A Polygenic Risk Score for Breast Cancer in US Latinas and Latin American Women.

BACKGROUND: More than 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Because most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry. METHODS: We conducted a pooled case-control analysis of US Latinas and Latin American women (4658 cases and 7622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (P < 5 × 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression, and assessed discrimination using an area under the receiver operating characteristic curve. We also assessed PRS performance across quartiles of Indigenous American genetic ancestry. All statistical tests were two-sided. RESULTS: Of 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally statistically significant (P < .05). The PRS was associated with breast cancer risk, with an odds ratio per SD increment of 1.58 (95% confidence interval [CI = 1.52 to 1.64) and an area under the receiver operating characteristic curve of 0.63 (95% CI = 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry. CONCLUSIONS: The 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

Breast Cancer Screening in the Precision Medicine Era: Risk-Based Screening in a Population-Based Trial.

Ongoing controversy over the optimal approach to breast cancer screening has led to discordant professional society recommendations, particularly in women age 40 to 49 years. One potential solution is risk-based screening, where decisions around the starting age, stopping age, frequency, and modality of screening are based on individual risk to maximize the early detection of aggressive cancers and minimize the harms of screening through optimal resource utilization. We present a novel approach to risk-based screening that integrates clinical risk factors, breast density, a polygenic risk score representing the cumulative effects of genetic variants, and sequencing for moderate- and high-penetrance germline mutations. We demonstrate how thresholds of absolute risk estimates generated by our prediction tools can be used to stratify women into different screening strategies (biennial mammography, annual mammography, annual mammography with adjunctive magnetic resonance imaging, defer screening at this time) while informing the starting age of screening for women age 40 to 49 years. Our risk thresholds and corresponding screening strategies are based on current evidence but need to be tested in clinical trials. The Women Informed to Screen Depending On Measures of risk (WISDOM) Study, a pragmatic, preference-tolerant randomized controlled trial of annual vs personalized screening, will study our proposed approach. WISDOM will evaluate the efficacy, safety, and acceptability of risk-based screening beginning in the fall of 2016. The adaptive design of this trial allows continued refinement of our risk thresholds as the trial progresses, and we discuss areas where we anticipate emerging evidence will impact our approach.

The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia.

The familial aggregation of breast cancer has been well-described with approximately 25% of breast cancers attributable to inherited mutations in currently known breast cancer susceptibility genes. PALB2 c.3113G>A (p.Trp1038*) is a protein-truncating mutation which has been associated with high estimated risk of breast cancer in Australian women (91%; 95% CI = 44-100) to age 70 years. This study screened for PALB2 c.3113G>A in germline DNA representing 871 unrelated individuals from "high-risk" breast and/or ovarian cancer families evaluated in the setting of a Familial Cancer Centre in Australia. The PALB2 c.3113G>A mutation was identified in eight of 871 probands (0.92%) from these families. Median age of diagnosis was 42 years. Five of these eight women had contra-lateral breast cancers. Available data suggests that PALB2 c.3113G>A is a rare mutation with estimated breast cancer risks similar in magnitude to that associated with BRCA2 mutations. Although the proportion of high-risk women carrying this PALB2 mutation is low, research efforts should continue in order to effect its translation into clinical genetic testing practice.