Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study

Maria Rosaria Valerio, Antonio Russo, Isabella Sperduti, Giulia Bon, Rosanna Mirabelli, Laura Pizzuti, Maddalena Barba, Manuela Porru, Maria Agnese Fabbri, Marcello Maugeri-Saccà, Gennaro Ciliberto, Enrico Cortesi, Rossella Loria, Paolo Marchetti, Valentina Laquintana, Eriseld Krasniqi, Giacomo Barchiesi, Ornella Garrone, Marina Cazzaniga, Silverio TomaoMarco Mazzotta, Angelo Di Leo, Domenico Corsi, Daniele Marinelli, Nicla La Verde, Nicla La Verde, Andrea Michelotti, Nicola D’Ostilio, Giuseppina Sarobba, Daniele Generali, Luca Moscetti, Pietro Del Medico, Emilio Bria, Claudio Zamagni, Francesco Giotta, Rita Falcioni, Teresa Gamucci, Patrizia Vici, Corrado Ficorella, Carlo Garufi, Vincenzo Adamo, Carlo Leonetti, Giuseppe Sanguineti, Anna Sapino, Andrea Michelotti, Clara Natoli, Mario Roselli, Enzo Veltri, Alessandra Cassano, Giuseppe Tonini, Rossana Berardi, Ida Paris, Caterina Marchiò, Lorenzo Livi, Ruggero De Maria

Risultato della ricerca: Articlepeer review

Abstract

Background: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines. Methods: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models. Results: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively). Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.
Lingua originaleEnglish
pagine (da-a)1-14
Numero di pagine14
RivistaJOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume39
Stato di pubblicazionePublished - 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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