The VEGF-Hypoxia Signature is Upregulated in Basal like Breast Tumors from Women of African Ancestry and Associated with Poor Outcomes in Breast Cancer.

PURPOSE: Black women experience the highest breast cancer mortality rate compared to women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry. EXPERIMENTAL DESIGN: We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n=182) and the University of Chicago (n=161). We also analyzed RNA sequencing data from Nigeria (n=84) and TCGA datasets (n=863). Patient prognosis was analyzed using multiple datasets. RESULTS: The VEGF-hypoxia signature was highest in the basal-like subtype compared to other subtypes, with greater expression in Black women compared to White women. In the TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared to non-necrosis tumors (p<0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation and necrosis. T cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in the TCGA dataset. Lastly, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (p<0.0001) and SCAN-B datasets (p=0.002). CONCLUSIONS: These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora.

Remote Monitoring and Data Collection for Decentralized Clinical Trials.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies. Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials. Design, Setting, and Participants: The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023. Exposure: Adoption of decentralized clinical trial technologies. Main Outcomes and Measures: The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics. Results: All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term. Conclusions and Relevance: These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.

Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. Objective: To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. Design, Setting, and Participants: In this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. Exposures: Self-reported bilateral oophorectomy (with or without salpingectomy). Main Outcomes and Measures: All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. Results: There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy. Conclusions and Relevance: In this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective: To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants: Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures: Entrance into an MRI surveillance program. Main Outcomes and Measures: Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results: A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Conclusion and Relevance: Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

Racial differences in familiarity, interest, and use of integrative medicine among patients with breast cancer.

Purpose Integrative medicine (IM) has received ASCO endorsement for managing cancer treatment-related side effects. Little is known about racial differences in familiarity, interest, and use of IM among breast cancer patients. Methods Breast cancer patients enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort were surveyed regarding familiarity, interest, and use of IM: acupuncture, massage, meditation, music therapy, and yoga. Familiarity and interest, measured by a 5-point Likert scale, was modeled using proportional odds. Use was self-reported, modeled using binary logistic regression. Results Of 1,300 respondents (71.4% White and 21.9% Black), Black patients were less likely than White patients to be familiar with acupuncture (aOR 0.60, 95% CI: 0.41-0.87). While there was no differences in interest in acupuncture between Black and White patients (aOR 1.12, 95% CI: 0.76-1.65), Black patients were more interested in massage (aOR 1.86, 95% CI: 1.25-2.77), meditation (aOR 2.03, 95% CI: 1.37-3.00), music therapy (aOR 2.68, 95% CI: 1.80-3.99) and yoga (aOR 2.10, 95% CI: 1.41-3.12). Black patients were less likely than White to have used acupuncture (aOR 0.49, 95% CI: 0.29-0.84); but there were no racial differences in use of massage (aOR 0.83, 95% CI: 0.53-1.30), meditation (aOR 0.82, 95% CI: 0.47-1.43), music therapy (aOR 1.65, 95% CI: 0.82-3.32) and yoga (aOR 0.67, 95% CI: 0.37-1.20). Conclusion Black patients expressed more interest in IM than their White counterparts; there were no racial differences in IM use, except lower acupuncture use among Black patients. A breast program focused on equity should provide access to these services for breast cancer patients.

Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.

Benign breast disease and breast cancer risk in African women: a case-control study.

PURPOSE: To examine the association between benign breast disease (BBD) and breast cancer (BC) in a heterogeneous population of African women. METHODS: BC cases and controls were enrolled in three sub-Saharan African countries, Nigeria, Cameroon, and Uganda, between 1998 and 2018. Multivariable logistic regression was used to test the association between BBD and BC. Risk factors dually associated with BBD and BC were selected. Using a parametric mediation analysis model, we assessed if selected BC risk factors were mediated by BBD. RESULTS: Of 6,274 participants, 55.6% (3,478) were breast cancer cases. 360 (5.7%) self-reported BBD. Fibroadenoma (46.8%) was the most commonly reported BBD. Women with a self-reported history of BBD had greater odds of developing BC than those without (adjusted odds ratio [aOR] 1.47, 95% CI 1.13-1.91). Biopsy-confirmed BBD was associated with BC (aOR 2.25, 95% CI 1.26-4.02). BBD did not significantly mediate the effects of any of the selected BC risk factors. CONCLUSIONS: In this study, BBD was associated with BC and did not significantly mediate the effects of selected BC risk factors.

Validation of the RSClin risk calculator in the National Cancer Data Base.

