Citations

Abstract Background: Germline cancer testing panels provide an effective method for identifying individuals at increased risk for breast cancer. However, estimates of risk for triple negative breast cancer (TNBC) (estrogen receptor-negative, progesterone receptor-negative, HER2-negative) associated with pathogenic mutations in panel genes have not been established. We sought to define the genes that contribute to TNBC. Methods:Germline hereditary cancer multigene panel testing results were obtained for 8,753 TNBCs evaluated by a clinical testing laboratory. Associations between pathogenic mutations in individual genes and TNBC were assessed by comparing mutation frequencies in TNBCs and in the Exome Aggregation Consortium, non-Finn European, non-Cancer Genome Atlas reference controls. Results: Inactivating mutations in 21 known cancer predisposition genes were identified in 14.6% of TNBCs. BRCA1, BRCA2, PALB2, BARD1, and RAD51D alterations were associated with high risks (odds ratio(OR)>5.0) of TNBC and variants in BRIP1, RAD51C, MSH6, and TP53 were associated with moderate risks (OR>2). In contrast, ATM, CHEK2, NBN, and RAD50 yielded no clinically relevant risks of TNBC. Pathogenic mutations in these established non-BRCA1/2 TNBC susceptibility genes were detected in 6.3% of TNBCs. Similar trends were observed among African American TNBCs. Overall, 5.5% of TNBCs with pathogenic mutations did not meet NCCN clinical testing criteria for BRCA1/2 due to a lack of significant family history and diagnosis over the age of 60. Conclusions: The identification of genes associated with elevated risk of TNBC will improve understanding of the etiology of this aggressive form of breast cancer and inform risk management of individuals receiving panel testing. The high frequency of pathogenic variants suggests that all patients with TNBC, regardless of age of diagnosis or family history of cancer, should be considered for multigene panel testing. Citation Format: Couch FJ, Shimelis H, LaDuca H, Hu C, Hart SN, Polley EC, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS. Triple negative breast cancer predisposition genes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-01.

Abstract Background: Clinical panel testing has become routine practice for patients that are diagnosed with breast cancer at a young age and/or have a personal or family history of cancer. Associations with known breast cancer genes and breast cancer subtypes have been previously identified, such as BRCA1 associations with estrogen receptor negative (ER-) and triple negative (ER-/PR-/HER2-) breast cancers. However, the cancer predisposition genes associated with each of the four clinical subtypes of breast cancer have not been fully defined. We evaluated 24,901 Caucasian female breast cancer cases receiving clinical panel testing for 23 cancer predisposition genes and assessed associations between mutations in each gene and breast cancer subtypes. Methods: Germline hereditary cancer multigene panel testing results for cancer predisposition genes were obtained for 24,901 Caucasian female breast cancer cases evaluated by a clinical testing laboratory. Information on tumor histology, personal and family history of cancer, age at diagnosis, and previous genetic testing was provided by clinical care providers of patients receiving clinical cancer genetic testing. Breast cancer cases were classified into clinical breast cancer subtypes based on estrogen/progesterone hormone receptor status (HR) and HER2 status: Luminal A (HR+/HER2-), Luminal B (HR+/HER2-), HER2 subtype (HR-/HER2+), and Triple Negative (HR-/HER2-). The frequency of pathogenic or likely pathogenic mutations observed in each subtype was compared against the Exome Aggregation Consortium (ExAC) non-TCGA non-Finnish European population to estimate risks. Results: ATM was associated with moderate risks (odds ratio (OR)>2.0) of Luminal A, Luminal B, and HER2 subtypes of breast cancer, but was not associated with the Triple Negative subtype. PALB2 was associated with moderate risk for Luminal B subtype, but high risk (OR>5.0) for Luminal A, HER2, and triple negative subtypes. TP53 was associated with high risks for Luminal B and HER2 tumors. NBN, MRE11A, and RAD50 were not associated with any subtype of breast cancer. Conclusions: Identifying associations between inherited mutations (odds ratio (OR)>2.0) and breast cancer subtypes can inform clinical risk management, treatment options, and therapeutic development efforts. Citation Format: Lilyquist J, Laduca H, Hu C, Na J, Polley EC, Hart SN, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS, Couch FJ. Associations between hereditary cancer panel predisposition genes and breast cancer histological subtypes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-02.

