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Background Associations between germline alterations in women and cancer risks among their relatives are largely unknown. Methods We identified women from 2 Swedish cohorts Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) and prevalent KARMA (pKARMA), including 28 362 women with genotyping data and 13 226 with sequencing data. Using Swedish Multi-Generation Register, we linked these women to 133 389 first-degree relatives. Associations between protein-truncating variants in 8 risk genes and breast cancer polygenic risk score in index women and cancer risks among their relatives were modeled via Cox regression. Results Female relatives of index women who were protein-truncating variant carriers in any of the 8 risk genes had an increased breast cancer risk compared with those of noncarriers (hazard ratio [HR] = 1.85, 95% confidence interval [CI] = 1.52 to 2.27), with the strongest association found for protein-truncating variants in BRCA1 and 2. These relatives had a statistically higher risk of early onset than late-onset breast cancer (P  = .001). Elevated breast cancer risk was also observed in female relatives of index women with higher polygenic risk score (HR per SD = 1.28, 95% CI = 1.23 to 1.32). The estimated lifetime risk was 22.3% for female relatives of protein-truncating variant carriers and 14.4% for those related to women in the top polygenic risk score quartile. Moreover, relatives of index women with protein-truncating variant presence (HR = 1.30, 95% CI = 1.06 to 1.59) or higher polygenic risk score (HR per SD = 1.04, 95% CI = 1.01 to 1.07) were also at higher risk of nonbreast hereditary breast and ovary cancer syndrome-related cancers. Conclusions Protein-truncating variants of risk genes and higher polygenic risk score in index women are associated with an increased risk of breast and other hereditary breast and ovary syndrome–related cancers among relatives. [ABSTRACT FROM AUTHOR]

Background: The Ontario Breast Screening Program recommends annual mammography to women age 50-74 years at increased risk because of family history of breast or ovarian cancer or personal history of ovarian cancer or mammographic density 75% or greater. Few studies have examined the diagnostic accuracy of recommendations based on risk factors and included screen film as well as digital mammography.Methods: A retrospective design identified concurrent cohorts of women age 50-74 years screened annually or biennially with digital mammography only between 2011 and 2014 and followed until 2016 or breast cancer diagnosis. Diagnostic accuracy measures were compared between women screened annually because of first-degree relative of breast or ovarian cancer or personal history of ovarian cancer (n = 67 795 women), mammographic density 75% or greater (n = 51 956), or both (n = 3758) and those screened biennially (n = 526 815). The association between recommendation and sensitivity and specificity was assessed using generalized estimating equation models. All P values are two-sided.Results: For annual screening because of family or personal history vs biennial, sensitivity was statistically significantly higher (81.7% vs 70.6%; OR = 1.86, 95% CI = 1.48 to 2.34), particularly for invasive cancers and postmenopausal women. Although there was no statistically significant difference in sensitivity for annual screening for mammographic density 75% or greater, specificity was statistically significantly lower (91.3%; OR = 0.87, 95% CI = 0.80 to 0.96) vs biennial (92.3%), particularly for women age 50-59 years.Conclusion: Compared with biennial screening, annual screening improved detection for women with a family or personal history of breast and/or ovarian cancer, supporting screening that is more frequent. The benefit for annual screening for women with higher mammographic density must be weighed against possible harms of increased false positives. [ABSTRACT FROM AUTHOR]

Background: Increased risk of malignancies other than pancreatic cancer (PC) has been reported among first-degree relatives (FDRs) of PC patients; however, the roles of susceptibility gene mutations are unclear. We assessed risk for 15 cancers among FDRs of unselected PC probands.Methods: Data on 17 162 FDRs, with more than 336 000 person-years at risk, identified through 2305 sequential PC probands enrolled at Mayo Clinic (2000-2016) were analyzed. Family history data were provided by the probands. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated, comparing malignancies observed among the FDRs with that expected using Surveillance, Epidemiology, and End Results (SEER) data. Genetic testing was performed among a subset of probands (n = 2094), enabling stratified analyses among FDRs based on whether the related proband tested positive or negative for inherited mutation in 22 sequenced cancer susceptibility genes. All statistical tests were two-sided.Results: Compared with SEER, PC risk was twofold higher among FDRs of PC probands (SIR = 2.04, 95% CI = 1.78 to 2.31, P < .001). Primary liver cancer risk was elevated among female FDRs (SIR = 2.10, 95% CI = 1.34 to 3.12, P < .001). PC risk was more elevated among FDRs of mutation-positive probands (SIR = 4.32, 95% CI = 3.10 to 5.86) than FDRs of mutation-negative probands (SIR = 1.77, 95% CI = 1.51 to 2.05, between-group P < .001). FDR PC risk was higher when the related proband was younger than age 60 years at diagnosis and mutation-positive (SIR = 5.24, 95% CI = 2.93 to 8.64) than when the proband was younger than age 60 years but mutation-negative (SIR = 1.76, 95% CI = 1.21 to 2.47, between-group P < .001). Breast (SIR = 1.29, 95% CI = 1.01 to 1.63) and ovarian (SIR = 2.38, 95% CI = 1.30 to 4.00) cancers were elevated among FDRs of mutation-positive probands.Conclusions: Our study substantiates twofold risk of PC among FDRs of PC patients and suggests increased risk for primary liver cancer among female FDRs. FDRs of susceptibility mutation carriers had substantially increased risk for PC and increased risk for breast and ovarian cancers. [ABSTRACT FROM AUTHOR]

In cascade testing, genetic testing for an identified familial pathogenic variant extends to disease-free relatives to allow genetically targeted disease prevention. We evaluated the results of an online initiative in which carriers of 1 of 30 cancer-associated genes, or their first-degree relatives, could offer low-cost testing to at-risk first-degree relatives. In the first year, 1101 applicants invited 2280 first-degree relatives to undergo genetic testing. Of invited relatives, 47.5% (95% confidence interval [CI] = 45.5 to 49.6%) underwent genetic testing, and 12.0% (95% CI = 9.2 to 14.8%) who tested positive continued the cascade by inviting additional relatives to test. Of tested relatives, 4.9% (95% CI = 3.8 to 6.1%) had a pathogenic variant in a different gene from the known familial one, and 16.8% (95% CI = 14.7 to 18.8%) had a variant of uncertain significance. These results suggest that an online, low-cost program is an effective approach to implementing cascade testing, and that up to 5% of the general population may carry a pathogenic variant in 1 of 30 cancer-associated genes. [ABSTRACT FROM AUTHOR]