BACKGROUND: Guidelines recommend the use of genomic assays such as OncotypeDx to aid in decisions regarding the use of chemotherapy for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. The RSClin prognostic tool integrates OncotypeDx and clinicopathologic features to predict distant recurrence and chemotherapy benefit, but further validation is needed before broad clinical adoption. METHODS: This study included patients from the National Cancer Data Base (NCDB) who were diagnosed with stage I-III HR+/HER2- breast cancer from 2010 to 2020 and received adjuvant endocrine therapy with or without chemotherapy. RSClin-predicted chemotherapy benefit was stratified into low (<3% reduction in distant recurrence), intermediate (3%-5%), and high (>5%). Cox models were used to model mortality adjusted for age, comorbidity index, insurance, and race/ethnicity. RESULTS: A total of 285,441 patients were identified for inclusion from the NCDB, with an average age of 60 years and a median follow-up of 58 months. Chemotherapy was associated with improved overall survival only for those predicted to have intermediate (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.60-0.79) and high benefit per RSClin (aHR, 0.66; 95% CI, 0.61-0.72). Consistent benefit was seen in the subset with a low OncotypeDx score (<26) and intermediate (aHR, 0.66; 95% CI, 0.53-0.82) or high (aHR, 0.71; 95% CI, 0.58-0.86) RSClin-predicted benefit. No survival benefit with chemotherapy was seen in patients with a high OncotypeDx score (≥26) and low benefit per RSClin (aHR, 1.70; 95% CI, 0.41-6.99). CONCLUSIONS: RSClin may identify high-risk patients who benefit from treatment intensification more accurately than OncotypeDx, and further prospective study is needed.

External Evaluation of a Mammography-based Deep Learning Model for Predicting Breast Cancer in an Ethnically Diverse Population.

Purpose: To externally evaluate a mammography-based deep learning (DL) model (Mirai) in a high-risk racially diverse population and compare its performance with other mammographic measures. Materials and Methods: A total of 6435 screening mammograms in 2096 female patients (median age, 56.4 years ± 11.2 [SD]) enrolled in a hospital-based case-control study from 2006 to 2020 were retrospectively evaluated. Pathologically confirmed breast cancer was the primary outcome. Mirai scores were the primary predictors. Breast density and Breast Imaging Reporting and Data System (BI-RADS) assessment categories were comparative predictors. Performance was evaluated using area under the receiver operating characteristic curve (AUC) and concordance index analyses. Results: Mirai achieved 1- and 5-year AUCs of 0.71 (95% CI: 0.68, 0.74) and 0.65 (95% CI: 0.64, 0.67), respectively. One-year AUCs for nondense versus dense breasts were 0.72 versus 0.58 (P = .10). There was no evidence of a difference in near-term discrimination performance between BI-RADS and Mirai (1-year AUC, 0.73 vs 0.68; P = .34). For longer-term prediction (2-5 years), Mirai outperformed BI-RADS assessment (5-year AUC, 0.63 vs 0.54; P < .001). Using only images of the unaffected breast reduced the discriminatory performance of the DL model (P < .001 at all time points), suggesting that its predictions are likely dependent on the detection of ipsilateral premalignant patterns. Conclusion: A mammography DL model showed good performance in a high-risk external dataset enriched for African American patients, benign breast disease, and BRCA mutation carriers, and study findings suggest that the model performance is likely driven by the detection of precancerous changes.Keywords: Breast, Cancer, Computer Applications, Convolutional Neural Network, Deep Learning Algorithms, Informatics, Epidemiology, Machine Learning, Mammography, Oncology, Radiomics Supplemental material is available for this article. © RSNA, 2023See also commentary by Kontos and Kalpathy-Cramer in this issue.

Patient-derived tumor organoids with p53 mutations, and not wild-type p53, are sensitive to synergistic combination PARP inhibitor treatment.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.

Race, Gene Expression Signatures, and Clinical Outcomes of Patients With High-Risk Early Breast Cancer.

Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race. Design, Setting, and Participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022. Exposure: Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. Main Outcomes and Measures: The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated. Results: The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor ß signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only. Conclusions and Relevance: The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

Breast Cancer Germline Genetic Counseling and Testing for Populations of African Heritage Globally: A Scoping Review on Research, Practice, and Bioethical Considerations.

PURPOSE: Despite the disproportionately high risk of breast cancer among women of African heritage, little is known about the facilitators and barriers to implementing germline genetic testing and counseling (GT/C). METHODS: This scoping review followed guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. Published manuscripts from database inception through 2021 were sourced from PubMed, Cumulative Index to Nursing and Allied Health Literature via EBSCO, Embase, Cochrane Library, and Scopus. Search terms were used to retrieve articles addressing (1) African heritage, (2) breast cancer, and (3) GT or GC. The screening involved abstract and title review and full-text review. Data were extracted for all articles meeting the inclusion criteria. RESULTS: A total of 154 studies were included. Most studies that took place were conducted in the United States (71.4%), and most first authors (76.9%) were from the United States. GT was conducted in 73 (49.7%) studies. BRCA1/BRCA2 were the most commonly studied genes for germline mutations. GC was conducted in 49 studies (33.3%), and perspectives on GC were evaluated in 43 (29.3%). The use of racial/ethnic categories varied broadly, although African American was most common (40.1%). Racism was mentioned in three studies (2.0%). CONCLUSION: There is a growing body of literature on GT/C for breast cancer in women of African heritage. Future studies on GT/C of African populations should consider increased clarity around racial/ethnic categorizations, continued community engagement, and intentional processes for informed consent.

