What Proportion of BRCA-Associated Breast Cancer Is Human Epidermal Growth Factor 2-Low and Eligible for Additional Targeted Therapy?

INTRODUCTION: DESTINY B04 provided clinical meaning to a new classification of human epidermal growth factor 2 (HER2) expression in breast cancer: HER2-low. Patients with germline breast cancer type 1 gene pathogenic variants (gBRCA1) often develop triple negative breast cancer (TNBC), but the proportion who could be classified as HER2-low and qualify for an additional targeted therapy option is unknown. This study aims to characterize the proportion of gBRCA1 or germline breast cancer type 2 gene pathogenic variants patients for whom these novel targeted therapies may be an option. METHODS: We performed a retrospective chart review of patients with gBRCA1/2 treated at our institution for invasive breast cancer from 2000 to 2021. Synchronous or metachronous contralateral breast cancers were recorded separately. HER2 status was determined by immunohistochemistry and fluorescence in situ hybridization. We excluded patients without complete HER2 data. RESULTS: Among the 95 breast cancers identified in our cohort of 85 gBRCA1/2 patients, 41 (43%) were TNBC, 38 (40%) were hormone receptor positive (HR+)/HER2-negative, and 16 (17%) were HER2-positive based on standard conventions. We found that 82% of the HR+/HER2-cancers and 66% of TNBCs would be reclassified as HER2-low. After stratifying by BRCA gene status, 64% of cancers in patients with gBRCA1 and 58% of cancers in patients with germline breast cancer type 2 gene pathogenic variants were HER2-low. CONCLUSIONS: A significant portion of gBRCA1/2 patients who were previously diagnosed with TNBC or HR+/HER2- breast cancer would now be classified as HER2-low and could be considered for the use of trastuzumab deruxtecan in the metastatic setting. Outcome differences from therapy changes in this cohort should now be assessed.

Physical activity assessment among men undergoing genetic counseling for inherited prostate cancer: a teachable moment for improved survivorship.

BACKGROUND: Genetic counseling (GC) presents an opportunity to address modifiable cancer risk factors, such as obesity, which is impacted by non-adherence to physical activity (PA) guidelines. Adherence to PA guidelines has not been assessed among men undergoing GC for prostate cancer (PCA). We conducted a targeted analysis of men undergoing PCA GC to assess adherence to PA recommendations. METHODS: Using a cross-sectional design, a total of 158 men from the Genetic Evaluation of Men (GEM) study at two academic cancer centers with a diagnosis or at risk for PCA completed a structured lifestyle survey, including questions about the number of days and intensity of PA over the past year. One-sample t tests assessed adherence of participants to PA recommendations. Chi-square analyses compared differences in PA adherence by PCA status, aggressiveness, family history, and body mass index. Logistic regression analyses identified predictors of PA adherence. RESULTS: High proportions of GEM participants were overweight (44.9%) or obese (38.0%, p = 0.002). Men with PCA engaged in less moderate (p = 0.019) and vigorous (p = 0.005) aerobic activity than men without PCA. Higher education was predictive of adherence to light (p = 0.008), moderate (p = 0.019), and vigorous (p = 0.002) intensity PA. Older age (p = 0.015) and higher education (p = 0.001) were predictive of adherence to strength-based recommendations. CONCLUSIONS: High proportions of men receiving PCA GC were overweight/obese and lacked adherence to PA recommendations. GC represents a teachable moment to address PA to reduce cancer risk and promote cancer survivorship.

Genetic Variants and Tumor Immune Microenvironment: Clues for Targeted Therapies in Inflammatory Breast Cancer (IBC).

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

Time to Surgery and the Impact of Delay in the Non-Neoadjuvant Setting on Triple-Negative Breast Cancers and Other Phenotypes.

