PMID- 25687356 OWN - NLM STAT- MEDLINE DCOM- 20151120 LR - 20211203 IS - 1573-7217 (Electronic) IS - 0167-6806 (Linking) VI - 150 IP - 1 DP - 2015 Feb TI - Sirolimus and trastuzumab combination therapy for HER2-positive metastatic breast cancer after progression on prior trastuzumab therapy. PG - 157-67 LID - 10.1007/s10549-015-3292-8 [doi] AB - 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. FAU - Acevedo-Gadea, Carlos AU - Acevedo-Gadea C AD - Section of Medical Oncology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA, usaguampa@gmail.com. FAU - Hatzis, Christos AU - Hatzis C FAU - Chung, Gina AU - Chung G FAU - Fishbach, Neal AU - Fishbach N FAU - Lezon-Geyda, Kimberly AU - Lezon-Geyda K FAU - Zelterman, Daniel AU - Zelterman D FAU - DiGiovanna, Michael P AU - DiGiovanna MP FAU - Harris, Lyndsay AU - Harris L FAU - Abu-Khalaf, Maysa M AU - Abu-Khalaf MM LA - eng PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150217 PL - Netherlands TA - Breast Cancer Res Treat JT - Breast cancer research and treatment JID - 8111104 RN - 0 (Biomarkers) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - P188ANX8CK (Trastuzumab) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use MH - Biomarkers MH - Breast Neoplasms/*drug therapy/*metabolism/pathology MH - Disease Progression MH - Female MH - Humans MH - Immunohistochemistry MH - Leukocytes, Mononuclear/metabolism MH - Middle Aged MH - Neoplasm Metastasis MH - Neoplastic Cells, Circulating/metabolism MH - Receptor, ErbB-2/*metabolism MH - Retreatment MH - Sirolimus/administration & dosage MH - TOR Serine-Threonine Kinases/metabolism MH - Trastuzumab/administration & dosage MH - Treatment Outcome EDAT- 2015/02/18 06:00 MHDA- 2015/12/15 06:00 CRDT- 2015/02/18 06:00 PHST- 2014/12/02 00:00 [received] PHST- 2015/01/28 00:00 [accepted] PHST- 2015/02/18 06:00 [entrez] PHST- 2015/02/18 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] AID - 10.1007/s10549-015-3292-8 [doi] PST - ppublish SO - Breast Cancer Res Treat. 2015 Feb;150(1):157-67. doi: 10.1007/s10549-015-3292-8. Epub 2015 Feb 17.