Killeen, Jeffrey

e18523 Background: Noninvasive breast cancers ( e.g. ductal and lobular carcinoma in situ) are highly treatable nonobligate precursors to invasive breast cancers. However, even after treatment, some women develop second breast cancers (SBCs), increasing their mortality risk. Prognosticators may inform treatment recommendations for women at higher risk of SBC. In this study, risk factors for SBC were evaluated using deidentified data from the Hawaiʻi Tumor Registry (HTR), an NCI SEER registry. The HTR covers a uniquely multiethnic, statewide population allowing for elucidation of disparities in understudied U.S. populations. Methods: Women initially diagnosed between 1973-2017 with noninvasive (ductal and lobular) breast cancer were identified. Patient demographics, cancer characteristics, and treatment information were collected. Univariate (UVA) and multivariate (MVA) logistic regression analyses were used to identify factors associated with SBC, defined as a breast cancer diagnosis > 6 months after their prior cancer. Results: Of 7,057 women diagnosed with a first noninvasive breast cancer, 696 (10%) developed SBC. Invasive ipsilateral (iiSBC) and invasive contralateral (icSBC) disease represented 9% and 20% of patients who developed SBC, respectively. The five most prevalent ethnic groups were Chinese, Filipino, Japanese, Native Hawaiian, and White. When adjusting for confounders, women who developed iiSBC were more likely to be Native Hawaiian (odds ratio [OR] = 3.20, 95% CI = 2.07-4.94) or Filipino (OR = 1.72, 95%CI = 1.02-2.91) when compared to Whites; diagnosed between 1990-1999 (OR = 2.06, 95%CI = 1.27-3.34); and not have undergone surgical treatment (OR = 2.93, 95%CI = 1.42-6.04). Women who developed iiSBC were less likely to be > 50 years old (OR = 0.67, 95%CI = 0.49-0.90); diagnosed between 2010-2017 (OR = 0.18, 95%CI = 0.09-0.35); received lumpectomy with radiation therapy (OR = 0.54, 95%CI = 0.35-0.72); and undergone mastectomy (OR = 0.48, 95%CI = 0.32-0.72). Women who developed an icSBC were more likely to be Native Hawaiian (OR = 1.58, 95%CI = 1.06-2.35) or Filipino (OR = 1.60, 95%CI = 1.06-2.42). These women were also less likely to have been diagnosed between 2010-2017 (OR = 0.30, 95%CI = 0.17-0.53). On a subset analysis separating all patients with SBC by first course treatment type, there were no statistically significant differences for treatment type based on race/ethnicity. Conclusions: Overall, in this observational study, Native Hawaiian women, Filipino women, and younger women had increased odds of developing invasive SBC. This study highlights racial disparities in SBC development risk that was not previously appreciated among disaggregated groups of Pacific Islanders and Asian women when compared to White women. This may help oncologists understand the risk of developing SBC in these understudied populations.

Abstract Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.