BACKGROUND: Characterization of breast cancer phenotypes has improved our ability to predict breast cancer behavior. Triple-negative (TN) breast cancers have higher and earlier rates of distant events. It has been suggested that this behavior necessitates treating TNs faster than others, including use of neoadjuvant chemotherapy (NACT) if time to surgery is not rapid. METHODS: A review of women diagnosed with non-inflammatory, invasive breast cancer was conducted using the National Cancer Database for patients not having NACT, diagnosed between 2010 and 2014. Changes in overall survival due to delay were measured by phenotype. RESULTS: Overall, 351,087 patients met the inclusion criteria, including 36,505 (10.4%) TNs, 77.9% hormone receptor-positive (HR+) and 11.7% human epidermal growth factor receptor 2 (HER2)-enriched (HER2+). Phenotype, among other factors, was predictive of treatment delays. Adjusted median days from diagnosis to surgery and chemotherapy were 29.9, 31.6 and 31.5 (p< 0.001), and 72.7, 78.0 and 74.4 (p< 0.001) for TNs, HR+ and HER2+ cancers, respectively. After diagnosis, OS declined for all patients per month of preoperative delay (hazard ratio 1.104; p< 0.001). In models separating or combining surgery and chemotherapy, this survival decline did not vary by breast cancer phenotype (p > 0.3). CONCLUSIONS: Delays cause small but measurable effects overall, but the effect on survival does not differ among breast cancer phenotypes. Our data suggest that urgency between diagnosis and surgery or chemotherapy is similar for breast cancers of different subtypes. Although NACT is sometimes advocated solely to avoid treatment delays, this study does not suggest a greater surgical urgency for TNs compared with other breast cancer phenotypes.

Genetic Variants Detected Using Cell-Free DNA from Blood and Tumor Samples in Patients with Inflammatory Breast Cancer.

We studied genomic alterations in 19 inflammatory breast cancer (IBC) patients with advanced disease using samples of tissue and paired blood serum or plasma (cell-free DNA, cfDNA) by targeted next generation sequencing (NGS). At diagnosis, the disease was triple negative (TN) in eleven patients (57.8%), ER+ Her2- IBC in six patients (31.6%), ER+ Her2+ IBC in one patient (5.3%), and ER- Her2+ IBC in one other patient (5.3%). Pathogenic or likely pathogenic variants were frequently detected in TP53 (47.3%), PMS2 (26.3%), MRE11 (26.3%), RB1 (10.5%), BRCA1 (10.5%), PTEN (10.5%) and AR (10.5%); other affected genes included PMS1, KMT2C, BRCA2, PALB2, MUTYH, MEN1, MSH2, CHEK2, NCOR1, PIK3CA, ESR1 and MAP2K4. In 15 of the 19 patients in which tissue and paired blood were collected at the same time point, 80% of the variants detected in tissue were also detected in the paired cfDNA. Higher concordance between tissue and cfDNA was found for variants with higher allele fraction in tissue (AFtissue ≥ 5%). Furthermore, 86% of the variants detected in cfDNA were also detected in paired tissue. Our study suggests that the genetic profile measured in blood cfDNA is complementary to that of tumor tissue in IBC patients.

Diet assessment among men undergoing genetic counseling and genetic testing for inherited prostate cancer: Exploring a teachable moment to support diet intervention.

BACKGROUND: Genetic counseling (GC) and genetic testing (GT) for prostate cancer (PCA) is a rapidly growing, affording opportunity for healthy lifestyle promotion in men aligned with cancer survivorship and cancer prevention goals. We conducted a targeted dietary analysis of men undergoing GC/GT for PCA for adherence to the United States Department of Agriculture (USDA) Food Pattern recommendations which align with preventing cancer and recurrences in the Genetic Evaluation of Men (GEM) study at two academic centers to inform future strategies for diet intervention. METHODS: Participants of GEM with PCA or at-risk for PCA completed a structured food frequency questionnaire indicating number of servings consumed per day or per week of fruits, vegetables, red meat, seafood, processed meat, and foods high in saturated fat. Adherence to the USDA recommendations was assessed for the total sample and by PCA status and aggressiveness, family history, and body mass index (BMI) through χ 2 contingency analyses. One-sample t tests were used to compare the dietary behaviors of men to USDA Recommendations. Levels of α were set a priori at P < 0.05. RESULTS: Of 239 males undergoing GC on the study, surveys were completed by 197 men (82.4%), and complete survey data was available on 113 men (47.3%). By the Centers for Disease Control and Prevention BMI classification, 82.3% of the cohort was overweight (45.1%) or obese (37.2%). GEM participants reported consuming less fruits (P = 0.015), less vegetables ( P < 0.001), less seafood ( P < 0.001), more processed meats ( P < 0.001), and more foods high in saturated fats ( P < 0.001) than recommended. CONCLUSION: A high proportion of men receiving GC/GT for PCA were overweight and/or obese with lack of adherence to national diet recommendations for cancer risk and recurrence, affording a teachable moment and supporting the systematic focus of introducing nutrition intervention during GC to promote survivorship.

Understanding of multigene test results among males undergoing germline testing for inherited prostate cancer: Implications for genetic counseling.

