Focus on human epidermal growth factor receptor 2 (HER2) positive metastatic colorectal cancer (HER2+ mCRC): A real world retrospective analysis.
Authors: Calegari Maria Alessandra , Formica Vincenzo , Zoratto Federica , Arrivi Giulia , Torsello Angela , Polito Mariam Grazia , Vincenzo Picone , Emiliani Alessandra , Cereda Vittore , Schirripa Marta , Caira Giulia , Spring Alexia , Chiofalo Laura , Morelli Cristina , Missori Francesca , Spoto Chiara , Mazzuca Federica , Artemi Adele , Dell'Aquila Emanuela , Salvatore Lisa 
Published: June 2024

3080 Background: HER2+ mCRCs, displaying HER2 overexpression or ERBB2 amplification, represent a rare molecular subset, accounting for 2- 6% of all mCRCs. HER2+ mCRCs are thought to be enriched in KRASwt pts and associated with distal primary tumor location. While its prognostic value is debated, HER2 seems a negative predictor for antiEGFR agents. Recently, its role as a potential actionable target has emerged, with promising results in refractory mCRC. Despite that, nowadays HER2 testing is not routinely included in the diagnostic workup of mCRC. Methods: This is an observational, retrospective, multicenter study, aiming to investigate and describe clinical and molecular features and prognostic value of HER2+ mCRCs from real world pts. Pts with mCRC tested for HER2 status who received at least one line of therapy (tx) at 11 Italian Institutions within the Lazio Region between Mar2011 and Jan2024 were enrolled. HER2 status was assessed either for HER2 overexpression using IHC according to the HERACLES diagnostic criteria or for ERBB2 amplification using NGS, followed by IHC confirmation for positive cases. Differences between groups for categorical variables were compared using the Chi Square test. Endpoint for prognostic assessment was OS, estimated with the Kaplan-Meier method and compared using log-rank test. Endpoints for predictive assessment were RR and DCR. Statistical significance was set at p .05. Results: 422 pts were included, of those 38 pts had a HER2+ mCRC (9%). HER2 positivity was more frequent among patients with RASwt tumor compared to RASmt (12.2 vs 6.1%; p .029), lung metastasis ( p .013) and synchronous metastatic disease ( p .044). No correlation with age, sex, primary tumor location, peritoneal spread, histologic grading and mucinous histology was observed. At a median FU of 19 months, OS was significantly shorter in HER2+ compared to HER2- mCRCs (HR 2.17, 95%CI 1.14-4.13; p .017). 104 pts with RASwt mCRC received an antiEGFR-based first line tx and were evaluable for response; of those 96 were HER2- and 12 HER2+. RR was higher for HER2- tumors (80 vs 42%; p .003), while no difference was observed for DCR (96 vs 83%; p .085). Of 38 HER2+ tumors, 14 received an antiHER2 tx, of those 11 were RASwt and 3 RASmt. RAS status did not impact on antiHER2 activity (DCR 64 vs 33% for RASwt and RASmt; p .347). Conclusions: We showed that HER2+ mCRCs are more frequently, although not exclusively, RASwt, display a lung tropism, present with synchronous metastases and have a negative prognosis. Moreover, in accordance with results from DESTINY-CRC02, the target actionability seems to be retained irrespective of RAS status. Given also the possible use in first line of antiHER2 tx in the near future, the baseline molecular diagnostic workup of mCRC must include HER2 status assessment, irrespective of RAS mutational status and primary tumor location.