title: Multiple gene aberrations and breast cancer: lessons from super-responders.
abstract: BACKGROUND
  The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.
  
  
  METHODS
  We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 g PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response.
  
  
  CONCLUSIONS
  Patients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Box 0455, Houston, TX, 77030, USA. jjwheler@mdanderson.org.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Box 0455, Houston, TX, 77030, USA. jtatkins@mdanderson.org.
authors.forename: Johnique T
authors.initials: JT
authors.lastname: Atkins
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1400 Holcombe Boulevard, Box 0455, Houston, TX, 77030, USA. fjanku@mdanderson.org.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. smoulder@mdanderson.org.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.affiliation: Foundation Medicine, Cambridge, MA, USA. ryelensky@foundationmedicine.com.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine, Cambridge, MA, USA. pstephens@foundationmedicine.com.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California at San Diego Moores Cancer Center, La Jolla, CA, USA. rkurzrock@ucsd.edu.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000077384:Anastrozole; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009570:Nitriles / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D000077384:Anastrozole; D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D009363:Neoplasm Proteins; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C546842:MTOR protein, human; C484760:PIK3CA protein, human