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LAPTM4B gene copy number gain is associated with inferior response to anthracycline-based chemotherapy in hormone receptor negative breast carcinomas

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Abstract

Purpose

To determine the associations between lysosomal-associated transmembrane protein 4b (LAPTM4B) gene copy number and response to different chemotherapy regimens in hormone receptor negative (HR-) primary breast carcinomas.

Patients and methods

Two cohorts were analyzed: (1) 69 core biopsies from HR-breast carcinomas treated with neoadjuvant chemotherapy (anthracycline based in 72.5% of patients and non-anthracycline based in 27.5% of patients). (2) Tissue microarray (TMA) of 74 HR-breast carcinomas treated with adjuvant therapy (77.0% of the patients received anthracycline, 17.6% of the patients non-anthracycline-based therapy, and in 5.4% of the cases, no treatment data are available). Interphase FISH technique was applied on pretreatment core biopsies (cohort I) and on TMAs (cohort II) using custom-made dual-labelled FISH probes (LAPTM4B/CEN8q FISH probe Abnova Corp.).

Results

In the neoadjuvant cohort in the anthracycline-treated group, we observed a significant difference (p = 0.029) of average LAPTM4B copy number between the non-responder and pathological complete responder groups (4.1 ± 1.1 vs. 2.6 ± 0.1). In the adjuvant setting, the anthracycline-treated group of metastatic breast carcinomas was characterized by higher LAPTM4B copy number comparing to the non-metastatic ones (p = 0.046). In contrast, in the non-anthracycline-treated group of patients, we did not find any LAPTM4B gene copy number differences between responder vs. non-responder groups or between metastatic vs. non-metastatic groups.

Conclusion

Our results confirm the possible role of the LAPTM4B gene in anthracycline resistance in HR− breast cancer. Analyzing LAPTM4B copy number pattern may support future treatment decision.

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Acknowledgements

We would like to thank Erzsébet Kovács for technical assistance and Stefan Vari-Kakas for manuscript revision.

Funding

This study was funded by seven grants: (1) New National Excellence Program (ÚNKP-17-4-II-SE-65); (2) New National Excellence Program (ÚNKP-17-4-III-SE-71); (3) National Talent Program (NTP-NFTÖ-17-B-0308) of the Ministry of Human Capacities; (4) NVKP_16-1-2016-0004; (5) STIA 19/2017, 6800313113, 68003F0043; (6) The Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 to Z.S.). (7) Breast Cancer Research Foundation (Z.S.).

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Author notes

  1. Orsolya Rusz and Orsolya Papp have contributed equally.

Authors and Affiliations

  1. Department of Oncotherapy, University of Szeged, Korányi fasor 12, Szeged, 6720, Hungary

    Orsolya Rusz & Zsuzsanna Kahán

  2. 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, 1091, Hungary

    Orsolya Papp, Laura Vízkeleti, Kristóf Csaba Bende, Gábor Lotz, Balázs Ács, Tamás Székely, Csilla Szundi, Janina Kulka, Zoltán Szállási & Anna-Mária Tőkés

  3. MTA-SE-NAP B Brain Metastasis Research Group, 2nd Department of Pathology, Semmelweis University, Budapest, Hungary

    Laura Vízkeleti & Zoltán Szállási

  4. 1st Department of Surgery, Semmelweis University, Üllői út 78, Budapest, 1082, Hungary

    Béla Ákos Molnár

  5. Department of Pathology, University of Szeged, Állomás u. 2, Szeged, 6725, Hungary

    Ágnes Báthori

  6. Department of Bio and Health Informatics, Technical University of Denmark, Kemitorvet 208, 2800, Lyngby, Denmark

    Zoltán Szállási

  7. Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Harvard University, 300 Longwood Avenue, Boston, MA, 02115, USA

    Zoltán Szállási

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  1. Orsolya Rusz
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Corresponding author

Correspondence to Anna-Mária Tőkés.

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Conflict of interest

The authors declare that they have no conflict of interest. Orsolya Rusz declares that she has no conflict of interest. Orsolya Papp declares that she has no conflict of interest. Laura Vízkeleti declares that she has no conflict of interest. Béla Ákos Molnár declares that he has no conflict of interest. Kristóf Csaba Bende declares that he has no conflict of interest. Gábor Lotz declares that he has no conflict of interest. Balázs Ács declares that he has no conflict of interest. Zsuzsanna Kahán declares that she has no conflict of interest. Tamás Székely declares that he has no conflict of interest. Ágnes Báthori declares that she has no conflict of interest. Csilla Szundi declares that she has no conflict of interest. Janina Kulka declares that she has no conflict of interest. Zoltán Szállási declares that he has no conflict of interest. Anna-Mária Tőkés declares that she has no conflict of interest.

Ethical approval

The study was ethically approved by the Semmelweis University Institutional Review Board (SE-TUKEB 120/2013). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The breast carcinoma cases were retrospectively selected from prospectively maintained databases (Primary breast carcinoma cases were diagnosed between 1999 and 2016), and accordingly, informed consent was not obtained from all individual participants included in the study.

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Rusz, O., Papp, O., Vízkeleti, L. et al. LAPTM4B gene copy number gain is associated with inferior response to anthracycline-based chemotherapy in hormone receptor negative breast carcinomas. Cancer Chemother Pharmacol 82, 139–147 (2018). https://doi.org/10.1007/s00280-018-3602-z

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