Cascade testing for hereditary cancer: comprehensive multigene panels identify unexpected actionable findings in relatives.

Current guidelines recommend single variant testing in relatives of patients with known pathogenic or likely pathogenic germline variants in cancer predisposition genes. This approach may preclude the use of risk-reducing strategies in family members who have pathogenic or likely pathogenic germline variants in other cancer predisposition genes. Cascade testing using multigene panels was performed in 3696 relatives of 7433 probands. Unexpected pathogenic or likely pathogenic germline variants were identified in 230 (6.2%) relatives, including 144 who were negative for the familial pathogenic or likely pathogenic variant but positive for a pathogenic or likely pathogenic variant in a different gene than the proband and 74 who tested positive for the familial pathogenic or likely pathogenic variant and had an additional pathogenic or likely pathogenic variant in a different gene than the proband. Of the relatives with unexpected pathogenic or likely pathogenic germline variants, 36.3% would have qualified for different or additional cancer screening recommendations. Limiting cascade testing to only the familial pathogenic or likely pathogenic variant would have resulted in missed, actionable findings for a subset of relatives.

Universal Germline-Genetic Testing for Breast Cancer: Implementation in a Rural Practice and Impact on Shared Decision-Making.

BACKGROUND: Whereas the National Comprehensive Cancer Network (NCCN) criteria restrict germline-genetic testing (GGT) to a subset of breast cancer (BC) patients, the American Society of Breast Surgeons recommends universal GGT. Although the yield of pathogenic germline variants (PGV) in unselected BC patients has been studied, the practicality and utility of incorporating universal GGT into routine cancer care in community and rural settings is understudied. This study reports real-world implementation of universal GGT for patients with breast cancer and genetics-informed, treatment decision-making in a rural, community practice with limited resources. METHODS: From 2019 to 2022, all patients with breast cancer at a small, rural hospital were offered GGT, using a genetics-extender model. Statistical analyses included Fisher's exact test, t-tests, and calculation of odds ratios. Significance was set at p < 0.05. RESULTS: Of 210 patients with breast cancer who were offered GGT, 192 (91.4%) underwent testing with 104 (54.2%) in-criteria (IC) and 88 (45.8%) out-of-criteria (OOC) with NCCN guidelines. Pathogenic germline variants were identified in 25 patients (13.0%), with PGV frequencies of 15 of 104 (14.4%) in IC and ten of 88 (11.4%) in OOC patients (p = 0.495). GGT informed treatment for 129 of 185 (69.7%) patients. CONCLUSIONS: Universal GGT was successfully implemented in a rural, community practice with > 90% uptake. Treatment was enhanced or de-escalated in those with and without clinically actionable PGVs, respectively. Universal GGT for patients with breast cancer is feasible within rural populations, enabling optimization of clinical care to patients' genetic profile, and may reduce unnecessary healthcare, resource utilization.

Nondisparate Survival of Non-Hispanic Black Women With Breast Cancer Despite Less Favorable Pathology: Effect of Access to and Provision of Care Within a Military Health Care System.

Introduction: Breast cancer mortality rates are 40% higher in non-Hispanic Blacks (NHBs) than in non-Hispanic White (NHWs) in the United States. All women treated within the Murtha Cancer Center at Walter Reed National Military Medical Center (MCC/WRNMMC) have health insurance and are provided multidisciplinary health care. Pathological factors and outcomes of NHBs and NHWs treated within the MCC/WRNMMC were evaluated to determine whether equal-access health care reduces disparate phenotypes and survival between the racial groups. Methods: Between 2001 and 2018, 368 NHB and 819 NHW women were diagnosed with breast cancer at MCC/WRNMMC. Differences between NHBs and NHWs in epidemiological and pathological characteristics were evaluated. Overall and breast cancer-specific 5- and 10-year survival rates were compared between races. Results: Compared with NHWs, NHBs were significantly more likely to have a body mass index ≥30 kg/m2, to be unmarried, to have tumors of higher grade, later stage, with lymph node metastases, and to be hormone receptor negative (HR-)/human epidermal growth factor receptor 2 positive (HER2+) or triple negative. After adjustment for demographic factors, NHBs remained significantly more likely to have tumors diagnosed at a higher grade and later stage, and to be HR-/HER2+ or triple negative. Neither 5- nor 10-year overall or breast cancer-specific survival differed significantly between the racial groups after adjusting for demographic and pathological variables. Discussion: Despite having tumors with less favorable pathological characteristics, overall and disease-free survival disparities were not observed for NHBs treated at MCC/WRNMMC. These data suggest that survival disparities of NHBs with breast cancer can be diminished with provision of quality care.

