Aims Oncotype DX has played a critical role in guiding treatment decisions for hormone receptor (HR)–positive, HER2‐negative early‐stage breast cancer. Clinically, a subset of patients with low Oncotype recurrent score (RS) will still progress on standard therapy and ultimately develop metastasis. Our goal was to explore potential molecular mechanisms, including specific genetic alterations and pathway activity associated with disease progression. Methods and results We retrospectively reviewed a small series of low RS breast cancers with subsequent metastasis and analysed the clinicopathological characteristics and comprehensive genomic profiling (CGP) data from tumour tissue and circulating tumour DNA (ctDNA) by liquid biopsy. Results These tumours demonstrated a range of histopathologic features and molecular profiles. Common findings included enrichment of PIK3CA and TP53 mutations and treatment‐emergent ESR1 mutations, observed in both tissue and ctDNA. CDKN2A , SPEN , KIT , CTNNB1 , MYC , EMSY , KMT2C , MAP3K1 gene alterations were only found in low RS group in low frequency. Copy number amplifications events were less common in low RS group. In cases with both tissue and ctDNA data, tissue CGP proved useful baseline for identifying driver mutations such as PIK3CA and for contextualizing ctDNA findings, and ctDNA analysis was adequate for disease monitoring and tracking molecular evolution over time. Conclusions Using real‐world CGP of tumour tissue and ctDNA, we identified key molecular features associated with endocrine resistance in patients with low RS who later developed metastases. PIK3CA mutation and other ER group‐related mutations contributed to the low RS. Tissue CGP provides baseline for interpreting ctDNA, and ctDNA monitoring PIK3CA, TP53 , ESR1 and other pathogenic or driver mutations in the early course of low RS cases may represent an excellent non‐invasive option for identifying targets and early intervention to prevent disease progression, though a large validation study is needed.
Liu et al. (Tue,) studied this question.