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Clinical Trial
. 2024 Mar 1;10(3):362-371.
doi: 10.1001/jamaoncol.2023.6038.

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial

Cynthia X Ma  1 , Vera J Suman  2 , Souzan Sanati  3 , Kiran Vij  1 , Meenakshi Anurag  4 , A Marilyn Leitch  5 , Gary W Unzeitig  6 , Jeremy Hoog  1 , Aranzazu Fernandez-Martinez  7 , Cheng Fan  7 , Richard A Gibbs  4 , Mark A Watson  1 , Travis J Dockter  2 , Olwen Hahn  8 , Joseph M Guenther  9 , Abigail Caudle  10 , Erika Crouch  1 , Amy Tiersten  11 , Monica Mita  3 , Wajeeha Razaq  12 , Tina J Hieken  13 , Yang Wang  14 , Mothaffar F Rimawi  4 , Anna Weiss  15 , Eric P Winer  16 , Kelly K Hunt  10 , Charles M Perou  7 , Matthew J Ellis  4 , Ann H Partridge  17 , Lisa A Carey  7
Affiliations
Clinical Trial

Endocrine-Sensitive Disease Rate in Postmenopausal Patients With Estrogen Receptor-Rich/ERBB2-Negative Breast Cancer Receiving Neoadjuvant Anastrozole, Fulvestrant, or Their Combination: A Phase 3 Randomized Clinical Trial

Cynthia X Ma et al. JAMA Oncol. .

Abstract

Importance: Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)-positive/ERBB2 (formerly HER2)-negative breast cancer. However, the combination has not been tested in early-stage disease.

Objective: To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone.

Design, setting, and participants: A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023.

Interventions: Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery.

Main outcomes and measures: The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression).

Results: Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], -90.4% [-95.2 to -81.9%] vs -76.7% [-89.0 to -55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%.

Conclusions and relevance: In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation.

Trial registration: ClinicalTrials.gov Identifier: NCT01953588.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ma reported grants from National Institutes of Health (NIH)/National Cancer Institute (NCI), Breast Cancer Research Foundation, AstraZeneca, Genentech, and Alliance for Clinical Trials in Oncology during the conduct of the study; personal fees (consulting) from Bayer, Novartis, Sanofi, Athenex, Biovica, AstraZeneca, Natera, Gilead, Olaris, TerSera, Pfizer, Stemline, and Daiichi Sankyo; research support from Puma and Pfizer; and grants (research support) from Susan G. Komen and St Louis Men’s Group Against Cancer outside the submitted work. Dr Suman reported grants from NCI and Breast Cancer Research Foundation during the conduct of the study. Dr Vij reported other from Breast Cancer Research Foundation (compensation for data generated paid to Washington University School of Medicine) during the conduct of the study. Dr Leitch reported grants from NCI LAPS Grant and other from ALLIANCE for Clinical Trial in Oncology (patient accrual costs) during the conduct of the study; and personal fees from AstraZeneca (advisory panel on BRCA genetic testing in breast cancer; no discussion of agents in this trial) outside the submitted work. Dr Watson reported grants from NCI (U24CA196171) during the conduct of the study. Dr Tiersten reported research support from Lilly, Gilead, Novartis, and Pfizer outside the submitted work. Dr Hieken reported grants from Genentech and SkylineDX BV outside the submitted work. Dr Rimawi reported grants from Genentech and personal fees from Pfizer, AstraZeneca, Novartis, Seagen, MacroGenics, and Sermonix outside the submitted work. Dr Weiss reported grants from Myriad and personal fees (advisory board) from Merck and Myriad outside the submitted work. Dr Hunt reported other from Alliance for Clinical Trials in Oncology (capitation for clinical trial accrual) during the conduct of the study; grants (research funding to institution) from Cairn Surgical, Eli Lilly & Co, and Lumicell and personal fees (medical advisory board) from ArmadaHealth and AstraZeneca outside the submitted work. Prof Perou reported grants from NCI Breast SPORE program (P50-CA58223) during the conduct of the study; personal fees from Bioclassifier LLC (equity stock holder and royalties) outside the submitted work; in addition, Prof Perou had a patent for US Patent No. 12,995,459 with royalties paid from Bioclassifier. Dr Ellis reported other from AstraZeneca (advisory board participation) during the conduct of the study; and other from AstraZeneca (employment after the study was completed) outside the submitted work; in addition, Dr Ellis had a patent for PAM50 with royalties paid from Veracyte for commercial PAM50-based products (Prosigna) not used in the study. Dr Carey reported other (research funding to institution for trial) from AstraZeneca and Genentech during the conduct of the study. No other disclosures were reported.

Figures

Figure.
Figure.. CONSORT Diagram
NCT indicates neoadjuvant chemotherapy; NET, neoadjuvant endocrine therapy.
See this image and copyright information in PMC

References

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