Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.

Adherence to hormonal therapy after surgery among older women with ductal carcinoma in situ: Implications for breast cancer-related adverse health events.

BACKGROUND: Evidence from randomized clinical trials (RCTs) shows that receipt of hormonal therapy after surgery for estrogen receptor-positive ductal carcinoma in situ (DCIS) reduces the risk of DCIS and contralateral invasive breast cancer (IBC) but not death from breast cancer. RCTs examined homogeneous samples, and therefore whether this evidence can be generalized to diverse populations is unclear. METHODS: Population-based data from four state cancer registries (California, New Jersey, New York, and Texas) were analyzed on women aged 65 years and older newly diagnosed with DCIS who underwent surgery with or without radiation during the years 2006-2013. Registry records were merged with Medicare enrollment in Parts A and/or B and D (prescription drugs) and associated claims. Whether adherence to hormonal therapy was associated with adverse breast cancer-related health events was analyzed. RESULTS: Achieving excellent adherence did not affect death from breast cancer. In contrast, the risk of developing a subsequent breast tumor was 6.24 percentage points (breast-conserving surgery [BCS] with radiation therapy [RT]) and 10.54 percentage points (BCS alone) lower for women with excellent versus low adherence (p < .00001). For excellent versus good adherence, the reduced risk among women who had BCS with and without RT was approximately 3 and 5 percentage points, respectively. A similar pattern emerged for the risk of IBC among women who achieved excellent versus good or low adherence, whereas good versus low adherence comparisons were not significant. CONCLUSIONS: This analysis of a diverse population-based cohort of women with DCIS demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors. PLAIN LANGUAGE SUMMARY: Our analysis of a diverse population-based cohort of women with ductal carcinoma in situ demonstrates that achieving excellent adherence to hormonal therapy is critical to minimizing the occurrence of developing subsequent breast tumors.

Nonclinical factors associated with the treatment of older women with newly diagnosed low-grade ductal carcinoma in situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is the most common form of noninvasive breast cancer and is associated with an excellent prognosis. As a result, there is concern about overdiagnosis and overtreatment of DCIS because most patients with DCIS are treated as though they have invasive breast cancer and undergo either breast-conserving surgery (BCS)-most commonly followed by radiation therapy (RT)-or mastectomy. Little research to date has focused on nonclinical factors influencing treatments for DCIS. METHODS: Population-based data were analyzed from five state cancer registries (California, Florida, New Jersey, New York, and Texas) on women aged 65 years and older newly diagnosed with DCIS during the years 2003 to 2014 using a retrospective cohort design and multinominal logistic modeling. The registry records with Medicare enrollment data and fee-for-service claims to obtain treatments (BCS alone, BCS with RT, or mastectomy) were merged. Surgeon practice structure was identified through physician surveys and internet searches. RESULTS: Patients of surgeons employed by cancer centers or health systems were less likely to receive BCS with RT or mastectomy than patients of surgeons in single specialty or multispecialty practices. There also was substantial geographic variation in treatments, with patients in New York, New Jersey, and California being less likely to receive BCS with RT or mastectomy than patients in Texas or Florida. CONCLUSIONS: These findings suggest nonclinical factors including the culture of the practice and/or financial incentives are significantly associated with the types of treatment received for DCIS. Increasing awareness and targeted efforts to educate physicians about DCIS management among older women with low-grade DCIS could reduce patient harm and yield substantial cost savings.

Iterative Development of an Interactive Website to Support Shared Decision-Making in Metastatic Breast Cancer.

