Testing For Breast Cancer Susceptibility Research Articles

Breast cancer risks associated with missense variants in breast cancer susceptibility genes

BackgroundProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.MethodsWe analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.ResultsThe most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.ConclusionsThese results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

The Screen Project: Guided Direct-To-Consumer Genetic Testing for Breast Cancer Susceptibility in Canada.

Simple SummaryThe Screen Project was initiated in 2017 to offer BRCA1 and BRCA2 genetic screening to all Canadians over the age of 18 who wish to know their mutation status. Study subjects registered online and were sent a saliva sample kit. Of the 1269 tested individuals between March 2017 and January 2019, 30 (2.4%) had a pathogenic mutation in BRCA1 or BRCA2 (20 women and 10 men). Seventy-five percent of the female mutation carriers underwent a bilateral mastectomy and/or salpingo-oophorectomy within a year of receiving a positive result. The study results endorse a model where genetic testing is offered directly to the consumer via a home-delivered kit and a saliva sample, and some clinical guidance for those with positive test results. We believe that testing has substantial benefits, and therefore, we would like to expand testing to as many eligible women as possible.There is limited information of the outcomes of direct-to-consumer testing for BRCA1 and BRCA2 mutations. The Screen Project was initiated in 2017 to offer BRCA1 and BRCA2 genetic screening to all Canadians over the age of 18 who wish to know their mutation status. Patients enrolled in the study from 2017 to 2019 and were followed for one year after the receipt of a genetic test result. Study subjects registered online and were sent a saliva sample kit, which was shipped to the reference laboratory. Pre-test genetic counselling and counselling for mutation-negative subjects was optional and at the individual’s discretion. There were 1269 tested individuals between March 2017 and January 2019. A total of 1157 (93%) were women and 87 (7%) were men. Sixty-six percent had a first- or second-degree relative with breast or ovarian cancer. Of the 1269 tested individuals, 30 (2.4%) had a pathogenic mutation in BRCA1 or BRCA2 (20 women and 10 men). Seventy-five percent of the female mutation carriers underwent a bilateral mastectomy and/or salpingo-oophorectomy within a year of receiving a positive result. Genetic counselling was available at no cost to all participants but was requested by only 5% of the non-carriers. The study subjects expressed a high degree of satisfaction with the process.

OP053 - The Screen Project: guided direct-to-consumer genetic testing for breast cancer susceptibility in Canada

There is limited information of the outcomes of direct-to-consumer testing for BRCA1 and BRCA2 mutations. The Screen Project was initiated in 2017 to offer BRCA1 and BRCA2 genetic screening to all Canadians over the age of 18 who wish to know their mutation status. Patients enrolled in the study from 2017 to 2019 and were followed for one year after the receipt of a genetic test result. Study subjects registered online and were sent a saliva sample kit, which was shipped to the reference laboratory. Pre-test genetic counselling and counselling for mutation-negative subjects was optional and at the individual’s discretion. There were 1269 tested individuals between March 2017 and January 2019. A total of 1157 (93%) were women and 87 (7%) were men. Sixty-six percent had a first- or second-degree relative with breast or ovarian cancer. Of the 1269 tested individuals, 30 (2.4%) had a pathogenic mutation in BRCA1 or BRCA2 (20 women and 10 men). Seventy-five percent of the female mutation carriers underwent a bilateral mastectomy and/or salpingo-oophorectomy within a year of receiving a positive result. Genetic counselling was available at no cost to all participants but was requested by only 5% of the non-carriers. The study subjects expressed a high degree of satisfaction with the process.

Abstract PS8-24: Clinical and pathologic characteristics of Turkish breast cancer (BC) patients screened with BRCA1, BRCA2 or 26 - gene inherited cancer panel testing: Single institution experience

