HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target

Ahcene-Djaballah, Selma; Daniel, Francesca; Milani, A.; Ricagno, Gianmarco

doi:10.1200/edbk_351354

Cited by 40 publications

(41 citation statements)

References 85 publications

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“…Moreover, a potential use in assessing the dynamics of RAS to monitor response and resistance to treatment has been suggested ( Table 2 ) [ 71 ]. Another example is HER2 , a well-known oncogenic driver in different tumor types [ 76 ]. Although its alterations are not common in CRC (3–5% of mCRC cases), when present, anti-HER2 therapy is an option [ 15 ].…”

Section: Cell-free Nucleic Acids As Crc Biomarkersmentioning

confidence: 99%

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Styk

Buglyó

Pös

et al. 2022

Cancers

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Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known genetic causes of CRC (distinguishing between sporadic and familial forms) and discusses potential and confirmed nucleic acid biomarkers obtainable from liquid biopsies, classified by their molecular features, focusing on clinical relevance. We comment on advantageous aspects such as better patient compliance due to blood sampling being minimally invasive, the possibility to monitor mutation characteristics of sporadic and hereditary CRC in a disease showing genetic heterogeneity, and using up- or down-regulated circulating RNA markers to reveal metastasis or disease recurrence. Current difficulties and thoughts on some possible future directions are also discussed. We explore current evidence in the field pointing towards the introduction of personalized CRC management.

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Section: Cell-free Nucleic Acids As Crc Biomarkersmentioning

confidence: 99%

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Styk

Buglyó

Pös

et al. 2022

Cancers

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“…HER2 was first established in gastric cancer in the ToGA trial in 2010, which overexpresses HER2 in up to 20% of cases as a clinically valuable target ( 56 ). In mCRC, alteration in HER2 accounts for only up to 5% of cases and appears to be enriched in RAS -WT CRC, accounting for up to 40% in cases showing resistance to EGFR base antibody therapies ( 57 , 58 ).…”

Section: Relevant Clinical Resistance Mechanismsmentioning

confidence: 99%

“…However, upfront testing of KRAS -WT CRC for HER2 amplification or mutation is currently not recommended in the ESMO or ASCO guidelines. Targeting HER2 in mCRC currently finds its place in second or later lines ( 58 , 61 ). First line trials are currently recruiting.…”

Section: Relevant Clinical Resistance Mechanismsmentioning

confidence: 99%

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

Doleschal¹,

Petzer²,

Rumpold³

2022

Front. Oncol.

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Anti-EGFR targeting is one of the key strategies in the treatment of metastatic colorectal cancer (mCRC). For almost two decades oncologists have struggled to implement EGFR antibodies in the mCRC continuum of care. Both sidedness and RAS mutational status rank high among the predictive factors for the clinical efficacy of EGFR inhibitors. A prospective phase III trial has recently confirmed that anti-EGFR targeting confers an overall survival benefit only in left sided RAS-wildtype tumors when given in first line. It is a matter of discussion if more clinical benefit can be reached by considering putative primary resistance mechanisms (e.g., HER2, BRAF, PIK3CA, etc.) at this early stage of treatment. The value of this procedure in daily routine clinical utility has not yet been clearly delineated. Re-exposure to EGFR antibodies becomes increasingly crucial in the disease journey of mCRC. Yet re- induction or re-challenge strategies have been problematic as they relied on mathematical models that described the timely decay of EGFR antibody resistant clones. The advent of liquid biopsy and the implementation of more accurate next-generation sequencing (NGS) based high throughput methods allows for tracing of EGFR resistant clones in real time. These displays the spatiotemporal heterogeneity of metastatic disease compared to the former standard radiographic assessment and re-biopsy. These techniques may move EGFR inhibition in mCRC into the area of precision medicine in order to apply EGFR antibodies with the increase or decrease of EGFR resistant clones. This review critically discusses established concepts of tackling the EGFR pathway in mCRC and provides insight into the growing field of liquid biopsy guided personalized approaches of EGFR inhibition in mCRC.

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“… 101 Thus far, patients with mCRC harboring tumor HER2 mutations have not responded to single-agent HER2 small molecule inhibitors in clinical trials 134 ; however, this may be due to the varying sensitivities of different HER2 mutations to anti-HER2 monotherapy. 135 In addition, only clinical trials of anti-HER2 combination therapies, not monotherapy, have demonstrated efficacy in HER2-expressing mCRC. 136 Dual HER2-targeted therapy has demonstrated anti-tumor activity in preclinical studies using xenograft models of HER2 -mutated mCRC 137 and anti-HER2 combination regimens continue to be evaluated in clinical trials for HER2 -positive patients with mCRC (NCT05350917, NCT03457896, NCT04639219, and NCT04579380).…”

Section: Extended Biomarker Testing Optionsmentioning

confidence: 99%

Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline

Aubin

Goodwin

et al. 2022

Ther Adv Med Oncol

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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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HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target

Cited by 40 publications

References 85 publications

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Extracellular Nucleic Acids in the Diagnosis and Progression of Colorectal Cancer

Current concepts of anti-EGFR targeting in metastatic colorectal cancer

Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline

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