Data from Negative Hyperselection of Patients with HER2<sup>+</sup> and <i>RAS</i> Wild-Type Metastatic Colorectal Cancer Receiving Dual HER2 Blockade: the PRESSING-HER2 Study
Randon G., Nakamura Y., Yaeger R., Lonardi S., Cremolini C., Elez E., Nichetti F., Ghelardi F., Nasca V., Bergamo F., Conca V., Ros J., Bando H., Maddalena G., Oldani S., Prisciandaro M., Raimondi A., Schrock AB., Agnelli L., Walch H., Yoshino T., Pietrantonio F.
<div>AbstractPurpose:<p>To demonstrate the negative prognostic impact of a panel of genomic alterations (PRESSING-HER2 panel) and lack of <i>HER2</i> amplification by next-generation sequencing (NGS) in patients with HER2<sup>+</sup>, <i>RAS</i> wild-type metastatic colorectal cancer receiving dual HER2 blockade.</p>Experimental Design:<p>The PRESSING-HER2 panel of <i>HER2</i> mutations/rearrangements and RTK/MAPK mutations/amplifications was assessed by NGS. <i>HER2</i> 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.</p>Results:<p>PRESSING-HER2 alterations included <i>HER2</i> mutations/rearrangements, <i>EGFR</i> amplification, and <i>BRAF</i> mutations and had a prevalence of 27% (9/33) and 3% (1/35) in resistant versus sensitive patients (<i>P</i> = 0.005) and 63% predictive accuracy. Overall, <i>HER2</i> nonamplified status by NGS had 10% prevalence. Median PFS and overall survival (OS) were worse in PRESSING-HER2<sup>+</sup> versus negative (2.2 vs. 5.3 months, <i>P</i> < 0.001; 5.4 vs. 14.9 months, <i>P</i> = 0.001) and in <i>HER2</i> nonamplified versus amplified (1.6 vs. 5.2 months, <i>P</i> < 0.001; 7.4 vs. 12.4 months, <i>P</i> = 0.157). These results were confirmed in multivariable analyses [PRESSING-HER2 positivity: PFS HR = 3.06, 95% confidence interval (CI), 1.40–6.69, <i>P</i> = 0.005; OS HR = 2.93, 95% CI, 1.32–6.48, <i>P</i> = 0.007]. Combining PRESSING-HER2 and <i>HER2</i> CNV increased the predictive accuracy to 75%.</p>Conclusions:<p>PRESSING-HER2 panel and <i>HER2</i> nonamplified status by NGS warrant validation as potential predictive markers in this setting.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-2580" target="_blank">See related commentary by Raghav et al., p. 260</a></i></p></div>