Abstract Background: BRCA1 and BRCA2 mutations are responsible for two thirds of hereditary BC. Germline genetic testing for BC susceptibility has evolved from a single-gene analysis to a multigene panel testing. Identification of a pathogenic mutation in BRCA and other panel represent a therapeutic opportunity today. Methods: We aimed to investigate clinical and pathologic characteristics of BC patients who were referred to our center between 2011-2019 and underwent BRCA1, BRCA2 or 26-gene inherited cancer panel testing based on NCCN criteria for hereditary breast/ovarian cancer testing. We analyzed the frequency of pathogenic mutations and its relationship with clinical and pathologic factors. Results: A total of 576 patients were identified. Among them 356 (63%) had their test in our university, 218 (38%) patients had their test at other centers. Sixty-six % (n:376) of patients had panel testing, 34% had only BRCA 1-2 mutation test. Median age was 42(22-87) and 5 patients were male. Ten % of patients had metastatic disease, 70% had early BC and 20% had locally advanced stage at the time of referral. The indication for genetic testing was family history in 169 (29%) patients, triple negative (TN) subtype in 100 (17%) patients and age <45 years in 260 (45%) patients. Seventy-nine % of patients were premenopausal. A total of 114 (19%) patients had pathogenic mutations. The most commonly mutated genes were BRCA1 (n:38, 6%), BRCA2 (n:35, 6%), ATM (n:6), p53 (n:5), PALB2 (n:5), CHEK2 (n:5). Six patients had more than one pathogenic mutation. Among patients with pathogenic mutations 58% had ER positive, 27% had TN and 15 % had Her-2 positive disease. Thirty-four % of patients with TN tumors have pathogenic mutations, 23% of patients with TN tumors had BRCA mutations. TP53, PALB2 and CHEK2 mutations were more frequent in HR positive disease. Age <35 (p:0.002), triple negative subtype (p: 0.005) and menopausal status (p:0.001) were significantly associated with having pathogenic mutations in multivariate analysis. Conclusion: Two thirds of BC patients <35 years-old and one third of patients with TN tumors have pathogenic germline mutations in BC predisposing genes when they were screened in line with NCCN criteria. Citation Format: Aysun Isiklar, Aykut Soyder, Kanay Yararbas, Cumhur Ekmekci, Hulya Yazici, Gul Basaran. Clinical and pathologic characteristics of Turkish breast cancer (BC) patients screened with BRCA1, BRCA2 or 26 - gene inherited cancer panel testing: Single institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-24.

Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

BackgroundGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.MethodsWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.ResultsProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)–positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.ConclusionsThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)

The contemporary landscape of genetic testing and breast cancer: Emerging issues

The landscape of genetic testing for breast cancer susceptibility has transformed dramatically over the last decade and a half. Traditionally, the process of genetic testing resided fully within a medical infrastructure, from identification of appropriate testing candidates to gene selection to risk mitigation recommendations. More recently, decreasing costs, advancing technology, and a growing understanding of therapeutic implications of certain genetic test results have led to more widespread uptake of testing that increasingly involves broad multigene panels. Germline genetic testing for breast cancer susceptibility can now be obtained through one of three approaches: through clinical care; a direct-to-consumer (DTC) approach that is entirely consumer-driven; or a hybrid, patient-initiated, provider-mediated model. Increased access to testing has led to extensive dialogue about the best way to conduct testing and act on results. Points of discussion include: selection of appropriate candidates for genetic testing; optimal composition of genes on panels; informed consent; safe return of results; privacy; and legal protections for those found to have relevant pathogenic or likely pathogenic variants. As more individuals undergo genetic testing, a growing population of individuals with inherited breast cancer predisposition informs optimal management of cancer risk and also highlights unanswered questions. This article aims to review the current state of genetic testing for inherited breast cancer susceptibility including testing approaches, the legal, ethical and social landscape, and selected contemporary management issues.

Broad Application of Multigene Panel Testing for Breast Cancer Susceptibility—Pandora’s Box Is Opening Wider

Broad Application of Multigene Panel Testing for Breast Cancer Susceptibility—Pandora’s Box Is Opening Wider

The spectrum of mutations predisposing to familial breast cancer in Poland.

To optimize genetic testing, it is necessary to establish the spectrum of breast cancer-predisposing mutations in particular ethnic groups. We studied 1,018 women with a strong family history for breast cancer (families with hereditary breast cancer; HBC) from genetically homogenous population of Poland, which is populated by ethnic Slavs, for mutations in 14 cancer susceptibility genes. Additionally, we compared the frequency of candidate pathogenic variants in breast cancer cases and controls. Germline mutations were detected in 512 of 1,018 probands with breast cancer (50.3%), including BRCA1/2 mutations detected in 420 families and non-BRCA mutations seen in 92 families. Thirteen BRCA1/2 founder mutations represented 84% of all BRCA1/2-positive cases. Seven founder mutations of CHEK2, PALB2, NBN and RECQL represented 73% of all non-BRCA-positive cases. Odds ratios for hereditary breast cancer were 87.6 for BRCA1, 15.4 for PALB2, 7.2 for CHEK2, 2.8 for NBN and 15.8 for RECQL. Odds ratios for XRCC2, BLM and BARD1 were below 1.3. In summary, we found that 20 founder mutations in six genes (BRCA1/2, CHEK2, PALB2, NBN and RECQL) are responsible for 82% of Polish hereditary breast cancer families. A simple test for these 20 mutations will facilitate genetic testing for breast cancer susceptibility in Poland. It may also facilitate genetic testing for breast cancer susceptibility in other Slavic populations and women of Slavic descent worldwide.

Abstract PD1-07: Population genetic testing for breast cancer susceptibility

Abstract Background. Germline mutations in certain genes account for a large proportion of inherited risk for breast and ovarian cancer. The identification of asymptomatic mutation carriers could significantly reduce the incidence of these diseases as active risk management can dramatically reduce the risk of developing cancer. In most countries, identifying high-risk individuals is based on their family history. In general, a family is first identified because one family member develops cancer and, because of high-risk indicators is referred to a familial cancer centre (FCC). However, current data suggests that many BRCA1 or BRCA2 mutation carriers do not have a remarkable history of cancer in a close relative. Population-based genetic testing would be a far more effective strategy for identification of at-risk individuals. To test the feasibility of such a strategy we are conducting a population genetic testing trial for actionable mutations in 11 breast/ovarian cancer predisposition genes (BRCA1, BRCA2, PALB2, ATM, CDH1, PTEN, STK11, TP53, BRIP1, RAD51C, RAD51D) among 15,000 healthy women from the Australian population. Methods. All subjects are female participants in the LifePool cohort (www.lifepool.org) who had no personal history of breast or ovarian cancer at the time of DNA collection. Participants found to carry an actionable germline mutation were notified by letter with an invitation to contact the PeterMac telephone genetic counselling service for further information and/or also invited for counselling at an FCC. Only participants with an actionable mutation were notified of their genetic testing result. Results. Of the 5,557 women tested to date, 40 (0.72%) were carriers of mutations that are currently actionable in the Australian context (BRCA1 n=7, BRCA2 n=15, PALB2 n=15, ATM n=3). All 40 women accepted the invitation to attend a familial cancer centre for formal predictive testing. Less than 20% of the women would have met the minimum threshold for clinical genetic testing under current guidelines. A further 16 participants (0.29%) carried mutations in BRIP1, RAD51C and RAD51D but were not notified of the result as these genes are not currently actionable in Australia. No mutations were identified in CDH1, PTEN, STK11 or TP53. Conclusions. A relatively large proportion of cancer free-women from Australia carry high-risk mutations in BRCA genes and subsequent uptake of clinical genetic testing was very high. Population-based genetic testing is well accepted and can identify a much larger proportion of the at risk-population than contemporary family history based approaches. Citation Format: Campbell IG, Rowley S, Devereux L, McInerny S, Grewal N, Young M-A, Lee A, Trainer A, James P. Population genetic testing for breast cancer susceptibility [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 PD1-07.

Disentangling the determinants of interest and willingness-to-pay for breast cancer susceptibility testing in the general population: a cross-sectional Web-based survey among women of Québec (Canada)

ObjectivesTo identify common and specific individual factors that favour or impede women’s interest in and willingness-to-pay (WTP) for breast cancer susceptibility testing (BCST) and to identify the most impactful factors...

Targeted massively parallel sequencing characterises the mutation spectrum of PALB2 in breast and ovarian cancer cases from Poland and Ukraine

Loss-of-function germline mutations in the PALB2 gene are associated with an increase of breast cancer risk. The purpose of this study was to characterise the spectrum of PALB2 mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron–exon junctions of PALB2 in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease. Targeted-sequencing identified two frameshift deletions: PALB2:c.509_510del; p.R170Ifs in three women affected with breast cancer and PALB2:c.172_175del;p.Q60Rfs in one woman affected with ovarian cancer. A number of other previously described missense (some predicted to be damaging by PolyPhen-2 and CADD) and synonymous mutations were also identified in this population. This study is consistent with previous reports that PALB2:c.509_510del and PALB2:c.172_175del are recurrent mutations associated with breast cancer predisposition in Polish women with a family history of the disease. Our study contributes to the accumulating evidence indicating that PALB2 should be included in genetic testing for breast cancer susceptibility in these populations to enhance risk assessment and management of women at high-risk of developing breast cancer. This data could also contribute to ongoing work that is assessing the possible association between ovarian cancer risk and PALB2 mutations for which there is currently no evidence.

Abstract P2-09-01: Patient reported outcomes of multiplex breast cancer susceptibility testing utilizing a tiered-binned counseling and informed consent model in BRCA1/2 negative patients

Abstract Background:The risks, benefits and utilities of multiplex panels for breast cancer susceptibility are unknown and new counseling and informed consent models are needed. We sought to obtain patient reported outcomes of multiplex testing in BRCA1/2 negative patients utilizing a novel, previously piloted tiered-binned counseling model for multiplex testing. Methods:BRCA1/2 negative participants completed pre(V1) and post-test counseling(V2) and surveys evaluating cognitive, affective and behavioral responses to a 25-gene multiplex testing panel. We used linear regressions with estimation by GEE where appropriate. Results:376 patients have been approached. To date, 124 participants(33%) have consented to the study, 21(6%) declined and 231(61%) are considering. Of 95 who have completed pre-test counseling(V1), 88(93%) elected to proceed with 25-gene panel testing and (81%) were classified as making an informed choice after tiered-binned counseling. 6/53(11%) participants received a positive result, including 1 mutation in MSH2 and 5 in moderate penetrance genes (2 ATM, 1 BARD1, 1 CHEK2, 1 PALB2). 22/53(42%) participants received a variant of unknown significance(VUS). General anxiety and perceived utility decreased significantly with pre-test counseling and after results (Table 1). Knowledge increased with pre-test counseling; cancer worry increased after receipt of multiplex results. Higher cancer worry was associated only with lower income (2.6 points/income category, p<0.01). Those with a VUS had greater decreases in perceived utility compared to negative (p=0.01) or positive (p=0.003) results. To date, there are no other significant differences in knowledge, distress or uncertainty by test result. Medical management recommendations for the proband changed in 3/6 with a positive result. Cascade testing in the family was discussed as an option in 3/6 with a positive result. Conclusions:Many BRCA1/2-negative patients proceed with 25-gene cancer susceptibility testing if offered and most make informed choices utilizing a tiered-binned genetic counseling model. The tiered-binned counseling model is associated with increased knowledge, decreases in general anxiety and uncertainty after pre-test counseling and disclosure of results, but an increase in cancer worry after result disclosure. The clinical utility, long-term outcomes and differences in patient reported outcomes by test result remain unknown. Table 1 Baseline, Mean(SD)After V1, Mean(SD)After V2, Mean(SD) N=75ˆ;N=49ˆˆN=75ˆ;N=49ˆˆN=49ˆˆGeneral Anxiety (range 0-21)6.4(3.9)*;6.9(3.9)**6.0(4.3)*;6.6(4.2)**5.8(4.5)**General Depression (range 0-212.8(2.9);3.1(3.2)3.0(3.5);3.1(3.6)3.0(3.7)State Anxiety (range 20-80)35.5(11.2);36.6(11.9)35.5(11.8);36.8(11.9)36.1(12.2)Cancer Worry (range 0-75)18.2(13.5);20.1(13.8)**16.7(12.5);17.2(11.9)**21.0(13.9)**Knowledge (range 17-82)65.7(5.0)**;66.5(5.0)**68.0(5.7)**;68.4(5.6)**67.3(4.9)**Uncertainty (range 0-15)5.8(3.9);6.2(4.3)5.6(3.7);5.4(3.2)5.6(3.5)Perceived Utility (range 24-120)75.2(14.0)*;75.9(14.0)**73.0(14.1)*;74.1(13.4)**68.4(16.9)***p≤0.05 **p≤0.01. ˆcompleted V1. ˆˆcompleted V1 & V2. To date, 53 have received results and 49 have completed post-disclosure surveys. Citation Format: Bradbury AR, Patrick-Miller L, Egleston BE, Maxwell KN, Brandt A, Brower J, DiGiovanni L, Long JM, Powers J, Stopfer J, Nathanson KL, Domchek SM. Patient reported outcomes of multiplex breast cancer susceptibility testing utilizing a tiered-binned counseling and informed consent model in BRCA1/2 negative patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-01.

