Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy—results from the ACOSOG Z1041 (Alliance) trial

<span class="paragraphSection"><div class="boxTitle">Background</div>HER2 (<span style="font-style:italic;">ERBB2</span>) gene amplification and its corresponding overexpression are present in 15–30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference.<div class="boxTitle">Patients and methods</div>In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR.<div class="boxTitle">Results</div>We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; <span style="font-style:italic;">P </span>=<span style="font-style:italic;"> </span>0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. <span style="font-style:italic;">ERBB2</span> and <span style="font-style:italic;">GRB7</span> were the genes most commonly observed in fusion events, and genomic copy number analysis of the <span style="font-style:italic;">ERBB2</span> locus indicated that cases with either no observable or low-level <span style="font-style:italic;">ERBB2</span> amplification were less likely to achieve a pCR (7/8 versus 17/40; <span style="font-style:italic;">P </span>=<span style="font-style:italic;"> </span>0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response.<div class="boxTitle">Conclusion</div>The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab.<div class="boxTitle">ClinicalTrials.gov identifiers</div>NCT00513292, NCT00353483</span>

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