BACKGROUND: Genetic testing (GT) for prostate cancer (PCA) is rising, with limited insights regarding genetic counseling (GC) needs of males. Genetic Evaluation of Men (GEM) is a prospective multigene testing study for inherited PCA. Men undergoing GC were surveyed on knowledge of cancer risk and genetics (CRG) and understanding of personal GT results to identify GC needs. METHODS: GEM participants with or high-risk for PCA were recruited. Pre-test GC was in-person, with video and handout, or via telehealth. Post-test disclosure was in-person, by phone, or via telehealth. Clinical and family history data were obtained from participant surveys and medical records. Participants completed measures of knowledge of CRG, literacy, and numeracy pre-test and post-test. Understanding of personal genetic results was assessed post-test. Factors associated with knowledge of CRG and understanding of personal genetic results were examined using multivariable linear regression or McNemar's test. RESULTS: Among 109 men who completed pre- and post-GT surveys, multivariable analysis revealed family history meeting hereditary cancer syndrome (HCS) criteria was significantly predictive of higher baseline knowledge (P = 0.040). Of 101 men who responded definitively regarding understanding of results, 13 incorrectly reported their result (McNemar's P < 0.001). Factors significantly associated with discordance between reported and actual results included having a variant of uncertain significance (VUS) (P < 0.001) and undergoing GC via pre-test video and post-test phone disclosure (P = 0.015). CONCLUSIONS: While meeting criteria for HCS was associated with higher knowledge of CRG, understanding of personal GT results was lacking among a subset of males with VUS. A more exploratory finding was lack of understanding of results among men who underwent GC utilizing video and phone. Studies optimizing GC strategies for males undergoing multigene testing for inherited PCA are warranted.

Lessons Learned from Implementing a Prostate Cancer Risk Assessment Program for Underserved High-Risk Men in the Community: the Prostate REACH Project.

Prostate cancer disproportionately affects Black men, who may also encounter barriers to participation in prostate cancer risk assessment. The Prostate Risk, Education and Assessment in the Community with Help (REACH) project was a community-based extension of a comprehensive prostate cancer risk assessment program at a comprehensive cancer center. The goals of the REACH project were the following: (1) establish a community prostate cancer risk assessment clinic, (2) conduct targeted recruitment, and (3) provide navigation services including follow-up for uninsured men. Key implementation steps included the following: (1) choosing a clinic site, (2) establishing patient access procedures, (3) establishing navigator services, (4) developing subsidy fund use guidelines, and (5) designing recruitment and promotion. Through community-based promotion, 64 men inquired about the program and 26 (41 %) participated. Of those screened, 46 % had abnormal results, and 2 men were diagnosed with prostate cancer. Here, we describe a unique demonstration project to implement a comprehensive prostate cancer risk assessment program in an underserved Black community and describe successes and challenges to inform future efforts to promote access to underserved men.

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States.

Aim: To examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Methods: A retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor-positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes. Results: When diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments. Conclusion: Clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.

A phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors.

This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m2, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m2. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.

Early onset HER2-positive breast cancer is associated with germline TP53 mutations.

BACKGROUND: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. METHODS: We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls). RESULTS: Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99). CONCLUSIONS: This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.

Genetic Contribution to Metastatic Prostate Cancer.

Recent studies show that the prevalence of germline pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes in metastatic prostate cancer is higher than previously recognized and higher than in unaffected men. Specific gene dysfunction is important in prostate cancer initiation and/or evolution to metastases. This article reviews key literature on individual genes, recognizing BRCA2 as the gene most commonly altered in the metastatic setting. This article discusses the importance of representative and diverse inclusion, and efforts to advance management for at-risk carrier populations to maximize clinical benefit.

The effect of neighborhood social environment on prostate cancer development in black and white men at high risk for prostate cancer.

