Factors that differentiate cancer risk management decisions among females with pathogenic/likely pathogenic variants in PALB2, CHEK2, and ATM.

PURPOSE: Following disclosure of pathogenic or likely pathogenic variants in hereditary cancer genes, patients face cancer risk management decisions. Through this mixed-methods study, we investigated cancer risk management decisions among females with pathogenic or likely pathogenic variants in PALB2, CHEK2, and ATM to understand why some patients follow National Comprehensive Cancer Network guidelines, whereas others do not. METHODS: Survey and interview data were cross-analyzed using a 3-stage approach. Identified factors were used to conduct coincidence analysis and differentiate between combinations of factors that result in following or not following guidelines. RESULTS: Of the 13 participants who underwent guideline inconsistent prophylactic surgery, 12 fit 1 of 3 unique patterns: (1) cancer-related anxiety in the absence of trust in care, (2) provider recommending surgery inconsistent with National Comprehensive Cancer Network guidelines, or (3) surgery occurring before genetic testing. Two unique patterns were found among 18 of 20 participants who followed guidelines: (1) anxiety along with trust in care or (2) lack of anxiety and no prophylactic surgery before testing. CONCLUSION: Health care provider recommendations and trust in care may influence whether individuals receive care that is congruent with risk levels conferred by specific genes. Interventions are needed to improve provider knowledge, patient trust in non-surgical care, and patient anxiety.

A pooled case-only analysis of obesity and breast cancer subtype among Black women in the southeastern United States.

PURPOSE: To evaluate the association between obesity and the relative prevalence of tumor subtypes among Black women with breast cancer (BC). METHODS: We conducted a pooled case-only analysis of 1,793 Black women with invasive BC recruited through three existing studies in the southeastern US. Multivariable case-only polytomous logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between obesity, measured by pre-diagnostic body mass index (BMI), and human epidermal growth factor receptor 2 + (HER2 +) and triple negative BC (TNBC) subtype relative to hormone receptor (HR) + /HER2- status (referent). RESULTS: Among 359 premenopausal women, 55.4% of cases were HR + /HER2 -, 20.1% were HER2 + , and 24.5% were TNBC; corresponding percentages among 1,434 postmenopausal women were 59.3%, 17.0%, and 23.6%. Approximately, 50-60% of both pre- and postmenopausal women were obese (BMI > 30 kg/m2), regardless of BC subtype. We did not observe a significant association between obesity and BC subtype. Among postmenopausal women, class I obesity (BMI 35 + kg/m2) was not associated with the development of HER2 + BC (OR 0.69; 95% CI 0.42-1.14) or TNBC (OR 0.93; 95% CI 0.60-1.45) relative to HR + /HER2- tumors. Corresponding estimates among premenopausal women were 1.03 (95% CI 0.43-2.48) and 1.13 (95% CI 0.48-2.64). CONCLUSION: In this large study of Black women with BC, there was no evidence of heterogeneity of BMI by BC subtype.

Qualitative Methods for Refining a Web-Based Educational Tool for Patients Focused on Inherited Cancer Predisposition.

To address the increasing demand for inherited cancer genetic testing, we developed and evaluated a web-based educational tool to streamline genetic counseling (GC). Consented patients viewed the initial prototype containing core content (Version 1-Core) and provided feedback through three open-ended survey questions. Additional data were collected through individual interviews from a subgroup who viewed an enhanced version (Version 1-Enhanced), consisting of the same core content and additional optional content. Data were coded to synthesize most commonly repeated themes and conceptualize action items to guide refinement strategies. Of 305 participants, 80 responded to open-ended survey questions to suggest refinement strategies, after viewing Version 1-Core. Interviews with a subgroup of seven participants, who viewed Version 1-Enhanced, provided additional feedback. Of 11 unique action items identified, five overlapped across datasets (provide instructions, simplify language, improve visuals, embed knowledge questions with explanations, include more insurance-related information), three were identified only through open-ended survey data (incorporate automatic progression, clarify test result information, increase interactive content), and three were identified only through interviews (ensure core content is viewed, incorporate progress bar, feature embedded optional content at the end of the tool). Ten action items aligned with underlying tool objectives to provide an interactive online pre-test GC solution and were used to guide refinement strategies. Our results demonstrate the value of rigorous qualitative data collection and analysis in health research and the use of the self-directed learning framework and eHealth strategies to leverage technology in scaling up and innovating the delivery of pre-test GC for inherited cancer.

