Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer

Authors:
Matteo LambertiniSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Marcello CeppiIRCCS Ospedale Policlinico San Martino, Genova, Italy

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Richard A. AndersonMRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom

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David A. CameronInstitute of Genomics and Cancer, The University of Edinburgh, Edinburgh, United Kingdom

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Marco BruzzoneIRCCS Ospedale Policlinico San Martino, Genova, Italy

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Maria Alice FranzoiGustave Roussy, Villjuif, France

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Claudia MassarottiIRCCS Ospedale Policlinico San Martino, Genova, Italy
University of Genova, Genova, Italy

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Sarra El-AbedBreast International Group, Brussels, Belgium

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Yingbo WangNovartis, Basel, Switzerland

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Christophe LecocqBrEAST Data Centre, Institut Jules Bordet, Brussels, Belgium

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Paolo NuciforoVall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, SOLTI BC Cooperative Group, Barcelona, Spain

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Rebecca RolyanceNorth Central London Cancer Alliance, London, United Kingdom

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Lajos PusztaiYale School of Medicine, New Haven, Connecticut

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Joohyuk SohnYonsei Cancer Center, Yonsei University Health System, Seoul, Korea

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Maria Maddalena LatoccaSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Luca AreccoSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Barbara PistilliGustave Roussy, Villjuif, France

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Kathryn J. RuddyMayo Clinic, Rochester, Minnesota

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Alberto BallestreroSchool of Medicine, University of Genova, Genova, Italy
IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Lucia Del MastroSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Fedro A. PeccatoriEuropean Institute of Oncology IRCCS, Milan, Italy

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Ann H. PartridgeDana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

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Cristina SauraVall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, SOLTI BC Cooperative Group, Barcelona, Spain

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Michael UntchHelios Hospital Berlin-Buch, Berlin, Germany

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Martine PiccartInstitut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Serena Di CosimoFondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Evandro de AzambujaInstitut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Isabelle DemeestereFertility Clinic, CUB-Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

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Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment–induced gonadotoxicity. Patients and Methods: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the “biological window” of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). Results: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33–42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56–2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45–2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01–0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. Conclusions: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Submitted May 29, 2022; final revision received August 9, 2022; accepted for publication August 9, 2022.

Previous presentation: A summary of these results was presented in abstract form at the 2022 ASCO Annual Meeting; June 4, 2022; Chicago, Illinois (J Clin Oncol 2022:40[Suppl]:Abstract 12084).

Author contributions: Conception and design: Lambertini, de Azambuja, Demeestere. Administrative support: Lambertini, Ceppi, Anderson, Cameron, Bruzzone, Franzoi, Massarotti, El-Abed, Wang, Lecocq, Rolyance, Pusztai, Sohn, Latocca, Arecco, Pistilli, Ruddy, Ballestrero, Del Mastro, Peccatori, Partridge, Saura, Untch, Piccart, Di Cosimo, de Azambuja. Collection and assembly of data: All authors. Data analysis and interpretation: Lambertini, Ceppi, Anderson, Bruzzone, de Azambuja, Demeestere. Manuscript writing: All authors.

Data availability statement: Qualified researchers can request access to individual patient-level data of the NeoALTTO trial by submitting a research project proposal to the Breast International Group. Further details on the Breast International Group’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents are available online.

Disclosures: Dr. Lambertini has disclosed serving as a scientific advisor for Roche, Lilly, Novartis, AstraZeneca, MSD, Seagen, Gilead, Pfizer, and Exact Sciences; receiving honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Takeda, Knight, Libbs, and Ipsen; and receiving a travel grant from and grant/research support from Gilead. Dr. Anderson has disclosed serving as a consultant for Roche. Dr. Cameron has disclosed receiving grant/research support from Novartis; and serving as a consultant for Roche, Pfizer, and Novartis. Dr. El-Abed has disclosed receiving grant/research support from Novartis, Roche/Genentech, AstraZeneca, and Pfizer. Dr. Wang is employed by Novartis and holds stock. Dr. Nuciforo has disclosed receiving grant/research support from Novartis, Roche/Genentech, MSD, Bayer, and Targos. Dr. Pusztai has disclosed serving as a consultant for and receiving honoraria from Seagen, Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, Genentech, Athenex, Radius, Clovis, and Roche; receiving grant/research support from Seagen, AstraZeneca, Merck, Pfizer, and Bristol Myers Squibb. Dr. Pistilli has disclosed serving as a scientific advisor for Puma Biotechnology, Novartis, Myriad Genetics, and Pierre Fabre; receiving personal fees from Novartis, AstraZeneca, MSD, and Pfizer; and grant/research support from Daiichi, Puma Biotechnology, Novartis, Merus, Pfizer, and AstraZeneca. Dr. Peccatori has disclosed serving as a consultant for Ipsen and Roche Diagnostics. Dr. Saura has disclosed serving as a consultant and scientific advisor for and receiving travel grants from AstraZeneca, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann–La Roche Ltd., MediTech, Merck Sharp & Dohme, NovarQs, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, SeaGen, and Zymeworks; and receiving grant/research support from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck Sharp & Dohme, Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Byondis B.V., and Zenith Pharma. Dr. Piccart has disclosed serving as a consultant and scientific advisor for and receiving honoraria from Roche and Novartis. Dr. Di Cosimo has disclosed serving as a consultant and scientific advisor for Pierre-Fabre, AstraZeneca, IQVIA, and MEDSIR. Dr. de Azambuja has disclosed receiving honoraria from and serving as a scientific advisor for Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre, and Lilly; receiving travel grants from Roche/Genentech and GlaxoSmithKline/Novartis; and receiving grant/research support from Roche/Genentech, AstraZeneca, Genentech/Novartis, and Servier. Dr. Demeestere has disclosed serving as a scientific advisor for and receiving grant/research support from Roche, receiving honoraria from Novartis, and receiving personal fees from Theramex and Ferring. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: The NeoALTTO trial received financial support from GlaxoSmithKline (until January 2015) and Novartis Pharma AG (as of January 2015). Research reported in this publication was supported by the Italian Association for Cancer Research under award number MFAG 2020 ID 246989 (M. Lambertini) and the Italian Ministry of Health (5x1000 funds 2017; M. Lambertini).

Disclaimer: The financial sponsors of the study had no role in the study design, data collection, analysis, interpretation, or writing of the report, and they had no access to the data. All authors had full access to the data and had final responsibility for the decision to submit for publication.

Correspondence: Matteo Lambertini, MD, PhD, Department of Medical Oncology, UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, University of Genova, Largo Rosanna Benzi 10, 16132 Genova, Italy. Email: matteo.lambertini@unige.it

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