Genomic characterisation of hormone receptor-positive breast cancer arising in very young women
- Author(s)
- Luen, SJ; Viale, G; Nik-Zainal, S; Savas, P; Kammler, R; Dell'Orto, P; Biasi, O; Degasperi, A; Brown, LC; Láng, I; MacGrogan, G; Tondini, C; Bellet, M; Villa, F; Bernardo, A; Ciruelos, E; Karlsson, P; Neven, P; Climent, M; Müller, B; Joshum, W; Bonnefoi, H; Martino, S; Davidson, NE; Geyer, C; Chia, SK; Ingle, JN; Coleman, R; Solbach, C; Thürlimann, B; Colleoni, M; COATES, AS; Goldhirsch, A; Fleming, GF; Francis, PA; Speed, TP; Regan, MM; Loi, S;
- Journal Title
- Annals of Oncology
- Publication Type
- epub ahead of print
- Abstract
- BACKGROUND: 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. PATIENTS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.
- Publisher
- Elsevier
- Keywords
- Breast cancer; genomics; hormone receptor positive; prognosis; young women
- Research Division(s)
- Bioinformatics
- PubMed ID
- 36709040
- Publisher's Version
- https://doi.org/10.1016/j.annonc.2023.01.009
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-03-17 11:09:12
Last Modified: 2023-03-17 11:15:58