Impact of molecular subtype and race on HR+, HER2- breast cancer survival.

PURPOSE: There is an urgent need to understand the biological factors contributing to the racial survival disparity among women with hormone receptor-positive (HR+), HER2- breast cancer. In this study, we examined the impact of PAM50 subtype on 10-year mortality rate in women with HR+, HER2- breast cancer by race. METHODS: Women with localized, HR+, HER2- breast cancer diagnosed between 2002 and 2012 from two population-based cohorts were evaluated. Archival tumors were obtained and classified by PAM50 into four molecular subtypes (i.e., luminal A, luminal B, HER2-enriched, and basal-like). The molecular subtypes within HR+, HER2- breast cancers and corresponding 10-year mortality rate were compared between Black and Non-Hispanic White (NHW) women using Cox proportional hazard ratios and survival analysis, adjusting for covariates. RESULTS: In this study, 318 women with localized, HR+, HER2- breast cancer were included-227 Black (71%) and 91 NHW (29%). Young Black women (age ≤ 50) had the highest proportion of HR+, non-luminal A tumors (47%), compared to young NHW (10%), older Black women (31%), and older NHW (30%). Overall, women with HR+, non-luminal A subtypes had a higher 10-year mortality rate compared to HR+, luminal A subtypes after adjustment for age, stage, and income (HR 4.21 for Blacks, 95% CI 1.74-10.18 and HR 3.44 for NHW, 95% CI 1.31-9.03). Among HR+, non-luminal A subtypes there was, however, no significant racial difference in 10-yr mortality observed (Black vs. NHW: HR 1.23, 95% CI 0.58-2.58). CONCLUSION: Molecular subtype classification highlights racial disparities in PAM50 subtype distribution among women with HR+, HER2- breast cancer. Among women with HR+, HER2- breast cancer, racial survival disparities are ameliorated after adjusting for molecular subtype.

Enhancing Cancer care of rural dwellers through telehealth and engagement (ENCORE): protocol to evaluate effectiveness of a multi-level telehealth-based intervention to improve rural cancer care delivery.

BACKGROUND: Despite lower cancer incidence rates, cancer mortality is higher among rural compared to urban dwellers. Patient, provider, and institutional level factors contribute to these disparities. The overarching objective of this study is to leverage the multidisciplinary, multispecialty oncology team from an academic cancer center in order to provide comprehensive cancer care at both the patient and provider levels in rural healthcare centers. Our specific aims are to: 1) evaluate the clinical effectiveness of a multi-level telehealth-based intervention consisting of provider access to molecular tumor board expertise along with patient access to a supportive care intervention to improve cancer care delivery; and 2) identify the facilitators and barriers to future larger scale dissemination and implementation of the multi-level intervention. METHODS: Coordinated by a National Cancer Institute-designated comprehensive cancer center, this study will include providers and patients across several clinics in two large healthcare systems serving rural communities. Using a telehealth-based molecular tumor board, sequencing results are reviewed, predictive and prognostic markers are discussed, and treatment plans are formulated between expert oncologists and rural providers. Simultaneously, the rural patients will be randomized to receive an evidence-based 6-week self-management supportive care program, Cancer Thriving and Surviving, versus an education attention control. Primary outcomes will be provider uptake of the molecular tumor board recommendation and patient treatment adherence. A mixed methods approach guided by the Consolidated Framework for Implementation Research that combines qualitative key informant interviews and quantitative surveys will be collected from both the patient and provider in order to identify facilitators and barriers to implementing the multi-level intervention. DISCUSSION: The proposed study will leverage information technology-enabled, team-based care delivery models in order to deliver comprehensive, coordinated, and high-quality cancer care to rural and/or underserved populations. Simultaneous attention to institutional, provider, and patient level barriers to quality care will afford the opportunity for us to broadly share oncology expertise and develop dissemination and implementation strategies that will enhance the cancer care delivered to patients residing within underserved rural communities. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04758338 . Registered 17 February 2021 - Retrospectively registered, http://www.clinicaltrials.gov/.

