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Randomized Controlled Trial
. 2023 Jul 1;9(7):946-954.
doi: 10.1001/jamaoncol.2023.0646.

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial

Oleg Gluz  1   2   3 , Ulrike A Nitz  1   2 , Matthias Christgen  4 , Sherko Kuemmel  1   5   6 , Johannes Holtschmidt  5   7 , Johannes Schumacher  8 , Andreas Hartkopf  9 , Jochem Potenberg  10 , Kerstin Lüedtke-Heckenkamp  11 , Marianne Just  12 , Christian Schem  13 , Raquel von Schumann  2 , Cornelia Kolberg-Liedtke  6   14 , Christine Zu Eulenburg  1   15 , Timo Schinköthe  16   17 , Monika Graeser  1   2   18 , Rachel Wuerstlein  1   16 , Ronald E Kates  1 , Hans Heinrich Kreipe  4 , Nadia Harbeck  1   16
Affiliations
Randomized Controlled Trial

Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial

Oleg Gluz et al. JAMA Oncol. .

Abstract

Importance: Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed.

Objective: To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC.

Design, setting, and participants: This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level).

Interventions: Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days.

Main outcomes and measures: The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies.

Results: Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm.

Conclusions and relevance: The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab.

Trial registration: ClinicalTrials.gov Identifier: NCT03272477.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gluz reported personal fees from Celgene, Roche, AstraZeneca, Amgen, MSD, Novartis, Pfizer, Lilly, Gilead, Genomic Health/Exact Sciences, Molecular Health, NanoString Technologies, Pierre Fabre, and Seagen; nonfinancial support from Daiichi Sankyo, all outside the submitted work; and serving as co-director of the West German Study Group. Prof Nitz reported institutional research funding from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Roche, and Sanofi; consulting fees from Genomic Health and Roche; honoraria from Agendia, Amgen, Celgene, Genomic Health, NanoString Technologies, Novartis, Pfizer, Roche/Genentech, and Teva; payment for expert testimony from Genomic Health; travel support from Genomic Health, Pfizer, and Roche; participation on a data safety monitoring board or advisory board for Roche, Seagen, and Exact Sciences, all outside of the submitted work; and serving as co-director and shareholder of the West German Study Group. Prof Christgen reported financial support for tumor tissue banking from the West German Study Group during the conduct of the study. Prof Kuemmel reported personal fees from Roche during the conduct of the study; personal fees from Roche, Novartis, Celgene, AstraZeneca, Pfizer, Lilly, Amgen, Somatex, Hologic, Genomic Health/Exact Sciences, Daiichi Sankyo, pfm medical, SonoScape, MSD, Gilead, Agendia, and Seagen outside the submitted work; and serving as co-director of the West German Study Group. Dr Holtschmidt reported nonfinancial support from Hologic and personal fees from Daiichi Sankyo, MSD Oncology, Novartis, Palleos Healthcare, Pfizer, Roche Pharma, and Seagen outside the submitted work. Dr Hartkopf reported personal fees from Roche, Lilly, Novartis, Pfizer, AstraZeneca, Exact Sciences, MSD, Gilead, Eisai, GSK, Daiichi Sankyo, Agenda, and Seagen outside the submitted work. Dr Lüdtke-Heckenkamp reported personal fees from Daiichi Sankyo, Roche, AstraZeneca, Novartis, Seagen, Gilead, and Pfizer outside the submitted work. Prof Schem reported compensation from the West German Study Group during the conduct of the study, as well as trial grants from Roche outside the submitted work. Prof Kolberg-Liedtke reported salary from Palleos Healthcare and personal fees from Roche during the conduct of the study, as well as personal fees from Seagen, Novartis, Exact Sciences, Gilead, Onkowissen, Novartis Ireland, and PINK outside the submitted work. Prof Schinköthe reported being the owner of CANKADO GmbH during the conduct of the study. Dr Graeser reported consulting fees from AstraZeneca and travel support from Daiichi Sankyo outside of the submitted work. Dr Wurstlein reported personal fees from Agendia, Amgen, Aristo, AstraZeneca, Boehringer Ingelheim, Carl Zeiss, Celgene, Clovis Oncology, Daiichi Sankyo, Eisai, Genomic Health/Exact Sciences, Gilead, GSK, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, NanoString Technologies, Novartis, Odonate, Paxman, Palleos Healthcare, Pfizer, Pierre Fabre, PINK, Puma Biotechnology, Riemser, Roche, Sandoz, Sanofi Genzyme, Seagen, Stemline, Tesaro Bio, Teva, Veracyte, Viatris, and Clinsol, as well as other financial or nonfinancial interests from the Forum for Medical Education in Germany, Aurikamed, Clinsol, and Pomme Med, all outside the submitted work. Prof Kreipe reported grants from and serving as co-director of the West German Study Group during the conduct of the study. Dr Harbeck reported institutional research funding from Lilly, MSD, Novartis, Pfizer, and Roche/Genentech; personal fees from Amgen, AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche/Genentech, Sandoz, and Seagen outside the submitted work; and serving as co-director of the West German Study Group. No other disclosures were reported.

Figures

Figure.
Figure.. CONSORT Diagram
ET indicates endocrine therapy; HR, hormone receptor; ITT, intention to treat; M1, distant metastasis; P, pertuzumab; T, trastuzumab.
See this image and copyright information in PMC

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