.C.)
| | - Ashley L. Cairns
- Department of Surgery, Wake Forest University, Winston-Salem, NC 27157, USA; (R.A.S.); (A.L.C.)
| | - Omeed Moaven
- Section of Surgical Oncology, Department of Surgery, Mayo Clinic Florida, Jacksonville, FL 32224, USA
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12
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Tayeb BA, Pringle HJ. The Sensitivity and Specificity of Novel Primers for Detection of BRAFV600E Mutation. Asian Pac J Cancer Prev 2020; 21:3191-3198. [PMID: 33247675 PMCID: PMC8033103 DOI: 10.31557/apjcp.2020.21.11.3191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Indexed: 11/25/2022] Open
Abstract
Objective: This study aimed to evaluate the sensitivity and specificity of a PCR-based novel technique for the detection of BRAF mutation in early stages of the cancer. Methods: Different lengths of primer sets, ranging from 8 bp to 20 bp, were designed and used in this study. These primers were developed by applying on cancer cell lines. After that, the sensitivity and specificity of the methodology was evaluated by making serial dilutions. Results: The quantitative allele specific discrimination PCR (QUASAqPCR) primer with 14 bp length was sensitive enough to detect significantly 1:1,000 ratio of BRAFV600E to wild-type background (P = 0.011), when using 150 nanograms of DNA from cell lines in the reactions. Conclusion: High sensitivity and specificity levels of QUASA-qPCR method can improve diagnostic accuracy for BRAF mutation testing in patients at early stages of cancers and help stratify the appropriate choice of treatment.
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Affiliation(s)
- Bizhar A Tayeb
- Molecular Pathology and Toxicology, Department of Molecular Microbiology, Central Laboratory in Ibrahim Al-khalil Zakho, Duhok, Kurdistan Region of Iraq
| | - Howard J Pringle
- Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK
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13
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Kanat O, Ertas H, Caner B. Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations. World J Gastrointest Oncol 2020; 12:1080-1090. [PMID: 33133378 PMCID: PMC7579731 DOI: 10.4251/wjgo.v12.i10.1080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/07/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Acıbadem Bursa Hospital, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Bursa City Hospital, Bursa 16059, Turkey
| | - Burcu Caner
- Department of Medical Oncoloy, Balıkesir Ataturk City Hospital, Bursa 16059, Turkey
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14
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Arnold L, Alexiadis V, Watanaskul T, Zarrabi V, Poole J, Singh V. Clinical validation of qPCR Target Selector™ assays using highly specific switch-blockers for rare mutation detection. J Clin Pathol 2020; 73:648-655. [PMID: 32132121 DOI: 10.1136/jclinpath-2019-206381] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 01/23/2020] [Accepted: 02/04/2020] [Indexed: 01/15/2023]
Abstract
AIMS The identification of actionable DNA mutations associated with a patient's tumour is critical for devising a targeted, personalised cancer treatment strategy. However, these molecular analyses are typically performed using tissue obtained via biopsy, which involves substantial risk and is often not feasible. In addition, biopsied tissue does not always reflect tumour heterogeneity, and sequential biopsies to track disease progression (eg, emergence of drug resistance mutations) are not well tolerated. To overcome these and other biopsy-associated limitations, we have developed non-invasive 'liquid biopsy' technologies to enable the molecular characterisation of a patient's cancer using peripheral blood samples. METHODS The Target Selector ctDNA platform uses a real-time PCR-based approach, coupled with DNA sequencing, to identify cancer-associated genetic mutations within circulating tumour DNA. This is accomplished via a patented blocking approach suppressing wild-type DNA amplification, while allowing specific amplification of mutant alleles. RESULTS To promote the clinical uptake of liquid biopsy technologies, it is first critical to demonstrate concordance between results obtained via liquid and traditional biopsy procedures. Here, we focused on three genes frequently mutated in cancer: EGFR (Del19, L858, and T790), BRAF (V600) and KRAS (G12/G13). For each Target Selector assay, we demonstrated extremely high accuracy, sensitivity and specificity compared with results obtained from tissue biopsies. Overall, we found between 93% and 96% concordance to blinded tissue samples across 127 clinical assays. CONCLUSIONS The switch-blocker technology reported here offers a highly effective method for non-invasively determining the molecular signatures of patients with cancer.
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Affiliation(s)
- Lyle Arnold
- Research and Development, Biocept Inc, San Diego, California, USA.,Aegea Biotechnologies, San Diego, California, USA
| | | | - Tim Watanaskul
- Research and Development, Biocept Inc, San Diego, California, USA
| | - Vahid Zarrabi
- Department of Molecular Pathology, UCLA, Los Angeles, California, USA
| | - Jason Poole
- Research and Development, Biocept Inc, San Diego, California, USA
| | - Veena Singh
- Clinical Laboratory, Biocept Inc, San Diego, California, USA
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15
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Dufraing K, Keppens C, Tack V, Siebers AG, Kafatos G, Dube S, Demonty G, Lowe K, Kroeze LI, Ligtenberg M, Normanno N, Tembuyser L, Sara VB, van Krieken JH, C Dequeker EM. Evolution of RAS testing over time: factors influencing mutation rates in metastatic colorectal cancer patients. COLORECTAL CANCER 2020. [DOI: 10.2217/crc-2019-0013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Aim: Correct identification of RAS gene variants is key for targeted treatment decisions in patients with metastatic colorectal cancer. Published RAS mutation rates differ and could be influenced by several factors including testing methods. This study aimed to describe the performance of laboratories to correctly identify RAS variants over time and to understand how RAS testing has evolved in Europe. Materials & methods: Misclassification and test failure rates were calculated and related to the used test methodology for 239 unique laboratories participating in external quality assessment for metastatic colorectal cancer between 2013 and 2018. In addition, 33 laboratories completed a survey aiming to obtain more details on their routine testing strategies, number of samples analyzed and RAS mutation rates between 2013 and 2017. Results: The mutation status was correctly analyzed in 96.1% (N = 5471) RAS and BRAF tests. A total of 4.6% (N = 2860) RAS tests included false-negative results. In 1.6% (N = 5562) RAS and BRAF tests, an analysis failure occurred. Misclassifications and technical failures both decreased between 2013 and 2018. The number of next-generation sequencing users increased from 6.9% (N = 130) in 2013 to 44.6% (N = 112) in 2018. Over time, more codons were included in the methodologies, yet 23.2% (N = 112) did not offer full RAS testing (exon 2, 3, 4) in 2018. Based on the survey the overall RAS mutation rate was estimated as 45.2% (N = 27,325). Conclusion: This is the largest observational study reporting RAS mutation rates to-date. There was no trend of RAS mutation rates over time despite having a clear shift to more sensitive tests and increased quality of testing.
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Affiliation(s)
- Kelly Dufraing
- Biomedical Quality Assurance Research Unit, Department of Public Health & Primary Care, University of Leuven, Leuven, Belgium
| | - Cleo Keppens
- Biomedical Quality Assurance Research Unit, Department of Public Health & Primary Care, University of Leuven, Leuven, Belgium
| | - Véronique Tack
- Biomedical Quality Assurance Research Unit, Department of Public Health & Primary Care, University of Leuven, Leuven, Belgium
| | - Albert Gerrit Siebers
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | | | | | | | - Leonie Ilse Kroeze
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marjolijn Ligtenberg
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nicola Normanno
- Cell Biology & Biotherapy Unit, Istituto Nazionale Tumori – Fondazione Pascale, Naples, Italy
| | - Lien Tembuyser
- Biomedical Quality Assurance Research Unit, Department of Public Health & Primary Care, University of Leuven, Leuven, Belgium
| | - Vander Borght Sara
- Pathologische Ontleedkunde, Department of Pathology, University Hospitals Leuven, Belgium
| | | | - Elisabeth Marie C Dequeker
- Biomedical Quality Assurance Research Unit, Department of Public Health & Primary Care, University of Leuven, Leuven, Belgium
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16
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Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges. Cancers (Basel) 2020; 12:cancers12020319. [PMID: 32019056 PMCID: PMC7072488 DOI: 10.3390/cancers12020319] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations in RAS, along with the mismatch repair gene deficiency, are currently routinely tested in clinics. Such biomarkers provide information for patient risk stratification and for the choice of the best treatment options. Nevertheless, reliable and powerful prognostic markers that can identify “high-risk” CRC patients, who might benefit from adjuvant chemotherapy, in early stages, are currently missing. To bridge this gap, genomic information has increasingly gained interest as a potential method for determining the risk of recurrence. However, due to several limitations of gene-based signatures, these have not yet been clinically implemented. In this review, we describe the different molecular markers in clinical use for CRC, highlight new markers that might become indispensable over the next years, discuss recently developed gene expression-based tests and highlight the challenges in biomarker research.
