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Correlation between trophoblast cell-surface antigen-2 (Trop-2) expression and pathological complete response in patients with HER2-positive early breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab

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Abstract

Purpose

The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study.

Methods

Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors. Then, it was classified by histochemical score (H-score) according to its intensity into low (0–9), intermediate (10–49), and high (≥ 50). The association between clinicopathologic features, pCR, and Trop-2 expression was performed with Fisher’s exact test.

Results

Forty-one patients with tissue evaluable for Trop-2 expression were included, with 28 (68.3%) Trop-2-positive tumors. Overall, 17 (41.46%), 14 (34.15%), and 10 (24.40%) tumors were classified as low, intermediate, and high, respectively. Trop-2 expression was significantly associated with decreased pCR rates (50.0% vs. 92.3%; odds ratio [OR] 0.05; 95% CI, 0.002–0.360]; p adjusted = 0.01) but was not correlated with any clinicopathologic features (p ≥ 0.05). Tumors with the highest Trop-2 H-score were less likely to obtain a pCR (OR 0.03; 95% CI, 0.001–0.290, p adjusted < 0.01). This association was confirmed in univariate and multivariate regression analyses.

Conclusion

These findings suggest a potential role of Trop-2 expression as a biomarker of resistance to neoadjuvant chemotherapy plus dual HER2 blockade and may become a strategic target for future combinations in HER2-positive EBC patients.

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Data availability

The datasets generated and analysed during the current study are not publicly available. This decision is underpinned by a profound dedication to ethical principles, scientific rigor, and the protection of privacy. We aim to safeguard the valuable data, protect the interests and trust of the patients who participated, and uphold the commitment we made to our fellow researchers. Our overarching goal is to ensure that any use of this data is conducted in an ethical and scientifically rigorous manner, reflecting the high standards of quality we have established in our research endeavors.

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Acknowledgements

We thank the patients and their caregivers for participating in the PHERGain study, as well as the medical team at each participating site. We also acknowledge Fundación Contigo for their funding support.

Funding

This work was entirely funded by Fundación Contigo.

Author information

Author notes

  1. María Gion and Juan José García-Mosquera contributed equally to this work.

Authors and Affiliations

  1. Hospital Universitario Ramón y Cajal, Madrid, Spain

    María Gion

  2. Dr. Rosell Oncology Institute (IOR), Dexeus University Hospital, Quironsalud Group, Barcelona, Spain

    Juan José García-Mosquera

  3. International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona, Spain

    José Manuel Pérez-García & Javier Cortés

  4. Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain

    José Manuel Pérez-García, José Antonio Guerrero, Laura López-Montero, Mario Mancino, José Rodríguez-Morató, Miguel Sampayo-Cordero, Antonio Llombart-Cussac & Javier Cortés

  5. Medica Scientia Innovation Research (MEDSIR), Ridgewood, NJ, USA

    José Manuel Pérez-García, José Antonio Guerrero, Laura López-Montero, Mario Mancino, José Rodríguez-Morató, Miguel Sampayo-Cordero, Antonio Llombart-Cussac & Javier Cortés

  6. Department of Pathology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

    Vicente Peg

  7. Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain

    Vicente Peg

  8. Hospital Universitario Virgen del Rocío, Sevilla, Spain

    Manuel Ruiz-Borrego

  9. Institut Català d’Oncologia L’Hospitalet, Hospitalet de Llobregat, Barcelona, Spain

    Agostina Stradella

  10. Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain

    Begoña Bermejo

  11. Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy

    Gabriele Antonarelli

  12. Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy

    Gabriele Antonarelli

  13. Hospital Arnau de Vilanova, Valencia, Spain

    Antonio Llombart-Cussac

  14. Universidad Católica de Valencia, Valencia, Spain

    Antonio Llombart-Cussac

  15. Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain

    Javier Cortés

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  1. María Gion
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Contributions

MG, JMP-G, MM, AL-C and JC contributed to the study conception and design. Material preparation, data collection and analysis were performed by MG, JJG-M, JMP-G, VP, MR-B, AS, BB, JAG, MM, MS-C, AL-C and JC. The first draft of the manuscript was written by JJG-M, JMP-G, LL-M, JR-M, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Antonio Llombart-Cussac or Javier Cortés.

Ethics declarations

Ethics approval and consent to participate

This retrospective study was conducted on already available data and biological material collected during the PHERGain trial. This trial was conducted in accordance with the Declaration of Helsinki and its amendments, the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines (ICH E6 GCP), and applicable local laws and regulations.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Competing interests

MG declares participation as a Consultant for Daiichi-Sankyo/AstraZeneca, Gilead, Novartis, Pfizer; receiving Honoraria from F. Hoffman La Roche and Travel grants from F. Hoffman La Roche, AstraZeneca, Pfizer. JJG-M declares Financial support for attending symposia from Lilly, Novartis, BMS, Roche, Palex; Employment or consultation from Trialing Health S.L., MEDSIR S.L. JMP-G declares Consulting or Advisory role for Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, Gilead, MSD; receiving Travel expenses from Roche, and Employment at MEDSIR. VP declares receiving fees as consultant, participating in advisory boards or receiving travel grants from Sysmex, Roche, MSD, AstraZeneca, Bayer, Exact Sciences, Daiichi-Sankyo. MR-B declares no conflicts of interest. AS declares Speaker’s bureau from Daiichi, Novartis, Astra Zeneca; Travel, accommodations or expenses from Eisai, Novartis, and Pfizer; Advisory role for Astra Zeneca, Boehringer Ingelheim, Novartis, Seagen, Gilead. BB declares receiving fees as consulting or advisory role for medical education from MSD, Roche, Pierre Fabre, Novartis, Astra Zeneca, Seagen; Speakers’ bureau for Pfizer, Roche, MSD, Palex, Eisai, Daichii, Astra Zeneca, Seagen. JAG, LL-M, MM and JR-M declare Employment at MEDSIR. GA declares honoraria and travel expenses from MEDSIR. MS-C declares Employment at MEDSIR and Advisory boards for Optimapharm, Ability Pharma, MD Anderson. AL-C declares Consulting/Advisory role for Roche, AstraZeneca, Seagen, Daiichi-Sankyo, Eli Lilly, Merck Sharp&Dohme, GSK, Gilead, Menarini, ExactSicences, Novartis, Agendia, Pfizer; Honararia from Roche, Novartis, Pfizer, Lilly, Daiichi Sankyo; Research funding to the Institution from Roche, AstraZeneca, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp&Dohme, Pfizer; Travel, accomodation, expenses from Roche, Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead; and Patents: HER2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Alex Prat, Antonio Llombart, Javier Cortés. US 2019/0338368 A1. JC declares Consulting/Advisory role for Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, Merck Sharp&Dohme, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Scorpion Therapeutics, Expres2ion Biotechnologies, Jazz Pharmaceuticals, Abbvie, BridgeBio; Honoraria from Roche, Novartis, Eisai, Pfizer, Lilly, Merck Sharp&Dohme, Daiichi Sankyo, Astrazeneca, Gilead, Steamline Therapeutics; Research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics,Iqvia, Queen Mary University of London; Travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead, Merck Sharp&Dhome, Steamline Therapeutics; Stock: MAJ3 Capital, Leuko (relative); Patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED, Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/ 0338368 A1. LICENSED. Non-financial interests: Agostina Stradella declares being a member of GEICAM’s Executive Board.

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Gion, M., García-Mosquera, J.J., Pérez-García, J. et al. Correlation between trophoblast cell-surface antigen-2 (Trop-2) expression and pathological complete response in patients with HER2-positive early breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07292-z

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