Physical Activity During Adolescence and Early-adulthood and Ovarian Cancer Among Women with a BRCA1 or BRCA2 Mutation.

In the general population, physical activity has been associated with a lower risk of several cancers; however, the evidence for ovarian cancer is not clear. It is suggested that early-life physical activity may differentially impact risk. Whether this is true among women at high risk due to a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes has not been evaluated. Thus, we performed a matched case-control study to evaluate the association between adolescent and early-adulthood physical activity and ovarian cancer. BRCA mutation carriers who completed a research questionnaire on various exposures and incident disease and with data available on physical activity were eligible for inclusion. Self-reported activity at ages 12-13, 14-17, 18-22, 23-29, and 30-34 was used to calculate the average metabolic equivalent of task (MET)-hours/week for moderate, vigorous, and total physical activity during adolescence (ages 12-17) and early-adulthood (ages 18-34). Conditional logistic regression was used to estimate the OR and 95% confidence intervals (CI) of invasive ovarian cancer associated with physical activity. This study included 215 matched pairs (mean age = 57.3). There was no association between total physical activity during adolescence (ORhigh vs. low = 0.91; 95% CI: 0.61-1.36; Ptrend = 0.85), early-adulthood (ORhigh vs. low = 0.78; 95% CI: 0.51-1.20; Ptrend = 0.38) and overall (ORhigh vs. low = 0.81; 95% CI: 0.54-1.23; Ptrend = 0.56) and ovarian cancer. Findings were similar for moderate (Ptrend ≥ 0.25) and vigorous (Ptrend ≥ 0.57) activity. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, physical activity should continue to be encouraged to promote overall health. SIGNIFICANCE: In this matched case-control study, we observed no association between physical activity during adolescence or early-adulthood and subsequent risk of ovarian cancer. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, being active remains important to promote overall health and well-being.

Unawareness of breast cancer family history among African women.

Introduction: comprehensive cancer risk assessment services are lacking in most sub-Saharan African countries and the use of accurate family history (FH) information could serve as a cheap strategy for risk evaluation. The aim of this study is to determine the proportion of women unaware of family history of cancer among female relatives and associated socio-demographic characteristics. Methods: using case-control data on breast cancer among 4294 women in Nigeria, Uganda and Cameroon, we investigated the proportion of women unaware of family history of cancer among their female relatives. The association between participants' response to their awareness of female relatives' cancer history and socio-demographic characteristics was analysed according to case-control status, family side and distance of relation. Results: the proportion of women unaware if any relative had cancer was 33%, and was significantly higher among controls (43.2%) compared to 23.9% among cases (p<0.001) (Adjusted Odds Ratio (OR) = 2.51, 95% CI = 2.14 - 2.95). Age, education and marital status remained significantly associated with being unaware of FH among controls on multiple regression. Conclusion: about a third of women interviewed did not know about cancer history in at least one of their female relatives. Efforts aimed at improving cancer awareness in sub-Saharan Africa (SSA) are needed. Our findings could be useful for future studies of cancer risk assessment in SSA.

Racial/Ethnic Disparities in Telemedicine Utilization and Satisfaction Among Breast Cancer Patients During the COVID-19 Pandemic: A Mixed-Methods Analysis.

Background: Telemedicine has expanded rapidly during the COVID-19 pandemic. Data on telemedicine utilization are lacking, and racial/ethnic disparities in utilization and satisfaction are unknown among breast cancer patients. Methods: This was a longitudinal study, with two surveys conducted in 2020 and 2021, among patients enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort. Telemedicine utilization was modeled using mixed-effects logistic regression. Telemedicine satisfaction, assessed using a 5-point Likert scale, was modeled using mixed-effects proportional odds regression. Qualitative data on satisfaction were coded and analyzed using grounded theory. Results: Of 1,721 respondents, most (70.3%) were White, followed by 23.6% Black, 3.1% Asian, and 3.0% Hispanic. The median duration from breast cancer diagnosis to survey was 5.5 years (interquartile range: 2.7-9.4). In 2020, 59.2% reported telemedicine use; in 2021, 64.9% did, with a statistically significant increase (p < 0.001). Black patients had greater odds of telemedicine use than White patients (adjusted odds ratio [AOR] = 1.55, 95% confidence interval [CI]: 1.17-2.05). In 2020, 90.3% reported somewhat-to-extreme satisfaction; in 2021, 91.2% did, with a statistically significant, although clinically small, increase (p = 0.038). There were no racial/ethnic differences in telemedicine satisfaction between Black (AOR = 1.05, 95% CI: 0.81-1.35), Asian (AOR = 0.63, 95% CI: 0.34-1.16), or Hispanic (AOR = 0.63, 95% CI: 0.33-1.21) and White patients. Major themes emerged from the respondents that explained their levels of satisfaction were convenience, safety, specialty dependence, and technical issues. Conclusions: Telemedicine utilization and satisfaction were high among breast cancer patients over time and across races/ethnicities. Telemedicine could have great potential in reducing barriers to care and promoting health equity for breast cancer patients. However, patients' perceived challenges in accessing high-quality virtual care should be addressed.