Recent treatment advances have resulted in significantly increased survival times following metastatic breast cancer (MBC) diagnosis. Novel treatment approaches-and their related side effects-have changed the landscape of MBC treatment decision-making. We developed a prototype of an online educational tool to prepare patients with MBC for shared decision-making with their oncologists. We describe the five phases of tool development: (1) in-depth, semi-structured qualitative interviews and (2) feedback on storyboards of initial content with patients with MBC and oncology providers. This was followed by three phases of iterative feedback with patients in which they responded to (3) initial, non-navigable website content and (4) a beta version of the full website. In the final phase (5), patients newly diagnosed with MBC (N = 6) used the website prototype for 1 week and completed surveys assessing acceptability, feasibility, treatment knowledge, preparation for decision-making, and self-efficacy for decision-making. Participants in Phase 1 characterized a cyclical process of MBC treatment decision-making and identified key information needs. Website content and structure was iteratively developed in Phases 2-4. Most participants in Phase 5 (n = 4) accessed the website 2-5 times. All participants who accessed the website at least once (n = 5) felt they learned new information from the website prototype and would recommend it to others newly-diagnosed with MBC. After using the website prototype, participants reported high preparation and self-efficacy for decision-making. This multiphase, iterative process resulted in a prototype intervention designed to support decision-making for MBC patients.

Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study.

BACKGROUND: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. METHODS: Women >60 years old with primary breast cancer (stages 0-III) (n = 400) were assessed before systemic therapy with frequency-matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor α (TNF-α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate-adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. RESULTS: Participants were aged 60-90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor-positive tumors (87.6%). Survivors had significantly higher IL-6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001-.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL-6, IL-10, and TNF-α were related to APE, with IL-6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates. CONCLUSIONS: Older breast cancer survivors had worse long-term neurocognitive performance than controls, and this relationship was explained in part by elevated IL-6.

Pilot Trial of Streamlined Genetic Education and Traceback Genetic Testing in Prostate Cancer Survivors.

BACKGROUND: Germline genetic testing is recommended for men with metastatic or high-risk prostate cancer to inform treatment and risk management for other cancers and inform genetic testing in at-risk relatives. However, relatively few patients with prostate cancer undergo genetic testing. Given the low rate of testing and increasing demands on genetic service providers, strategies are needed that reduce barriers to testing while conserving genetic counseling resources. The primary goal of this study was to determine whether a proactive and streamlined "traceback" approach could yield increased genetic testing participation among prostate cancer survivors. METHODS: We randomized 107 survivors of metastatic and high-risk prostate cancer to streamlined testing (ST) versus enhanced usual care (EUC). ST participants were proactively provided with print genetic education materials and the option to proceed to genetic testing without pre-test genetic counseling. EUC participants were sent a letter from their physician advising them of their eligibility for genetic testing and recommending they schedule genetic counseling. The primary outcome was genetic testing participation. Secondary outcomes were distress, knowledge, decision satisfaction, and regret. RESULTS: In the ST group, 41.5% of participants completed genetic testing compared with 27.8% in the EUC group. After adjusting for education and marital status, the odds of testing were more than twice as high for the ST group as for the EUC group (odds ratio, 2.57; 95% CI, 1.05-6.29). The groups did not differ on any of the psychosocial outcomes at the 3-month follow-up. CONCLUSIONS: Proactive outreach paired with streamlined genetic testing delivery may be a safe, effective, and resource-efficient approach to facilitate traceback genetic testing in prostate cancer survivors.

Measuring high-risk parents' opinions about direct-to-consumer genetic testing for adult-onset inherited cancer syndromes in their adolescent and young adult children.