Survival Disparities in US Black Compared to White Women with Hormone Receptor Positive-HER2 Negative Breast Cancer.

Black women in the US have significantly higher breast cancer mortality than White women. Within biomarker-defined tumor subtypes, disparate outcomes seem to be limited to women with hormone receptor positive and HER2 negative (HR+/HER2-) breast cancer, a subtype usually associated with favorable prognosis. In this review, we present data from an array of studies that demonstrate significantly higher mortality in Black compared to White women with HR+/HER2-breast cancer and contrast these data to studies from integrated healthcare systems that failed to find survival differences. Then, we describe factors, both biological and non-biological, that may contribute to disparate survival in Black women.

Effect of Differences in Access to Screening, Healthcare, and Treatment on Cancer Disparities.

Cancer is a heterogeneous disease with over 100 recognized types that differ by organ site and cellular origins [...].

Cancer Incidence and Etiology in the Active Duty Population of U.S. Military.

INTRODUCTION: As members of the military, all active duty service members (ADS) must meet physical fitness requirements and are provided with equal-access healthcare through the DoD. In addition, 92% of ADS are ≤40 years of age. Together, these characteristics suggest that ADS represent a healthy population that may have a low risk of cancer. Each year, however, >800 ADS are diagnosed with cancer and the resulting in time off for treatment, reassignment, or medical retirement may significantly impact force readiness. MATERIAL AND METHODS: Relevant literature was identified by searching the PubMed database using search terms ACTIVE DUTY and CANCER. Only articles written in English were included. RESULTS: Melanoma is the most common cancer in ADS, while testicular cancer is the most common cancer in males and breast cancer is the most common in females. Cancer incidence patterns in ADS differ from those in the general U.S. population and from military veterans. Tumor etiology in ADS may be influenced by military-enriched exposures such as prolonged use of oral contraceptives, suboptimal use of sunscreen, exposure to volatile organic compounds, or germline predisposition/family history. CONCLUSIONS: The etiology of cancer within ADS remains largely unknown. A number of new research programs may provide the means to improve understanding of the etiology of cancer in ADS. Together, these efforts will improve prevention, early detection, and clinical management, thus improving the outcomes of ADS and preserving force readiness.

Eligibility, uptake and response to germline genetic testing in women with DCIS.

