Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies.

Background: Prior exposure to adjuvant endocrine therapy (ET) and timing to recurrence are crucial factors for first-line treatment choices in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) and in clinical trial eligibility, classifying metastatic HR+/HER2- BC as endocrine sensitive (ES) or primary (1ER)/secondary (2ER) resistant. However, this classification is largely based on expert opinion and no proper evidence exists to date to support its possible prognostic and clinical impact.
Methods: This analysis included individual patient-level data from 4 adjuvant phase III randomized trials by the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. The impact of endocrine resistance/sensitivity classification on overall survival (mOS, defined as time between date of distant relapse and death) was assessed in both univariate and multivariate Cox proportional hazards models.
Findings: Between November 1992 and July 2012, 9058 patients were randomized in 4 trials, of whom 6612 had HR+/HER2- BC. Median follow-up was 9.1 years (interquartile range [IQR] 5.6-15.0). In the whole cohort, disease-free survival and OS were 90.4% and 96.6% at 5 years, and 79.1% and 89.4% at 10 years, respectively. The estimated hazard of recurrence raised constantly during the first 15 years from diagnosis, being more pronounced during the first 2 years and less pronounced after year 7. Among the 493 patients with a distant relapse as first disease-free survival event and available date on ET completion, 72 (14.6%), 207 (42.0%) and 214 (43.4%) were classified as having 1ER, 2ER and ES, respectively. Median follow-up from diagnosis of a distant relapse was 3.8 years (IQR 1.6-7.5). Patients with 1ER were significantly more likely to be younger, to have N2/N3 nodal status, grade 3 tumours and to develop visceral metastases. Site of first distant relapse was significantly different between the 3 groups (p = 0.005). In patients with 1ER, 2ER and ES breast cancer, median mOS was 27.2, 38.4 and 43.2 months, respectively (p = 0.03). As compared to patients with ES disease, a higher risk of death was observed in those with 1 ER (adjusted Hazard Ratio [aHR] 1.54; 95% CI 1.03-2.30) and 2ER (aHR 1.17; 95% CI 0.87-1.56) (p = 0.11).
Interpretation: This large analysis with long-term follow-up provides evidence on the prognostic and clinical impact of the currently adopted endocrine resistance/sensitivity classification in patients with HR+/HER2- advanced BC. This classification may be considered a valid tool to guide clinical decision-making and to design future ET trials in the metastatic setting.
Funding: AIRC.
Competing Interests: ML reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, and Takeda; travel Grants from Gilead outside the submitted work. EB reports research grant (to the Institution) from Gilead Science. SDP reports honoraria from Roche, Novartis, Pfizer, Celgene, Eli Lilly, AstraZeneca, Clovis, Seagen, Daichii Sankyo, and MSD outside the submitted work. MDL reports personal fees from Pfizer, Novartis, Roche, AstraZeneca, Eli Lilly, MSD, Daiichi-Sankyo, GSK, Sanofi, Celtrion, Organon and Seagen, outside the submitted work. MM reports consulting fees/honoraria and participation on Advisory Board from Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, Astra Zeneca, Gentili outside the submitted work. FM reports consultancy fees from Roche, Astra Zeneca, Daiichi Sankyo, SeaGen, MSD, Eli Lilly, Pierre Fabre, Novartis; travel Grants from Roche outside the submitted work. AFr reports advisory role for Roche, Astrazeneca, Lilly, Novartis, Seagen, Daiichi Sankyo, Gilead outside the submitted work. AT reports honoraria from Novartis, Pfizer, Lilly, Roche; travel/accommodation expenses from Roche, AstraZeneca, Gentili, Pfizer outside the submitted work. ST reports consultant fee for Incyte MSD, Roche, Merck, AStrazeneca outside the submitted work. RC reports consultant fees for Novartis, Lilly, Roche, MSD, Gilead, Daiichi Sankyo, AstraZeneca outside the submitted work. CDA reports consulting/advisory role for Roche, AstraZeneca, Lilly, GSK, Novartis, Pfizer, Seagen; speaker honoraria from Novartis, Pfizer, Lilly; research funding to the Institution: Novartis, Daiichi Sankyo; travel/accommodation expenses from Roche, AstraZeneca, Lilly, GSK, Novartis, Celgene, Pfizer outside the submitted work. EA reports consultancy fees/honoraria from Eli Lilly, Sandoz; travel grants from Novartis, Roche, Eli Lilly, Genetic, Istituto Gentili outside the submitted work. EdA reports honoraria and/or advisory board from Roche/GNE, Novartis, Seattle Genetics, Zodiac, Libbs and Pierre Fabre; Travel grants from Roche/GNE and GSK/Novartis; research grant to his institution from Roche/GNE, Astra-Zeneca, GSK/Novartis and Servier. FP reports participation on Advisory Board from AstraZeneca; consultancy fees/honoraria from Eli Lilly, and Novartis; travel grants from Daichii Sankyo, and Gilead outside the submitted work. LDM reports grants or contracts from Eli Lilly, Novartis, Roche, Daiichi Sankyo, and Seagan; fees/honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, and Ipsen; support for attending meetings or travel from Roche, Pfizer, and Eisai; participation on a Data Safety Monitoring Board or Advisory Board from Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sankyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, and AstraZeneca outside the submitted work. All other authors declare no competing interests.
(© 2023 The Author(s).)