ESMO @ ECC 2015: Comprehensive Genomic Profiling Detects High Frequency of ERBB2 Extracellular Domain Mutations in Multiple Cancer Types

Results from comprehensive genomic profiling of a large series of tumour samples were reported at the European Cancer Congress (ECC 2015), convening in Vienna, Austria, 25 - 29 September 2015, that determined the incidence of mutations within the extracellular domains of ERBB2 that can be targeted by existing anti-HER2 therapies. 

Oncogenic mutations in the extracellular domain (ECD) of ERBB2 are generally mutually exclusive of ERBB2 amplification and occur in a wide variety of human cancers. The majority of ERBB2 ECD mutations consist of S310F and S310Y base substitutions. Recent reports have demonstrated that tumours with these genomic alterations associate with dramatic responses to anti-HER2 targeted therapies.     

Prof. Jeffrey Ross, Pathology Department, Medical Centre, Albany, USA and Medical Director of Foundation Medicine, Inc., Cambridge, MA USA, lead author of the study,pointed to several examples of ERBB2 ECD mutation positive tumour response to anti-HER2 targeted therapies, including currently available and experimental kinase inhibitors and available antibody therapeutics.

Clinically relevant genomic alterations revealed by CGP that are undetectable by other modalities 

This study employed comprehensive genomic profiling (CGP) to analyse 37,772 clinical paraffin embedded (FFPE) cancer samples using hybridisation capture of exonic regions from 315 cancer-related genes and select introns from 19 genes commonly rearranged in cancer.

The investigators used ≥ 50 ng samples of DNA, which were extracted and sequenced to high, uniform median coverage (623X) to assess base substitutions, short INDELs, copy number alterations, gene fusions/rearrangements, and to identify clinically relevant genomic alterations (CRGA), defined as sequences that corresponded to targets of existing anti-cancer drugs that are either on the market or being used in registered clinical trials.

CGP revealed that S310F or S310Y ERBB2 ECD mutations occurred in 177 (0.5%) of the 37,772 clinical samples that were sequenced while just 34 (0.01%) non-ECD ERBB2 point mutations were identified in this series.

The majority (76%) of the ERBB2 ECD mutations were confined to 7 tumour types, including bladder/kidney urothelial carcinoma (UC), carcinoma of unknown primary (CUP), biliary tract carcinoma (BTC), lung cancer, colorectal carcinoma (CRC), breast cancer, and gastroesophageal carcinoma.

The incidence of ERBB2 ECD extracellular domain alterations was significant, as compared to other tumour types: in UC (18%) with mutations occurring in 3.20% of tumours (p < 0.0001), CUP (18%) where it was present in 0.96% of tumours (p = 0.00049), and BTC (7%) where it was present in 1.10% of tumours (p = 0.0045) (see Table).

ERBB2 ECD mutation was also highly associated with the micropapillary variant of UC compared to conventional UC (p < 0.0001). More than 30 other tumour types accounted for the remaining 24% of the ERBB2 ECD mutations identified.

CGP detected genomic sequence alterations that are not detectable by routine side based methods (IHC and FISH) and thus are missed when ERBB2 status is determined by routine/conventional methods only; Prof. Ross reported that normal ERBB2 copy number was detected in 154 (87%) of the ERBB2 ECD mutated cancers and, therefore, would not have been identified as ERBB2 “positive” by FISH or IHC testing.

Conclusions 

The authors emphasise that, although ERBB2 ECD mutations are rare, these important targetable genomic alterations occur across a wide range of tumour types and are enriched in specific tumours, making these tumours potential targets for existing therapies. 

These ERBB2 sequence alterations remain undetectable by other modalities, such as IHC or FISH, and represent a promising new opportunity to utilise comprehensive genomic profiling to personalise treatment for patients with advanced and refractory malignancies.

Reference 

P144: Therapeutically relevant extracellular domain mutations in ERBB2/HER2 are observed across multiple tumor types and are sssociated with major responses to anti-HER2 targeted therapies