Background: Ductal carcinoma in situ (DCIS) is a malignant, yet pre-invasive disease of the breast. While the majority of DCIS have low risk of recurrence, a subset of women with germline pathogenic variants (PV) in cancer predisposition genes are at increased risk for recurrence. Uptake of genetic testing and subsequent surgical intervention in women with DCIS has not been well-studied. The aim of this study was to evaluate test eligibility parameters, uptake of clinical testing, impact on surgical decision making and second cancer events (SCE) in women with DCIS. Methods: Four-hundred eighty-four women diagnosed with unilateral DCIS 2001-2020 were eligible for this study. Demographic, commercial genetic test results and surgical procedures were extracted from the database. Test-eligibility was assigned using National Comprehensive Cancer Network (NCCN) criteria. Panel genetic testing was performed in the research laboratory across 94 cancer predisposition genes. Statistical analyses were performed using Fisher's exact tests and Chi-square analyses with p < 0.05 defining significance. Results: Forty-four percent of women were test-eligible at diagnosis of which 63.4% pursued genetic testing before definitive surgery; 9.9% pursued testing only after a second cancer event. Bilateral mastectomy (BM) was significantly higher (p<0.001) in women who had testing before definitive surgery (46.9%) compared to those who had testing afterword (10.8%) and in women who underwent testing before definitive surgery with PV (75%) compared to those without PV (37.5%. p=0.045). Of the 39 women with PV, 20 (51.3%) were detected only in the research setting, with 7 (17.9%) of these women not eligible for genetic testing based on NCCN criteria. In women who did not undergo BM at diagnosis, SCE were significantly higher (p=0.001) in women with PV (33.3%) compared to those without PV (11.9%). Conclusion: Pursuit of genetic testing and subsequent use of risk-reducing surgeries in women with PV was suboptimal in women with a primary diagnosis of DCIS. In conjunction, >50% of PV were detected only in the research setting. Because omission of genetic testing in women with DCIS may represent a lost opportunity for prevention, genetic testing at the time of diagnosis should be standard for all women with DCIS.

Influence of germline test results on surgical decision making in women with invasive breast cancer.

BACKGROUND: While therapeutic mastectomy with contralateral prophylactic mastectomy (TM+CPM) and/or bilateral salpingo-oophorectomy (BSO) are recommended for women with pathogenic variants (PV) in some cancer predisposition genes, evidence for the utility of these surgeries for women with PV in other genes currently is insufficient. In conjunction, current guidelines recommend that clinical management should not be influenced by a return of a variant of uncertain significance (VUS). Return of germline test results may, however, influence surgical decision making regardless of current guidelines. We thus evaluated surgical choices amongst a cohort of women with invasive breast cancer who underwent clinical genetic testing. METHODS: Germline test results and all surgical procedures were extracted for women who had unilateral invasive breast cancer and had clinical testing before definitive surgery (n = 591). Results were classified as pathogenic/likely pathogenic (PV, 17.1%), VUS (19.5%) or benign/likely benign (63.4%). Data were analyzed using chi-square tests with p<0.05 defining significance. RESULTS: Rates of TM+CPM and BSO were not significantly different for women with VUS compared to those with benign findings. Rates of TM+CPM were significantly higher for women with PV in BRCA1 and BRCA2, PALB2, PTEN and TP53, as well in genes with insufficient data to recommend risk-reducing mastectomy. Rates of BSO were significantly higher in women with PV in BRCA1 and BRCA2, PALB2, PTEN and TP53 and BRIP1, RAD51C and RAD51D compared to those with benign findings. CONCLUSION: Overall, surgical choices for women with a VUS were more similar to those from women with benign variants than to those with PV, however, in the group with PV in genes for which insufficient evidence exists for the benefit of risk-reducing mastectomy, rates of TM+CPM were high. Thus, while the management of women with VUS is in agreement with ACMG guidelines, patients with mutations in other cancer genes demonstrate a preference for more aggressive breast surgeries.

Relationship between Cigarette Smoking and Cancer Characteristics and Survival among Breast Cancer Patients.

Carcinogenic effects of tobacco smoke may affect breast tumorigenesis. To assess whether cigarette smoking is associated with breast cancer characteristics, we investigated the relationships between smoking, pathological characteristics, and outcomes in 2153 women diagnosed with breast cancer 2001-2016. Patients were classified as never, former, or current smokers at the time of diagnosis. Logistic regression and multivariable Cox proportional hazards analysis were performed to determine whether smoking was associated with tumor characteristics. Multivariable Cox proportional hazards analysis was conducted to compare former or current smokers to never smokers in survival with adjustment for the potential confounders. The majority of women (61.8%) never smoked, followed by former smokers (26.2%) and current smokers (12.0%). After adjustment for demographic variables, body mass index, and comorbidities, tumor characteristics were not significantly associated with smoking status or pack-years smoked. Ten-year overall survival was significantly lower for former and current smokers compared to never smokers (p = 0.0105). However, breast cancer specific survival did not differ significantly between groups (p = 0.1606). Although cigarette smoking did not alter the underlying biology of breast tumors or breast cancer-specific survival, overall survival was significantly worse in smokers, highlighting the importance of smoking cessation in the recently diagnosed breast cancer patient.

