Racial disparities in breast cancer hereditary risk assessment referrals.

For poorly understood reasons, Black non-Hispanic (BNH) women meeting National Comprehensive Cancer Network (NCCN) criteria for genetic testing for breast cancer risk are less likely than White non-Hispanic (WNH) women to undergo testing (Armstrong, Micco, Carney, Stopfer, & Putt, JAMA, 293, 1729 and 2005). We compared physician referral rates and uptake for genetic testing of BNH and WNH women meeting select NCCN criteria (breast cancer under age 50, two primary breast cancers, triple-negative disease under age 60) in the Cancer Center at George Washington University (GWCC) between 2015 and 2018. Of the 723 BNH and WNH patients treated for breast cancer at GWCC, 28% met study criteria for genetic counseling referral (n = 252; BNH n = 115, WNH n = 137). Physician referral rates to genetic counseling differed significantly by race (BNH 75.7%, n = 87 and WNH 92.7%; n = 127; χ2  = 14.19, p-value < .01). Once referred, though, there was no significant difference in uptake of genetic counseling by race (BNH 95.4%, n = 83; WNH 97.6%, n = 124, χ2  = 1.33, p-value = .25) for patients appropriately referred.

The Perils of Single-Site Genetic Testing for Hereditary Cancer Syndromes in the Era of Next-Generation Sequencing.

A challenge in counseling patients with a family history suggesting a hereditary cancer syndrome is deciding which genetic tests or panels to order. In this article, we discuss the identification of multiple familial mutations through genetic counseling and panel testing. For patients meeting National Comprehensive Cancer Network criteria for clinical genetic testing, providers should consider expanded panels to provide a more complete assessment of one's genetic risk. The continued use of expanded panel testing in the clinical setting will help inform optimal management of cancer patients, as well as the management of their unaffected family members. The mutation discovered in this case was in the ATM gene. The clinical significance of the mutation, potential therapeutic targets, and proper clinical management are discussed. KEY POINTS: With single-site genetic testing, there is the potential to miss hereditary genetic syndromes that can be managed clinically.Between 4% and 6% of hereditary breast and ovarian cancer syndromes are caused by genes other than BRCA1 and BRCA2.ATM is a DNA mismatch repair gene associated with double-stranded DNA break repair and cell cycle checkpoint arrest.The risk of developing female breast cancer by age 50 and by age 80 in ATM heterozygotes is 9% and 17%-52%, respectively.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints included the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) is associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Body composition and chemotherapy toxicity among women treated for breast cancer: a systematic review.

PURPOSE: Toxicity is a significant problem among women receiving systemic chemotherapy for breast cancer, with up to 60% experiencing hematologic and 14% experiencing non-hematologic toxicity. Chemotherapy is dosed using body surface area, which does not account for heterogeneity in lean body mass (LBM) and adipose tissue (AT). This systematic review, registered with the PROSPERO International Prospective Register of Systematic Reviews (#CRD42021279874), evaluates associations between body composition and chemotherapy-related toxicity during breast cancer treatment. METHODS: Scientific literature databases (PubMed, Scopus, CINAHL, and CENTRAL) were systematically searched in November 2021 for studies evaluating associations between body composition (assessed using computed tomography or dual x-ray absorptiometry) and chemotherapy-related toxicity among women receiving breast cancer treatment. Eligibility was not limited by year or country of publication. Article screening and data abstraction was conducted using the Covidence Systematic Review Management System. Predetermined criteria were used to evaluate rigor of participant recruitment, representativeness of the population, and use of validated measures of body composition and toxicity. RESULTS: An inverse association between LBM and toxicity was reported in seven of the eight included studies, although definitions of low LBM differed across studies. Three studies evaluated the association between AT and chemotherapy toxicity with inconsistent findings. Heterogeneity in body composition measures/definitions and treatment regimens precluded the ability to perform meta-analyses. CONCLUSION: Low LBM appears to be a risk factor for chemotherapy toxicity, but the role of AT is unclear. IMPLICATIONS FOR CANCER SURVIVORS: Further research that accounts for guideline concordance in chemotherapy prescriptions and the use of supportive care medications is needed.

Adjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study.

Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

Evaluating the efficacy of a priming dose of cyclophosphamide prior to pembrolizumab to treat metastatic triple negative breast cancer.

PURPOSE: Triple negative breast cancer (TNBC) is characterized by the presence of immune cells in the tumor microenvironment, however, the response to single-agent immune checkpoint inhibitor (ICI) therapy is modest. Preclinical models have demonstrated that intratumoral regulatory T cells (Tregs) dampen the antitumor response to ICI. We performed a single-arm phase II trial to evaluate the efficacy of a single low dose of cyclophosphamide (Cy) to deplete Tregs administered before initiating pembrolizumab. PATIENTS AND METHODS: 40 patients with pretreated metastatic TNBC were enrolled. The primary endpoints were progression-free survival (PFS) and change in peripheral blood Tregs after Cy. Secondary endpoints included overall response rate (ORR), duration of response, overall survival, treatment-related adverse events (AEs), and correlative evaluations. RESULTS: Median PFS was 1.8 months, and the ORR was 21%. Tregs were not significantly decreased after Cy prior to ICI (-3.3%, p=0.19), and increased significantly after the first cycle of therapy (+21% between cycles 1 and 2, p=0.005). Immune-related AEs were similar to historical pembrolizumab monotherapy, and were associated with response to therapy (p=0.02). Patients with pretreatment tumors harboring increased expression of B cell metagene signatures and increased circulating B cell receptor repertoire diversity were associated with clinical response and immune-related toxicity (IRT). CONCLUSIONS: Among patients with heavily pretreated TNBC, Cy prior to pembrolizumab did not significantly deplete Tregs, and in those with decreased numbers there was rapid recovery following therapy. Increased B cell gene expression in baseline samples was associated with clinical response and IRT.

Assessing Breast Cancer Survivors' Perceptions of Using Voice-Activated Technology to Address Insomnia: Feasibility Study Featuring Focus Groups and In-Depth Interviews.

BACKGROUND: Breast cancer survivors (BCSs) are a growing population with a higher prevalence of insomnia than women of the same age without a history of cancer. Cognitive behavioral therapy for insomnia (CBT-I) has been shown to be effective in this population, but it is not widely available to those who need it. OBJECTIVE: This study aimed to better understand BCSs' experiences with insomnia and to explore the feasibility and acceptability of delivering CBT-I using a virtual assistant (Amazon Alexa). METHODS: We first conducted a formative phase with 2 focus groups and 3 in-depth interviews to understand BCSs' perceptions of insomnia as well as their interest in and comfort with using a virtual assistant to learn about CBT-I. We then developed a prototype incorporating participant preferences and CBT-I components and demonstrated it in group and individual settings to BCSs to evaluate acceptability, interest, perceived feasibility, educational potential, and usability of the prototype. We also collected open-ended feedback on the content and used frequencies to describe the quantitative data. RESULTS: We recruited 11 BCSs with insomnia in the formative phase and 14 BCSs in the prototype demonstration. In formative work, anxiety, fear, and hot flashes were identified as causes of insomnia. After prototype demonstration, nearly 79% (11/14) of participants reported an interest in and perceived feasibility of using the virtual assistant to record sleep patterns. Approximately two-thirds of the participants thought lifestyle modification (9/14, 64%) and sleep restriction (9/14, 64%) would be feasible and were interested in this feature of the program (10/14, 71% and 9/14, 64%, respectively). Relaxation exercises were rated as interesting and feasible using the virtual assistant by 71% (10/14) of the participants. Usability was rated as better than average, and all women reported that they would recommend the program to friends and family. CONCLUSIONS: This virtual assistant prototype delivering CBT-I components by using a smart speaker was rated as feasible and acceptable, suggesting that this prototype should be fully developed and tested for efficacy in the BCS population. If efficacy is shown in this population, the prototype should also be adapted for other high-risk populations.

Relationship Between Hereditary Cancer Syndromes and Oncotype DX Recurrence Score.