Remotely Delivered Cancer Genetic Testing in the Making Genetic Testing Accessible (MAGENTA) Trial: A Randomized Clinical Trial.

Importance: Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress. Objective: To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing. Design, Setting, and Participants: Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US residents, and had access to the internet and a health care professional. Previous cancer genetic testing or counseling was exclusionary. In the family history cohort, participants had a personal or family history of breast or ovarian cancer. In the familial pathogenic variant (PV) cohort, participants reported 1 biological relative with a PV in an actionable cancer susceptibility gene. Data analysis was performed between December 13, 2020, and May 31, 2023. Intervention: Participants completed baseline questionnaires, watched an educational video, and were randomized to 1 of 4 arms: the control arm with pretest and/or posttest genetic counseling, or 1 of 3 study arms without pretest and posttest counseling. Genetic counseling was provided by phone appointments and testing was done using home-delivered saliva kits. Main Outcomes and Measures: The primary outcome was participant distress measured by the Impact of Event Scale 3 months after receiving the results. Secondary outcomes included completion of testing, anxiety, depression, and decisional regret. Results: A total of 3839 women (median age, 44 years [range 22-91 years]), most of whom were non-Hispanic White and college educated, were randomized, 3125 in the family history and 714 in the familial PV cohorts. In the primary analysis in the family history cohort, all experimental arms were noninferior for distress at 3 months. There were no statistically significant differences in anxiety, depression, or decisional regret at 3 months. The highest completion rates were seen in the 2 arms without pretest counseling. Conclusions and Relevance: In the MAGENTA clinical trial, omitting individualized pretest counseling for all participants and posttest counseling for those without PV during remote genetic testing was not inferior with regard to posttest distress, providing an alternative care model for genetic risk assessment. Trial Registration: ClinicalTrials.gov Identifier: NCT02993068.

Benign breast disease and breast cancer risk in African women: A case-control study.

Purpose: To examine the association between benign breast disease (BBD) and breast cancer (BC) in a heterogeneous population of African women. Methods: BC cases and matched controls were enrolled in three sub-Saharan African countries, Nigeria Cameroon, and Uganda, between 1998-2018. Multivariable logistic regression was used to test the association between BBD and BC. Risk factors dually associated with BBD and BC were selected. Using a parametric mediation analysis model, we assessed if selected BC risk factors were mediated by BBD. Results: Of 6418 participants, 55.7% (3572) were breast cancer cases. 360 (5.7%) self-reported BBD. Fibroadenoma (46.8%) was the most reported BBD. Women with a self-reported history of BBD had greater odds of developing BC than those without (adjusted odds ratio [aOR] = 1.47, 95% CI: 1.13-1.91). Biopsy-confirmed BBD was associated with BC (aOR = 3.11, 95% CI: 1.78-5.44). BBD did not significantly mediate the effects of any of the selected BC risk factors. Conclusions: In this study, BBD was associated with BC and did not significantly mediate the effects of selected BC risk factors.

PTPN2 copper-sensing rapidly relays copper level fluctuations into EGFR/CREB activation and associated CTR1 transcriptional repression.

Fluxes in human intra- and extracellular copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate (cAMP). We herein applied an unbiased temporal evaluation of the whole-genome transcriptional activities modulated by fluctuations in copper levels to identify the copper sensor proteins responsible for driving these activities. We found that fluctuations in physiologically-relevant copper levels rapidly modulate EGFR/MAPK/ERK signal transduction and activation of the transcription factor cAMP response element-binding protein (CREB). Both intracellular and extracellular assays support Cu 1+ inhibition of the EGFR-phosphatase PTPN2 (and potentially the homologous PTPN1)-via direct ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism of copper-stimulated EGFR signal transduction activation. Depletion of copper represses this signaling pathway. We additionally show i ) copper supplementation drives transcriptional repression of the copper importer CTR1 and ii ) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper-stimulated MAPK/ERK/CREB-signaling and CTR1 expression, thereby uncovering a previously unrecognized link between copper levels and cellular signal transduction.