Search

Introduction: De-regulation of the class I phosphoinositide 3’-kinase (PI3K) pathway has long been known to contribute to the development and progression of many tumors. However, the FDA only recently approved the first selective inhibitor of PIK3CA, the p110-alpha catalytic subunit of PI3K, specifically for use in treatment of a subset of PIK3CA-mutant breast carcinomas. Given the emergence of this therapeutic class of agents, we sought to identify other subsets of breast tumors that may be driven largely by PIK3CA mutations and which therefore could be candidates for these therapies. In breast fibroepithelial neoplasms, mutations in PIK3CA have been occasionally reported in borderline and malignant phyllodes tumors. In contrast, mutations in MED12 are common and recurrent across the entire spectrum of benign and malignant breast fibroepithelial tumors, and are enriched in borderline/malignant phyllodes cases that still have benign fibroadenoma-like areas. In the current study, we sought to define the histologic and molecular features of PIK3CA-mutant phyllodes tumors. Methods: From 2014 to 2019, we analyzed clinical tumor samples using comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform. We searched our case archive to find breast phyllodes tumors with known or likely pathogenic alterations in PIK3CA and other known tumor-related genes. All cases were clinically advanced. We reviewed pathology reports, histopathology, and patient clinical data. Results: We identified 12 (16%) of 76 breast phyllodes tumors in our case archive as PIK3CA-mutant. Median patient age for PIK3CA-mutant phyllodes tumors was 56 years. Cases consisted of 6 primary tumors, 2 local recurrences, and 4 lung metastases. Primary tumor size measured from 38 to 220 mm (median 100 mm; mean 114 mm). Digital slides were available for histology review in 9 cases. Cases showed uniformly malignant histology, with no benign or fibroadenoma-like regions. 3 cases showed malignant heterologous elements. Compared to the rest of our breast phyllodes tumor cohort, PIK3CA-mutant cases showed significantly fewer pathogenic genomic alterations in MED12 (8% vs. 55%, p=0.0037) and TP53 (17% vs. 56%, p=0.0245), as well as a trend to fewer mutations in RB1 (0% vs. 22%, p=0.11). The other most frequently mutated genes in the PIK3CA-mutant group were TERTp (70%), CDKN2A (67%), and NF1 (50%). Conclusions: PIK3CA-mutant phyllodes tumors define a unique subset of tumors characterized by aggressive histologic features and largely lacking the MED12 mutations seen in many fibroepithelial neoplasms. These findings provide compelling rationale for comprehensive genomic profiling of advanced cases of this disease in an effort to inform therapeutic options including clinical trials of PI3K-targeted agents in this setting. Citation Format: Erik A Williams, Ethan S Sokol, Dean C Pavlick, Nikunj Shah, Julia A Elvin, Jo-Anne Vergilio, Jonathan K Killian, Nhu Ngo, Douglas Lin, Vincent A Miller, Jeffrey S Ross. PIK3CA-mutant breast phyllodes tumors show a uniformly aggressive histology and significant mutual exclusivity with MED12 mutation [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-07.

Introduction: One major form of vulvar squamous cell carcinoma (vSCC) is associated with detectable high-risk strains of human papillomavirus (hrHPV) and is often accompanied by usual-type vulvar intraepithelial neoplasia (VIN). The second major form of vSCC is often associated with chronic dystrophic or inflammatory lesions in postmenopausal women, does not harbor detectable HPV infection, and is often preceded by p53-mutant differentiated VIN. While studies have examined the two subtypes, no large-scale genomic study has been performed to our knowledge. We sought to assess the genomics of a large cohort of aggressive vSCCs, with an aim to identify distinct mutational signatures based on the presence or absence of hrHPV genome reads. Methods: 280 vSCC were tested by hybridization capture of up to 406 cancer-related genes evaluated for base substitutions, small indels, amplification (amp), and rearrangements. HPV genome sequences were detected by de novo assembly of non-human sequencing reads and BLASTn comparison against all viral nucleotide sequences in the NCBI RefSeq database. Tumor mutational burden (TMB, mutations/Mb) was determined on ~1.1 Mbp of sequenced DNA. PD-L1 status was determined by IHC (Dako 22C3), with ≥50% tumor proportion score defined as high positive. Results: 102/280 vSCCs contained hrHPV sequences. Of these, 90 were HPV-16, 7 HPV-18, 1 HPV-31, 3 HPV-33, 1 HPV-58, and 1 HPV-67. Patients were significantly younger in the HPV(+) group (median 59 v. 64 years, p=0.001). Compared with the HPV(–) cohort, HPV(+) cases showed significantly more pathogenic genomic alterations (GA) in PIK3CA (31% vs. 17%, p=0.004), PTEN (14% vs. 2%, p10*6%24%3%19% Conclusions: vSCCs show significant differences in molecular profile based on HPV status. 63% of metastatic HPV(+) cases (54% overall) have a potentially actionable alteration in the PI3K/mTOR pathway, and 42% of metastatic HPV(–) cases (39% overall) have at least one potential predictive biomarker* for response to immunotherapy. Our findings provide compelling rationale for tandem comprehensive genomic profiling and HPV assessment of advanced vulvar SCCs to more fully inform therapeutic options and stratification in clinical trials. Citation Format: Erik A Williams, Adrienne J Werth, Meagan Montesion, Ethan S Sokol, Dean C Pavlick, Nikunj A Shah, Jo-Anne Vergilio, Natalie A Danziger, Jonathan K Killian, Douglas A Lin, Vincent A Miller, Jeffrey S Ross, Julia A Elvin. Vulvar squamous cell carcinoma: Comprehensive genomic profiling of HPV(+) versus HPV(–) forms reveals a different set of potentially actionable biomarkers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B091. doi:10.1158/1535-7163.TARG-19-B091