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Sirolimus and trastuzumab combination therapy for HER2-positive metastatic breast cancer after progression on prior trastuzumab therapy

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Abstract

Constitutive activation of the PI3K/Akt/mTOR pathway has been suggested as a mechanism of resistance to trastuzumab therapy. This phase II trial was designed to evaluate the safety and clinical activity of daily oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in combination with trastuzumab in HER2-positive metastatic breast cancer following disease progression on prior trastuzumab therapy. Sirolimus 6 mg oral daily dose was administered with a standard dose and schedule of trastuzumab weekly or every 3 weeks. Pharmacodynamic studies included Western blot analysis of S6K1, phosphoS6K1, and mTOR in peripheral mononuclear cells, circulating tumor cells (CTC), and endothelial cells (CEC). Eleven patients were evaluable for safety; and nine were evaluable for response assessment. Subsequent enrollment was stopped due to slow accrual. Study treatment-related grade 3 toxicity included pneumonitis, myelosuppression (leukopenia/anemia), and dermatologic reactions (mucositis, nail changes and rash), with no grade 4 events. One patient received eight cycles (58 weeks) and achieved a partial response. Five patients treated for a total of 101 weeks (median 12 weeks, range 8–47 weeks) achieved stable disease as best response. Overall response rate was 1/9 (11 %) and clinical benefit rate was 4/9 (44 %). There was no statistically significant correlation between response and post-treatment change in levels of the mTOR pathway biomarkers, CTCs, HER2 CTCs, or CECs. Sirolimus 6 mg administered daily with trastuzumab appears to be well tolerated in patients with metastatic HER2-positive breast cancer following disease progression on prior trastuzumab therapy, with evidence of disease activity. mTOR inhibition may overcome resistance to trastuzumab in some HER2-positive tumors.

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Conflict of interest

Maysa Abu-Khalaf and Michael DiGiovanna—Clinical trial funding from Genentech

Funding

The clinical trial was funded by Genentech. The biomarker analysis on this study was funded by Susan G Komen for the Cure Clinical and Translational Award (M124188/BCTR0707898).

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Authors and Affiliations

  1. Section of Medical Oncology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA

    Carlos Acevedo-Gadea

  2. Section of Medical Oncology, Yale University School of Medicine, 300 George Street, Suite 120, New Haven, CT, 06511, USA

    Christos Hatzis, Gina Chung, Michael P. DiGiovanna & Maysa M. Abu-Khalaf

  3. Yale University School of Medicine, 111 Beach Rd, Fairfield, CT, 06824, USA

    Neal Fishbach

  4. Yale Cancer Center, Yale University School of Medicine, 15 York Street, New Haven, CT, 06510-3221, USA

    Kimberly Lezon-Geyda

  5. Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, CT, 06520, USA

    Daniel Zelterman

  6. Department of Medicine, University Case Hospital, 11100 Euclid Ave, Cleveland, OH, 44106, USA

    Lyndsay Harris

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  1. Carlos Acevedo-Gadea
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  9. Maysa M. Abu-Khalaf
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Correspondence to Maysa M. Abu-Khalaf.

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Acevedo-Gadea, C., Hatzis, C., Chung, G. et al. Sirolimus and trastuzumab combination therapy for HER2-positive metastatic breast cancer after progression on prior trastuzumab therapy. Breast Cancer Res Treat 150, 157–167 (2015). https://doi.org/10.1007/s10549-015-3292-8

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