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17
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Doxorubicin conjugated AuNP/biopolymer composites facilitate cell cycle regulation and exhibit superior tumor suppression potential in KRAS mutant colorectal cancer. J Biotechnol 2019; 306:149-158. [DOI: 10.1016/j.jbiotec.2019.09.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/04/2019] [Accepted: 09/27/2019] [Indexed: 02/07/2023]
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18
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de la Fouchardière C, Cohen R, Malka D, Guimbaud R, Bourien H, Lièvre A, Cacheux W, Artru P, François E, Gilabert M, Samalin-Scalzi E, Zaanan A, Hautefeuille V, Rousseau B, Senellart H, Coriat R, Flippot R, Desseigne F, Lardy-Cleaud A, Tougeron D. Characteristics of BRAFV600E Mutant, Deficient Mismatch Repair/Proficient Mismatch Repair, Metastatic Colorectal Cancer: A Multicenter Series of 287 Patients. Oncologist 2019; 24:e1331-e1340. [PMID: 31152084 PMCID: PMC6975964 DOI: 10.1634/theoncologist.2018-0914] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 04/05/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND BRAFV600E mutations occurring in about 10% of metastatic colorectal cancers (mCRCs) are usually associated with a poor outcome. However, their prognostic factors are unknown. MATERIALS AND METHODS We built a multicenter clinico-biological database gathering data from patients with BRAFV600E -mutant mCRC treated in one of the 16 French centers from 2006 to 2017. The primary endpoint was to identify prognostic factors using a Cox model. RESULTS We included 287 patients (median age, 67 years [28-95]; female, 57%). Their median overall survival was 20.8 months (95% confidence interval [CI], 17.97-27.04), and median progression-free survival in the first-line setting was 4.34 months (95% CI, 3.81-5.03). Chemotherapy regimen and biological agents (antiangiogenic or anti-epidermal growth factor receptor) were not associated with overall and progression-free survival. Stage IV disease (synchronous metastases) and absence of curative-intent surgery were statistically associated with poor overall survival. Among the 194 patients with mismatch repair (MMR) status available, overall survival was significantly longer in patients with deficient MMR tumors compared with those with proficient MMR tumors (adjusted hazard ratio = 0.56; p = .009). CONCLUSION Despite that BRAFV600E -mutant mCRCs are associated with poor overall and progression-free-survival, patients with deficient MMR tumors and/or resectable disease experienced a longer survival. These results highlight the importance of MMR testing and resectability discussion in patients with BRAFV600E mCRC in day-to-day practice. IMPLICATIONS FOR PRACTICE Mismatch repair (MMR) testing and resectability discussion in patients with BRAFV600E metastatic colorectal cancer (mCRC) should be performed in day-to-day practice to steer treatment decision making in patients with BRAFV600E -mutant mCRC.
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Affiliation(s)
| | - Romain Cohen
- Medical Oncology Department, AP-HP, Saint-Antoine Hospital, Sorbonne University, Paris, France
| | - David Malka
- Gastrointestinal Oncology Unit, Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - Rosine Guimbaud
- Department of Medical Oncology, University Hospital Toulouse, Paul Sabatier University, Toulouse, France
| | - Héloïse Bourien
- Department of Medical Oncology, Eugène Marquis Cancer Institute, Rennes, France
| | - Astrid Lièvre
- Gastroenterology Department, Rennes University Hospital, Rennes 1 University, Rennes, France
| | - Wulfran Cacheux
- Medical Oncology Department, Institut Curie, René Huguenin Hospital, Saint-Cloud, France
| | - Pascal Artru
- Gastrointestinal Oncology, Jean-Mermoz Hospital, Lyon, France
| | - Eric François
- Gastroenterology Department, Antoine Lacassagne Cancer Centre, Nice, France
| | - Marine Gilabert
- Medical Oncology Department, Paoli-Calmettes Institute, Aix-Marseille University, Marseille, France
| | | | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Sorbonne Paris Cité, INSERM UMR-S1147, Paris, France
| | | | - Benoit Rousseau
- Department of Oncology, Henri Mondor Hospital, AP-HP, Créteil, France
| | | | - Romain Coriat
- Gastrointestinal Oncology Unit, CHU Cochin-Port-Royal, Paris, France
| | - Ronan Flippot
- Gastrointestinal Oncology Unit, Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - Françoise Desseigne
- Medical Oncology Department, Centre Leon Berard, Lyon I University, Lyon, France
| | - Audrey Lardy-Cleaud
- Clinical Research and Innovation Department, Leon Berard Cancer Centre, Lyon, France
| | - David Tougeron
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France
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19
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Vacante M, Borzì AM, Basile F, Biondi A. Biomarkers in colorectal cancer: Current clinical utility and future perspectives. World J Clin Cases 2018; 6:869-881. [PMID: 30568941 PMCID: PMC6288499 DOI: 10.12998/wjcc.v6.i15.869] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/30/2018] [Accepted: 11/07/2018] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer death worldwide. CRC has poor prognosis and there is a crucial need for new diagnostic and prognostic biomarkers to avoid CRC-related deaths. CRC can be considered a sporadic disease in most cases (75%-80%), but it has been suggested that crosstalk between gene mutations (i.e., mutations of BRAF, KRAS, and p53 as well as microsatellite instability) and epigenetic alterations (i.e., DNA methylation of CpG island promoter regions) could play a pivotal role in cancer development. A number of studies have focused on molecular testing to guide targeted and conventional treatments for patients with CRC, sometimes with contrasting results. Some of the most useful innovations in the management of CRC include the possibility to detect the absence of KRAS, BRAF, NRAS and PIK3CA gene mutations with the subsequent choice to administer targeted adjuvant therapy with anti-epidermal growth factor receptor antibodies. Moreover, CRC patients can benefit from tests for microsatellite instability and for the detection of loss of heterozygosity of chromosome 18q that can be helpful in guiding therapeutic decisions as regards the administration of 5-FU. The aim of this review was to summarize the most recent evidence on the possible use of genetic or epigenetic biomarkers for diagnosis, prognosis and response to therapy in CRC patients.
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Affiliation(s)
- Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Maria Borzì
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Francesco Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Biondi
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
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20
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Safyan RA, Neugut AI. Anti-EGFR Therapy in Small Bowel Adenocarcinoma. Oncologist 2018; 23:275-276. [PMID: 29438094 PMCID: PMC5905695 DOI: 10.1634/theoncologist.2017-0688] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 01/03/2018] [Indexed: 12/19/2022] Open
Abstract
Small bowel adenocarcinoma is a rare disease occurring 50–100‐fold less often than colorectal cancer. This commentary describes similarities and differences between the two diseases and related results of recent clinical trials.
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Affiliation(s)
- Rachael A Safyan
- Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, New York, USA
| | - Alfred I Neugut
- Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, New York, USA
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21
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Survey of KRAS, BRAF and PIK3CA mutational status in 209 consecutive Italian colorectal cancer patients. Int J Biol Markers 2018; 27:e366-74. [DOI: 10.5301/jbm.2012.9765] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2012] [Indexed: 12/17/2022]
Abstract
Molecular testing for KRAS and BRAF mutations in tumor tissue is a fundamental tool to identify patients with metastatic colorectal cancer (CRC) who are eligible for anti-EGFR monoclonal antibody therapy. We here report a molecular analysis by high-resolution melting analysis and direct sequencing of KRAS, BRAF and PIK3CA hot spot mutations in 209 Italian CRC patients. One hundred and ten patients (51%) were identified who were potentially nonresponders to anti-EGFR therapy: 90/209 patients (43%) harboring KRAS mutations, 13/117 (11.1%) with the V600E BRAF mutation, and 7/209 (3.3%) with mutations in PIK3CA exon 20. The prevalence of BRAF and PIK3CA mutations was significantly higher in patients older than 65 years (p=0.014 and p=0.018), while patients with triple-negative tumors were significantly younger than mutation carriers (p=0.000011). Patients with gene mutations also showed a trend towards preferential tumor location in the colon (p=0.026). Moreover, although involving a relatively small number of samples, we report the presence of a discordant mutational profile between primary tumors and secondary lesions (3/9 patients), suggesting that it is worthwhile to test other available tissues in order to better define the efficacy of targeted therapy. Further correlations of specific clinical features with tumor mutational profile could be helpful to predict the response of CRC patients to monoclonal antibody therapy.