IMProving care After inherited Cancer Testing (IMPACT) study: protocol of a randomized trial evaluating the efficacy of two interventions designed to improve cancer risk management and family communication of genetic test results.

BACKGROUND: Implementing genetic testing for inherited cancer predisposition into routine clinical care offers a tremendous opportunity for cancer prevention and early detection. However, genetic testing itself does not improve outcomes; rather, outcomes depend on implemented follow-up care. The IMPACT study is a hybrid type I randomized effectiveness-implementation trial to simultaneously evaluate the effectiveness of two interventions for individuals with inherited cancer predisposition focused on: 1) increasing family communication (FC) of genetic test results; and 2) improving engagement with guideline-based cancer risk management (CRM). METHODS: This prospective study will recruit a racially, geographically, and socioeconomically diverse population of individuals with a documented pathogenic/likely pathogenic (P/LP) variant in an inherited cancer gene. Eligible participants will be asked to complete an initial trial survey and randomly assigned to one of three arms: A) GeneSHARE, a website designed to increase FC of genetic test results; B) My Gene Counsel's Living Lab Report, a digital tool designed to improve understanding of genetic test results and next steps, including CRM guidelines; or C) a control arm in which participants continue receiving standard care. Follow-up surveys will be conducted at 1, 3, and 12 months following randomization. These surveys include single-item measures, scales, and indices related to: 1) FC and CRM behaviors and behavioral factors following the COM-B theoretical framework (i.e., capability, opportunity, and motivation); 2) implementation outcomes (i.e., acceptability, appropriateness, exposure, and reach); and 3) other contextual factors (i.e., sociodemographic and clinical factors, and uncertainty, distress, and positive aspects of genetic test results). The primary outcomes are an increase in FC of genetic test results (Arm A) and improved engagement with guideline-based CRM without overtreatment or undertreatment (Arm B) by the 12-month follow-up survey. DISCUSSION: Our interventions are designed to shift the paradigm by which individuals with P/LP variants in inherited cancer genes are provided with information to enhance FC of genetic test results and engagement with guideline-based CRM. The information gathered through evaluating the effectiveness and implementation of these real-world approaches is needed to modify and scale up adaptive, stepped interventions that have the potential to maximize FC and CRM. TRIAL REGISTRATION: This study is registered at Clinicaltrials.gov (NCT04763915, date registered: February 21, 2021). PROTOCOL VERSION: September 17th, 2021 Amendment Number 04.

Family communication of genetic test results among women with inherited breast cancer genes.

Identification of inherited breast cancer may guide care. These benefits can be amplified through communication of genetic test results with at-risk family members and subsequent family testing (FT). Females with a pathogenic/likely pathogenic (P/LP) variant in BRCA1/2, PALB2, CHEK2, and/or ATM were surveyed about family communication (FC) of genetic test results and FT. Comparisons were made across genes. The 235 participants with P/LP variants (186 BRCA1/2, 28 PALB2, 15 CHEK2, and 6 ATM) had a median age of 54 and most were non-Hispanic whites (89%) with a prior breast cancer diagnosis (61%). When controlling for other variables, FC was higher among younger participants (p<.0001), those with high FC self-efficacy (p=.019), and those with P/LP variants in BRCA1/2 compared to PALB2 (p =.040) and ATM/CHEK2 (p =.032). Higher rates of FC and FT were also observed among female relatives and relatives of closer kinship. Overall 94% of participants would find one or more resources helpful with FC and 70% reported using FC resources when telling family members about their genetic test result. The three most commonly used resources included the following: (a) a family sharing letter (38%); (b) printed materials (30%); and (c) web-based information (23%). Among the 86% who spoke with a genetic counselor (GC), 93% were given at least one FC resource and the three most common resources GCs provided to participants overlapped with the resources participants would find helpful and those that were used. Our results suggest lower FC and FT rates among women with P/LP variants in genes other than BRCA1/2, the reasons for which should be evaluated in future studies. As more data to refine cancer risks and management are generated across these other inherited breast cancer genes, strategies to improve FC and FT are needed to amplify the benefits of genetic testing.