Neither direct-to-consumer (DTC) genetic testing nor predictive genetic testing for adult-onset conditions is recommended for minor children due to ethical concerns and low clinical utility. However, parents with pathogenic variants (PVs) in disease-causing genes may be interested in pursuing genetic testing that includes the familial PV for their children. The Pediatric Testing Attitudes Scale (P-TAS) was previously developed to examine high-risk parents' opinions about pediatric BRCA genetic testing for adult-onset breast/ovarian cancer. Here, the psychometric properties of the P-TAS were examined in a new sample of N = 126 parents (M age = 47.2 years) with PVs in a more complete set of cancer risk genes represented on DTC panel tests. The mean score on the P-TAS was 44 out of a maximum score of 60, indicating that a majority of parents generally held favorable opinions about testing their children for adult-onset inherited cancer syndromes. The internal consistency of the full scale was high (α = 0.91). A factor analysis identified two-component scales, labeled Attitudes and Beliefs (α = 0.93) and Decision Making and Communication (α = 0.83). In a multivariable regression model, P-TAS co-factors accounted for 34% of variance in parental opinions, including the frequency of prior family communication about cancer and the likelihood of utilizing DTC genetic testing with children (R2  = 0.34, p < 0.001). Results suggest that the P-TAS remains a reliable measure to assess high-risk parents' opinions about pediatric DTC genetic testing for adult-onset conditions, with promising validity. Applications of the P-TAS include informing genetic counseling practice, pediatric medical care, and policy guidelines surrounding DTC genetic testing.

Exploring Racial Differences in Treatment Decision-making in Chinese Immigrant and White American Breast Cancer Patients: the Role of Patient-Provider Communication.

Chinese immigrant cancer patients report suboptimal patient-provider communication, which increases the likelihood of decisional conflict and unsatisfactory treatment decision-making (TDM) outcomes (e.g., low satisfaction and perceived control over cancer care). This cross-sectional study explored whether (1) communication and decisional conflict factors associated with TDM outcomes differed between Chinese immigrant and non-Hispanic White breast cancer patients, and (2) the association between patient-provider communication and the outcomes were mediated by TDM factors, regardless of race. Ninety-eight breast cancer patients, diagnosed at stage I-III participated in cross-sectional survey interviews. TDM outcomes and possible predictors of the outcomes (e.g., patient-provider communication, decisional conflict, preference for who makes the treatment decision) were assessed. Linear regression and mediational testing were performed to examine associations among variables of interest. Of the 98, 85 were included for analysis. Chinese patients with limited English proficiency (n = 37) had poorer patient-provider communication, higher decisional conflict, and preferred providers to make decisions than non-Hispanic White patients (n = 48; all p < .05). They also had lower satisfaction with their TDM process after controlling for predictors (e.g., patient-provider communication) (p < .001). There were no significant racial differences in perceived control, controlling for covariates. Regardless of race, patients who reported quality patient-provider communication reported less decisional conflict. These patients also reported increased satisfaction and perceived control. The disparities Chinese immigrant cancer patients experienced in the TDM process may be related to their cultural communication style with providers. Facilitating Chinese patients' communication and partnership with providers may reduce decisional conflicts and increase their TDM outcomes.

HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane.

PURPOSE: To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel). METHODS: Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score). RESULTS: Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea. CONCLUSION: Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

Molecular characterization of ESR1 variants in breast cancer.

PURPOSE: Estrogen receptor 1 (ESR1) mutations and fusions typically arise in patients with hormone receptor-positive breast cancer after aromatase inhibitor therapy, whereby ESR1 is constitutively activated in a ligand-independent manner. These variants can impact treatment response. Herein, we characterize ESR1 variants among molecularly profiled advanced breast cancers. METHODS: DNA next-generation sequencing (592-gene panel) data from 9860 breast cancer samples were retrospectively reviewed. Gene fusions were detected using the ArcherDx fusion assay or whole transcriptome sequencing (n = 344 and n = 4305, respectively). Statistical analyses included Chi-square and Fisher's exact tests. RESULTS: An ESR1 ligand-binding domain (LBD) mutation was detected in 8.6% of tumors evaluated and a pathogenic ESR1 fusion was detected in 1.6%. Most ESR1 LBD mutations/fusions were from estrogen receptor (ER)-positive samples (20.1% and 4.9%, respectively). The most common ESR1 LBD mutations included D538G (3.3%), Y537S (2.3%), and E380Q (1.1%) mutations. Among biopsy sites, ESR1 LBD mutations were most observed in liver metastases. Pathogenic ESR1 fusions were identified in 76 samples (1.6%) with 40 unique fusion partners. Evaluating co-alterations, ESR1 variant (mutation/fusion) samples more frequently expressed androgen receptor (78.0% vs 58.6, P < 0.0001) and less frequently immune checkpoint proteins than ESR1 wild-type (PD-1 20.0% vs 53.4, P < 0.05; immune cell PD-L1 10.0% vs 30.2, P < 0.0001). CONCLUSION: We have described one of the largest series of ESR1 fusions reported. ESR1 LBD mutations were commonly identified in ER-positive disease. Limited data exists regarding the clinical impact of ESR1 fusions, which could be an area for future therapeutic exploration.