INTRODUCTION: Neighborhood socioeconomic (nSES) factors have been implicated in prostate cancer (PCa) disparities. In line with the Precision Medicine Initiative that suggests clinical and socioenvironmental factors can impact PCa outcomes, we determined whether nSES variables are associated with time to PCa diagnosis and could inform PCa clinical risk assessment. MATERIALS AND METHODS: The study sample included 358 high risk men (PCa family history and/or Black race), aged 35-69 years, enrolled in an early detection program. Patient variables were linked to 78 nSES variables (employment, income, etc.) from previous literature via geocoding. Patient-level models, including baseline age, prostate specific antigen (PSA), digital rectal exam, as well as combined models (patient plus nSES variables) by race/PCa family history subgroups were built after variable reduction methods using Cox regression and LASSO machine-learning. Model fit of patient and combined models (AIC) were compared; p-values<0.05 were significant. Model-based high/low nSES exposure scores were calculated and the 5-year predicted probability of PCa was plotted against PSA by high/low neighborhood score to preliminarily assess clinical relevance. RESULTS: In combined models, nSES variables were significantly associated with time to PCa diagnosis. Workers mode of transportation and low income were significant in White men with a PCa family history. Homeownership (%owner-occupied houses with >3 bedrooms) and unemployment were significant in Black men with and without a PCa family history, respectively. The 5-year predicted probability of PCa was higher in men with a high neighborhood score (weighted combination of significant nSES variables) compared to a low score (e.g., Baseline PSA level of 4ng/mL for men with PCa family history: White-26.7% vs 7.7%; Black-56.2% vs 29.7%). DISCUSSION: Utilizing neighborhood data during patient risk assessment may be useful for high risk men affected by disparities. However, future studies with larger samples and validation/replication steps are needed.

Treatment times in breast cancer patients receiving neoadjuvant vs adjuvant chemotherapy: Is efficiency a benefit of preoperative chemotherapy?

BACKGROUND/OBJECTIVE: Delays in times to surgery, chemotherapy, and radiotherapy impair survival in breast cancer patients. Neoadjuvant chemotherapy (NAC) confers equivalent survival to adjuvant chemotherapy (AC), but it remains unknown which approach facilitates faster initiation and completion of treatment. METHODS: Women ≥18 years old with nonrecurrent, noninflammatory, clinical stage I-III breast cancer diagnosed between 2004 and 2015 who underwent both surgery and chemotherapy were reviewed from the National Cancer Database. RESULTS: Among 155 606 women overall, 28 241 patients received NAC and 127 365 patients received AC. NAC patients had higher clinical T and N stages (35.8% T3/4 vs 4.9% T3/4; 14.4% N2/3 vs 3.7% N2/3). After adjusting for stage and other factors, NAC patients had longer times to begin treatment (36.1 vs 35.4 days adjusted, P = .15), and took significantly longer to start radiotherapy (240.8 vs 218.2 days adjusted, P < .0001), and endocrine therapy (301.6 vs 275.7 days adjusted, P < .0001). Unplanned readmissions (1.2% vs 1.7%), 30-day mortality (0.04% vs 0.01%), and 90-day mortality (0.30% vs 0.08%) were all low and clinically insignificant between NAC and AC. CONCLUSION: Compared to patients receiving AC, those receiving NAC do not start treatment sooner. In addition, patients receiving NAC do not complete treatment faster. Although there are clear indications for administering NAC vs AC, rapidity of treatment should not be considered a benefit of giving chemotherapy preoperatively.

Patterns of Care and Efficacy of Chemotherapy and Radiotherapy in Skin-Involved Breast Cancers of All Sizes.

BACKGROUND: The management of small skin-involved (SI) invasive breast cancers is controversial because although they are considered unresectable, their prognosis is far better than their stage III classification. This study was undertaken to determine how SI lesions are treated in the United States and to discern the benefit of systemic therapy. PATIENTS AND METHODS: Data of patients diagnosed with stage I-III breast cancer in the National Cancer Data Base between 2004 and 2011 were reviewed. Treatment patterns were examined and overall survival assessed. RESULTS: A total of 3485 patients had SI and 456,287 patients had non-SI breast cancers. Chemotherapy was administered to 68.5% of SI and 45.9% of non-SI tumors (P < .001), including 77.2% of SI and 33% of non-SI tumors < 2 cm (P < .001). After adjusting for patient and tumor characteristics, SI patients were 19.4% more likely to receive chemotherapy than non-SI patients. Radiotherapy was provided to 61.1% of SI and 64.3% of non-SI tumors (P < .001), including 65.5% of SI and 66.5% non-SI tumors < 2 cm (P = .711). After adjusting for patient and tumor characteristics, SI patients were 76.6% more likely to receive radiotherapy than non-SI patients. Chemotherapy and radiotherapy provided an overall survival benefit for stage II and III SI and non-SI tumors. CONCLUSION: Despite controversy regarding staging and prognosis of SI tumors, the majority of patients are provided systemic therapy and radiotherapy. Varied patterns of chemotherapy administration for SI tumors suggests that further treatment guidance and standardization are required, especially because chemotherapy and radiotherapy are equally efficacious in SI and non-SI tumors alike.