Targeted massively parallel sequencing of a panel of putative breast cancer susceptibility genes in a large cohort of multiple-case breast and ovarian cancer families

IntroductionGene panel testing for breast cancer susceptibility has become relatively cheap and accessible. However, the breast cancer risks associated with mutations in many genes included in these panels are unknown.MethodsWe...

Personalization of loco-regional care for primary breast cancer patients (part 2).

Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.

Personalization of loco-regional care for primary breast cancer patients (part 1).

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.

Abstract P4-12-10: Uptake and outcomes of multiplex testing for breast cancer susceptibility

Abstract Background: New counseling models for multiplex genetic testing for breast cancer susceptibility are needed. Further, the risks, benefits and utilities of multiplex genetic panels are unknown. Purpose: To obtain stakeholder feedback on an innovative tiered-binned model for pretest counseling and informed consent for multiplex testing and to evaluate the uptake of, cognitive and affective responses to and perceived utility of panel testing. Methods: Patients previously BRCA1/2- or BRCA1/2 untested completed in-person pre-test (V1) and post-test counseling (V2) and surveys regarding the novel counseling model and evaluating cognitive and affective responses to, and perceived utility of the 26 gene Myriad MyRisk panel for cancer susceptibility. Results: 49 patients (62% of eligible) enrolled and completed V1. 38% of decliners were not interested in panel testing. BRCA1/2- were more likely to proceed with MyRisk (89%) than BRCA1/2 untested (48%, p<0.01). Although not statistically significant, those who declined panel testing after V1 had higher anxiety, depression and cancer worry, but no difference in knowledge. They also had lower perceived utility (p=0.005). Most patients would not change anything about their V1 (86%) or V2 (91%) counseling. Surveys suggest that patients value the engagement, personalization, organization and visual aids of the novel counseling model. Potential refinements include enhancing assessments of informational overload, confusion and psychosocial needs, particularly with uncertain results. As shown in Table 1, event anxiety, depression, uncertainty and cancer worry did not change, while general anxiety decreased. Knowledge increased and perceived utility and satisfaction decreased significantly. Exploratory analyses by results to date (positive = 5; VUS = 9; negative =22), suggest no difference in uncertainty by test result. Patients with a positive result might experience greater event anxiety and have less decline in perceived utility (p=0.02) than those with a negative or VUS result. Table 1 BaselinePost V1Post V2 Mean (SD)Mean (SD)Mean (SD)General Anxiety6.8 (3.9)*6.1 (4.0)* 7.2 (3.5)*6.1 (3.6)*5.8 (4.2)*General Depression2.6 (3.0)2.3 (2.6) 2.6 (2.9)2.3 (2.6)2.9 (3.6)Event Anxiety37.1 (9.6)37.7 (9.5) 37.0 (8.9)37.3 (8.5)37.3 (9.4)Cancer Worry18.3 (15.7)16.9 (14.1) 18.4 (15.4)15.7 (14.1)6.6 (14.7)Knowledge (K) Total61.8 (6.1)**63.9 (6.4)** 62.1 (6.7)**64.1 (6.8)**66.3 (6.9)**K-Inheritance29.5 (3.2)30.0 (3.2) 29.7 (3.5)29.8 (3.3)30.3 (3.7)K-Benefits12.0 (1.4)12.3 (1.8) 12.0 (1.4)12.4 (1.7)12.4 (1.9)K-Limitations20.3 (3.2)**21.6 (2.8)** 20.4 (3.4)**21.9 (3.0)**23.6 (2.6)**Satisfaction 42.8 (3.8) 42.9 (3.6)*41.4 (2.6)*Uncertainty7.5 (4.3)6.9 (4.6) 7.7 (4.0)6.5 (4.5)6.7 (4.6)Perceived Utility 37.2 (7.9) 37.7 (7.0)*33.8 (8.6)**p,0.05, **p<0.001 Conclusion: With a tiered-binned counseling model, patients experience increased knowledge. Uptake of panel testing varies by prior testing and potentially by patient affective factors. Most patients do not experience negative psychological responses, although this may vary by test result. Declines in satisfaction and perceived utility may also vary by test result and may reflect the current unclear utility and uncertainty of multiplex testing. Citation Format: Angela R Bradbury, Linda Patrick-Miller, Brian L Egleston, Amanda Brandt, Jessica Long, Jacquelyn Powers, Jill Stopfer, Laura DiGiovanni, Jamie Brower, Susan M Domchek. Uptake and outcomes of multiplex testing for breast cancer susceptibility [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-10.