Abstract Background: Endemic nasopharyngeal carcinoma (NPC) refers to non-keratinizing (NK) subtypes harboring Epstein Barr virus (EBV) that frequently express programmed death-ligand 1 (PD-L1). We recently reported ≥30% of NPC harbor MHC class 1 gene alterations in a whole genome study. Method: We investigated the activity of nivolumab (NIVO) & relationship with PD-L1 & HLA expression (exp) in tumor cells (TC) & tumor infiltrating cells (TIL). Eligible patient (pt)s had to fail ≥ 1 prior line of platinum-based chemo. NIVO (3mg/kg IV, q2 weeks) was given until disease progression (PD). Archived tumors were analyzed for PD-L1 (DAKO) & HLA mutations (indicated by loss of HLA-A &/or B exp). Result: A total of 45 pts were enrolled across 11 sites from Oct 2015 to June 2016. Overall, 43 and 44 pts were evaluable respectively for response rate (RR, RECIST) & adverse events (AE). The median age was 57 years, 77% pts were males & 84% were Asians. The median number of prior chemo was 3 (range 1-9 lines). Of the 43 evaluable pts, there were 8 confirmed (19%, 95% CI: 8-33%) & 1 unconfirmed partial response (PR), 17 PD (40%), 14 stable disease (SD, 33%) & 3 pts were not assessed. One pt (MD015-027) had an unconfirmed clinical CR in an occipital metastasis (met). Pts received a median of 3 cycles of NIVO (range 1 - 14). Median overall survival has not been reached yet. Of the 44 pts evaluable for AE, 8 (18.2%) had grade 3 or higher treatment-related AEs & 1 pt died of sepsis. The most common grade 3 or higher AEs were increase in alanine/aspartate aminotransferase (n=3), & 1 pt respectively for hyponatremia, neutropenia, fatigue & diarrhea. Of the 21 tumor samples analyzed, 11/21 (52%) had >1% PD-L1 expressed mainly in TC. Table 1 outlines relationship between RR & PD-L1 exp. All pts with PR had >5% PD-L1 exp & one pt (34003-022) with CR (nasopharynx) & PR (lung mets) had the highest exp (80%). Majority of pts with PD had <1% PD-L1 exp tumors. One primary progressor (34003-032) had a PD-L1 +ve tumor harboring a complete loss of HLA-B signal (TC), but intact signal in TILs & stromal cells. Conclusion: NIVO is active in this heavily pre-treated group of pts with NK-NPC and longer follow-up is needed for survival endpoints. Preliminary result suggests PD-L1 exp may predict benefit from NIVO. The analytical result of all 45 tumors will be presented. Table 1.PD-L1 exp and RECIST response in 21 ptsPD-L1%espRR%PRSDPD0-11<1%-265%24-10%--120%-1-30%11-80%1--Total498 Citation Format: Brigette B. Ma, Boon Cher Goh, Wan T. Lim, Kwok W. Lo, Edwin P. Hui, Jonathan W. Riess, Mark Agulnik, Alex Y. Chang, Julie A. Kish, Dean W. Lim, Douglas R. Adkins, Kevin J. Cullen, Barbara J. Gitlitz, Nathan R. Foster, Adam M. Pettinger, Sanna Mckinzie, Ka F. To, Brian Costello, Howard Streicher, Anthony T. Chan. Multicenter phase II study of nivolumab in previously treated patients with recurrent and metastatic non-keratinizing nasopharyngeal carcinoma - Mayo clinic Phase 2 Consortium P2C-MN026, NCI9742, NCT02339558 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT076. doi:10.1158/1538-7445.AM2017-CT076