BACKGROUND: Oncotype DX (ODX) is a genomic assay of tumor tissue that is utilized to predict the likelihood of recurrence and benefit of chemotherapy in breast cancer patients. Five to 10% of breast cancers are hereditary, and hereditary syndromes may not be uncovered through family history alone. We hypothesized that high ODX recurrence score (RS) may signal a potential hereditary cancer risk. PATIENTS AND METHODS: We performed a retrospective analysis of data from hormone receptor-positive breast cancer patients who had undergone ODX and germline genetic testing. The chi-square test and Fisher exact test were used to examine univariable association between RS and germline mutation status. Multivariable logistic regression was utilized to examine if there was an association of RS with germline mutation status. RESULTS: In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). In the multivariable logistic regression model predicting germline mutation status, RS level remained significantly associated with germline mutation, in particular BRCA1 or BRCA2. The mean RS for those with non-BRCA1/2 germline mutations versus those without germline mutations was not significant (P = .38). CONCLUSION: High RS is associated with germline mutation status. Breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. If confirmed prospectively, oncologists may consider referring patients with high RS for genetic risk assessment and counseling to inform management plans, as well as counseling of family members.

A Feasibility Study of Group-Delivered Behavioral Interventions for Insomnia Among Breast Cancer Survivors: Comparing Cognitive Behavioral Therapy for Insomnia and a Mind-Body Intervention.

Objectives: An estimated 30%-50% of breast cancer survivors (BCSs) report persistent insomnia, which may affect daytime functioning and quality of life, and lead to longer term health complications. Although the gold standard insomnia intervention, cognitive behavioral therapy for insomnia (CBT-I), has demonstrated efficacy, accessibility is limited due to a scarcity of trained providers, and adherence to therapy is variable. Group-delivered alternative therapies may offer an opportunity to reach and treat BCSs with insomnia. This pilot study was designed to assess feasibility of a group-delivered mind-body intervention compared with group-delivered CBT-I among BCSs. Design: The authors recruited n = 25 stages I - IV BCSs to a 9-week trial of group therapy for insomnia. Eligible women were assigned to the next upcoming group until it was full. Primary outcomes were to assess intervention feasibility measured by (1) qualitative focus group feedback and (2) attendance. The feasibility of using the Insomnia Severity Index (ISI) was also assessed in this population and ISI change scores were gathered to allow for power calculations in a future trial. Means and frequencies were used to describe participant demographics and attendance. Results: The authors found higher attendance (86% vs. 67% of sessions) and greater satisfaction with the intervention (84.6% vs. 57.1%) reported among mind-body participants than among CBT-I participants. Qualitative feedback suggested more group cohesion among the mind-body group and lower incentive to attend in-person among the CBT-I group. Conclusions: The results suggest that delivering a mind-body intervention for BCSs is feasible and acceptable, based on attendance and qualitative feedback.

Effects of Cancer Genetic Panel Testing on at-Risk Individuals.

OBJECTIVE: To evaluate the role of screening patients at increased risk for hereditary cancer syndromes with an extended panel of cancer predisposition genes to identify actionable genetic mutations. METHODS: A retrospective chart review was conducted of all patients presenting to a multidisciplinary cancer program for genetic counseling and testing from January 2015 to December 2016. Individuals presenting to the program were identified as at-risk by a personal or family history of cancer, by their health care provider, or by self-referral. All participants met current National Comprehensive Cancer Network criteria for genetic risk evaluation for hereditary cancer. The results of testing and its implications for management, based on National Comprehensive Cancer Network guidelines, were recorded. RESULTS: Of 670 at-risk patients who underwent genetic testing, 66 (9.9%) had BRCA-limited testing; of these, 26 of 670 (3.9%) had a deleterious or likely pathogenic mutation. Expanded panel testing was done for 560 of the 670 patients (83.4%), and abnormal results were found in 65 of 670 (9.7%); non-BRCA mutations (predominantly CHEK2) were found in 49 of the 65 (75%). Abnormal genetic testing was associated with increased surveillance in 96% of those with deleterious mutations, whereas negative testing for a known familial mutation in 45 patients was associated with a downgrade of their risk and reduction of subsequent surveillance and management. CONCLUSION: Guideline-based management is frequently altered by genetic testing, including panel testing, in patients at risk for cancer. We recommend that obstetrics and gynecology providers routinely refer at-risk patients for genetic counseling and testing when clinically appropriate.