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Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial.

ABSTRACT: The optimal adjuvant endocrine therapy for HR-positive/HER2-positive breast cancer patients is unknown. We included in this analysis 784 patients with HR-positive/HER2-positive BC from the randomized ShortHER trial of adjuvant trastuzumab (1 year vs 9 weeks) + chemotherapy. At a median follow-up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4 vs 79.7%, log-rank P = 0.013 (HR 1.52, 95% CI 1.09-2.11). In multivariate analysis, the type of endocrine therapy maintained a significant association with DFS (HR 1.64, 95% CI 1.07-2.52, p = 0.025 for TAM/TAM-AI vs AI). Among premenopausal patients aged ≤45 years, the use of GnRHa was associated with longer DFS: 8-yr DFS rate 85.2 vs 62.6% (log-rank p = 0.019, HR 0.41, 95% CI 0.19-0.88). In this post-hoc analysis of the ShortHER trial adjuvant treatment with AI was independently associated with improved DFS. Subgroup analysis in premenopausal patients suggests benefits with ovarian suppression.Trial registration: NCI ClinicalTrials.gov number: NCT00629278.

SUBMITTER: Dieci MV

PROVIDER: S-EPMC9899279 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial.

Dieci Maria Vittoria MV Bisagni Giancarlo G Bartolini Stefania S Frassoldati Antonio A Vicini Roberto R Balduzzi Sara S D'amico Roberto R Conte Pierfranco P Guarneri Valentina V

NPJ breast cancer 20230204 1

The optimal adjuvant endocrine therapy for HR-positive/HER2-positive breast cancer patients is unknown. We included in this analysis 784 patients with HR-positive/HER2-positive BC from the randomized ShortHER trial of adjuvant trastuzumab (1 year vs 9 weeks) + chemotherapy. At a median follow-up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4 vs 79.7%, log-rank P = 0.013 (HR 1.52, 95% CI 1.09-2.11). In multivariate analy ...[more]

PMID: 36739285

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Project description:BackgroundThere is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm.Patients and methodsStromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years.ResultsMedian TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015).ConclusionsTILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

Project description:BackgroundRibociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) advanced breast cancer. New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2- early nonmetastatic breast cancer (EBC).Methods/designNATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2- EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day [investigator's discretion] plus goserelin [men or premenopausal women]) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival.DiscussionThe 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2- EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment.Trial registrationClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334).

Project description:We reviewed randomized phase II/III trials comparing first- or second-line endocrine therapy as monotherapy or in combination with targeted therapies for treatment of postmenopausal patients with hormone receptor-positive advanced breast cancer. First-line was defined as treatment for endocrine therapy-naïve advanced breast cancer or advanced disease treated with endocrine therapy in the adjuvant/neoadjuvant setting. Second-line was defined as endocrine therapy for advanced breast cancer following disease progression on endocrine therapy for advanced disease. Publications reporting progression-free survival (PFS)/time to progression (TTP) or overall survival (OS) for FDA-approved agents anastrozole, exemestane, fulvestrant 250 mg, fulvestrant 500 mg, letrozole (0.5 and 2.5 mg), megestrol acetate, and tamoxifen as monotherapy, or in combination with everolimus, palbociclib or ribociclib, were assessed. First-line monotherapy with anastrozole, fulvestrant 500 mg or letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; however, only fulvestrant 500 mg improved OS. For endocrine therapy in combination with targeted therapies, palbociclib plus letrozole 2.5 mg, and ribociclib plus letrozole 2.5 mg significantly improved PFS versus letrozole 2.5 mg alone first-line. For second-line monotherapies, exemestane, fulvestrant 500 mg and letrozole 2.5 mg significantly improved PFS/TTP versus comparator endocrine therapy; only fulvestrant 500 mg and letrozole 2.5 mg improved OS. For second-line combination therapies, everolimus plus exemestane, and palbociclib plus fulvestrant 500 mg, improved PFS versus endocrine therapy alone. In both first- and second-line settings, aromatase inhibitors demonstrated PFS benefits versus comparator endocrine therapy; however, fulvestrant 500 mg was the only endocrine therapy included in our review to show both PFS and OS advantages compared with other endocrine therapies. Targeted agents in combination with endocrine therapy have demonstrated PFS improvements both first- and second-line; OS data are awaited.

Dataset Information

Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial.

Publications

Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial.

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