Psychosocial and Quality of Life in Women Receiving the 21-Gene Recurrence Score Assay: The Impact of Decision Style in Women with Intermediate RS

Multigene assays such as the 21-gene recurrence score (RS) quantify risk for recurrence and potential benefit from chemotherapy in early-stage, ER+ breast cancers. Few studies have assessed the impact of testing on patient-reported outcomes such as cancer-related distress or quality of life. The few studies that have assessed these outcomes do not consider potential modifiers, such as the patients’ level of involvement in the treatment decision-making process. In the current study, 81 breast cancer patients who received the RS assay completed cross-sectional surveys. We used linear multiple regression to assess whether test result, decision-making role (passive versus shared/active), and their interaction contributed to current levels of distress, quality of life, and decisional conflict. There were no associations between these variables and test result or decision-making role. However, women who received an intermediate RS and took a passive role in their care reported higher-cancer-related distress and cancer worry and lower quality of life than those who took a shared or active role. These data should be confirmed in prospective samples, as these poorer outcomes could be amenable to intervention

Culturally targeted video improves psychosocial outcomes in latina women at risk of hereditary breast and ovarian cancer

Latina women at risk of hereditary breast and ovarian cancer (HBOC) have lower awareness, knowledge, and use of genetic counseling and testing services (GCT) than non-Latina Whites. Few interventions have been developed to reduce these disparities among at-risk Latinas. This pilot study assessed the impact of a culturally targeted narrative video developed by our team. The study included 40 Latina immigrants living in the United States who were at risk of HBOC, including a ected and una ected women. We assessed pre-post di erences in psychosocial outcomes. Participants were 47.35 years old on average (SD = 9.48). Most (70%) were una ected with cancer, had an annual income of $40,000 or less (65%), an education of High School or less (62.5%), and were uninsured (77.5%). The video significantly enhanced knowledge (p < 0.001), positive attitudes (p < 0.05), anticipatory positive emotions (p < 0.05), and intentions to participate in counseling (p < 0.001). Importantly, the video also significantly reduced negative attitudes (p < 0.05), and attitudinal ambivalence (p < 0.001). The culturally targeted video shows preliminary evidence in improving psychosocial outcomes related to GCT uptake in Latinas at risk for HBOC. This intervention is a promising easily-disseminable strategy to address disparities in GCT utilizationThis research was funded by the National Cancer Institute (R03CA191543; Hurtado-de-Mendoza and Sheppard, MPIs). This project was also supported by Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) by Federal Funds; the National Center for Advancing Translational Sciences (NCATS); and the National Institutes of Health (NIH), through the Clinical and Translational Science Awards Program (CTSA) (KL2TR001432; Hurtado-de-Mendoza. PI), and by the Ministry of Science, Innovation, and Universities in Spain (PGC2018-093821-B-I00, FEDER, MICINN, Carrera, PI)

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Randomized Noninferiority Trial of Telephone vs In-Person Genetic Counseling for Hereditary Breast and Ovarian Cancer: A 12-Month Follow-Up

Background: Telephone delivery of genetic counseling is an alternative to in-person genetic counseling because it may extend the reach of genetic counseling. Previous reports have established the noninferiority of telephone counseling on short-term psychosocial and decision-making outcomes. Here we examine the long-term impact of telephone counseling (TC) vs inperson counseling (usual care [UC]). Methods: We recruited high-risk women for a noninferiority trial comparing TC with UC. Of 1057 potentially eligible women, 669 were randomly assigned to TC (n = 335) or UC (n = 334), and 512 completed the 12-month follow-up. Primary outcomes were patient-reported satisfaction with genetic testing decision, distress, and quality of life. Secondary outcomes were uptake of cancer risk management strategies. Results: TC was noninferior to UC on all primary outcomes. Satisfaction with decision (d = 0.13, lower bound of 97.5% confidence interval [CI] = -0.34) did not cross its one-point noninferiority limit, cancer-specific distress (d = -2.10, upper bound of 97.5% CI = -0.07) did not cross its four-point noninferiority limit, and genetic testing distress (d = -0.27, upper bound of 97.5% CI = 1.46), physical function (d = 0.44, lower bound of 97.5% CI = -0.91) and mental function (d = -0.04, lower bound of 97.5% CI = -1.44) did not cross their 2.5-point noninferiority limit. Bivariate analyses showed no differences in risk-reducing mastectomy or oophorectomy across groups; however, when combined, TC had significantly more risk-reducing surgeries than UC (17.8% vs 10.5%; chi(2) = 4.43, P = .04). Conclusions: Findings support telephone delivery of genetic counseling to extend the accessibility of this service without long-termadverse outcomes.This study was supported by grants (R01 CA108933 and P30 CA051008) from the National Cancer Institute and by the Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research.Peer Reviewe

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 50 end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Correction: Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.

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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores