4577 - Pan-Cancer Genomic Landscape of the Cyclin D1/FGF3,4,19 (11q13) Amplicon Including Associations with HPV Status, and ESR1 and AR Alterations

Background

The amplicon of CCND1, FGF3, FGF4, and FGF19 on chromosome 11q13 encodes cyclinD1, regulator of the CDK4/6 cell cycle kinase and FGF ligands for FGFR kinases, which are targets for drug development. We sought to characterize the pan-cancer genomic landscape of this amplicon.

Methods

Tumor samples from 255,117 patients with clinically advanced cancers underwent comprehensive genomic profiling (CGP) with an adaptor-ligation/hybrid capture-based assay of coding DNA of up to 395 cancer-related genes and select introns of 28 genes that are frequently involved in genomic rearrangements to detect base substitutions, insertions and deletions, copy number alterations, and rearrangements.

Results

4% (10,202/255,117) of all cases harbored the 11q13 amplicon (+). The median copy number was 12 (range 6-176). Of the 10 cancers where 11q13+ was most frequent, five were squamous cell carcinomas (SCC) including esophagus SCC (ESCC) (47.3% 11q13+) as the most enriched, head and neck SCC (HNSCC) (17.0%), as well as lung SCC (LSCC) (10.8%). Given ESCC and LSCC are overwhelmingly HPV-, we assessed 11q13 occurrence by HPV status in HNSCC. 3.4% of the 11q13+ HNSCC cases were HPV+, compared to 36.8% of the 11q13- HNSCC samples (p = 9.4e-52). 2 (20%) of the 10 cancers most frequently 11q13+ were the classically ER+ breast invasive lobular carcinoma (17.7%) and breast carcinoma NOS (16.6%). In 441 ER+ breast cancers, 286 (19.8%) were 11q13+. Of these ER+/11q13+ cases, 19.2% also featured ESR1. In contrast, only 14.3% of the ER+/11q13- cases also had ESR1 mutations (p = 0.05). Similarly, in 7103 cases of predominantly castrate resistant prostate cancers, 210 (3.0%) featured 11q13+. 38.6% of the 11q13+ prostate cancer cases also harbored mutations in AR while only 19.9% of the 11q13- cases harbored AR mutations (p = 6.2e-11).

Conclusions

SCCs are enriched for 11q13+ with preliminary evidence for linking them to HPV- status. The co-occurrence of 11q13+ with both ESR1 and AR mutations suggests a co-operative role in acquired resistance to hormonal therapy, but not to TKIs. Further investigation will be 11q13+ in the development of SCC and acquired resistance to hormonal therapies appears warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Foundation Medicine.

Funding

Foundation Medicine.

Disclosure

J.Johnson: Consultant: Foundation Medicine Consultant: Rakuten-Aspyrian. J. Lee: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. R. Madison: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. A.B. Schrock: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Advisory / Consultancy: Revolution Medicines. B.M. Alexander: Leadership role, Full / Part-time employment: Foundation Medicine; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Schlesinger Associates; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Precision Health Economics; Research grant / Funding (self): Puma; Research grant / Funding (self): Celgene; Research grant / Funding (self): Eli Lilly. J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Officer / Board of Directors: Celsius Therapeutics. J. Chung: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Incysus Therapeutics; Advisory / Consultancy: Revolution Medicines.