PMID- 31088410 OWN - NLM STAT- MEDLINE DCOM- 20190910 LR - 20200225 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 19 IP - 1 DP - 2019 May 14 TI - Everolimus in hormone receptor-positive metastatic breast cancer: PIK3CA mutation H1047R was a potential efficacy biomarker in a retrospective study. PG - 442 LID - 10.1186/s12885-019-5668-3 [doi] LID - 442 AB - BACKGROUND: Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), has been shown to increase the efficacy of endocrine therapies in hormone receptor (HR)-positive metastatic breast cancer. However, because breast cancer is a highly heterogeneous disease, the responses of different patients to everolimus may vary. Therefore, we performed this study to better select patients who will benefit most from or be resistant to everolimus. METHODS: Patients with HR-positive breast cancer who were treated with everolimus at the Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to March 2017 were enrolled in the present study. Mutations in ctDNA were assayed in 1021 tumor-related genes via gene panel target capture-based next-generation sequencing. RESULTS: In total, 120 patients with metastatic breast cancer who were treated with everolimus were enrolled in the present study. The median progression-free survival (PFS) of all patients was 5.1 months (95% confidence interval [CI] 3.9-6.3 months). No difference in survival was observed between patients who received endocrine drugs used in previous treatment regimens and patients who did not receive these drugs (median PFS 5.2 and 5.1 months, respectively, p > 0.05). Additionally, we did not find any difference in outcomes between patients who had primary resistance to previously used endocrine drugs and patients who had nonprimary resistance to previous treatments (p > 0.05). Multivariate analysis showed that < 3 metastatic sites, < 2 lines of previous endocrine therapy, < 2 lines of previous chemotherapy, and treatment with everolimus combined with fulvestrant were associated with improved survival (p < 0.05). Sixteen patients underwent ctDNA analysis before everolimus treatment. The frequency of PIK3CA gene mutations was 62.5%, and H1047R was the most frequently detected mutation. Patients with the PIK3CA/H1047R mutation had longer PFS than patients with wild-type or other mutant forms of PIK3CA, and the median PFS in these two groups of patients was 8.8 and 4.1 months, respectively (p < 0.05). CONCLUSIONS: Our data suggest that patients who receive more lines of chemotherapy or endocrine therapy are less likely to benefit from everolimus. For everolimus combination therapy, we can even select endocrine drugs that gave rise to primary resistance in previous treatments. Additionally, the PIK3CA/H1047R mutation may be a potential biomarker of sensitivity to everolimus. FAU - Yi, Zongbi AU - Yi Z AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. FAU - Ma, Fei AU - Ma F AUID- ORCID: 0000-0001-9432-1902 AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. drmafei@126.com. FAU - Liu, Binliang AU - Liu B AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. FAU - Guan, Xiuwen AU - Guan X AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. FAU - Li, Lixi AU - Li L AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. FAU - Li, Chunxiao AU - Li C AD - State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. FAU - Qian, Haili AU - Qian H AD - State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. FAU - Xu, Binghe AU - Xu B AD - Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.17, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China. LA - eng GR - 81472453/National Natural Science Foundation of China/ GR - D161100000816004/Major Project of Beijing Municipal Science and Technology Commission/ GR - CAMS-12M-1-010, 2017-I2M-3-004/CAMS Initiative for Innovative Medicine/ PT - Journal Article DEP - 20190514 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Biomarkers, Tumor) RN - 0 (Receptors, Steroid) RN - 22X328QOC4 (Fulvestrant) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (PIK3CA protein, human) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/therapeutic use MH - Biomarkers, Tumor/*genetics MH - Breast Neoplasms/*drug therapy/genetics/metabolism MH - Class I Phosphatidylinositol 3-Kinases/*genetics MH - Everolimus/*administration & dosage/therapeutic use MH - Female MH - Fulvestrant/*administration & dosage/therapeutic use MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Middle Aged MH - *Mutation MH - Neoplasm Metastasis MH - Patient Selection MH - Precision Medicine MH - Receptors, Steroid/metabolism MH - Retrospective Studies MH - Sequence Analysis, DNA MH - Survival Analysis MH - Treatment Outcome PMC - PMC6515626 OTO - NOTNLM OT - Biomarkers OT - Breast neoplasms OT - Everolimus OT - ctDNA COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: The study was reviewed and approved by the ethics committee at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. The collection and sequencing of peripheral blood samples of patients who consented to participate in ctDNA analysis were approved by the ethics committee (ref: 16-038/1117). Written informed consent was obtained from all patients who participated in the ctDNA analysis. Due to the retrospective approach of this study, the need for informed consent from patients who did not participate int he ctDNA analysis was waived by the ethics committees. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/05/16 06:00 MHDA- 2019/09/11 06:00 PMCR- 2019/05/14 CRDT- 2019/05/16 06:00 PHST- 2018/02/27 00:00 [received] PHST- 2019/05/01 00:00 [accepted] PHST- 2019/05/16 06:00 [entrez] PHST- 2019/05/16 06:00 [pubmed] PHST- 2019/09/11 06:00 [medline] PHST- 2019/05/14 00:00 [pmc-release] AID - 10.1186/s12885-019-5668-3 [pii] AID - 5668 [pii] AID - 10.1186/s12885-019-5668-3 [doi] PST - epublish SO - BMC Cancer. 2019 May 14;19(1):442. doi: 10.1186/s12885-019-5668-3.