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22
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Liu Y, Meucci S, Sheng L, Keilholz U. Meta-analysis of the mutational status of circulation tumor cells and paired primary tumor tissues from colorectal cancer patients. Oncotarget 2017; 8:77928-77941. [PMID: 29100436 PMCID: PMC5652825 DOI: 10.18632/oncotarget.18272] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/16/2017] [Indexed: 12/21/2022] Open
Abstract
As predictive markers for anti-EGFR therapy, KRAS and BRAF mutations are routinely detected in primary and metastatic colorectal cancer (CRC) cells, but seldom in circulating tumor cells (CTCs). Detecting mutations in CTCs could help explain mutational differences between tumor cells at local sites and distant metastases, thereby improving treatment outcomes. Here, we conducted a systematic review and meta-analysis to compare KRAS and BRAF mutations in paired CTCs and primary tumors from CRC patients, to detect any possible discordance. A total of 244 CRC patients from nine studies were included. Our subgroup meta-analysis demonstrated that the total odds ratio for mutations in CTCs was only 55% of that in primary tumors in the stage IV subgroup. We also found low heterogeneity among studies and differences in mutations between CTCs and primary tumors in the stage IV subgroup (I2 = 0%, P = 0.01). We observed a higher frequency of KRAS mutations in CTCs than in primary tumors at early stages (I + II), a similar frequency in stage III, and a lower frequency in stage IV. There were also differences among the Epcam-targeted CTC enrichment, PCR-based mutation profiling, and ≥ 3 CTCs enriched (I2 = 0%, P = 0.03) subgroups. These finding indicate mutational discordance between CTCs and primary CRCs, particularly in the stage IV and KRAS subgroups. We suggest large-sample studies stratified by clinical stage and KRAS subtype are urgently warranted to accurately evaluate mutational variations in CTCs compared to primary and metastatic CRC cells.
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Affiliation(s)
- Yong Liu
- Surgical Department of Colorectal Cancer, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China.,Charité Comprehensive Cancer Center, Labor AG Keilholz, Berlin, Germany
| | - Stefano Meucci
- Charité Comprehensive Cancer Center, Labor AG Keilholz, Berlin, Germany
| | - Liming Sheng
- Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China
| | - Ulrich Keilholz
- Charité Comprehensive Cancer Center, Labor AG Keilholz, Berlin, Germany
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23
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Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Bryan Rumble R, Temple-Smolkin R, B Ventura C, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2017; 141:625-657. [PMID: 28165284 DOI: 10.5858/arpa.2016-0554-cp] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES - To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. METHODS - The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. RESULTS - Twenty-one guideline statements were established. CONCLUSIONS - Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.
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Affiliation(s)
- Antonia R Sepulveda
- From the 1 Department of Pathology and Cell Biology, Columbia University, New York, NY
| | | | - Carmen J Allegra
- 5 Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
| | - Wayne Grody
- 6 Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, UCLA Medical Center, Los Angeles, CA
| | | | - William K Funkhouser
- 8 Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
| | | | - Christopher Lieu
- 9 Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
| | | | - Bruce D Minsky
- 4 Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
| | | | - Daniel J Sargent
- 12 Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - Joseph Willis
- 14 Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Jennifer Clark
- 15 ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
| | - Carol Colasacco
- 16 Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - R Bryan Rumble
- 17 American Society of Clinical Oncology, Alexandria, VA
| | | | - Christina B Ventura
- 16 Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - Jan A Nowak
- From the 1 Department of Pathology and Cell Biology, Columbia University, New York, NY
- 2 Department of Pathology
- 3 Department of Gastrointestinal (GI) Medical Oncology
- 4 Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
- 5 Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
- 6 Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, UCLA Medical Center, Los Angeles, CA
- 7 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha
- 8 Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
- 9 Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
- 10 Department of Medical Genetics, Mayo Clinic, Scottsdale, AZ
- 11 Castle Biosciences, Friendswood, TX
- 12 Department of Health Sciences Research, Mayo Clinic, Rochester, MN
- 13 Biocept, San Diego, CA
- 14 Department of Pathology, Case Western Reserve University, Cleveland, OH
- 15 ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
- 16 Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
- 17 American Society of Clinical Oncology, Alexandria, VA
- 18 Association for Molecular Pathology, Bethesda, MD
- 19 Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY
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Prawira A, Pugh T, Stockley T, Siu L. Data resources for the identification and interpretation of actionable mutations by clinicians. Ann Oncol 2017; 28:946-957. [DOI: 10.1093/annonc/mdx023] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Rumble RB, Temple-Smolkin R, Ventura CB, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer. Am J Clin Pathol 2017; 147:221-260. [PMID: 28165529 PMCID: PMC7263311 DOI: 10.1093/ajcp/aqw209] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Results: Twenty-one guideline statements were established. Conclusions: Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.
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Affiliation(s)
- Antonia R. Sepulveda
- From theDepartment of Pathology and Cell Biology, Columbia University, New York, NY; Departments of
| | | | - Carmen J. Allegra
- Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
| | - Wayne Grody
- Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics UCLA Medical Center, Los Angeles, CA
| | | | - William K. Funkhouser
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
| | | | - Christopher Lieu
- Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
| | | | - Bruce D. Minsky
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
| | | | | | | | - Joseph Willis
- Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Jennifer Clark
- ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
| | - Carol Colasacco
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | | | | | - Christina B. Ventura
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - Jan A. Nowak
- Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY
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Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Rumble RB, Temple-Smolkin R, Ventura CB, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn 2017; 19:187-225. [PMID: 28185757 PMCID: PMC5971222 DOI: 10.1016/j.jmoldx.2016.11.001] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 11/07/2016] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. METHODS The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. RESULTS Twenty-one guideline statements were established. CONCLUSIONS Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented. Key Words: Molecular diagnostics; Gastrointestinal; Histology; Genetics; Oncology.
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Affiliation(s)
- Antonia R Sepulveda
- Department of Pathology and Cell Biology, Columbia University, New York, NY.
| | - Stanley R Hamilton
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - Carmen J Allegra
- Division of Hematology and Oncology, University of Florida Medical Center, Gainesville
| | - Wayne Grody
- Departments of Pathology and Laboratory Medicine, Pediatrics, and Human Genetics, UCLA Medical Center, Los Angeles, CA
| | | | - William K Funkhouser
- Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill
| | - Scott E Kopetz
- Department of Gastrointestinal (GI) Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
| | - Christopher Lieu
- Division of Medical Oncology, University of Colorado Denver School of Medicine, Denver
| | | | - Bruce D Minsky
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston
| | | | - Daniel J Sargent
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | | | - Joseph Willis
- Department of Pathology, Case Western Reserve University, Cleveland, OH
| | - Jennifer Clark
- ASCP Institute for Science, Technology, and Policy, American Society for Clinical Pathology, Washington, DC
| | - Carol Colasacco
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | | | | | - Christina B Ventura
- Laboratory and Pathology Quality Center, College of American Pathologists, Northfield, IL
| | - Jan A Nowak
- Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY
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Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, Kopetz SE, Lieu C, Lindor NM, Minsky BD, Monzon FA, Sargent DJ, Singh VM, Willis J, Clark J, Colasacco C, Rumble RB, Temple-Smolkin R, Ventura CB, Nowak JA. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35:1453-1486. [PMID: 28165299 DOI: 10.1200/jco.2016.71.9807] [Citation(s) in RCA: 229] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Purpose Molecular testing of colorectal cancers (CRCs) to improve patient care and outcomes of targeted and conventional therapies has been the center of many recent studies, including clinical trials. Evidence-based recommendations for the molecular testing of CRC tissues to guide epidermal growth factor receptor (EGFR) -targeted therapies and conventional chemotherapy regimens are warranted in clinical practice. The purpose of this guideline is to develop evidence-based recommendations to help establish standard molecular biomarker testing for CRC through a systematic review of the literature. Methods The American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for patients with CRC. A comprehensive literature search that included over 4,000 articles was conducted to gather data to inform this guideline. Results Twenty-one guideline statements (eight recommendations, 10 expert consensus opinions and three no recommendations) were established. Recommendations Evidence supports mutational testing for genes in the EGFR signaling pathway, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize molecular testing for predictive and prognostic molecular biomarkers involve selection of assays, type of specimens to be tested, timing of ordering of tests and turnaround time for testing results. Additional information is available at: www.asco.org/CRC-markers-guideline and www.asco.org/guidelineswiki.
