e-Article
Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.
Document Type
Author
Luen, S J; Viale, G; Nik-Zainal, S; Savas, P; Kammler, R; Dell'Orto, P; Biasi, O; Degasperi, A; Brown, L C; Láng, I; MacGrogan, G; Tondini, C; Bellet, M; Villa, F; Bernardo, A; Ciruelos, E; Karlsson, Per, 1963; Neven, P; Climent, M; Müller, B; Joshum, W; Bonnefoi, H; Martino, S; Davidson, N E; Geyer, C; Chia, S K; Ingle, J N; Coleman, R; Solbach, C; Thürlimann, B; Colleoni, M; Coates, A S; Goldhirsch, A; Fleming, G F; Francis, P A; Speed, T P; Regan, M M; Loi, S
Source
Annals of oncology : official journal of the European Society for Medical Oncology. 34(4):397-409
Subject
Language
English
ISSN
1569-8041
Abstract
Very young premenopausal women diagnosed with hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained.Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the SOFT clinical trial to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1,276 patients (deep targeted sequencing, N=1258; whole-exome sequencing in a young-age, case-control subsample, N=82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI), and overall survival (OS).Younger women (<40 years, N=359) compared with older women (≥40 years, N=917) had significantly higher frequencies of mutations in GATA3 (19%vs16%) and CN-amplifications (47%vs26%), but significantly lower frequencies of mutations in PIK3CA (32%vs47%), CDH1 (3%vs9%), and MAP3K1 (7%vs12%). Additionally, significantly higher frequencies of features suggestive of HRD (27%vs21%), and a higher proportion of PIK3CA mutations with concurrent CN-amplifications (23%vs11%).Genomic features suggestive of HRD, PIK3CA mutations with CN-amplifications, and CN-amplifications associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% ≥40 years. Poor prognostic features (N=584[46%]) vs none (N=692[54%]) had an 8-year DRFI of 84%vs94% and OS of 88%vs96%. Younger women (<40) had the poorest outcomes: 8-year DRFI 74%vs85% and OS of 80%vs93% respectively.These results provide insights into genomic alterations that are enriched in young women with HR+HER2-EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.