Abstract
Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).
Highlights
With the advent of massive parallel sequencing, the simultaneous evaluation of multiple genes has been greatly improved in terms of turnaround times, sequencing cost efficiency, and detection accuracy
Mutation analysis through digital droplet PCR and Next-generation sequencing (NGS), including multi-gene testing, revealed that ESR1 mutations are predominant in the metastatic setting rather than in primary tumors and paved the way for the evaluation of ESR1 mutational status for therapy decision-making in estrogen receptor (ER)-positive breast cancer [79]
Regarding the other above-mentioned genomic alterations that can be potentially evaluated through multi-gene testing, namely gene amplifications or deletions and fusion genes, only a limited number are under investigation in the metastatic triple-negative breast cancer (mTNBC) setting (e.g., PIK3CA mutations in combination with androgen receptor expression and NTRK fusions), but none of them have been investigated in clinical trials using targeted panels
Summary
With the advent of massive parallel sequencing, the simultaneous evaluation of multiple genes has been greatly improved in terms of turnaround times, sequencing cost efficiency, and detection accuracy. Breast cancer is the cancer type with highest incidence worldwide [5], and despite the increased cure rate of this neoplasm and the increased life expectation of advanced disease, new efficient targeted therapies are required to improve breast cancer outcome. Despite the improvement of (neo)adjuvant therapies in recent years, which has led to a significant increase of cure rates in patients with limited-stage disease (stage I-III), metastatic TNBC (mTNBC) remains almost invariably incurable, with a median overall survival of 12–18 months [6,7]. The possibility to comprehensively characterize human cancer through the NGS, and eventually other integrated approaches, opens the way not just to a deeper molecular understanding of cancer, and of TNBCs, and (and above all) to a more appropriate and adequate classification of patients who may benefit from standard therapeutic approaches or experimental interventions in the context of clinical trials
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