Patient feedback and early outcome data with a novel tiered-binned model for multiplex breast cancer susceptibility testing.

The risks, benefits, and utilities of multiplex panels for breast cancer susceptibility are unknown, and new counseling and informed consent models are needed. We sought to obtain patient feedback and early outcome data with a novel tiered-binned model for multiplex testing. BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing. Of 73 patients, 49 (67%) completed pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing (86%) than those untested for BRCA1/2 (43%; P < 0.01). Many patients declining testing reported concern for uncertainty and distress. Most patients would not change anything about their pre- (76%) or posttest (89%) counseling sessions. Thirty-three patients (72%) were classified as making an informed choice, including 81% of those who proceeded with multiplex testing. Knowledge increased significantly. Anxiety, depression, uncertainty, and cancer worry did not significantly increase with multiplex testing. Some patients, particularly those without prior BRCA1/2 testing, decline multiplex testing. Most patients who proceeded with testing did not experience negative psychological responses, but larger studies are needed. The tiered-binned approach is an innovative genetic counseling and informed consent model for further study in the era of multiplex testing.Genet Med 18 1, 25-33.

Psychosocial Factors Affecting the Use of Mammography Testing for Breast Cancer Susceptibility: An Eight-Month Follow-Up Study in a Middle-Aged Japanese Woman Sample

We examined the psychosocial factors affecting middle-aged Japanese women’s intentions to undergo mammography, as well as their actual usage of mammography by applying the Parallel Processing Model (PPM) of self regulation longitudinally. A total of 1030 middle-aged women living in all parts of Japan participated in this study through internet research from September 2010 to May 2011. The participants were evaluated on the basis of a battery of questionnaires mainly including demographics, perceived breast cancer risk, worry about breast cancer, mammography testing beliefs, intentions to use mammography, seeking information about mammography, and actual usage of mammography thrice over an eight-month period. The main results were as follows: 1) Perceived risk and cancer worry affected the intention of undergoing mammography, and this effect was mediated by beliefs about mammography testing. 2) Intention to use mammography and past mammography usage predicted future usage of mammography, with past mammography usage being the strongest predictor. 3) Information seeking about mammography was the strongest predictor of using mammography during the eight-month follow-up period of middle-aged women who had not undergone any mammography testing. PPM was a useful model to explain the mechanism behind middle-aged Japanese women’s intentions to use mammography, as well as their actual usage of mammography. In addition, past mammography experience was the strongest predictor of regular mammography usage and information seeking was a critical factor for the first-usage of mammography.

Individual and family characteristics associated with BRCA1/2 genetic testing in high‐risk families

Little is known about family members' interrelated decisions to seek genetic testing for breast cancer susceptibility. The specific aims of this cross-sectional, descriptive, cohort study were (i) to examine whether individual and family characteristics have a direct effect on women's decisions to use genetic testing for hereditary susceptibility to breast cancer and (ii) to explore whether family characteristics moderate the relationships between individual characteristics and the decision to use genetic testing. Participants were women (>18 years old) who (i) received genetic testing for hereditary breast cancer and who agreed to invite one of their female relatives into the study and (ii) female relatives who had NOT obtained genetic testing and were identified by pedigree analysis as having >10% chances of hereditary susceptibility to breast cancer. The final sample consisted of 168 English-speaking, family dyads who completed self-administered, mailed surveys with validated instruments. Multivariate conditional logistic regression analyses showed that the proposed model explained 62% of the variance in genetic testing. The factors most significantly associated with genetic testing were having a personal history of cancer; perceiving genetic testing to have more benefits than barriers; having greater family hardiness; and perceiving fewer negative consequences associated with a breast cancer diagnosis. No significant interaction effects were observed. Findings suggest that both individual and family characteristics are associated with the decision to obtain genetic testing for hereditary breast cancer; hence, there is a need for interventions that foster a supportive family environment for patients and their high-risk relatives.

Psychosocial Factors Affecting the Intentions to Use Mammography Testing for Breast Cancer Susceptibility: An Exploratory Study for Japanese Non-Clinical College Woman Sample

Psychosocial Factors Affecting the Intentions to Use Mammography Testing for Breast Cancer Susceptibility: An Exploratory Study for Japanese Non-Clinical College Woman Sample