Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial.

Background: We aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis.
Methods: In this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0-1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m ² ) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual.
Findings: Between Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1-11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3-94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3-98·3), 10-year overall survival was 94·3% (95% CI 91·8-96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6-100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00-1·52]; p=0·047) and recurrence-free interval (1·45 [1·09-1·93]; p=0·011).
Interpretation: Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population.
Funding: Genentech.
Competing Interests: Declaration of interests SMT has received grant support (paid to institution) from AstraZeneca, Merck, Nektar, Novartis, Pfizer, Genentech (Roche), Gilead, Exelixis, BMS, Eisai, NanoString, Cyclacel, Sanofi, Seagen, and Eli Lilly; and has received consulting or advisory board fees (paid to self) from AstraZeneca, Eli Lilly, Merck, Novartis, Pfizer, Genentech (Roche), Gilead, BMS, Eisai, Sanofi, SeaGen, Daiichi-Sankyo, Athenex, OncoPep, Kyowa Kirin Pharma, CytomX, Certara, Mersana Therapeutics, Ellipses Pharma, 4D Pharma, OncoSec, Infinity Therapeutics, BeyondSpring Pharma, OncXerna, Zymeworks, Zentalis, ARC Therapeutics, Reveal Genomics, Blueprint Medicines, Myovant, Umoja Biopharma, Stemline (Menarini), and Artios Biopharma. PT has received consulting or advisory board fees from AstraZeneca, Daiichi-Sankyo, and Lilly and has received payment or honoraria for educational events from AstraZeneca and Daiichi-Sankyo. NT has received honoraria for a Clinical Research Workshop at the San Antonio Breast Cancer Symposium. LP is an employee of Reveal Genomics and has a patent (EP 20 382 679.7—in vitro method for the prognosis of patients suffering from HER2-positive breast cancer). GV has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from MSD, GSK, Pierre Fabre, and Pfizer and has participated on a data safety monitoring board or advisory board for AstraZeneca. CTD has received research funding from Genentech (Roche) and Puma and has received consulting fees from Daiichi-Sankyo, Novartis, Pfizer, Gilead, Seagen, and Genentech (Roche). DAY has received funding (paid to institution) for the present manuscript from Dana-Farber Cancer Institute; grant support (paid to institution) from Ambrx, Amgen, BIOMARIN, Biothera Pharmaceuticals, Clovis Pharma, Dana-Farber Cancer Institute, Lilly, Genentech (Roche), G1 Therapeutics, Gilead Sciences, Incyte, Innocrin Pharmaceuticals, Macrogenics, MedImmune, Medivation, Merck, Merrimack Pharmaceuticals, Nektar Therapeutics, Novartis, the National Surgical Adjuvant Breast and Bowel Project, Pfizer, and Polyphor; and has received consulting fees (paid to institution) from AstraZeneca, Athenex, bioTheranostics, G1 Therapeutics, Gilead Sciences, Immunomedics, Merck, Novartis, Pfizer, and Sanofi-Aventis. PKM has received support (paid to institution) for the present manuscript from Genentech; has participated on a data safety monitoring board for Genentech (Roche); has stock or stock options in Veracyte; and was a full-time employee of Veracyte at time of manuscript submission. KSA has received funding (paid to institution) for the present manuscript from Dana-Farber Cancer Institute for data management support. HSR has received grant funding (paid to UC Regents only) from Ambrx, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Genentech (Roche), Gilead Sciences, GSK, Lilly, Merck & Co, Novartis Pharmaceuticals, OBI Pharma, Pfizer, Pionyr Immunotherapeutics, Seattle Genetics, Sermonix Pharmaceuticals, Taiho Oncology, and Veru; has received consulting fees from Puma, Napo Pharmaceuticals, and Blueprint; and has received support for attending meetings and travel from Merck, AstraZeneca, and Gilead. MJE has reported a PAM50 Bioinformatics for Prosigna royalty-bearing license to Veracyte; and and has been an employee of AstraZeneca since March 7, 2022 (AstraZeneca had no role in this study and the author's involvement in this study preceded his employment with AstraZeneca). LAC has received research funding (paid to institution) from Syndax, Novartis, NanoString Technologies, Seattle Genetics, Veracyte, and AstraZeneca and declares participation in uncompensated consulting activities for Eisai (to self), Sanofi (to self), Lilly (to self), Seagen (to self), Novartis (to institution), G1 Therapeutics (to institution), Genentech (Roche; to institution), GSK (to institution), AstraZeneca (to institution), and Daiichi-Sankyo (to institution). RBS has received consulting fees from AstraZeneca, Libbs, Daiichi-Sankyo, Eli Lilly, Pfizer, Novartis, MSD, and Roche; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or education events from AstraZeneca, Libbs, Daiichi-Sankyo, Eli Lilly, Pfizer, Novartis, MSD, and Roche; has received support for attending meetings and travel from Daiichi-Sankyo, Eli Lilly, MSD, and Roche; has participated on a data safety monitoring board or advisory board for AstraZeneca, Daiichi-Sankyo, and Roche; and is a member of the Clinical Research Committee of the Brazilian Society of Clinical Oncology. JGTZ has stock or stock options in Loncar Cancer Immunotherapy ETF, iShares Genomics Immunology and Healthcare ETF, iShares Biotechnology ETF, SPDR S&P Biotech ETF, Adaptive Biotechnologies, 2seventy bio, and bluebird bio. NW has received grant support from AstraZeneca; has received consulting fees from Relay Therapeutics, Flare Therapeutics, Eli Lilly, and Section 32; has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Genentech; and has stock or stock options in Relay Therapeutics and Flare Therapeutics. AHP has received royalties from UpToDate. AGW has received grant support (paid to institution) from Macrogenics, Genentech, and Merck and has received consulting fees (paid to self) from AstraZeneca. CAH is Chief Executive Officer at the American Society of Clinical Oncology, which pays 100% of the author's personal annual earned income. IEK has received support for the present manuscript from Genentech (Roche); has received grant support from Macrogenics and Pfizer; has received consulting fees from Daiichi-Sankyo, Macrogenics, Roche, Seagen, and AstraZeneca; and has participated on a data safety monitoring board or advisory board for Novartis, Merck, Daiichi-Sankyo, Macrogenics, Roche, Seagen, and AstraZeneca. AP has received funding for the present manuscript from Reveal Genomics; has received grants (paid to institution) from Roche, Daiichi-Sankyo, and Reveal Genomics; has received royalties or licenses from Reveal Genomics (paid to institution); has received consulting fees (paid to self) from Roche, Novartis, Daiicki-Sankyo, and AstraZeneca; has patents licensed to Reveal Genomics: HER2DX, ERBB2, and DNADX genomic tools; and has stock or stock options in Reveal Genomics and Oncolytics Biotech. All other authors declare no competing interests.
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