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Affiliation(s)
- Antonia R Sepulveda
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Stanley R Hamilton
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Carmen J Allegra
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Wayne Grody
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Allison M Cushman-Vokoun
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - William K Funkhouser
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Scott E Kopetz
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Christopher Lieu
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Noralane M Lindor
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Bruce D Minsky
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Federico A Monzon
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Daniel J Sargent
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Veena M Singh
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Joseph Willis
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Jennifer Clark
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Carol Colasacco
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - R Bryan Rumble
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Robyn Temple-Smolkin
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Christina B Ventura
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
| | - Jan A Nowak
- Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY
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28
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Papadopoulou E, Metaxa-Mariatou V, Tsaousis G, Tsoulos N, Tsirigoti A, Efstathiadou C, Apessos A, Agiannitopoulos K, Pepe G, Bourkoula E, Nasioulas G. Molecular predictive markers in tumors of the gastrointestinal tract. World J Gastrointest Oncol 2016; 8:772-785. [PMID: 27895815 PMCID: PMC5108979 DOI: 10.4251/wjgo.v8.i11.772] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 07/11/2016] [Accepted: 08/31/2016] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal malignancies are among the leading causes of cancer-related deaths worldwide. Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppressor genes or activation of oncogenes. Advances in Molecular Biology techniques have allowed for more accurate analysis of tumors’ genetic profiling using new breakthrough technologies such as next generation sequencing (NGS), leading to the development of targeted therapeutical approaches based upon biomarker-selection. During the last 10 years tremendous advances in the development of targeted therapies for patients with advanced cancer have been made, thus various targeted agents, associated with predictive biomarkers, have been developed or are in development for the treatment of patients with gastrointestinal cancer patients. This review summarizes the advances in the field of molecular biomarkers in tumors of the gastrointestinal tract, with focus on the available NGS platforms that enable comprehensive tumor molecular profile analysis.
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Llovet P, Sastre J, Ortega JS, Bando I, Ferrer M, García-Alfonso P, Donnay O, Carrato A, Jiménez A, Aranda E, León A, Grávalos C, Cámara JC, Feliú J, Sanchíz B, Caldés T, Díaz-Rubio E. Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy. Mol Diagn Ther 2016; 19:397-408. [PMID: 26341080 DOI: 10.1007/s40291-015-0165-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Mutational analysis of RAS is required for anti-epidermal growth factor receptor (EGFR) treatment for patients with metastatic colorectal cancer (mCRC). However, most patients with KRAS wild-type tumors still do not respond. Other molecules downstream of the EGFR may also play a role in resistance to EGFR therapies. OBJECTIVE Our objective was to investigate the clinical importance of biomarkers in relation to response, progression-free survival, and overall survival in patients with mCRC receiving first-line treatment with anti-EGFR therapy plus chemotherapy. METHODS We studied the EGFR pathway [EGFR, NRAS, BRAF, PIK3CA, phosphatase and tensin homolog (PTEN), amphiregulin (AREG), and epiregulin (EREG)] in 105 patients with mCRC KRAS codon 12 wild type. We analysed objective response, progression-free survival, and overall survival in molecularly defined subgroups of the patients receiving anti-EGFR therapy plus chemotherapy as first-line treatment. RESULTS We found a significant association between RAS wild-type, BRAF wild-type, EREG, and AREG overexpression and response to anti-EGFR therapy (p = 0.003, p = 0.015, p = 0.05, and p = 0.009, respectively). Progression-free survival and overall survival were lower in patients with RAS (p = 0.36 and p ≤ 0.001, respectively) or BRAF (p = 0.003 and p = 0.002, respectively) mutant tumors. Patients with EREG and AREG messenger RNA (mRNA) expression had longer survival than those with low-expression tumors; progression-free survival and overall survival were significant for AREG (p = 0.001 and p = 0.05, respectively). Patients with EGFR amplification tumors responded better to treatment and had better survival rates, although this was not significant. PIK3CA and PTEN were not associated with either response or survival. The multivariate logistic regression model for response showed only BRAF as a significant predictor after adjustment for the other covariates (p = 0.04, odds ratio 8.3, 95 % confidence interval 0.81-86.0). CONCLUSIONS RAS, BRAF, AREG, and EREG predict for efficacy of first-line anti-EGFR therapy in patients with mCRC.
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Affiliation(s)
- Patricia Llovet
- Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
| | - Javier Sastre
- Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain.,Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | | | - Inmaculada Bando
- Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
| | - Milagros Ferrer
- Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain
| | | | - Olga Donnay
- Department of Medical Oncology, Hospital La Princesa, La Paz, Madrid, Spain
| | - Alfredo Carrato
- Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain
| | - Ana Jiménez
- Department of Medical Oncology, Hospital Getafe, Madrid, Spain
| | - Enrique Aranda
- Department of Medical Oncology, Hospital Reina Sofía, Córdoba, Spain
| | - Ana León
- Department of Medical Oncology, Fundación Jiménez Díaz, Madrid, Spain
| | - Cristina Grávalos
- Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain
| | | | - Jaime Feliú
- Department of Medical Oncology, Hospital La Paz, Madrid, Spain
| | - Bárbara Sanchíz
- Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain.,Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Trinidad Caldés
- Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
| | - Eduardo Díaz-Rubio
- Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain. .,Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
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30
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Hou J, Zhang Y, Zhu Z. Gene heterogeneity in metastasis of colorectal cancer to the lung. Semin Cell Dev Biol 2016; 64:58-64. [PMID: 27590223 DOI: 10.1016/j.semcdb.2016.08.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Accepted: 08/30/2016] [Indexed: 12/21/2022]
Abstract
Colorectal cancer (CRC) as a heterogeneous disease, is one of the most common and serious cancers with high metastases and mortality. Lung is one of the most common sites of CRC metastases with high heterogeneity between cells, pathways, or molecules. The present review will focus on potential roles of gene heterogeneity in KRAS pathway in the development of CRC metastasis to lung and clinical therapies, which would lead to better understanding of the metastatic control and benefit to the treatment of metastases. KRAS is the central relay for pathways originating at the epidermal growth factor receptor (EGFR) family. KRAS mutation exists in about 40% CRC, associated with higher cumulative incidence of CRC lung metastasis, and acts as an independent predictor of metastasis to lung. Mutations in KRAS can lead to poor response of patients to panitumumab, and inferior progression-free survival. However, most patients with KRAS wild-type tumors still do not respond, which indicates other mutations. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation was associated with lung metastases in metastatic colorectal cancer. PIK3CA mutation in exon 20 was found to be correlated with patient survival in the metastatic setting after the treatment with cetuximab and chemotherapy. The heterogeneity of KRAS pathway was found in the phosphatase and tensin homologue deleted on chromosome ten loss, disheveled binding antagonist of beta catenin 2 overexpression and increased dual-specificity protein phosphatase 4 expression of CRC lung metastasis.
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Affiliation(s)
- Jiayun Hou
- Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Biomedical Research Center, Shanghai, China
| | - Yong Zhang
- Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai Institute of Clinical Bioinformatics, Biomedical Research Center, Shanghai, China.
| | - Zhitu Zhu
- Jinzhou Hospital of Jinzhou Medical University, JinZhou, China.
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31
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Alvi MA, McArt DG, Kelly P, Fuchs MA, Alderdice M, McCabe CM, Bingham V, McGready C, Tripathi S, Emmert-Streib F, Loughrey MB, McQuaid S, Maxwell P, Hamilton PW, Turkington R, James JA, Wilson RH, Salto-Tellez M. Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility. Oncotarget 2016; 6:20863-74. [PMID: 26315110 PMCID: PMC4673235 DOI: 10.18632/oncotarget.4576] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 07/20/2015] [Indexed: 01/22/2023] Open
Abstract
Small bowel accounts for only 0.5% of cancer cases in the US but incidence rates have been rising at 2.4% per year over the past decade. One-third of these are adenocarcinomas but little is known about their molecular pathology and no molecular markers are available for clinical use. Using a retrospective 28 patient matched normal-tumor cohort, next-generation sequencing, gene expression arrays and CpG methylation arrays were used for molecular profiling. Next-generation sequencing identified novel mutations in IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p < 0.01). Merging gene expression and DNA methylation data revealed CHN2 as consistently hypermethylated and downregulated in this disease (Spearman −0.71, p < 0.001). Mutations in TP53 which were found in more than half of the cohort (15/28) and Kazald1 hypomethylation were both were indicative of poor survival (p = 0.03, HR = 3.2 and p = 0.01, HR = 4.9 respectively). By integrating high-throughput mutational, gene expression and DNA methylation data, this study reveals for the first time the distinct molecular profile of small bowel adenocarcinoma and highlights potential clinically exploitable markers.
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Affiliation(s)
- Muhammad A Alvi
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Darragh G McArt
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Paul Kelly
- Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Marc-Aurel Fuchs
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Matthew Alderdice
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Clare M McCabe
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Victoria Bingham
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Claire McGready
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Shailesh Tripathi
- Computational Biology and Machine Learning Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Frank Emmert-Streib
- Computational Biology and Machine Learning Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Maurice B Loughrey
- Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Stephen McQuaid
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.,Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Perry Maxwell
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.,Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Peter W Hamilton
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Richard Turkington
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Jacqueline A James
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.,Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
| | - Richard H Wilson
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Manuel Salto-Tellez
- Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.,Tissue Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
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32
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Caiazza F, Elliott L, Fennelly D, Sheahan K, Doherty GA, Ryan EJ. Targeting EGFR in metastatic colorectal cancer beyond the limitations of KRAS status: alternative biomarkers and therapeutic strategies. Biomark Med 2016; 9:363-75. [PMID: 25808440 DOI: 10.2217/bmm.15.5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Patients with metastatic colorectal cancer have a very poor prognosis. Incorporation of targeted molecular therapies, such as the anti-EGFR receptor monoclonal antibodies cetuximab and panitumumab, into treatment regimens has improved outcomes for patients with wild-type RAS tumors. Yet, response rates remain low and overall survival times are short. Increased understanding of oncogenic signaling pathways within the tumor, and how these are regulated by the inflammatory tumor microenvironment, is a priority to facilitate the development of biomarkers to better guide the use of existing therapies and to develop new ones. Here, we review recent preclinical and clinical progress in the development of biomarkers for predicting response to anti-EGFR therapy in metastatic colorectal cancer.
