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Radić J, Nikolić I, Kolarov-Bjelobrk I, Vasiljević T, Djurić A, Vidović V, Kožik B. Prognostic and Predictive Significance of Primary Tumor Localization and HER2 Expression in the Treatment of Patients with KRAS Wild-Type Metastatic Colorectal Cancer: Single-Centre Experience from Serbia. J Pers Med 2024; 14:879. [PMID: 39202071 PMCID: PMC11355236 DOI: 10.3390/jpm14080879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/02/2024] [Accepted: 08/15/2024] [Indexed: 09/03/2024] Open
Abstract
The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.
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Affiliation(s)
- Jelena Radić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivan Nikolić
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Ivana Kolarov-Bjelobrk
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Tijana Vasiljević
- Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia; (J.R.); (I.N.); (I.K.-B.); (T.V.)
- Department of Pathology and Laboratory Diagnostic, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia
| | - Aleksandar Djurić
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Vladimir Vidović
- Department of Medical Oncology, Oncology Institute of Vojvodina, 21204 Sremska Kamenica, Serbia; (A.D.); (V.V.)
| | - Bojana Kožik
- Laboratory for Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
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Ashouri K, Wong A, Mittal P, Torres-Gonzalez L, Lo JH, Soni S, Algaze S, Khoukaz T, Zhang W, Yang Y, Millstein J, Lenz HJ, Battaglin F. Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review. Cancers (Basel) 2024; 16:2796. [PMID: 39199569 PMCID: PMC11353018 DOI: 10.3390/cancers16162796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/04/2024] [Accepted: 08/07/2024] [Indexed: 09/01/2024] Open
Abstract
Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.
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Affiliation(s)
- Karam Ashouri
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Alexandra Wong
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Pooja Mittal
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Lesly Torres-Gonzalez
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Jae Ho Lo
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Sandra Algaze
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Taline Khoukaz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Yan Yang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Joshua Millstein
- Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; (K.A.); (A.W.)
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Lee SM, Oh H. RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification. Sci Rep 2024; 14:11432. [PMID: 38763942 PMCID: PMC11102903 DOI: 10.1038/s41598-024-62096-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 05/13/2024] [Indexed: 05/21/2024] Open
Abstract
HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established. In this study, we assessed the prevalence of HER2 amplification and microsatellite instability (MSI) status of 992 patients with primary CRC. In addition, molecular alterations of HER2 amplified and unamplified CRCs were examined and compared by next-generation sequencing. HER2 amplifications were found in 41 (4.1%) of 992 primary CRCs. HER2 amplification was identified in 1.0% of the right colonic tumors, 5.1% of the left colonic tumors, and 4.8% of the rectal tumors. Approximately 95% of HER2 amplification was observed in the left colon and rectum. Seven (87.5%) of eight metastatic tumors showed HER2 amplification. Most clinicopathologic features were unrelated to HER2 amplification except tumor size and MSI status. All 41 HER2 amplified CRCs were microsatellite stable. In a molecular analysis of frequently identified somatic mutations in CRCs, HER2 amplified CRCs showed a lower rate of KRAS mutations (24.4%) but a higher rate of TP53 mutations (83%) than unamplified CRCs. No BRAF and NRAS mutations were identified in HER2 amplified CRCs. Our study suggests that HER2 amplified CRCs are mutually exclusive of MSI and harbor less frequent KRAS/NRAS/BRAF mutations but frequent T53 mutations.
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Affiliation(s)
- Sun Mi Lee
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W. 11th Street, Indianapolis, IN, 46202, USA.
- Department of Pathology, Jeju National University Hospital, Jeju-si, South Korea.
| | - Hyunjoo Oh
- Department of Internal Medicine, Jeju National University Hospital, Jeju-si, South Korea
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Robinson HR, Messersmith WA, Lentz RW. HER2-Positive Metastatic Colorectal Cancer. Curr Treat Options Oncol 2024; 25:585-604. [PMID: 38539034 DOI: 10.1007/s11864-024-01183-7] [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] [Accepted: 01/17/2024] [Indexed: 04/24/2024]
Abstract
OPINION STATEMENT Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.