Breast cancer screening implications of risk modeling among female relatives of ATM and CHEK2 carriers.

BACKGROUND: With the increasing use of multigene panel tests, pathogenic and likely pathogenic (P/LP) variants are identified more frequently in the moderate-penetrance breast cancer genes ATM and CHEK2. Lifetime breast cancer risk among women with P/LP variants in these genes generally exceeds 20%, meeting the threshold at which high-risk breast cancer screening through breast magnetic resonance imaging (MRI) is recommended. METHODS: Among a registry-based sample of 56 ATM and 69 CHEK2 carriers, the authors sought to determine the percentage of relatives in whom a P/LP variant would impact breast cancer surveillance. Lifetime breast cancer risks for unaffected, female first-degree and second-degree relatives were estimated using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). RESULTS: Among first-degree relatives of ATM and CHEK2 carriers, only 22.6% and 14.9%, respectively, were found to have lifetime breast cancer risks of ≥20% based on family cancer history alone; however, when including the proband's P/LP variant in the model, these percentages increased significantly to 56.6% and 55.3%, respectively (P < .0001 and P < .0001, respectively). Similar increases in lifetime breast cancer risks were found among second-degree relatives. CONCLUSIONS: The results of the current study suggest that the majority of female first-degree and second-degree relatives of ATM and CHEK2 carriers do not qualify for breast MRI based on family cancer history alone. Therefore, testing for these genes, as well as awareness of positive moderate-penetrance breast cancer gene results in the family, may impact MRI eligibility. These findings highlight the potential usefulness of and need for breast cancer risk models that incorporate moderate-penetrance gene positivity to inform screening recommendations among at-risk family members.

Cancer risk management among female BRCA1/2, PALB2, CHEK2, and ATM carriers.

PURPOSE: Identification of inherited breast cancer may guide cancer risk management. We sought to compare risk management practices across women with inherited breast cancer genes. METHODS: Females with a pathogenic/likely pathogenic (P/LP) variant in BRCA1/2, PALB2, CHEK2, and/or ATM were surveyed about cancer risk management. Comparisons were made across genes. RESULTS: The 235 participants with P/LP variants (186 BRCA1/2, 28 PALB2, 15 CHEK2, and 6 ATM) had a median age of 54 and 61% had a prior breast cancer diagnosis. For women with P/LP variants in BRCA1/2, PALB2, and ATM/CHEK2, bilateral mastectomy (BM) rates were 79%, 61%, and 52%, and bilateral oophorectomy (BO) rates were 89%, 30%, and 37%, respectively. Among women with P/LP variants in PALB2 and ATM/CHEK2, 27% of those who had a BO had a family history of ovarian cancer. Contralateral mastectomy rates for women with P/LP variants in PALB2 and ATM/CHEK2 with unilateral breast cancer were 60% and 58%, and BM rates for those without breast cancer were 57% and 29%, respectively. CONCLUSION: These findings suggest high rates of both contralateral mastectomies among those with unilateral breast cancer and BM among those without a breast cancer diagnosis across women with P/LP variants in high and moderate penetrance breast cancer genes. BO was also often utilized for risk reduction across these women. These findings suggest potential overtreatment through risk-reducing surgery, and highlight the importance of promoting guideline-adherent, risk-appropriate care.

Disparities in BRCA counseling across providers in a diverse population of young breast cancer survivors.