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Affiliation(s)
- Francesco Caiazza
- Centre for Colorectal Disease, St. Vincent's University Hospital, Elm Park, Dublin, Ireland
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33
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Orlandi A, Calegari A, Inno A, Berenato R, Caporale M, Niger M, Bossi I, Di Bartolomeo M, de Braud F, Pietrantonio F. BRAF in metastatic colorectal cancer: the future starts now. Pharmacogenomics 2015; 16:2069-81. [PMID: 26615988 DOI: 10.2217/pgs.15.140] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BRAF mutations are detectable in about 5-15% of metastatic colorectal cancer (mCRC) patients and represent a clear negative prognostic factor. While in BRAF-mutated (BRAFmt) metastatic melanoma TKI target therapies (BRAF and MEK inhibitor), both alone or in combination, have shown significant efficacy, in BRAFmt CRC single-agent BRAF-inhibitors as well as chemotherapy seem to be ineffective. The critical role of EGFR in CRC and its multiple downstreaming pathways seem to be involved in this lack of response. In recent years, preclinical investigations and retrospective studies slowly increased our knowledge on BRAFmt CRC. This review analyses preclinical data and discusses several clinical trials in order to explore new therapeutic strategies targeting BRAFmt mCRC.
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Affiliation(s)
- Armando Orlandi
- Medical Oncology Department, Università Cattolica del Sacro Cuore, Rome, Italy.,Medical Oncology, Sacro Cuore Don Calabria Hospital, Negrar - Verona, Italy.,Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Calegari
- Medical Oncology Department, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandro Inno
- Medical Oncology, Sacro Cuore Don Calabria Hospital, Negrar-Verona Italy
| | - Rosa Berenato
- Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | - Marta Caporale
- Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | - Monica Niger
- Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | - Ilaria Bossi
- Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | - Maria Di Bartolomeo
- Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
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Erstad DJ, Tumusiime G, Cusack JC. Prognostic and Predictive Biomarkers in Colorectal Cancer: Implications for the Clinical Surgeon. Ann Surg Oncol 2015. [DOI: 10.1245/s10434-015-4706-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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35
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Colorectal Cancer Classification and Cell Heterogeneity: A Systems Oncology Approach. Int J Mol Sci 2015; 16:13610-32. [PMID: 26084042 PMCID: PMC4490512 DOI: 10.3390/ijms160613610] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 06/04/2015] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer is a heterogeneous disease that manifests through diverse clinical scenarios. During many years, our knowledge about the variability of colorectal tumors was limited to the histopathological analysis from which generic classifications associated with different clinical expectations are derived. However, currently we are beginning to understand that under the intense pathological and clinical variability of these tumors there underlies strong genetic and biological heterogeneity. Thus, with the increasing available information of inter-tumor and intra-tumor heterogeneity, the classical pathological approach is being displaced in favor of novel molecular classifications. In the present article, we summarize the most relevant proposals of molecular classifications obtained from the analysis of colorectal tumors using powerful high throughput techniques and devices. We also discuss the role that cancer systems biology may play in the integration and interpretation of the high amount of data generated and the challenges to be addressed in the future development of precision oncology. In addition, we review the current state of implementation of these novel tools in the pathological laboratory and in clinical practice.
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36
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Gonzalez RS, Cates JMM, Washington MK, Beauchamp RD, Coffey RJ, Shi C. Adenoma-like adenocarcinoma: a subtype of colorectal carcinoma with good prognosis, deceptive appearance on biopsy and frequent KRAS mutation. Histopathology 2015; 68:183-90. [PMID: 25913616 DOI: 10.1111/his.12725] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 04/22/2015] [Indexed: 12/24/2022]
Abstract
AIMS A subset of colorectal carcinomas (CRCs) architecturally and cytologically resembles adenomatous change, making them difficult to diagnose on biopsy. This subset has not been well characterized to date. METHODS AND RESULTS For 35 carcinomas with adenomatous-like areas (cytological and surface architectural appearance that would be insufficient to warrant a diagnosis of adenocarcinoma if evaluated on biopsy), we recorded staging information, molecular data, clinical outcome, whether precursor adenoma was present and whether previous biopsy had been diagnosed as malignant. Despite advanced T-category in 23 (66%) tumours, only seven (20%) had nodal metastases, and only five patients (15%) developed distant metastases. Fifteen cases (43%) had been diagnosed as adenoma on biopsy. Twenty-one resections (60%) showed no residual associated adenoma, including nine called adenoma on biopsy. Median follow-up was 44 months. Four patients (12%) died of disease; 22 were alive at last follow-up. KRAS mutation was seen in 14 of 24 (58%) and four of 17 (24%) were microsatellite-unstable. Patients had significantly improved survival compared to a cohort of patients with conventional well-differentiated CRC after controlling for age and stage (P = 0.011). CONCLUSIONS Adenoma-like adenocarcinoma is an uncommon variant of CRC with a low rate of metastasis and good prognosis. Biopsy diagnosis of this lesion may be challenging.
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Affiliation(s)
- Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Justin M M Cates
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mary Kay Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Robert Daniel Beauchamp
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Robert J Coffey
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Chanjuan Shi
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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Wang Q, Hu WG, Song QB, Wei J. BRAF V600E mutation as a predictive factor of anti-EGFR monoclonal antibodies therapeutic effects in metastatic colorectal cancer: a meta-analysis. ACTA ACUST UNITED AC 2015; 29:197-203. [PMID: 25429742 DOI: 10.1016/s1001-9294(14)60070-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
OBJECTIVE To investigate the correlation between BRAF V600E mutation and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) therapeutic effects in metastatic colorectal cancer. METHODS Studies were included into meta-analysis to investigate the association between BRAF V600E mutation and clinical outcome in metastatic colorectal cancer patients treated with anti-EGFR MoAbs. RESULTS A total of 7 studies were included in this meta-analysis. The 7 studies included 1352 patients in total, sample sizes ranged from 67 to 493. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were collected from included studies and were used to assess the strength of the relation. In patients with wild-type KRAS, the pooled odds ratio for ORR of mutant BRAF over wild-type BRAF was 0.27 (95% CI=0.10-0.70). BRAF mutation predicted a deterioration in PFS and OS in wild-type KRAS patients treated with anti-EGFR MoAbs (hazard ratio=2.78, 95% CI=1.62-4.76; hazard ratio=2.54, 95% CI=1.93-3.32). CONCLUSION BRAF V600E mutation is related to lack of response and worse survival in wild-type KRAS metastatic colorectal cancer patients treated with anti-EGFR MoAbs.
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Affiliation(s)
- Qi Wang
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Wei-guo Hu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Qi-bin Song
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jia Wei
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China
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BRAFV600E mutation analysis by immunohistochemistry in patients with thoracic metastases from colorectal cancer. Pathology 2015; 46:311-5. [PMID: 24798160 DOI: 10.1097/pat.0000000000000113] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The BRAF(V600E) mutation confers worse prognosis to metastatic colorectal cancer (mCRC) patients. In addition, this mutation has a negative predictive value for response to treatment with monoclonal antibodies against EGFR in patients with KRAS wild-type (wt) mCRC. The utility of immunohistochemistry (IHC) as an alternative approach for detection of BRAF(V600E) in the thoracic metastases of sporadic mCRC patients has not been evaluated until now. The purpose of this study was to compare BRAF(V600E) IHC staining with molecular biology methods and to define the diagnostic value of the VE1 antibody for the detection of BRAF(V600E) in this population. BRAF mutations were analysed by two DNA sequencing methods (pyrosequencing and Sanger sequencing) in a Caucasian population of 310 sporadic mCRC with thoracic metastases patients expressing KRAS wt. Detection of the BRAF(V600E) mutation was performed in the corresponding tumours by IHC using the VE1 antibody and compared to results of the DNA-based assays. Thirty-nine out of 310 (13%) of tumours harboured a BRAF mutation, which corresponded to either a BRAF(V600E) in 34 of 310 (11%) cases or a non-BRAF(V600E) mutation in 5 of 310 (2%) cases. IHC with VE1 was strongly positive in 32 of 34 (88%) BRAF(V600E) mutated tumours and negative in non-BRAF(V600E) mutated tumours. IHC using the VE1 clone is a specific and sensitive method for the detection of BRAF(V600E) and may be either a complementary or an alternative method to molecular testing in mCRC patients.