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Affiliation(s)
- Hannah R Robinson
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E. 17Th Avenue, Aurora, CO, 80045, USA
| | - Wells A Messersmith
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E. 17Th Avenue, Aurora, CO, 80045, USA
| | - Robert W Lentz
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, MS 8117, 12801 E. 17Th Avenue, Aurora, CO, 80045, USA.
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5
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Lawler T, Parlato L, Warren Andersen S. Racial disparities in colorectal cancer clinicopathological and molecular tumor characteristics: a systematic review. Cancer Causes Control 2024; 35:223-239. [PMID: 37688643 PMCID: PMC11090693 DOI: 10.1007/s10552-023-01783-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 08/21/2023] [Indexed: 09/11/2023]
Abstract
PURPOSE African Americans have the highest colorectal cancer (CRC) mortality of all racial groups in the USA, which may relate to differences in healthcare access or advanced stage at diagnosis. Recent evidence indicates that differences in tumor characteristics may also underlie disparities in mortality. To highlight recent findings and areas for investigation, we completed the first systematic review of racial disparities in CRC tumor prognostic markers, including clinicopathological markers, microsatellite instability (MSI), oncogene mutations, and novel markers, including cancer stem cells and immune markers. METHODS Relevant studies were identified via PubMed, limited to original research published within the last 10 years. Ninety-six articles were identified that compared the prevalence of mortality-related CRC tumor characteristics in African Americans (or other African ancestry populations) to White cases. RESULTS Tumors from African ancestry cases are approximately 10% more likely to contain mutations in KRAS, which confer elevated mortality and resistance to epidermal growth factor receptor inhibition. Conversely, African Americans have approximately 50% lower odds for BRAF-mutant tumors, which occur less frequently but have similar effects on mortality and therapeutic resistance. There is less consistent evidence supporting disparities in mutations for other oncogenes, including PIK3CA, TP53, APC, NRAS, HER2, and PTEN, although higher rates of PIK3CA mutations and lower prevalence of MSI status for African ancestry cases are supported by recent evidence. Although emerging evidence suggests that immune markers reflecting anti-tumor immunity in the tumor microenvironment may be lower for African American cases, there is insufficient evidence to evaluate disparities in other novel markers, cancer stem cells, microRNAs, and the consensus molecular subtypes. CONCLUSION Higher rates of KRAS-mutant tumors in in African Americans may contribute to disparities in CRC mortality. Additional work is required to understand whether emerging markers, including immune cells, underlie the elevated CRC mortality observed for African Americans.
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Affiliation(s)
- Thomas Lawler
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Lisa Parlato
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Shaneda Warren Andersen
- Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
- School of Medicine and Public Health, Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA.
- University of Wisconsin-Madison, Suite 1007B, WARF, 610 Walnut Street, Madison, WI, 53726, USA.
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Dao V, Heestand G. Beyond EGFR inhibitors in advanced colorectal cancer: Targeting BRAF and HER2. Curr Probl Cancer 2023; 47:100960. [PMID: 37285606 DOI: 10.1016/j.currproblcancer.2023.100960] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 06/09/2023]
Abstract
The addition of antiepidermal growth factor receptor (EGFR) monoclonal antibodies, cetuximab or panitumumab, to conventional chemotherapy has improved clinical outcomes for rat sarcoma virus (RAS) wild-type advanced colorectal cancer patients, however, durable responses and 5-year overall survival rates remain limited. BRAF V600E somatic mutation and human epidermal growth factor receptor (HER2) amplification/overexpression have been separately implicated in primary resistance to anti-EGFR therapeutic strategies via aberrant activation of the mitogen-activated protein kinase (MAPK) signaling pathway, resulting in poorer outcomes. In addition to being a negative predictive biomarker for anti-EGFR therapy, BRAF V600E mutation and HER2 amplification/overexpression serve as positive predictors of response to therapies targeting these respective tumor promoters. This review will highlight key clinical studies that support the rational use of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and HER2-targeted therapies, often in combination with other targeted agents, cytotoxic chemotherapy, and immune checkpoint inhibitors. We discuss current challenges with BRAF and HER2-targeted therapies in metastatic colorectal cancer and potential opportunities for improvement.
