Dataset Information

Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer.

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.

SUBMITTER: Guarini C

PROVIDER: S-EPMC8268006 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer.

Guarini Chiara C Grassi Teresa T Pezzicoli Gaetano G Porta Camillo C

International journal of molecular sciences 20210624 13

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 ...[more]

PMID: 34202896

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Project description:BackgroundAnti-EGFR antibody-based treatment is an important therapeutic strategy for advanced colorectal cancer (CRC); despite this, several mutations--including KRAS, BRAF, and PIK3CA mutations, and HER2 amplification--are associated with the mechanisms underlying the development of resistance to anti-EGFR therapy. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC.MethodsKRAS, BRAF, and PIK3CA mutations were determined by Cobas real-time polymerase chain reaction (PCR) in 191 advanced CRC patients with distant metastasis. Microsatellite instability (MSI) status was determined by a fragmentation assay and HER2 amplification was assessed by silver in situ hybridization. In addition, KRAS mutations were investigated by the Sanger sequencing method in 97 of 191 CRC cases.ResultsMutations in KRAS, BRAF, and PIK3CA were found in 104 (54.5%), 6 (3.1%), and 25 (13.1%) cases of advanced CRC, respectively. MSI-high status and HER2 amplification were observed in 3 (1.6%) and 16 (8.4%) cases, respectively. PIK3CA mutations were more frequently found in KRAS mutant type (18.3%) than KRAS wild type (6.9%) (P = 0.020). In contrast, HER2 amplifications and BRAF mutations were associated with KRAS wild type with borderline significance (P = 0.052 and 0.094, respectively). In combined analyses with KRAS, BRAF and HER2 status, BRAF mutations or HER2 amplifications were associated with the worst prognosis in the wild type KRAS group (P = 0.004). When comparing the efficacy of detection methods, the results of real time PCR analysis revealed 56 of 97 (57.7%) CRC cases with KRAS mutations, whereas Sanger sequencing revealed 49 cases (50.5%).ConclusionsKRAS mutations were found in 54.5% of advanced CRC patients. Our results support that subgrouping using PIK3CA and BRAF mutation or HER2 amplification status, in addition to KRAS mutation status, is helpful for managing advanced CRC patients.

Project description:PurposeERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known.Experimental designDana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts.ResultsERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer.ConclusionsCo-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted.

Dataset Information

Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer.

Publications

Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer.

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