Abstract P3-07-05: Non-amplification ERBB2 genomic alterations in 5,605 cases of refractory and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies
Authors: Ross JS , Wang K , Ali SM , Chumsri S , Elvin JA , Vergilio J-A , Suh J , Yelensky R , Lipson D , Chmielecki J , Miller VA , Stephens PJ 
Published: May 2016

Background: Non-amplification ERBB2 alterations (ERBB2 mut) in advanced/metastatic breast cancer (mBC) are not detected by IHC or FISH, but when detected by DNA sequencing assays can lead to clinical responses to anti-HER2 targeted therapy. We queried a database of more than 43,000 clinical cases to uncover the frequency, type and associated genomic alterations (GA) in mBC driven by ERBB2 mut and highlight clinical responses to small molecule drug and antibody-based anti-HER2 therapeutics.

Methods: DNA was extracted from 40 microns of FFPE sections from 5,605 mBC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay of up to 315 genes to a mean coverage depth of &gt;600X. The results were analyzed for base substitutions, short insertions and deletions, selected rearrangements, and copy number changes.

Results: 698 (12.5%) of 5,605 mBC featured ERBB2 alterations. 596 (10.6%) featured ERBB2 amplifications and 137 (2.4%) featured ERBB2mut. 35 (0.6%) of total mBC had both ERBB2amp and ERBB2mut, which accounted for 5.0% of all ERBB2 altered mBC. The 137 ERBB2mut mBC cases had a median age of 61 years (range 29 to 93 years) and were sequenced to a mean depth of 600X. Samples utilized for CGP included 52 (38%) from the patient's primary BC and 85 (62%) from metastatic sites including bone/soft tissue/skin (12%), liver (20%), LN (14%), serous cavities (6%), lung (4%) and miscellaneous sites (6%). 71 (52%) mBC were submitted as carcinoma NOS, 44 (32%) as IDC, 22 (16%) as ILC and 1 (1%) as mucinous mBC. Of the 137 ERBB2mut cases, 8 featured more than 1 ERBB2 mut. There were 124 (85%) ERBB2 kinase domain mutations and 15 (10%) extra-cellular domain ERBB2mut. The most common genes co-altered in ERBB2mut mBC were TP53 (49%), PIK3CA (42%), CDH1 (37%), MYC (17%), and CCND1 (16%). The enrichment of ERBB2mut in CDH1 mut mBR was significant (p=0.0006) and associated with relapsed lobular mBC. Multiple case examples of kinase domain and extra-cellular domain ERBB2mut mBC responding to a variety of anti-HER2 targeted therapies will be presented.

Conclusions: In this large series of 5,605 mBC, 20% of the total ERBB2 alterations were non-amplification ERBB2mut not detectable by standard of care IHC and FISH slide-based HER2 tests. Given the demonstration of ERBB2mut driven mBC responsive to anti-HER2 targeted therapies in this study, expansion of clinical trials designed to detect these ERBB2mut cases with CGP and optimize the targeted therapies for these patients is strongly recommended.

Citation Format: Ross JS, Wang K, Ali SM, Chumsri S, Elvin JA, Vergilio J-A, Suh J, Yelensky R, Lipson D, Chmielecki J, Miller VA, Stephens PJ. Non-amplification ERBB2 genomic alterations in 5,605 cases of refractory and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-05.