Background: Metastatic breast cancer remains incurable. Next-generation sequencing (NGS) offers the ability to identify actionable genomic alterations in tumours which may then be matched with targeted therapies, but the implementation and utility of this approach is not well defined for patients with metastatic breast cancer. Methods: We recruited patients with advanced breast cancer of any subtype for prospective targeted NGS of their most recent tumour samples, using a panel of 108 breast cancer-specific genes. Genes were classified as actionable or non-actionable using the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines. Results: Between February 2014 and May 2019, 322 patients were enrolled onto the study, with 72% (n = 234) of patients successfully sequenced (n = 357 samples). The majority (74%, n = 171) of sequenced patients were found to carry a potentially actionable alteration, the most common being a PIK3CA mutation. Forty-three percent (n = 74) of patients with actionable alterations were referred for a clinical trial or referred for confirmatory germline testing or had a change in therapy outside of clinical trials. We found alterations in AKT1, BRCA2, CHEK2, ESR1, FGFR1, KMT2C, NCOR1, PIK3CA and TSC2 to be significantly enriched in our metastatic population compared with primary breast cancers. Concordance between primary and metastatic samples for key driver genes (TP53, ERBB2 amplification) was > 75%. Additionally, we found that patients with a higher number of mutations had a significantly worse overall survival. Conclusion: Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.
There is limited knowledge on the benefit of the α-subunit specific PI3K inhibitor alpelisib in later lines of therapy for advanced ER+HER2- and triple negative breast cancer (TNBC). We conducted a phase 2 multi-cohort study of alpelisib monotherapy in patients with advanced PI3K pathway mutant ER+HER2- and TNBC. In the intention to treat ER+ cohort, the overall response rate was 30% and the clinical benefit rate was 36%. Decline in PI3K pathway mutant ctDNA levels from baseline to week 8 while on therapy was significantly associated with a partial response, clinical benefit and improved progression free-survival (HR 0.24 95% CI 0.083 - 0.67, P = 0.0065). Detection of ESR1 mutations at baseline in plasma was also associated with clinical benefit and improved progression free survival (HR 0.22 95% CI 0.078 - 0.60, P = 0.003).
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