Association of markers of tumor aggressivity and cognition in women with breast cancer before adjuvant treatment: The Thinking and Living with Cancer Study.

PURPOSE: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of cognition prior to adjuvant therapy and tumor aggressivity in older breast cancer patients. METHODS: Women diagnosed with non-metastatic breast cancer (n = 705) ages 60-98 were enrolled from August 2010-March 2020. Cognition was measured post-surgery, pre-systemic therapy using self-reported (FACT-Cog Perceived Cognitive Impairment [PCI]) and objective tests of attention, processing speed, and executive function (APE domain) and learning and memory [LM domain]. Linear regression tested associations of pre-treatment tumor features and cognition, adjusting for age, race, and study site. HER2 positivity and higher stage (II/III vs. 0/I) were a priori predictors of cognition; in secondary analyses we explored associations of other tumor features and cognitive impairment (i.e., PCI score < 54 or having 2 tests < 1.5 SD or 1 test < 2 SD from the mean APE or LM domain score). RESULTS: HER2 positivity and the hormone receptor negative/HER2 + molecular subtype were associated with lower adjusted mean self-reported cognition scores and higher impairment rates (p values < .05). Higher stage of disease was associated with lower objective performance in APE. Other tumor features were associated with cognition in unadjusted and adjusted models, including larger tumor size and lower PCI scores (p = 0.02). Tumor features were not related to LM. CONCLUSIONS: Pre-adjuvant therapy cognition was associated with HER2 positivity and higher stage of disease and other features of aggressive tumors. Additional research is needed to confirm these results and assess potential mechanisms and clinical management strategies.

Psychosocial impact of proactive rapid genetic counseling following breast cancer diagnosis.

OBJECTIVE: As germline genetic referral becomes increasingly routine as part of the care of newly diagnosed breast cancer patients, it is important to understand the psychosocial impact of genetic counseling at the time of diagnosis. We examined the psychosocial and quality of life (QOL) impact of providing proactive rapid genetic counseling and testing (RGCT) in the immediate aftermath of a breast cancer diagnosis. METHODS: We randomized 330 patients in a 2:1 ratio to proactive rapid genetic counseling (RGCT; N = 222) versus usual care (UC; N = 108). Participants completed a baseline telephone survey before randomization and definitive surgery and a follow-up survey at 1-month post-randomization. We evaluated the impact of RGCT versus UC on breast cancer genetic knowledge, distress, QOL, and decisional conflict. Given that 43% of UC participants and 86% of RGCT participants completed genetic counseling prior to the 1-month assessment, we also evaluated the impact of genetic counseling participation over and above group assignment. RESULTS: The RGCT intervention led to increased breast cancer genetic knowledge relative to UC but did not differentially impact other study outcomes. Across groups patients who participated in genetic counseling had significantly increased knowledge and improved QOL compared to those who did not participate in genetic counseling. CONCLUSIONS: While prior research has documented the impact of genetic counseling and testing on surgical decisions, these results confirm that participation in genetic counseling at the time of diagnosis can yield improvements in knowledge and QOL in the short-term.

Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. METHODS: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. RESULTS: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). CONCLUSIONS: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

PURPOSE: HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years. METHODS: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients. RESULTS: Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines. CONCLUSIONS: Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

BRCA1/2 mutations and risk-reducing bilateral salpingo-oophorectomy among Latinas: The UPTAKE study.

Bilateral salpingo-oophorectomy (BSO) is a risk management approach with strong evidence of mortality reduction for women with germline mutations in the tumor suppressor genes BRCA1 and BRCA2 (BRCA1/2). Few studies to date have evaluated uptake of BSO in women from diverse racial and ethnic backgrounds who carry BRCA1/2 mutations. The objective of the UPTAKE study was to explore rates and predictors of risk-reducing BSO among Latinas affected and unaffected with breast cancer who had a deleterious BRCA1/2 mutation. We recruited 100 Latina women with deleterious BRCA1/2 mutations from community hospitals, academic health systems, community, and advocacy organizations. Women completed interviews in Spanish or English. We obtained copies of genetic test reports for participants who provided signed medical release. After performing threefold cross-validation LASSO for variable selection, we used multiple logistic regression to identify demographic and clinical predictors of BSO. Among 100 participants, 68 had undergone BSO at the time of interview. Of these 68, 35 were US-born (61% of all US-born participants) and 33 were not (77% of the non-US-born participants). Among Latinas with BRCA1/2 mutations, older age (p = 0.004), personal history of breast cancer (p = 0.003), higher income (p = 0.002), and not having a full-time job (p = 0.027) were identified as variables significantly associated with uptake of BSO. Results suggest a high rate of uptake of risk-reducing BSO among a sample of Latinas with BRCA1/2 mutations living in the US. We document factors associated with BSO uptake in a diverse sample of women. Relevant to genetic counseling, our findings identify possible targets for supporting Latinas' decision-making about BSO following receipt of a positive BRCA1/2 test.

Improving our model of cascade testing for hereditary cancer risk by leveraging patient peer support: a concept report.

Consensus and evidence suggest that cascade testing is critical to achieve the promise of cancer genetic testing. However, barriers to cascade testing include effective family communication of genetic risk information and family members' ability to cope with genetic risk. These barriers are further complicated by the developmental needs of unaffected family members during critical windows for family communication and adaptation. Peer support could address these barriers. We provide two illustrative examples of ongoing BRCA1/2-related clinical trials that apply a peer support model to improve family communication and functioning. Peer support can augment currently available genetic services to facilitate adjustment to and effective use of cancer genetic risk information. Importantly, this scalable approach can address the presence of cancer risk within families across multiple developmental stages. This applies a family-centered perspective that accommodates all potentially at-risk relatives. This peer support model can be further applied to emerging topics in clinical genetics to expand reach and impact.

The Genetic Education for Men (GEM) Trial: Development of Web-Based Education for Untested Men in BRCA1/2-Positive Families.

Cascade testing for hereditary breast/ovarian cancer is an important public health priority. Increasing attention has been paid to the relevance of testing for men within BRCA1/2-positive families given that such testing may provide important information about their cancer risks, particularly for prostate cancer, and risks to their offspring. However, men are much less likely to seek genetic counseling and testing than their at-risk female relatives. To facilitate access to pre-test information and testing, we developed a web-based intervention (WI) for men that we are evaluating in a pilot randomized controlled trial (RCT). This paper describes three phases of research in the development of the WI: (1) formative (qualitative) research among men from BRCA1/2 families to assess needs and preferences for education; (2) a detailed description of the organization, format, and content of the WI; and (3) usability testing. We discuss the aims and hypotheses of the pilot RCT in which the WI is being compared with an enhanced usual care condition among at-risk men. We expect that the WI described here will foster informed decisions and lead to increased use of BRCA1/2 counseling and testing, potentially yielding improved cancer control outcomes for this understudied group, and for their at-risk relatives.

Symptom burden among older breast cancer survivors: The Thinking and Living With Cancer (TLC) study.