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Oikonomou E, Koustas E, Goulielmaki M, Pintzas A. BRAF vs RAS oncogenes: are mutations of the same pathway equal? Differential signalling and therapeutic implications. Oncotarget 2014; 5:11752-11777. [PMID: 25361007 PMCID: PMC4322985 DOI: 10.18632/oncotarget.2555] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/30/2014] [Indexed: 02/05/2023] Open
Abstract
As the increased knowledge of tumour heterogeneity and genetic alterations progresses, it exemplifies the need for further personalized medicine in modern cancer management. Here, the similarities but also the differential effects of RAS and BRAF oncogenic signalling are examined and further implications in personalized cancer diagnosis and therapy are discussed. Redundant mechanisms mediated by the two oncogenes as well as differential regulation of signalling pathways and gene expression by RAS as compared to BRAF are addressed. The implications of RAS vs BRAF differential functions, in relevant tumour types including colorectal cancer, melanoma, lung cancer are discussed. Current therapeutic findings and future viewpoints concerning the exploitation of RAS-BRAF-pathway alterations for the development of novel therapeutics and efficient rational combinations, as well as companion tests for relevant markers of response will be evaluated. The concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance posed a major therapy hindrance.
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Affiliation(s)
- Eftychia Oikonomou
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, 11635, Greece
| | - Evangelos Koustas
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, 11635, Greece
| | - Maria Goulielmaki
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, 11635, Greece
| | - Alexander Pintzas
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, 11635, Greece
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Colorectal liver metastases are more often super wild type. Toward treatment based on metastatic site genotyping? Target Oncol 2014; 10:415-21. [PMID: 25420993 DOI: 10.1007/s11523-014-0346-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 11/12/2014] [Indexed: 12/14/2022]
Abstract
Recent data showed that metastatic colorectal (mCRC) tumors exhibiting extended RAS-BRAF mutations were resistant to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, making these drugs suitable for the so-called "super" wild-type (WT) patients only. This study aimed to compare the extended RAS-BRAF mutation frequency and characteristics according to location of tumor sampling. All consecutive mCRC specimens (N = 1659) referred to our institution from January 2008 till June 2014 were included in the analysis. Tumor genotyping (first for KRAS exon 2, then for BRAF exon 15, and later for KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4) was performed with high-resolution melting analysis or allelic discrimination. The factors predicting for the presence of mutation were explored using multivariate binary logistic regression. Overall, the prevalence of KRAS exon 2 was 36.8%, and it was lower in liver metastases (N = 138/490; 28.2%) in comparison with primary tumors (N = 442/1086; 40.7%), lung metastases (16/32; 50%), or other metastatic sites (15/51; 29.4%; P < 0.0001). Similarly, in the 1428 samples analyzed, BRAF mutations were less often found in liver metastases (N = 9/396; 2.3%) as compared to primary tumors (N = 79/959; 8.2%), lung metastases (N = 2/29; 6.9%), or other metastatic locations (N = 2/44; 4.5%; P < 0.0002). Overall occurrence of extended RAS mutation was 51.7%. Of the 503 samples tested, the prevalence of extended RAS-BRAF mutations was twice as low in liver metastases (N = 53/151; 34.2 %) as compared to primary tumors (N = 191/322; 59.3%, P < 0.0001). Univariate analysis identified age ≤65 years, male gender, and liver localization as predictors of super WT status. At multivariate analysis, only liver metastases were retained (RR 2.85 [95% CI 1.91-4.30]). Colorectal liver metastases are twice as likely to exhibit a super WT genotype as compared to other tumor locations independently from other factors. This molecular feature has the potential to influence therapeutic strategy in mCRC patients.
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VE1 immunohistochemistry accurately detects BRAF V600E mutations in colorectal carcinoma and can be utilized in the detection of poorly differentiated colorectal serrated adenocarcinoma. Virchows Arch 2014; 464:637-43. [DOI: 10.1007/s00428-014-1555-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 01/22/2014] [Accepted: 02/09/2014] [Indexed: 12/28/2022]
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Hansen TF, Andersen RF, Pallisgaard N, Spindler KLG, Pløen J, Keldsen N, Lindebjerg J, Sørensen FB, Jakobsen A. A 3-weekly schedule of irinotecan and panitumumab for wild-type KRAS metastatic colorectal cancer. COLORECTAL CANCER 2014. [DOI: 10.2217/crc.13.85] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
SUMMARY Aim: We investigated the combination of irinotecan and panitumumab as a 3-weekly schedule in patients with wild-type KRAS metastatic colorectal cancer, who had progressed after standard chemotherapy. Material & methods: Patients received concomitant irinotecan (350 mg/m2) and panitumumab (9 mg/kg) once every 3 weeks. The primary end point was response rate. Secondary end points included progression-free survival (PFS), overall survival (OS) and translational research. Results: Inclusion was stopped early owing to lack of efficacy (n = 31). The response rate was 16%, median PFS and OS was 2.0 months (95% CI: 1.9–4.0) and 7.8 months (95% CI: 4.6–8.8), respectively. The most commonly encountered adverse event was skin rash (84% any grade). Pretreatment cell-free DNA levels were significantly related to disease control (p = 0.04), PFS (p = 0.04) and OS (p = 0.002), respectively. Conclusion: The present treatment regimen was less effective than expected and is not recommended. The clinical importance of cell-free DNA deserves further research.
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Affiliation(s)
- Torben Frøstrup Hansen
- Department of Oncology, Vejle Hospital part of Lillebaelt Hospital, Vejle, Denmark
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | | | - Niels Pallisgaard
- Department of Biochemistry, Vejle Hospital part of Lillebaelt Hospital, Vejle, Denmark
| | - Karen-Lise Garm Spindler
- Department of Oncology, Vejle Hospital part of Lillebaelt Hospital, Vejle, Denmark
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - John Pløen
- Department of Oncology, Vejle Hospital part of Lillebaelt Hospital, Vejle, Denmark
| | - Nina Keldsen
- Department of Oncology, Herning Hospital, Herning, Denmark
| | - Jan Lindebjerg
- Department of Clinical Pathology, Vejle Hospital part of Lillebaelt Hospital, Vejle, Denmark
| | - Flemming Brandt Sørensen
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Department of Clinical Pathology, Vejle Hospital part of Lillebaelt Hospital, Vejle, Denmark
| | - Anders Jakobsen
- Department of Oncology, Vejle Hospital part of Lillebaelt Hospital, Vejle, Denmark
- Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
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Shen WD, Chen HL, Liu PF. EGFR gene copy number as a predictive biomarker for resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer treatment: a meta-analysis. Chin J Cancer Res 2014; 26:59-71. [PMID: 24653627 DOI: 10.3978/j.issn.1000-9604.2014.01.10] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Accepted: 07/22/2013] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The epidermal growth factor receptor (EGFR) inhibitors monoclonal antibodies (MoAbs) have already shown the therapeutic effectiveness in patients with metastatic colorectal cancer (mCRC). But many patients resist to the treatment. The aim of this meta-analysis was to assess EGFR gene copy number (GCN) as a candidate predictive biomarker for resistance to anti-EGFR MoAbs in mCRC treatment. METHODS Systematic computerized searches of the PubMed, EMBase and Cochrane Library were performed. The primary endpoint was objective response rate (ORR). The second endpoints included progression-free survival (PFS), and overall survival (OS). The pooled odd ratio (OR) and pooled sensitivity, specificity, and summary receiver operator characteristic (SROC) for ORR were estimated. The pooled hazard ratios (HR) for PFS and OS were also calculated. RESULTS Fourteen studies with 1,021 patients were included. Increased EGFR GCN was associated with increased ORR (OR=6.905; 95% CI: 4.489-10.620). It was also found in wild-type KRAS mCRC patients, with the pooled OR of 8.133 (95% CI: 4.316-15.326). GCN has medium value for predicting ORR, with the pooled sensitivity of 0.79 (95% CI: 0.73-0.84), the pooled specificity of 0.59 (95% CI: 0.55-0.62). In wild-type KRAS mCRC patients, the sensitivity and the specificity were 0.80 (95% CI: 0.70-0.87) and 0.60 (95% CI: 0.53-0.66), respectively. Increased EGFR GCN was associated with increased PFS (HR=0.557; 95% CI: 0.382-0.732) and OS (HR=0.579; 95% CI: 0.422-0.737). CONCLUSIONS This meta-analysis suggests that EGFR GCN represents a predictive biomarker for tumor response in mCRC patients treated with MoAbs regardless of KRAS mutation. mCRC patients with increased EGFR GCN are more likely to have a better response, PFS, and OS when treated with cetuximab or panitumumab.
