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Supplementary Figure S2 from Negative Hyperselection of Patients with HER2+ and RAS Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study

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posted on 2024-01-17, 08:20 authored by Giovanni Randon, Yoshiaki Nakamura, Rona Yaeger, Sara Lonardi, Chiara Cremolini, Elena Elez, Federico Nichetti, Filippo Ghelardi, Vincenzo Nasca, Francesca Bergamo, Veronica Conca, Javier Ros, Hideaki Bando, Giulia Maddalena, Simone Oldani, Michele Prisciandaro, Alessandra Raimondi, Alexa B. Schrock, Luca Agnelli, Henry Walch, Takayuki Yoshino, Filippo Pietrantonio

Kaplan Meier curves for PFS (panel A) and OS (panel B) in the overall study population.

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Fondazione AIRC per la ricerca sul cancro ETS (AIRC)

Foundation for the National Institutes of Health (FNIH)

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ARTICLE ABSTRACT

To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of HER2 amplification by next-generation sequencing (NGS) in patients with HER2+, RAS wild-type metastatic colorectal cancer receiving dual HER2 blockade. The PRESSING-HER2 panel of HER2 mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. HER2 amplification was confirmed by NGS if copy-number variation (CNV) was ≥ 6. With a case–control design, hypothesizing 30% and 5% PRESSING-HER2 positivity in resistant [progression-free survival (PFS) <4 months and no RECIST response] versus sensitive cohorts, respectively, 35 patients were needed per group. PRESSING-HER2 alterations included HER2 mutations/rearrangements, EGFR amplification, and BRAF mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (P = 0.005) and 63% predictive accuracy. Overall, HER2 nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2+ versus negative (2.2 vs. 5.3 months, P < 0.001; 5.4 vs. 14.9 months, P = 0.001) and in HER2 nonamplified versus amplified (1.6 vs. 5.2 months, P < 0.001; 7.4 vs. 12.4 months, P = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40–6.69, P = 0.005; OS HR = 2.93, 95% CI, 1.32–6.48, P = 0.007]. Combining PRESSING-HER2 and HER2 CNV increased the predictive accuracy to 75%. PRESSING-HER2 panel and HER2 nonamplified status by NGS warrant validation as potential predictive markers in this setting.See related commentary by Raghav et al., p. 260

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