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Affiliation(s)
- Vinh Dao
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California
| | - Gregory Heestand
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.
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Colorectal Cancer Liver Metastases: Genomics and Biomarkers with Focus on Local Therapies. Cancers (Basel) 2023; 15:cancers15061679. [PMID: 36980565 PMCID: PMC10046329 DOI: 10.3390/cancers15061679] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/23/2023] [Accepted: 03/03/2023] [Indexed: 03/11/2023] Open
Abstract
Molecular cancer biomarkers help personalize treatment, predict oncologic outcomes, and identify patients who can benefit from specific targeted therapies. Colorectal cancer (CRC) is the third-most common cancer, with the liver being the most frequent visceral metastatic site. KRAS, NRAS, BRAF V600E Mutations, DNA Mismatch Repair Deficiency/Microsatellite Instability Status, HER2 Amplification, and NTRK Fusions are NCCN approved and actionable molecular biomarkers for colorectal cancer. Additional biomarkers are also described and can be helpful in different image-guided hepatic directed therapies specifically for CRLM. For example, tumors maintaining the Ki-67 proliferation marker after thermal ablation was shown to be particularly resilient to ablation. Ablation margin was also shown to be an important factor in predicting local recurrence, with a ≥10 mm minimal ablation margin being required to attain local tumor control, especially for patients with mutant KRAS CRLM.
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Yu IS, Aubin F, Goodwin R, Loree JM, Mather C, Sheffield BS, Snow S, Gill S. Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline. Ther Adv Med Oncol 2022; 14:17588359221111705. [PMID: 35898967 PMCID: PMC9310231 DOI: 10.1177/17588359221111705] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/17/2022] [Indexed: 11/17/2022] Open
Abstract
The systemic therapy management of metastatic colorectal cancer (mCRC) has evolved from primarily cytotoxic chemotherapies to now include targeted agents given alone or in combination with chemotherapy, and immune checkpoint inhibitors. A better understanding of the pathogenesis and molecular drivers of colorectal cancer not only aided the development of novel targeted therapies but led to the discovery of tumor mutations which act as predictive biomarkers for therapeutic response. Mutational status of the KRAS gene became the first genomic biomarker to be established as part of standard of care molecular testing, where KRAS mutations within exons 2, 3, and 4 predict a lack of response to anti- epidermal growth factor receptor therapies. Since then, several other biomarkers have become relevant to inform mCRC treatment; however, there are no published Canadian guidelines which reflect the current standards for biomarker testing. This guideline was developed by a pan-Canadian advisory group to provide contemporary, evidence-based recommendations on the minimum acceptable standards for biomarker testing in mCRC, and to describe additional biomarkers for consideration.
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Affiliation(s)
- Irene S. Yu
- Department of Medical Oncology, BC Cancer
Surrey, Surrey, BC, Canada
| | - Francine Aubin
- Division of Hematology and Oncology, Department
of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, QC,
Canada
| | - Rachel Goodwin
- Division of Medical Oncology, Department of
Medicine, Ottawa Hospital Cancer Centre, Ottawa, ON, Canada
| | - Jonathan M. Loree
- Department of Medical Oncology, BC Cancer
Agency - Vancouver Centre, Vancouver, BC, Canada
| | - Cheryl Mather
- Department of Laboratory Medicine and
Pathology, University of Alberta, Edmonton, AB, Canada
| | - Brandon S. Sheffield
- Division of Advanced Diagnostics, William Osler
Health System, Brampton, ON, Canada
| | - Stephanie Snow
- Department of Medicine, Queen Elizabeth II
Health Sciences Centre, Halifax, NS, Canada
| | - Sharlene Gill
- Department of Medical Oncology, BC Cancer
Agency – Vancouver Centre, 600 W 10th Ave, Vancouver, BC, V5Z 4E6,
Canada
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Fencer MG, Davis CH, Spencer KR. Current Updates on HER2–Directed Therapies in Metastatic Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2022. [DOI: 10.1007/s11888-022-00475-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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10
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Guarini C, Grassi T, Pezzicoli G, Porta C. Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer. Int J Mol Sci 2021; 22:6813. [PMID: 34202896 PMCID: PMC8268006 DOI: 10.3390/ijms22136813] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/31/2022] Open
Abstract
The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2's role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.