Abstract Purpose: The relevance of inherited pathogenic variants in cancer predisposition genes to pancreatic cancer (PC) is not well understood. Several small studies have identified pathogenic variants in 4% to 14% of unselected PC patients using multigene panels of predisposition genes, but only BRCA2, ATM, and PALB2 have been clearly implicated in this disease. We aimed to assess the clinical and molecular characteristics of PC patients referred for hereditary cancer genetic testing, and to estimate the risk of PC associated with pathogenic variants in panel-based cancer predisposition genes. Methods: PC patients (n=1,819) were ascertained from a large cohort of over 140,000 patients undergoing multigene panel testing (MGPT) of predisposition genes between March 2012 and June 2016 at a single diagnostic laboratory. Clinical histories and molecular results were reviewed and summarized. Gene-level variant frequencies among PC cases were compared to those from the Exome Aggregation Consortium (ExAC) to calculate gene-specific pancreatic cancer risk ratios. Results: PC patients were predominantly Caucasian (76.5%) and female (58.9%), with a median age at diagnosis of 61 years (51.7). Of these, 33.5% reported additional cancer primaries, and 44.8% reported a family history of PC. Overall, 15.4% of PC patients were found to have at least one pathogenic/likely pathogenic variant in panel-based predisposition genes. Genes with the highest frequencies of pathogenic/likely pathogenic variants included BRCA2 (3.9%), ATM (3.6%), CHEK2 (excluding p.Ile157Thr) (2.0%), PALB2 (1.5%), VHL (1.4%), CDKN2A (1.2%), BRCA1 (0.8%), and MSH6 (0.8%). 21.8% of BRCA1 and BRCA2 carriers did not meet BRCA1/2 testing criteria and 61.5% of MSH6 carriers did not meet Lynch syndrome testing criteria. No CDKN2A families met diagnostic criteria for familial atypical multiple mole melanoma syndrome, and 44% did not report any personal or family history of melanoma. To estimate associations between pathogenic variants and pancreatic cancer, Caucasian PC cases were compared to non-Finnish European, non-TCGA ExAC reference controls. Pathogenic variants in ATM, BRCA2, CDKN2A, MSH6, and PALB2 were significantly associated with high PC risks. Pathogenic variants in BRCA1 were associated with a moderate risk of PC (RR=2.7). Conclusions: These findings shed light on the spectrum of mutations that can be expected for PC patients referred for cancer predisposition testing. The results confirm the associations of CDKN2A and BRCA2 variants with PC, and expand on the phenotypic spectrum associated with these variants. Furthermore, these results suggest that ATM, PALB2, and MSH6 may be high-risk PC genes, warranting further investigation in case-control and family-based studies. Citation Format: Holly LaDuca, Chunling Hu, Hermela Shimelis, Eric Polley, Jenna Lilyquist, Mary Helen Black, Brigette Tippin Davis, David E. Goldgar, Jill Dolinsky, Fergus J. Couch. What have we learned from pancreatic cancer patients undergoing multigene panel testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2017-4286

Abstract Background: NPC is endemic to Asia and over 40% of cases harbor PIK3CA amplification. MK2206 is an allosteric AKT inhibitor with activity in NPC in vitro. Methods: Pts who had progressed after palliative chemotherapy (chemo) for metastatic or recurrent NPC, received oral MK-2206 at 200 mg on Days 1, 8, 15 & 22 of each 28-day cycle until disease progression. Plasma samples were collected at serial time points during cycle 1 for EBV DNA analysis, archived tumor samples were collected where feasible. The primary dual endpoints (2-stage design) consisted of RECIST-defined tumor response rate (RR) and 6-month (m) progression-free survival (PFS) rate. Secondary endpoints were overall survival (OS), PFS and adverse events (AEs). Results: Of the 21 pts enrolled, the median age was 47 years (range: 32-67), 91% were male, 81% had prior radiotherapy and 81% had > 1 prior line of palliative chemo. At the time of analysis, 20 out of 21 pts have ended treatment. The best responses were: 1 partial response (PR, 5%) lasting 4 ms; 10 stable disease (SD, 50%), 9 progressive disease (PD, 45%). The 6-m PFS rate was 38.9% (95% CI: 18.1-59.3%) and median PFS was 2.7 ms (95% CI: 0.9-7.2 ms). The 6-m OS rate was 67.9% (95% CI: 41.8-84.1%) and median survival has not been reached. In 7 pts who had SD more than or equal to 6 ms, the duration of treatment ranged from 6.4-13.9 ms. Of the 21 pts evaluable for AEs, 12 pts (57%) had at least one grade 3 AE [[Unable to Display Character: –]] macular rash (6 pts - 29%), dysphagia (2 pts - 10%), hyperglycemia (2 pts - 10%) (see Table 1). The tumor samples of 7 pts were analyzed by FISH; 3 showed PIK3CA amplification, including 1 pt with chromosome 3 polysomy. Amongst these pts, 1 had SD more than 6ms, 1 had SD more than 12 ms, and 1 is still on treatment. Pts who had SD less than 6 m or PD did not have PIK3CA amplification. Conclusions: MK2206 is well tolerated and has signs of activity in unselected pts with NPC. Preliminary results suggest that PIK3CA amplification may be related to prolonged disease stabilization from MK2206, and analysis for other PIK3CA gene alterations in more samples will be undertaken. Result of the plasma EBV DNA result will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B273. Citation Format: Brigette B. Ma, Boon Cher Goh, Wan Teck Lim, Eng Huat Tan, Gilberto de Lima Lopes, Edwin P. Hui, Ann D. King, Kwok Wai Lo, Herbert Loong, Leung Li, Nathan Foster, Michael Kam, Sing Fai Leung, Charles Erlichman, Anthony TC Chan. Multicenter Phase II study of MK-2206 in previously treated patients (pts) with recurrent and metastatic nasopharyngeal carcinoma (NPC): Mayo Clinic Phase II Consortium (Protocol: MC1079). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B273.