Abstract P4-15-03: Activating mutations in ERBB2/HER2 as found by FoundationOneTM represent potential therapeutic targets in breast cancer
Authors: Palmer Gary A , Ross Jeffrey S , Wang Kai , Frampton Garrett M , Ali Siraj M , Palma Norma , Morosini Deborah , Miller Vincent A , Yelensky Roman , Lipson Doron , Stephens Philip J , Chmielecki Juliann 
Published: May 2015

Background: Targeted ERBB2/HER2 inhibitors are FDA-approved for the treatment of breast and gastric cancers. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) to test for overexpression and amplification of ERBB2/HER2, respectively, are performed as part of routine clinical care. Recently, activating mutations in ERBB2 have been reported and may confer sensitivity to targeted agents. Testing for these mutations is not routine, and testing for amplifications is not done outside of approved indications. We explored the complete spectrum of activating ERBB2 mutations and amplifications across a collection of ∼7,300 solid tumor specimens, including a large number of breast cancer specimens, to determine a)how many breast cancer patients could benefit from HER2-targeted therapy due to activating mutations in ERBB2 and b)how widespread ERBB2 alterations are across the solid tumor spectrum.

Methods: Extracted DNA from clinical tumor samples underwent comprehensive genomic profiling using FoundationOne . 3769 exons of 236 cancer-related genes and 47 introns from 19 genes that are frequently rearranged in cancer were fully sequenced to high, uniform coverage and results were analyzed for base substitutions, insertions and deletions, amplifications/deletions, and rearrangements.

Results: Known oncogenic ERBB2 alterations were identified in approximately 6% of all solid tumors across 27 different histologies. Of all the ERBB2 alterations, activating mutations in ERBB2 were identified in 131 samples and amplifications were observed in 246 samples. Two samples harbored an ERBB2 rearrangement. Ten samples harbored multiple ERBB2 mutations, yet mutations and amplifications were mutually exclusive in 91% of mutated cases. ERBB2 amplification in breast and gastric cancers accounted for only 30% of these alterations. Breast cancer accounted for 37% of all the ERBB2 alterations detected, and included primarily amplifications. 25% of the alterations found in breast cancers were activating base substitutions. Standard tests for overexpression or amplification of ERBB2 would fail to detect these potentially treatable mutations. Non-amplification ERBB2 alterations were enriched in cases of relapsed lobular breast cancer. Multiple breast cancer patients with non-amplification ERBB2 alterations have responded to combinations of anti-HER2 targeted therapies.

Conclusions: Comprehensive genomic profiling through FoundationOne identifies 25% more breast cancers that may be susceptible to HER2 targeted therapy due to the presence of activating mutations in ERBB2. Also, many more solid tumor cases could potentially benefit as well from ERBB2 testing. The current policy of testing only breast and gastric tumors for only HER2 amplifications is greatly limiting the potential value of the ERBB2/HER2 inhibitors.

Citation Format: Gary A Palmer, Jeffrey S Ross, Kai Wang, Garrett M Frampton, Siraj M Ali, Norma Palma, Deborah Morosini, Vincent A Miller, Roman Yelensky, Doron Lipson, Philip J Stephens, Juliann Chmielecki. Activating mutations in ERBB2/HER2 as found by FoundationOneTM represent potential therapeutic targets in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-03.