PMID- 28550065 OWN - NLM STAT- MEDLINE DCOM- 20170922 LR - 20211204 IS - 2373-2873 (Electronic) IS - 2373-2873 (Linking) VI - 3 IP - 5 DP - 2017 Sep TI - Exceptional durable response to everolimus in a patient with biphenotypic breast cancer harboring an STK11 variant. LID - 10.1101/mcs.a000778 [doi] LID - a000778 AB - Metastatic triple-negative breast cancer comprises 12%-17% of breast cancers and carries a poor prognosis relative to other breast cancer subtypes. Treatment options in this disease are largely limited to systemic chemotherapy. A majority of clinical studies assessing efficacy of targeted therapeutics (e.g., the mammalian target of rapamycin [mTOR] inhibitor everolimus) in advanced breast cancer patients have not utilized predictive genomic biomarker-based selection and have reported only modest improvement in the clinical outcome relative to standard of care. However, recent reports have highlighted significant clinical responses of breast malignancies harboring alterations in genes involved in the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway to mTOR-inhibitor-involving regimens, underscoring the potential clinical benefit of treating subsets of breast cancer patients with molecularly matched targeted therapies. As the paradigm of cancer treatment shifts from chemotherapeutic regimens to more personalized approaches, the identification of additional reliable biomarkers is essential for identifying patients likely to derive maximum benefit from targeted therapies. Herein, we report a near-complete and ongoing 14-mo response to everolimus therapy of a heavily pretreated patient with biphenotypic, metastatic breast cancer. Genomic profiling of the metastatic triple-negative liver specimen identified a single reportable point mutation, STK11 F354L, that appears to have undergone loss of heterozygosity. No other alterations within the PI3K/mTOR pathway were observed. Published functional biochemical data on this variant are conflicting, and germline data, albeit with unclear zygosity status, are suggestive of a benign polymorphism role. Together with the preclinical data, this case suggests further investigation of this variant is warranted to better understand its role as a potential biomarker for mTOR inhibitor sensitivity in the appropriate clinical context. CI - (c) 2017 Parachoniak et al.; Published by Cold Spring Harbor Laboratory Press. FAU - Parachoniak, Christine A AU - Parachoniak CA AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Rankin, Andrew AU - Rankin A AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Gaffney, Bernadette AU - Gaffney B AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Hartmaier, Ryan AU - Hartmaier R AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Spritz, Dan AU - Spritz D AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Erlich, Rachel L AU - Erlich RL AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Miller, Vincent A AU - Miller VA AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Morosini, Deborah AU - Morosini D AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Stephens, Phil AU - Stephens P AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. FAU - Ross, Jeffrey S AU - Ross JS AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. AD - Albany Medical College, Albany, New York 12208, USA. FAU - Keech, John Jr AU - Keech J Jr AD - MultiCare Regional Cancer Center, Gig Harbor, Washington 98335, USA. FAU - Chmielecki, Juliann AU - Chmielecki J AD - Foundation Medicine, Cambridge, Massachusetts 02141, USA. LA - eng PT - Case Reports PT - Journal Article DEP - 20170901 PL - United States TA - Cold Spring Harb Mol Case Stud JT - Cold Spring Harbor molecular case studies JID - 101660017 RN - 0 (Biomarkers, Tumor) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (STK11 protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Biomarkers, Tumor/genetics MH - Breast Neoplasms/drug therapy MH - Drug Resistance, Neoplasm MH - Everolimus/*therapeutic use MH - Female MH - Humans MH - Loss of Heterozygosity/genetics MH - Middle Aged MH - Phosphoinositide-3 Kinase Inhibitors MH - Precision Medicine/methods MH - Protein Serine-Threonine Kinases/*genetics/metabolism MH - Proto-Oncogene Proteins c-akt/antagonists & inhibitors MH - Signal Transduction MH - TOR Serine-Threonine Kinases/genetics/metabolism MH - Triple Negative Breast Neoplasms/*drug therapy/*genetics PMC - PMC5593157 OTO - NOTNLM OT - neoplasm of the breast EDAT- 2017/05/28 06:00 MHDA- 2017/09/25 06:00 PMCR- 2017/09/01 CRDT- 2017/05/28 06:00 PHST- 2015/10/27 00:00 [received] PHST- 2017/05/23 00:00 [accepted] PHST- 2017/05/28 06:00 [pubmed] PHST- 2017/09/25 06:00 [medline] PHST- 2017/05/28 06:00 [entrez] PHST- 2017/09/01 00:00 [pmc-release] AID - mcs.a000778 [pii] AID - 10.1101/mcs.a000778 [doi] PST - epublish SO - Cold Spring Harb Mol Case Stud. 2017 Sep 1;3(5):a000778. doi: 10.1101/mcs.a000778. Print 2017 Sep.