The DNA damage repair landscape in Black women with breast cancer.

BACKGROUND: Estrogen receptor positive (ER+) breast cancer is one of the most commonly diagnosed malignancies in women irrespective of their race or ethnicity. While Black women with ER+ breast cancer are 42% more likely to die of their disease than White women, molecular mechanisms underlying this disparate outcome are understudied. Recent studies identify DNA damage repair (DDR) genes as a new class of endocrine therapy resistance driver that contributes to poor survival among ER+ breast cancer patients. Here, we systematically analyze DDR regulation in the tumors and normal breast of Black women and its impact on survival outcome. METHOD: Mutation and up/downregulation of 104 DDR genes in breast tumor and normal samples from Black patients relative to White counterparts was assessed. For DDR genes that were differently regulated in the tumor samples from Black women in multiple datasets associations with survival outcome were tested. RESULTS: Overall, Black patient tumors upregulate or downregulate RNA levels of a wide array of single strand break repair (SSBR) genes relative to their white counterparts and uniformly upregulate double strand break repair (DSBR) genes. This DSBR upregulation was also detectable in samples of normal breast tissue from Black women. Eight candidate DDR genes were reproducibly differently regulated in tumors from Black women and associated with poor survival. A unique DDR signature comprised of simultaneous upregulation of homologous recombination gene expression and downregulation of SSBR genes was enriched in Black patients. This signature associated with cell cycle dysregulation (p < 0.001), a hallmark of endocrine therapy resistance, and concordantly, with significantly worse survival outcomes in all datasets analyzed (hazard ratio of 9.5, p < 0.001). CONCLUSION: These results constitute the first systematic analysis of DDR regulation in Black women and provide strong rationale for refining biomarker profiles to ensure precision medicine for underserved populations.

Genetic testing in Non-Hispanic Black women with breast cancer treated within an equal-access healthcare system.

PURPOSE: Identification of women with hereditary forms of cancer allows for precision medicine approaches to improve survival. Non-Hispanic Black (NHB) women in the US general population are less likely to undergo genetic testing or utilize risk-reducing strategies. Whether these disparities exist within the equal-access US military healthcare system is not known. METHODS: Genetic test information and surgical procedures were extracted for all NHB and Non-Hispanic Whites (NHW) with invasive breast cancer. National Comprehensive Cancer Network criteria from the year of diagnosis were assessed for all patients. Data were analyzed using chi-square analysis with P < .05 defining significance. RESULTS: NHB were significantly (P = .009) more likely to meet criteria for genetic testing compared to NHW, however, test uptake did not differ significantly between populations (P = .292). While 81% of both populations with BRCA1/2 pathogenic variants elected for double mastectomy, NHW were two times more likely to undergo risk-reducing bilateral salpingo-oophorectomy. CONCLUSION: These data demonstrate that when barriers, such as cost and lack of insurance, were removed, NHB were as willing to pursue testing as their NHW counterparts. Increasing the availability of testing and clinical management for NHB with hereditary forms of cancer may help reduce disparate survival seen in the US general population.

Frequency and spectrum of mutations across 94 cancer predisposition genes in African American women with invasive breast cancer.