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Affiliation(s)
- Chiara Guarini
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Teresa Grassi
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Gaetano Pezzicoli
- Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘Aldo Moro’, 70124 Bari, Italy;
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
| | - Camillo Porta
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, 70124 Bari, Italy; (T.G.); (C.P.)
- Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, 70124 Bari, Italy
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11
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Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:329-359. [PMID: 33724754 DOI: 10.6004/jnccn.2021.0012] [Citation(s) in RCA: 880] [Impact Index Per Article: 220.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
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Affiliation(s)
- Al B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Alan P Venook
- UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | | | | | - Stacey Cohen
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Linda Farkas
- UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | | | | | | | - Steven Hunt
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Smitha Krishnamurthi
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | - Eric D Miller
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Mary F Mulcahy
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | - Katrina Pedersen
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
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12
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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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Li QH, Wang YZ, Tu J, Liu CW, Yuan YJ, Lin R, He WL, Cai SR, He YL, Ye JN. Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance. Gastroenterol Rep (Oxf) 2020; 8:179-191. [PMID: 32665850 PMCID: PMC7333932 DOI: 10.1093/gastro/goaa026] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 04/09/2020] [Indexed: 12/24/2022] Open
Abstract
Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.
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Affiliation(s)
- Qing-Hai Li
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Ying-Zhao Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jian Tu
- Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Chu-Wei Liu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Jie Yuan
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Run Lin
- Department of Radiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Wei-Ling He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Shi-Rong Cai
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Long He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jin-Ning Ye
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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Kwon MJ, Soh JS, Lim SW, Kang HS, Lim H. HER2 as a limited predictor of the therapeutic response to neoadjuvant therapy in locally advanced rectal cancer. Pathol Res Pract 2019; 215:910-917. [PMID: 30772061 DOI: 10.1016/j.prp.2019.01.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 01/02/2019] [Accepted: 01/25/2019] [Indexed: 12/23/2022]
Abstract
Human epidermal growth factor 2 (HER2) is a candidate therapeutic and prognostic marker for rectal cancer treated with neoadjuvant chemoradiotherapy. The specific frequency and prognostic role of HER2 protein expression and HER2 gene amplification in those rectal cancers has not been fully investigated. Pretreatment biopsied and surgically resected formalin-fixed paraffin-embedded tissues from 74 patients were retrospectively evaluated for HER2 protein expression and HER2 gene copy number using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. The tumor response to chemoradiation was evaluated with TNM staging and tumor regression grading (TRG) systems. Good response to chemoradiation therapy (TRG3), poor response (22 TRG1 and 19 TRG2), and TNM downstaging achieved in 33 (44.6%), 41 (55.4%), and 42 (56.8%) patients, respectively. The frequency of HER2 positivity is 17.6%, all of which were low-level HER2 gene amplification with 2.2 of median gene copy number ratio, detected in IHC0 (3/39), IHC1+ (2/18), IHC2+ (5/14) and IHC3+ (2/3). There was no association of HER2 positivity with clinicopathological parameters or survival. However, older age (≥61 years) and HER2 positivity were the independent predictive factors for non-down staging, while poorly differentiation and the papillary pattern were predictors for poor response. In multivariate analysis, good response proved as an only independent favorable prognostic factor affecting survivals. In conclusion, HER2 positivity may be predictive for a high-risk therapeutic resistance in rectal cancers. The discrepancy between IHC and gene amplification may result from the low-level amplification, which may explain lack of prognostic impact of HER2 positivity.