BACKGROUND: Little is known about longitudinal symptom burden, its consequences for well-being, and whether lifestyle moderates the burden in older survivors. METHODS: The authors report on 36-month data from survivors aged ≥60 years with newly diagnosed, nonmetastatic breast cancer and noncancer controls recruited from August 2010 through June 2016. Symptom burden was measured as the sum of self-reported symptoms/diseases as follows: pain (yes or no), fatigue (on the Functional Assessment of Cancer Therapy [FACT]-Fatigue scale), cognitive (on the FACT-Cognitive scale), sleep problems (yes or no), depression (on the Center for Epidemiologic Studies Depression scale), anxiety (on the State-Trait Anxiety Inventory), and cardiac problems and neuropathy (yes or no). Well-being was measured using the FACT-General scale, with scores from 0 to 100. Lifestyle included smoking, alcohol use, body mass index, physical activity, and leisure activities. Mixed models assessed relations between treatment group (chemotherapy with or without hormone therapy, hormone therapy only, and controls) and symptom burden, lifestyle, and covariates. Separate models tested the effects of fluctuations in symptom burden and lifestyle on function. RESULTS: All groups reported high baseline symptoms, and levels remained high over time; differences between survivors and controls were most notable for cognitive and sleep problems, anxiety, and neuropathy. The adjusted burden score was highest among chemotherapy-exposed survivors, followed by hormone therapy-exposed survivors versus controls (P < .001). The burden score was related to physical, emotional, and functional well-being (eg, survivors with lower vs higher burden scores had 12.4-point higher physical well-being scores). The composite lifestyle score was not related to symptom burden or well-being, but physical activity was significantly associated with each outcome (P < .005). CONCLUSIONS: Cancer and its treatments are associated with a higher level of actionable symptoms and greater loss of well-being over time in older breast cancer survivors than in comparable noncancer populations, suggesting the need for surveillance and opportunities for intervention.

Actionable co-alterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway.

PURPOSE: Homologous recombination (HR)-deficient breast tumors may have genomic alterations that predict response to treatment with PARP inhibitors and other targeted therapies. METHODS: Comprehensive molecular profiles of 4647 breast tumors performed at Caris Life Sciences using 592-gene NGS were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, PALB2, RAD50/51/51B, and WRN, as well as 41 markers that may be associated with treatment response to targeted anticancer therapies. RESULTS: 17.9% of breast tumors had HR mutations (HR-MT, 831/4647) [ER/PR+ , HER2- 18.3%, n = 2183; TNBC 18.2%, n = 1568; ER/PR+ , HER2+ 15.6%, n = 237; ER/PR-, HER2+ 12.9%, n = 217; unknown n = 442]. Mean TMB was higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 h-wild type (HR-WT), p ≤ 0.0001) and independent of microsatellite status. MSI-H/dMMR was more frequent among HR-MT tumors (2.1% HR-MT vs 0.2% HR-WT, p ≤ 0.0001), as was tumor PD-L1 overexpression (13.2% HR-MT vs 11.0% HR-WT, p = 0.08). Additional co-alterations were similar between HR-MT and HR-WT, with the exception of PIK3CA (30.3% HR-WT vs 26.4% HR-MT, p = 0.024) and AKT1 (3.7% HR-WT vs 2.1% HR-MT, p = 0.021). AR overexpression and PIK3CA mutations were more common among ER/PR+ tumors. ERBB2 mutations were seen in both HER2+ and HER2- tumors. CONCLUSIONS: HR-MT was common across breast cancer subtypes and co-occurred more frequently with markers of response to immunotherapy (MSI-H/dMMR, TMB) compared to HR-WT tumors. Mutations were identified in both HR-MT and HR-WT tumors that suggest other targets for treatment. Clinical trials combining HRD-targeted agents and immunotherapy are underway and could be enriched through comprehensive molecular profiling.