Clinical implications of prospective genomic profiling of metastatic breast cancer patients

Abstract

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.

Implementation of Precision Oncology for Patients with Metastatic Breast Cancer in an Interdisciplinary MTB Setting

“…Other recent studies, such as the one by Geelen et al, which accrued 357 breast cancer patients of whom 74% had a potentially actionable alteration, also demonstrated feasibility of using molecular diagnostics to detect actionable molecular alterations. This suggests that clinical utility of genomic profiling in combination with more available targeted therapies will expand over time [ 46 ].…”

Breast Cancer Genomics: Primary and Most Common Metastases

“…Moreover, the α-specific PI3K inhibitor alpelisib combined with the estrogen receptor antagonist fulvestrant has demonstrated itself effective in the treatment of BC with PIK3CA mutations. These mutations are common in ER+/HER2-metastatic BC, with about 40% of HR+/HER2− BC patients having an activating mutation in the PIK3CA gene [42,43]. In a phase 3 clinical trial, patients with HR+/HER2−, PIK3CA-mutated BC who…”

Akt Isoforms: A Family Affair in Breast Cancer

“…Similar mutation in Akt2 and Akt3 was rare [ 3 , 60 ]. Based on next-generation sequencing analysis, genetic alteration in Akt1 (E17K and other pathologic mutations) was significantly enriched in metastatic breast cancer compared to primary breast cancer and Akt1, but not Akt2 or Akt3, was identified as an actionable target [ 61 ].…”