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Affiliation(s)
- Wei-Dong Shen
- 1 Department of Gastroenterology, the Affiliated Jiangyin Hospital of Nantong University, Shoushan Road 163#, Jiangyin 214400, China ; 2 Nantong University, Qixiu Road 19#, Nantong 226019, China
| | - Hong-Lin Chen
- 1 Department of Gastroenterology, the Affiliated Jiangyin Hospital of Nantong University, Shoushan Road 163#, Jiangyin 214400, China ; 2 Nantong University, Qixiu Road 19#, Nantong 226019, China
| | - Peng-Fei Liu
- 1 Department of Gastroenterology, the Affiliated Jiangyin Hospital of Nantong University, Shoushan Road 163#, Jiangyin 214400, China ; 2 Nantong University, Qixiu Road 19#, Nantong 226019, China
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Cui D, Cao D, Yang Y, Qiu M, Huang Y, Yi C. Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: a meta-analysis of randomized studies. Mol Biol Rep 2014; 41:1291-8. [PMID: 24390240 DOI: 10.1007/s11033-013-2974-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 12/24/2013] [Indexed: 02/05/2023]
Abstract
Anti-EGFR monoclonal antibodies (anti-EGFR MoAbs) in metastatic colorectal cancer (mCRC) treatment are still not effective in all patients. This study aimed to evaluate the relationship between BRAF V600E mutation and the tumor response of anti-EGFR MoAbs for first-line treatment in mCRC patients. We searched the MEDLINE and EMBASE databases, using the key words that included colorectal cancer, cetuximab, panitumumab, and BRAF mutation and retrieved 445 articles. Among them four were included in the systematic review. Relative risks (RRs) with 95% confidence intervals (CI) for response rate were calculated. BRAF mutation carriers had worse ORR than non-carriers in mCRC patients with KRAS wild-type in first-line treatment whether adding anti-EGFR MoAb to chemotherapy or not (RR = 0.43, [95% CI 0.16-0.75]; RR = 0.38, [95% CI 0.20-0.73]). But in the unselected patients whose KRAS mutation were unknown, BRAF mutation carriers had similar ORR whether adding cetuximab to chemotherapy or not (RR = 0.45, [95% CI 0.18-1.09]; RR = 0.57, [95% CI 0.15-2.23]). In BRAF mutation carriers adding anti-EGFR MoAb to chemotherapy was similar to chemotherapy alone whether in patients with wild-type KRAS or unselected patients (RR = 1.61, [95% CI 0.57-4.47]; RR = 0.71, [95% CI 0.18-2.77]). But in the BRAF mutation non-carriers, adding anti-EGFR MoAb produced a clear benefit in response rate than chemotherapy alone and this advantage was restricted to KRAS wild-type patients (RR = 1.48, [95% CI 1.28-1.71]). BRAF mutation decreases tumor response in first-line treatment whether cetuximab was given or not in patients with KRAS wild-type, and anti-EGFR MoAb produces a clear benefit in response rate in patients with BRAF and KRAS wild-type.
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Affiliation(s)
- Dandan Cui
- Division of Abdominal Cancer, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan, China
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Yanus GA, Belyaeva AV, Ivantsov AO, Kuligina ES, Suspitsin EN, Mitiushkina NV, Aleksakhina SN, Iyevleva AG, Zaitseva OA, Yatsuk OS, Gorodnova TV, Strelkova TN, Efremova SA, Lepenchuk AY, Ochir-Garyaev AN, Paneyah MB, Matsko DE, Togo AV, Imyanitov EN. Pattern of clinically relevant mutations in consecutive series of Russian colorectal cancer patients. Med Oncol 2013; 30:686. [PMID: 23943423 DOI: 10.1007/s12032-013-0686-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2013] [Accepted: 07/31/2013] [Indexed: 12/18/2022]
Abstract
One hundred and ninety-five consecutive surgically treated Russian colorectal cancer (CRC) patients were retrospectively analyzed for the presence of mutations in KRAS, NRAS, BRAF and PIK3CA genes as well as for the microsatellite instability status. Comparison between high-resolution melting analysis, co-amplification at lower denaturation temperature PCR, DNA sequencing and allele-specific PCR for the detection of KRAS codon 12/13 mutations revealed that none of these methods alone provided satisfactory results in 100 % of the analyzed cases; this experience supports the use of more than one mutation-detecting technique at least in some circumstances. KRAS codon 12/13 substitutions were detected in 70 (35.9 %) CRC cases. Other mutations in the RAS/RAF genes occurred in 22 (11.3 %) cases and included rare KRAS (n = 6), NRAS (n = 8) and BRAF (n = 8) alterations. 5 BRAF mutations affected codon 600, while the remaining 3 potentially functional substitutions were located in the position 594. Twenty-four (12.3 %) CRC cases carried mutations in the PIK3CA, and 18 of these tumors also contained activating alteration in the RAS/RAF genes (p = 0.007). Only 3 (1.5 %) CRC cases showed high-level microsatellite instability (MSI-H) as determined by a panel of mononucleotide markers. Overall, the distribution of potentially predictive mutations in Russian CRC cases is similar to the one observed in other patient series of European descent. Noticeable occurrence of D594G mutation in BRAF oncogene and low frequency of MSI-H may deserve specific attention.
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Affiliation(s)
- Grigoriy A Yanus
- Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
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Xu Q, Xu AT, Zhu MM, Tong JL, Xu XT, Ran ZH. Predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor monoclonal antibodies: a meta-analysis. J Dig Dis 2013; 14:409-16. [PMID: 23615046 DOI: 10.1111/1751-2980.12063] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This study aimed to evaluate the predictive and prognostic roles of BRAF mutation in patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs). METHODS Computer searches of the literature on BRAF mutation in mCRC patients were performed. Studies with objective response rate (ORR) to anti-EGFR MoAbs and/or overall survival (OS) and progression-free survival (PFS) with different BRAF gene expression in mCRC patients were eligible. RESULTS A total of 19 studies including 2875 patients was enrolled in the meta-analysis. BRAF mutation was detected in 246 patients. The ORR was 18.4% (40/217) in mutant BRAF group and 41.7% (831/1993) in the wild-type BRAF group. The overall risk ratio (RR) for the ORR of BRAF mutation patients compared with wild-type BRAF patients was 0.58 (95% confidence intervals [CI] 0.35-0.94, P = 0.027). The median PFS of patients with BRAF mutation was significantly shorter than that of patients with wild-type BRAF (hazard ratio [HR] 2.98, 95% CI 2.07-4.27, P < 0.001) and the median OS of patients with BRAF mutation was also significantly shorter than that of those with wild-type BRAF (HR 2.85, 95% CI 2.31-3.52, P < 0.001). CONCLUSION BRAF mutation is associated with poor response to anti-EGFR MoAbs and it is an adverse prognostic biomarker of the survival of patients with mCRC.
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Affiliation(s)
- Qi Xu
- Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Institute of Digestive Disease, Shanghai, China
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Yuan ZX, Wang XY, Qin QY, Chen DF, Zhong QH, Wang L, Wang JP. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis. PLoS One 2013; 8:e65995. [PMID: 23776587 PMCID: PMC3679027 DOI: 10.1371/journal.pone.0065995] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Accepted: 04/29/2013] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND BRAF mutation has been investigated as a prognostic factor in metastatic colorectal cancer (mCRC) undergoing anti-EGFR monoclonal antibodies (moAbs), but current results are still inconclusive. The aim of this meta-analysis was to evaluate the relationship between BRAF mutation status and the prognosis of mCRC patients treated with moAbs. METHODS Eligible studies were identified by systematically searching Pubmed, the Cochrane Library, Web of Knowledge, and OVID. Risk ratio (RR) for overall response rate (ORR), Hazard ratios (HRs) for Progression free survival (PFS) and Overall survival (OS) were extracted or calculated. Prespecified subgroup analyses were conducted in KRAS wild-type and in different study types. The source of between-trial variation was explored by sensitivity analyses. Quality assessment was conducted by the Hayden's criteria. RESULTS A total of twenty one trials including 5229 patients were identified for the meta-analysis. 343 patients displayed BRAF mutations of 4616 (7.4%) patients with known BRAF status. Patients with BRAF wild-type (WT) showed decreased risks of progression and death with an improved PFS(HR 0.38, 95% confidence intervals 0.29-0.51) and an improved OS (HR 0.35 [0.29-0.42]), compared to BRAF mutant. In KRAS WT population, there were even larger PFS benefit (HR 0.29[0.19,0.43]) and larger OS benefit (HR 0.26 [0.20,0.35]) in BRAF WT. A response benefit for BRAF WT was observed (RR 0.31[0.18,0.53]) in KRAS WT patients, but not observed in unselected patients (RR 0.76 [0.43-1.33]). The results were consistent in the subgroup analysis of different study types. Heterogeneity between trials decreased in the subgroup and explained by sensitivity analysis. No publication bias of ORR, PFS and OS were detected. CONCLUSIONS The results indicate that BRAF mutant is a predictive biomarker for poor prognosis in mCRC patients undergoing anti-EGFR MoAbs therapy, especially in KRAS WT patients. Additional large prospective trials are required to confirm the predictive role of BRAF status.