Hematologic toxicity in BRCA1 and BRCA2 mutation carriers during chemotherapy: A retrospective matched cohort study.

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild-type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild-type patients and among BRCA2 carriers vs matched wild-type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild-type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild-type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild-type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild-type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short-term repetitive hematopoietic stressors.

Intensive Surveillance with Biannual Dynamic Contrast-Enhanced Magnetic Resonance Imaging Downstages Breast Cancer in BRCA1 Mutation Carriers.

PURPOSE: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer.Experimental Design: We performed dynamic contrast-enhanced MRI every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. RESULTS: Between 2004 and 2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: 4 ductal carcinoma in situ (DCIS) and 13 early-stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis, and no interval invasive cancers occurred. The sensitivity of biannual MRI alone was 88.2% and annual MG plus biannual MRI was 94.1%. The cancer detection rate of biannual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus biannual MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. CONCLUSIONS: Biannual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus biannual MRI screening.See related commentary by Kuhl and Schrading, p. 1693.

Effects of a randomized trial comparing standard and enhanced counseling for men at high risk of prostate cancer as a function of race and monitoring style.

Despite conflicting guidelines, a significant subset of high-risk men decide to undergo routine prostate cancer screening. Yet, there is a scarcity of available programs, and no studies evaluating interventions to support men in dealing with the psychosocial impact of screening. In this study, one of the first to explore the responses of high-risk men enrolling in a Prostate Cancer Risk Assessment Program ( N = 128), patients underwent a prostate cancer risk counseling visit immediately followed by either a cognitive-affective preparation session designed to help them process the information they received or a general health education session. All men in this self-selected sample chose to participate in prostate cancer screening. Men were assessed 3 weeks and 6 months post-counseling. The impact of the enhanced counseling condition on knowledge, perceived risk, expectancies, and intrusive ideation was a function of racial and coping style group. Implications for tailored interventions to maximize preparedness for risk and screening counseling are discussed.

Racial Disparities in the Molecular Landscape of Cancer.

BACKGROUND/AIM: African Americans (AA) have the highest incidence and mortality of any racial/ethnic group in the US for most cancer types. Heterogeneity in the molecular biology of cancer, as a contributing factor to this disparity, is poorly understood. To address this gap in knowledge, we explored the molecular landscape of colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and high-grade glioma (HGG) from 271 AA and 636 Caucasian (CC) cases. MATERIALS AND METHODS: DNA from formalin-fixed paraffin-embedded tumors was sequenced using next-generation sequencing. Additionally, we evaluated protein expression using immunohistochemistry. The Exome Aggregation Consortium Database was evaluated for known ethnicity associations. RESULTS: Considering only pathogenic or presumed pathogenic mutations, as determined by the American College of Medical Genetics and Genomics guidelines, and using Bonferroni and Benjamini-Hochberg corrections for multiple comparisons, we found that CRC tumors from AA patients harbored significantly more mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) than those from CC patients. CRC tumors in AA patients also appeared to harbor more mutations of mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1), MPL proto-oncogene (MPL), thrombo-poietin receptor, and neurofibromin 1 (NF1) than those from CC patients. In contrast, CRCs from AA patients were likely to carry fewer mutations of ataxia-telangiectasia mutated (ATM), as well as of proto-oncogene B-Raf (BRAF), including the V600E variant, than those from CC patients. Rates of immunohistochemical positivity for epidermal growth factor receptor (EGFR) and DNA topoisomerase 2-alpha (TOP2A) tended to be higher in CRCs from AA patients than in CC patients. In NSCLC adenocarcinoma, BRAF variants appeared to be more frequent in the AA than in the CC cohort, whereas in squamous cell lung carcinoma, programmed death-ligand 1 (PD-L1) expression tended to be lower in the AA than in CC group. Moreover, HGG tumors from AA patients showed a trend toward harboring more mutations of protein tyrosine phosphatase non-receptor 11 (PTPN11), than HGG tumors from the CC cohort. In contrast, mutations of phosphatase and tensin homolog (PTEN) and tumor protein 53 (TP53) appeared to be higher in HGG tumors in CC patients than in their AA counterparts. CONCLUSION: Our data revealed significant differences and trends in molecular signatures of the three cancer types in AA and CC cohorts. These findings imply that there may be differences in carcinogenesis between AA and CC patients and that race may be a factor that should be considered regarding cancer incidence and outcome.

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.