African American women are at increased risk of being diagnosed at a young age and/or with triple negative breast cancer, both factors which are included in current guidelines for identifying women who may benefit from genetic testing. Commercial breast cancer predisposition genetic panels, based largely on data derived from women of European ancestry, may not capture the full spectrum of cancer predisposition genes associated with breast cancer in African American women. Between 2001 and 2018, 488 unselected African American women with invasive breast cancer enrolled in the Clinical Breast Care Project. National Comprehensive Cancer Network (NCCN) Hereditary Cancer testing criteria version 1.2020 were applied to determine genetic risk. Targeted sequencing was performed using the TruSight Cancer panel and variants classified using the ClinVar database. Using NCCN criteria, 64.1% of African American women would be eligible for genetic testing. Fifty pathogenic or likely pathogenic mutations were detected in 19 genes with the highest frequencies in BRCA2 (29.4%) and BRCA1 (15.7%). Mutation frequencies in test-eligible and test-ineligible women were 13.1% and 3.5%, respectively. One-third of women harbored variants that could not be classified. While these data do not suggest a need to expand current commercial gene panels, NCCN criteria would fail to identify 12.5% of African American women with mutations in hereditary cancer predisposing genes.

Cancer Previvors in an Active Duty Service Women Population: An Opportunity for Prevention and Increased Force Readiness.

BACKGROUND: The majority of active duty service women (ADS) are young, have access to healthcare, and meet fitness standards set by the U.S. military, suggesting that ADS represent a healthy population at low risk of cancer. Breast cancer is, however, the most common cancer in ADS and may have a significant effect on troop readiness with lengthy absence during treatment and inability to return to duty after the treatment. The identification of unaffected ADS who carry germline mutations in cancer predisposition genes ("previvors") would provide the opportunity to prevent or detect cancer at an early stage, thus minimizing effects on troop readiness. In this study, we determined (1) how many high-risk ADS without cancer pursued genetic testing, (2) how many previvors employed risk-reducing strategies, and (3) the number of undiagnosed previvors within an ADS population. METHODS: The Clinical Breast Care Project (protocol WRNMMC IRB #20704) database of the Murtha Cancer Center/Walter Reed National Military Medical Center was queried to identify all ADS with no current or previous history of cancer. Classification as high genetic risk was calculated using National Comprehensive Cancer Network 2019 guidelines for genetic testing for breast, ovary, colon, and gastric cancer. The history of clinical genetic testing and risk-reducing strategies was extracted from the database. Genomic DNA from ADS with blood specimens available for research purposes were subjected to next-generation sequencing technologies using a cancer predisposition gene panel. RESULTS: Of the 336 cancer-free ADS enrolled in the Clinical Breast Care Project, 77 had a family history that met National Comprehensive Cancer Network criteria for genetic testing for BRCA1/2 and 2 had a family history of colon cancer meeting the criteria for genetic testing for Lynch syndrome. Of the 28 (35%) high-risk women who underwent clinical genetic testing, 11 had pathogenic mutations in the breast cancer genes BRCA1 (n = 5), BRCA2 (n = 5), or CHEK2 (n = 1). Five of the six ADS who had a relative with a known pathogenic mutation were carriers of the tested mutation. All of the women who had pathogenic mutations detected through clinical genetic testing underwent prophylactic double mastectomy, and three also had risk-reducing salpingo-oophorectomy. Two (6%) of the 33 high-risk ADS tested only in the research setting had a family history of breast/ovarian cancer and carried pathogenic mutations: one carried a BRCA2 mutation, whereas the other carried a mutation in the colon cancer predisposition gene PMS2. No mutations were detected in the 177 low-risk women tested in the research setting. DISCUSSION: Within this unaffected cohort of ADS, 23% were classified as high risk. Although all of the previvors engaged in risk-reduction strategies, only one-third of the high-risk women sought genetic testing. These data suggest that detailed family histories of cancer should be collected in ADS and genetic testing should be encouraged in those at high risk. The identification of previvors and concomitant use of risk-reduction strategies may improve health in the ADS and optimize military readiness by decreasing cancer incidence.

Heritability of Low ER Staining/HER2-Breast Tumors: Are We Missing an Opportunity for Germline Testing?