PURPOSE: All women diagnosed with breast cancer (BC) ≤age 50 should be referred for genetic counseling (GC) and testing. We sought to compare differences in provider practices and access across a racially and ethnically diverse population of young BC survivors. METHODS: A registry-based sample of women diagnosed with invasive BC ≤age 50 from 2009 to 2012 was recruited through the Florida Cancer Registry, and completed a questionnaire and medical record release. Differences were compared across those tested with or without the involvement of a board-certified or credentialed genetics health professional (GHP) in (1) clinical and demographic variables and (2) pretest GC elements. RESULTS: Of 1622 participants, there were 440 Blacks, 285 Hispanics, and 897 Non-Hispanic Whites. Of 831 participants with medical record verification of testing provider, 170 (20%) had documentation of GHP involvement. Among the 613 who recalled a pretest discussion and had GC elements collected, those with GHP involvement were significantly more likely to recall the seven recognized GC elements. CONCLUSION: GHP involvement was associated with adherence to nationally recommended best practices. With the expanding importance of identifying inherited cancers, it is critical to ensure equitable access to best practices across all populations.

A Web-Based Tool to Automate Portions of Pretest Genetic Counseling for Inherited Cancer.

BACKGROUND: Increasing demand for genetic testing for inherited cancer risk coupled with a shortage of providers trained in genetics highlight the potential for automated tools embedded in the clinic process to meet this demand. We developed and tested a scalable, easy-to-use, 12-minute web-based educational tool that included standard pretest genetic counseling elements related to panel-based testing for multiple genes associated with cancer risk. METHODS: The tool was viewed by new patients at the Vanderbilt Hereditary Cancer Clinic before meeting with a board-certified genetics professional. Pre- and post-tool surveys measured knowledge, feeling informed/empowered to decide about testing, attitudinal values about genetic testing, and health literacy. Of the initial 100 participants, 50 were randomized to only have knowledge measured on the post-tool survey to assess for a priming effect. RESULTS: Of 360 patients approached, 305 consented and completed both the pre- and post-tool surveys, with a mean age of 47 years, including 80% female patients and 48% patients with cancer. Survey results showed an increase in knowledge and feeling informed/empowered after viewing the tool (P<.001), but no significant change in attitude (P=.64). Post-tool survey data indicated no difference in median knowledge between low and high health literacy groups (P=.30). No priming effect was present among the initial 100 participants (P=.675). CONCLUSIONS: Viewing the educational tool resulted in significant gains in knowledge across health literacy levels, and most individuals felt informed and empowered to decide about genetic testing. These findings indicate that the use of an automated pretest genetic counseling tool may help streamline the delivery of genetic services.

Caring for Individuals with Chronic Illness and Minor Depression: Latino Perceptions of Caregiver Burden.

Informal caregiving can be fundamental to disease management. Yet, the psychosocial, physical, and financial burden experienced by caregivers can be significant. In the US, Latinos experience increasing rates of chronic conditions, the highest uninsured rates in the country, and a growing dependence on informal caregivers. This article explores the impact of caregiving on caregivers of individuals with comorbid chronic disease and depression. Findings highlight the impact of caregiving on financial insecurity, balancing competing demands, increased emotional distress, and community supports. Findings support the inclusion of caregivers in disease management programs to enhance psychosocial outcomes for both caregivers and their patients.

Inherited Cancer Knowledge Among Black Females with Breast Cancer Before and After Viewing a Web-Based Educational Video.

Purpose: Scalable solutions are needed to make pre-test genetic education about inherited cancer risk accessible across diverse and underserved populations. We evaluated an automated strategy to deliver genetic education through a web-based video among young Black females with breast cancer. Methods: 96 participants were recruited through state cancer registries in Florida and Tennesee. All participants viewed a 12 min video and completed a ten question quiz on inherited cancer knowledge before and after viewing the video. Median pre- and postvideo knowledge scores were categorized as <60% versus ≥60% and compared across demographic and clinical characteristics using binary logistic regression. Results: Of the 96 participants, mean age was 51, over 50% had income <$50 K, over 40% did not graduate college or have private insurance, and over 70% had previous genetic testing. Median knowledge scores significantly increased after viewing the video (p < 001), with no significant differences in those with or without prior testing. A higher post-video knowledge score was associated with an income ≥$50 K, a college degree, and private insurance (all p < .05). Conclusion: Among a population of young Black breast cancer patients, the educational video significantly increased knowledge. Findings support the use of automated pre-test educational tools as a scalable solution to make these services more accessible across populations.

Applying the framework for developing and evaluating complex interventions to increase family communication about hereditary cancer.

