Relapsed Classic E-Cadherin (CDH1) Mutated Invasive Lobular Breast Cancer (ILC) Features IHC/FISH Negative HER2 (ERBB2) Gene Mutations Sensitive to Anti-HER2 Targeted Therapies: A Next Generation Sequencing (NGS) Study
Jeffrey S Ross, Christine Sheehan, Ann Boguniewicz, Geoff Otto, Sean Downing, John Curran, Gary Palmer, Siraj Ali, Roman Yelensky, Doron Lipson, Vincent Miller, Philip Stephens. Albany Medical College, Albany, NY; Foundation Medicine Inc., Cambridge, MA
Background: Although ILC generally has a favorable prognosis, relapsed ILC may follow an aggressive clinical course. In this study, we queried whether NGS could identify novel and unanticipated targets of therapy for patients with relapsed ILC.
Design: NGS was performed on hybridization-captured, adaptor ligation based libraries using DNA extracted from 4 FFPE sections cut at 10 microns from 12 ILC that had relapsed after primary surgery and adjuvant hormonal therapy. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 to at an average depth of 983X and evaluated for genomic alterations (GA) including point mutations (mut), insertions, deletions, copy number alterations (amp), and select gene fusions/rearrangements. Actionable GA were defined as those identifying anti-cancer drugs on the market or in registered clinical trials (CT).
Results: The 12 ILC (mean age 54) included 10 (83%) grade II and 2 (17%) grade III tumors. Three ILC (25%) were Stage III and 9 (75%) were Stage IV at the time of NGS. NGS was performed on: primary ILC 4 (33%), lymph node metastases 3 (25%), liver metastases 2 (18%), pleural fluid cell blocks 2 (18%), a skin recurrence 1 (1%) case(s). NGS found a total of 38 GA in the ILC series with an average of 3.2 GA per tumor. 17 GA (1.4 per tumor) were potentially associated with clinical benefit of targeted therapies and 1 (0.1 per tumor) GA associated with targeted therapy resistance. Eleven/twelve (92%) of patients' tumors harbored at least one GA potentially associated with clinical benefit of targeted therapies. The GA generated potential entry into a total of 47 CT (average 3.9 per tumor). ILC GA included mut in CDH1 (100%); TP53 (42%); PIK3CA (42%); RB1 (18%); and KRAS and RUNX1 each at (9%) and amp in myc (18%), FGFR1 (18%) and ESR1 (9%). Two (18%) of ILC had mut in HER2 (ERBB2) in tumors that were HER2 negative by IHC and FISH. Both patients demonstrated significant disease regression during treatment by anti HER2 targeted therapy with trastuzumab and lapatinib.
Conclusions: NGS of CDH1 mutated ILC uncovers an unexpectedly high frequency of GA including HER2 mut sensitive to anti-HER2 targeted therapies. Deep sequencing of genomic DNA can provide a broad cancer-related gene survey at a depth of coverage that provides sensitive detection for all classes of GA, and when applied to ILC patients can reveal actionable GA that inform treatment decisions.
Tuesday, March 5, 2013 11:15 AM
Proffered Papers: Section B, Tuesday Morning