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Affiliation(s)
- Mi Jung Kwon
- Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
| | - Jae Seung Soh
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
| | - Sang-Woo Lim
- Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea.
| | - Ho Suk Kang
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
| | - Hyun Lim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Gyeonggi-do 431-070, Republic of Korea
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Overcoming Intrinsic and Acquired Cetuximab Resistance in RAS Wild-Type Colorectal Cancer: An In Vitro Study on the Expression of HER Receptors and the Potential of Afatinib. Cancers (Basel) 2019; 11:cancers11010098. [PMID: 30650638 PMCID: PMC6357064 DOI: 10.3390/cancers11010098] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/08/2019] [Accepted: 01/14/2019] [Indexed: 12/16/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is an important therapeutic target in colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies such as cetuximab, therapeutic resistance poses a challenging problem and limits the success of effective anti-EGFR cancer therapies in the clinic. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. The objective of this study was to investigate the expression of human epidermal growth factor (HER) receptors and the efficacy of afatinib, a second-generation irreversible EGFR-tyrosine kinase inhibitor, in RAS wild-type CRC cell lines with different cetuximab sensitivities. CRC cell lines with different sensitivities to cetuximab showed rather low EGFR expression but high HER2 and HER3 expression. These results were in line with the The Cancer Genome Atlas (TCGA) data from CRC patients, where higher mRNA levels of HER2 and HER3 were also detected compared to EGFR. Therefore, the targets of afatinib were indeed expressed on the CRC cell lines used in this study and in CRC patients. Furthermore, cetuximab resistance had no significant influence on the expression levels of HER receptors in CRC cell lines (p ≥ 0.652). This study also demonstrated that afatinib was able to induce a concentration-dependent cytotoxic effect in RAS wild-type CRC cell lines with different cetuximab sensitivities. Neither cetuximab resistance (p = 0.233) nor hypoxia (p = 0.157) significantly influenced afatinib’s cytotoxic effect. In conclusion, our preclinical data support the hypothesis that treatment with afatinib might be a promising novel therapeutic strategy for CRC patients experiencing intrinsic and acquired cetuximab resistance.
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Kanat O, Ertas H, Caner B. Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status. World J Clin Cases 2018; 6:418-425. [PMID: 30294606 PMCID: PMC6163141 DOI: 10.12998/wjcc.v6.i11.418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 05/15/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.
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Affiliation(s)
- Ozkan Kanat
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
| | - Hulya Ertas
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
| | - Burcu Caner
- Department of Medical Oncology, Faculty of Medicine, Uludag University, Bursa 16059, Turkey
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Buhmeida A, Assidi M, Al-Maghrabi J, Dallol A, Sibiany A, Al-Ahwal M, Chaudhary A, Abuzenadah A, Al-Qahtani M. Membranous or Cytoplasmic HER2 Expression in Colorectal Carcinoma: Evaluation of Prognostic Value Using Both IHC & BDISH. Cancer Invest 2018; 36:129-140. [PMID: 29504811 DOI: 10.1080/07357907.2018.1439054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Human epidermal growth factor recptor-2 (HER2) was identified as a driver gene in several types of cancers with both prognostic and predictive value. However, the molecular association of HER2 gene mutation with HER2 gene amplification and/or protein expression in cancer tissues has not been clearly defined. Moreover, there is little information available on HER2 status role in tumor progression and metastasis in colorectal carcinoma (CRC) compared to other solid tumors. The aim of this study was to evaluate both HER2 amplification and protein expression profiles using immunohistochemistry (IHC) and bright-field dual in situ hybridization (BDISH) techniques, respectively. PATIENTS AND METHODS Tissue microarray (TMA) was constructed to accommodate a total of 243 CRC formalin-fixed paraffin embedded (FFPE) samples of consent patients and stained by IHC and BDISH methods. The expression patterns of HER2 protein status were evaluated and correlated to HER2 gene amplification status and then assessed for its prognostic value. RESULTS The expression profile of 58% samples showed cytoplasmic expression patterns of different categories. Interestingly, only 1% showed strong (+3) membranous expression pattern of HER2 with perfect match with their corresponding gene amplification status (>2). However, the cytoplasmic HER2 protein status did not show significant correlation with most clinicopathological features and survival outcomes except with age (p = 0.04) and tumor size (p = 0.03). CONCLUSION We demonstrated that the membranous HER2 gene/protein status is infrequent, while the main fraction of HER2 overexpression was cytoplasmic and lacking prognostic value. This cytoplasmic HER2 overexpression was induced through a gene-amplification independent pathway, making the HER2 gene status evaluation approach in those cases not worthy. Further investigations about the molecular pathways of the cytoplasmic HER2 protein in CRC and its associations with survival outcomes are required to allow either a breakthrough in CRC management; or to confirm the hypothesis of a marginal role in CRC onset and progression.
