Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit

• Published in: Frontiers in oncology 2024-05, Vol.14, p.1342346-1342346
• Main Authors: Walsh, Robert John, Ong, Rebecca, Cheo, Seng Wee, Low, Peter Q J, Jayagopal, Aishwarya, Lee, Matilda, Ngoi, Natalie, Ow, Samuel G, Wong, Andrea L A, Lim, Siew Eng, Lim, Yi Wan, Heong, Valerie, Sundar, Raghav, Soo, Ross A, Chee, Cheng Ean, Yong, Wei Peng, Goh, Boon Cher, Lee, Soo Chin, Tan, David S P, Lim, Joline S J
• Format: Article
• Language: English
• Subjects: breast cancer; molecular profiling; next-generation sequencing (NGS); Oncology; phase I; precision oncology
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2024.1342346

Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre. Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022. A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes affected in 62% (98/158) patients and 43% of tumours harbouring a alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of -altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment unmatched, with median OS (mOS) of 30.1 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75). Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.