Objective: Evaluate an intervention to increase family communication (FC) of positive hereditary cancer test results using the Framework for Developing and Evaluating Complex Interventions (FDECI). Methods: We developed 'programme theory' during the FDECI development phase by aligning intervention components with behavior change techniques (BCTs) and theoretical factors expected to improve FC. During the feasibility phase, we obtained feedback from 12 stakeholder interviews. Results: Intervention components aligned with a total of 14 unique BCTs for which prior evidence links the BCT to theoretical factors that influence behavior change. Constructive stakeholder feedback included: more information desired, rewording to support autonomy by highlighting options, and improvements to navigation, visuals, and audio. Positive comments included: comprehensiveness of materials, modeling of conversations, and usefulness of the materials for helping a person prepare to share positive test results. Conclusion: The first FDECI phases were helpful for improving the intervention and planning our ongoing effectiveness and future implementation phases. Innovation: Our application of the FDECI is novel, including plans to test our 'programme theory' using coincidence analysis (CNA) to determine who accesses which intervention materials, how utilizing certain materials impact the aligned theoretical factors, and whether these in turn make a difference in the behavioral outcome.

Sharing genetic test results with family members of BRCA, PALB2, CHEK2, and ATM carriers.

OBJECTIVE: This study explored motivators and challenges/barriers to sharing personal genetic test results (GTR) with family members (FM). METHODS: Semi-structured, in-depth interviews were conducted with 62 women who had a pathogenic or likely pathogenic (P/LP) variant in aBRCA, PALB2, CHEK2, or ATM gene. Selective qualitative data analysis focused on eliciting motivators and challenges/barriers identified by participants when sharing their GTR with FM. RESULTS: Motivators to sharing personal GTR with FM included: health protection and prevention; moral obligation; decisional empowerment; familial ties; written resources; and contextualization for a familial cause for cancer. Challenges/barriers to family sharing included: concern for FM reactions; complexities of information; lack of closeness; perceived relevance; and emotional impact. CONCLUSIONS: All motivators and challenges/barriers were identified across BRCA and non-BRCA carriers, demonstrating commonalities in family sharing of GTR among high- to moderate-penetrance hereditary BC (breast cancer) genes. Despite challenges/barriers, participants disclosed their GTR with most close FM, yet restrictions in communication and/or strain on the timing, manner of disclosing, and strategies used varied across certain FM. PRACTICE IMPLICATIONS: These findings offer healthcare providers and researchers preliminary practical implications for broadly improving family sharing interventions across P/LP variants in BC risk genes by demonstrating important elements to include in family sharing letters.

A Pooled Case-only Analysis of Reproductive Risk Factors and Breast Cancer Subtype Among Black Women in the Southeastern United States.

BACKGROUND: We investigated the association between reproductive risk factors and breast cancer subtype in Black women. On the basis of the previous literature, we hypothesized that the relative prevalence of specific breast cancer subtypes might differ according to reproductive factors. METHODS: We conducted a pooled analysis of 2,188 (591 premenopausal, 1,597 postmenopausal) Black women with a primary diagnosis of breast cancer from four studies in the southeastern United States. Breast cancers were classified by clinical subtype. Case-only polytomous logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for HER2+ and triple-negative breast cancer (TNBC) status in relation to estrogen receptor-positive (ER+)/HER2- status (referent) for reproductive risk factors. RESULTS: Relative to women who had ER+/HER2- tumors, women who were age 19-24 years at first birth (OR, 1.78; 95% CI, 1.22-2.59) were more likely to have TNBC. Parous women were less likely to be diagnosed with HER2+ breast cancer and more likely to be diagnosed with TNBC relative to ER+/HER2- breast cancer. Postmenopausal parous women who breastfed were less likely to have TNBC [OR, 0.65 (95% CI, 0.43-0.99)]. CONCLUSIONS: This large pooled study of Black women with breast cancer revealed etiologic heterogeneity among breast cancer subtypes. IMPACT: Black parous women who do not breastfeed are more likely to be diagnosed with TNBC, which has a worse prognosis, than with ER+/HER2- breast cancer.