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Affiliation(s)
- Zi-Xu Yuan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Xiao-Yan Wang
- Gastrointestinal Disease Institute of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Qi-Yuan Qin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - De-Feng Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Qing-Hua Zhong
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Lei Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Gastrointestinal Disease Institute of Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Jian-Ping Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Gastrointestinal Disease Institute of Sun Yat-sen University, Guangzhou, People’s Republic of China
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Clancy C, Burke JP, Coffey JC. KRAS mutation does not predict the efficacy of neo-adjuvant chemoradiotherapy in rectal cancer: a systematic review and meta-analysis. Surg Oncol 2013; 22:105-11. [PMID: 23473635 DOI: 10.1016/j.suronc.2013.02.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 01/30/2013] [Accepted: 02/03/2013] [Indexed: 01/12/2023]
Abstract
INTRODUCTION The current management of locally advanced rectal cancer involves total mesorectal excision, which may be preceded by neo-adjuvant chemoradiotherapy (CRT). Individual patient response to CRT is variable and reproducible biomarkers of response are needed. The role of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) in rectal cancer remains equivocal. The aim of the current study was to systematically appraise the effect of KRAS mutation on outcomes following CRT for rectal cancer. METHODS A comprehensive search for published studies examining the effect of KRAS mutation on outcome after neo-adjuvant CRT in rectal cancer was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data. RESULTS Data was retrieved from 8 series describing 696 patients. Neo-adjuvant treatment regimens varied in usage of chemotherapeutic agents and interval to surgery. KRAS mutation was present in an average of 33.2 ± 11.8% of patients with rectal cancer. KRAS mutation was not associated with decreased rates of pathological complete response (odds ratio (OR): 0.778, 95% confidence interval (CI): 0.424-1.428, P = 0.418), tumor down-staging (OR: 0.846, 95% CI: 0.331-2.162, P = 0.728) or an increase in cancer related mortality (OR: 1.239, 95% CI: 0.607-2.531, P = 0.555). CONCLUSIONS Based on these data, the presence of KRAS mutation does not affect tumor down-staging or cancer specific survival following neo-adjuvant CRT and surgery for rectal cancer.
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Affiliation(s)
- Cillian Clancy
- Department of Colorectal Surgery, University Hospital Limerick, Graduate Entry Medical School, University of Limerick, Ireland
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Guedes JG, Veiga I, Rocha P, Pinto P, Pinto C, Pinheiro M, Peixoto A, Fragoso M, Raimundo A, Ferreira P, Machado M, Sousa N, Lopes P, Araújo A, Macedo J, Alves F, Coutinho C, Henrique R, Santos LL, Teixeira MR. High resolution melting analysis of KRAS, BRAF and PIK3CA in KRAS exon 2 wild-type metastatic colorectal cancer. BMC Cancer 2013; 13:169. [PMID: 23548132 PMCID: PMC3623853 DOI: 10.1186/1471-2407-13-169] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2012] [Accepted: 03/19/2013] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND KRAS is an EGFR effector in the RAS/RAF/ERK cascade that is mutated in about 40% of metastatic colorectal cancer (mCRC). Activating mutations in codons 12 and 13 of the KRAS gene are the only established negative predictors of response to anti-EGFR therapy and patients whose tumors harbor such mutations are not candidates for therapy. However, 40 to 60% of wild-type cases do not respond to anti-EGFR therapy, suggesting the involvement of other genes that act downstream of EGFR in the RAS-RAF-MAPK and PI3K-AKT pathways or activating KRAS mutations at other locations of the gene. METHODS DNA was obtained from a consecutive series of 201 mCRC cases (FFPE tissue), wild-type for KRAS exon 2 (codons 12 and 13). Mutational analysis of KRAS (exons 3 and 4), BRAF (exons 11 and 15), and PIK3CA (exons 9 and 20) was performed by high resolution melting (HRM) and positive cases were then sequenced. RESULTS One mutation was present in 23.4% (47/201) of the cases and 3.0% additional cases (6/201) had two concomitant mutations. A total of 53 cases showed 59 mutations, with the following distribution: 44.1% (26/59) in KRAS (13 in exon 3 and 13 in exon 4), 18.6% (11/59) in BRAF (two in exon 11 and nine in exon 15) and 37.3% (22/59) in PIK3CA (16 in exon 9 and six in exon 20). In total, 26.4% (53/201) of the cases had at least one mutation and the remaining 73.6% (148/201) were wild-type for all regions studied. Five of the mutations we report, four in KRAS and one in BRAF, have not previously been described in CRC. BRAF and PIK3CA mutations were more frequent in the colon than in the sigmoid or rectum: 20.8% vs. 1.6% vs. 0.0% (P=0.000) for BRAF and 23.4% vs. 12.1% vs. 5.4% (P=0.011) for PIK3CA mutations. CONCLUSIONS About one fourth of mCRC cases wild-type for KRAS codons 12 and 13 present other mutations either in KRAS, BRAF, or PIK3CA, many of which may explain the lack of response to anti-EGFR therapy observed in a significant proportion of these patients.
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Affiliation(s)
- Joana G Guedes
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Isabel Veiga
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Patrícia Rocha
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Pedro Pinto
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Carla Pinto
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Manuela Pinheiro
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Ana Peixoto
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
| | - Maria Fragoso
- Departments of Oncology, Portuguese Oncology Institute, Porto, Portugal
| | - Ana Raimundo
- Departments of Oncology, Portuguese Oncology Institute, Porto, Portugal
| | - Paula Ferreira
- Departments of Oncology, Portuguese Oncology Institute, Porto, Portugal
| | - Manuela Machado
- Departments of Oncology, Portuguese Oncology Institute, Porto, Portugal
| | - Nuno Sousa
- Departments of Oncology, Portuguese Oncology Institute, Porto, Portugal
| | - Paula Lopes
- Departments of Pathology, Portuguese Oncology Institute, Porto, Portugal
| | | | - Joana Macedo
- S. Sebastião Hospital, Santa Maria da Feira, Portugal
| | - Fernando Alves
- Trás-os-Montes e Alto Douro Hospital Center, Vila Real, Portugal
| | | | - Rui Henrique
- Departments of Pathology, Portuguese Oncology Institute, Porto, Portugal
- Abel Salazar Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
| | - Lúcio L Santos
- Departments of Surgery, Portuguese Oncology Institute, Porto, Portugal
| | - Manuel R Teixeira
- Departments of Genetics, Portuguese Oncology Institute, Porto, Portugal
- Abel Salazar Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
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Erkasap N, Ozkurt M, Erkasap S, Yasar F, Uzuner K, Ihtiyar E, Uslu S, Kara M, Bolluk O. Leptin receptor (Ob-R) mRNA expression and serum leptin concentration in patients with colorectal and metastatic colorectal cancer. Braz J Med Biol Res 2013; 46:306-10. [PMID: 23558862 PMCID: PMC3854369 DOI: 10.1590/1414-431x20122559] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2012] [Accepted: 12/04/2012] [Indexed: 02/07/2023] Open
Abstract
The objective of the present study was to investigate the effect of leptin on the
progression of colorectal carcinoma to metastatic disease by analyzing the serum
leptin concentration and Ob-R gene expression in colon cancer tissues. Tissue
samples were obtained from 31 patients who underwent surgical resection for
colon (18 cases) and metastatic colon (13 cases) cancer. Serum leptin
concentration was determined by an enzyme-linked immunosorbent assay (ELISA) and
Ob-R mRNA expression by real-time polymerase chain reaction (RT-PCR) for both
groups. ELISA data were analyzed by the Student t-test and
RT-PCR data were analyzed by the Mann-Whitney U-test. RT-PCR results
demonstrated that mRNA expression of Ob-R in human metastatic colorectal cancer
was higher than in local colorectal cancer tissues. On the other hand, mean
serum leptin concentration was significantly higher in local colorectal cancer
patients compared to patients with metastatic colorectal cancer. The results of
the present study suggest a role for leptin in the progression of colon cancer
to metastatic disease without weight loss. In other words, significantly
increased Ob-R mRNA expression and decreased serum leptin concentration in
patients with metastatic colon cancer indicate that sensitization to leptin
activity may be a major indicator of metastasis to the colon tissue and the
determination of leptin concentration and leptin gene expression may be used to
aid the diagnosis.
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Affiliation(s)
- N Erkasap
- Department of Physiology, Osmangazi University Medical Faculty, Meselik, Eskisehir, Turkey.
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