In ER+ eBC, extending AIs beyond 5 years reduces late recurrences at the price of increased skeletal events. Germline SNPs of CYP19A1 may affect aromatase activity, potentially leading to decreased AIs efficacy and toxicity. We conducted a prospective study to assess the impact of SNPs on outcomes of 886 postmenopausal patients treated with AIs.
The study included 2 cohorts of patients who were free of relapse 3-6 years from diagnosis. Patients of GIM5 cohort received 5 years letrozole after 4-6 years tamoxifen. Those of GIM4 cohort were randomized to 3-2 or 5 years letrozole after 2-3 years tamoxifen. Germline DNA was genotyped with PCR for SNPs rs4646, rs10046, rs749292, rs727479. Cumulative incidence of metastasis was analyzed in a competing risk model (CRM) with contralateral BC, second malignancy, and death without BC as competing risk. Cumulative incidence of skeletal events was analyzed in CRM with invasive BC/relapse, second malignancy, death as competing risk. Fine-Gray model was used to estimate subdistribution HR (sHR) in the CRM. Overall survival was analyzed with log-rank and Cox model.
Homozygosis of T allele (T/T) in rs10046, rs749292, and hetero and homozygosis of T allele in rs727479 (T/G + T/T) were high-risk genotypes associated with incidence of metastasis and worse OS (Table). 3 groups were identified based on number of high-risk genotypes (0, 1, >1). Genotypes-based groups identified patients with 15-year metastasis incidence of 2.5%, 8.3%, and 10.9%, respectively, and were associated with worse OS in a multivariable model (Table). Genotype-based groups were negatively associated with skeletal events (p=0.025); even after adjusting for age, BMI, smoke (p=0.028).
*cumulative incidence function
Cum. incidence of metastasis Overall survival rs10046 (T/T vs C/T + C/C) 1.57 (0.96-2.57) 0.071 1.51 (0.97-2.39) 0.070 rs749292 (T/T vs C/T + C/C) 1.83 (1.09-3.08) 0.023 1.64 (1.04-2.67) 0.050 rs727479 (T/T + T/G vs G/G) 2.62 (1.17-5.83) 0.060 2.20 (1.02-4.78) 0.040 0 high-risk genotype, N=132 1 (ref.) 0.035 1 (ref.) 0.030 1 high-risk genotype, N=524 2.54 (1.00-6.41) 2.30 (0.99-5.36) >1 high-risk genotypes, N=222 3.45 (1.32-9.04) 2.90 (1.19-7.05)
SNPs of CYP19 predict metastasis and skeletal events in patients receiving AIs, opening the opportunity to individualize therapy in ER+ BC survivors.
EudraCT 2005-001213-18.
Italy - Italian Medicines Agency.
CONSORZIO ONCOTECH, a public-private consortium funding the investigator-driven trial of the Gruppo Italiano Mammella.
B. Conte: Financial Interests, Personal, Invited Speaker: Veracyte. O. Garrone: Financial Interests, Personal, Advisory Board: Eisai, Daiichi Sankyo, AstraZeneca, Seagen, Gilead, MSD; Financial Interests, Personal, Invited Speaker: Novartis, Pfizer, Eli Lilly. S. de Placido: Financial Interests, Personal, Advisory Board: Lilly, GSK, MSD, Seagen, Daiichi Sankyo, Gilead, Eisai, Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Novartis, Pfizer, Roche. F. Schettini: Other, Personal, Sponsor/Funding, travel expenses: Novartis, Gilead; Other, Personal, Invited Speaker: Novartis, Gilead, Daiichi Sankyo. F. Montemurro: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Seagen, Pierre Fabre, AstraZeneca, Pfizer, MSD. C. Bighin: Other, Personal, Other, Personal fee: Novartis, Roche, Elly Lilly. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, MSD, Exact Science; Financial Interests, Personal, Research Grant, outside de submitted work: Gilead; Financial Interests, Personal, Invited Speaker: Sandoz, Libbs, Daiichi Sankyo, Takeda. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Invited Speaker, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Invited Speaker, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. All other authors have declared no conflicts of interest.