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Affiliation(s)
- Abdelbaset Buhmeida
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mourad Assidi
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Jaudah Al-Maghrabi
- c Department of Pathology, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Ashraf Dallol
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Abdulrahman Sibiany
- d Department of Surgery, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mahmoud Al-Ahwal
- e Department of Internal Medicine, Faculty of Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Adeel Chaudhary
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Adel Abuzenadah
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia.,b KACST Technology Innovation Center in Personalized Medicine , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Mohammed Al-Qahtani
- a Center of Excellence in Genomic Medicine Research , King Abdulaziz University , Jeddah , Saudi Arabia
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Clinicopathological significance and diagnostic accuracy of HER2 immunohistochemistry in colorectal cancer: a meta-analysis. Int J Biol Markers 2016; 31:e389-e394. [PMID: 27102863 DOI: 10.5301/jbm.5000208] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2016] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The aim of this study was to elucidate the clinicopathological significance of HER2 expression and the diagnostic accuracy of HER2 immunohistochemistry (IHC) in colorectal cancer (CRC). A total of 2,573 CRC cases from 13 eligible studies were included. METHODS We performed a meta-analysis to examine the correlations between HER2 expression and clinicopathological characteristics in CRC. Concordance analysis between HER2 IHC and in situ hybridization (ISH) and diagnostic test accuracy review was conducted. RESULTS The estimated rate of HER2 IHC overexpression was 0.162 (95% confidence interval [CI] 0.106-0.240). HER2 IHC overexpression was significantly correlated with lymph node metastasis and distant metastasis but not tumor depth. HER2 IHC overexpression was not correlated with overall survival. The concordance rates between IHC and ISH were 0.968 (95% CI 0.881-0.992), 0.377 (95% CI 0.225-0.557) and 0.780 (95% CI 0.390-0.952) for HER2 IHC scores of 0/1+, 2+ and 3+, respectively. The diagnostic test accuracy review of HER2 IHC revealed that the pooled sensitivity and specificity were 0.71 (95% CI 0.58-0.82) and 0.96 (95% CI 0.94-0.97), respectively. The diagnostic odds ratio and area under the summary receiver operating characteristic curve were 51.34 (95% CI 3.82-690.54) and 0.9704, respectively. CONCLUSIONS HER2 IHC overexpression was significantly correlated with lymph node metastasis and distant metastasis. CRC cases with HER2 IHC scores of 0/1+ exhibited good agreement with the ISH data. However, additional ISH analysis is needed to confirm HER2 status in cases with IHC scores of 2+ or 3+.
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Fusco N, Bosari S. HER2 aberrations and heterogeneity in cancers of the digestive system: Implications for pathologists and gastroenterologists. World J Gastroenterol 2016; 22:7926-7937. [PMID: 27672288 PMCID: PMC5028807 DOI: 10.3748/wjg.v22.i35.7926] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Revised: 08/01/2016] [Accepted: 08/10/2016] [Indexed: 02/06/2023] Open
Abstract
Management of cancers of the digestive system has progressed rapidly into the molecular era. Despite the significant recent achievements in the diagnosis and treatment of these patients, the number of deaths for these tumors has currently plateaued. Many investigations have assessed the role of HER2 in tumors of the digestive system in both prognostic and therapeutic settings, with heterogeneous results. Novel testing and treatment guidelines are emerging, in particular in gastric and colorectal cancers. However, further advances are needed. In this review we provide a comprehensive overview of the current state-of-knowledge of HER2 alterations in the most common tumors of the digestive system and discuss the operational implications of HER2 testing.
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