In 2010, the genetic testing criteria was changed to allow women diagnosed ≤ 60 years old with triple negative breast cancer (TNBC) to undergo germline testing. In the same year, estrogen receptor (ER) positivity was defined as having ≥1% ER staining cells. While tumors with 1-10% ER staining cells and HER2 negative (HER2-) status share characteristics with TNBC, the utility of germline testing in women with ER low positive/HER2- (ERLP/HER2-) tumors is not well-understood. To this end, all patients with hormone receptor positive staining cells ≤ 10% and negative HER2 status were identified. Clinical genetic test results were extracted for patients who underwent testing. Panel testing was performed for those women who had genomic DNA available for research purposes. ERLP/HER2-tumors constituted 2.7% of all tumors in the database. Patients did not differ significantly from those with TNBC by age at diagnosis, ethnicity, family history or tumor size, stage or grade (p > 0.05). Mutation frequency did not differ significantly (p = 0.757) between groups (ERLP/HER2- 16.1%; TNBC 16.7%). Hereditary forms of breast cancer were similar in both ERLP/HER2- and TNBC, thus current guidelines may result in the under testing of women with low ER tumors, resulting in missed opportunities to improve patient management.

Should Genetic Testing for Cancer Predisposition Be Standard-of-Care for Women with Invasive Breast Cancer? The Murtha Cancer Center Experience.

Currently, genetic testing is offered only to women diagnosed with breast cancer who meet a defined set of criteria and is not included as standard-of-care treatment at the time of diagnosis. Thus, a significant number of women diagnosed with breast cancer may miss the opportunity for precision medical treatment and risk management. The effects of eligibility, timing, and uptake of genetic testing were evaluated in a cohort of women with invasive breast cancer diagnosed between 2001-2018. Risk status was estimated using NCCN BRCA1/2 testing criteria and panel testing was performed for all women who had genomic DNA available. Of the 1231 women, 57.8% were eligible for genetic testing. Uptake of testing within high-risk women was 42.7% of which 6.6% pursued clinical testing only after a second tumor event. Mutation frequencies were 15.8%, 5.5%, and 4.0% in high-risk women with clinical testing, high-risk women without clinical testing, and low-risk women, respectively. More than 4% of all patients harbored pathogenic or likely pathogenic mutations detected only in the research setting. Inclusion of panel testing at the time of diagnosis would allow for appropriate surveillance and treatment strategies to be employed to reduce the risk of secondary tumors and improve patient outcome.

A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements.

Triple negative breast cancer (TNBC), representing 10-15% of breast tumors diagnosed each year, is a clinically defined subtype of breast cancer associated with poor prognosis. The higher incidence of TNBC in certain populations such as young women and/or women of African ancestry and a unique pathological phenotype shared between TNBC and BRCA1-deficient tumors suggest that TNBC may be inherited through germline mutations. In this article, we describe genes and genetic elements, beyond BRCA1 and BRCA2, which have been associated with increased risk of TNBC. Multigene panel testing has identified high- and moderate-penetrance cancer predisposition genes associated with increased risk for TNBC. Development of large-scale genome-wide SNP assays coupled with genome-wide association studies (GWAS) has led to the discovery of low-penetrance TNBC-associated loci. Next-generation sequencing has identified variants in noncoding RNAs, viral integration sites, and genes in underexplored regions of the human genome that may contribute to the genetic underpinnings of TNBC. Advances in our understanding of the genetics of TNBC are driving improvements in risk assessment and patient management.

Evaluation of Surgical Disparities Between African American and European American Women Treated for Breast Cancer Within an Equal-Access Military Hospital.

BACKGROUND: Survival disparities between African American women (AAW) and European American women (EAW) with invasive breast cancer may be attributable, in part, to access to or quality of medical care. In this study, we evaluated surgical disparities between AAW and EAW treated within an equal-access military treatment facility (MTF). METHODS: All AAW (N = 271) and EAW (N = 628) with Stage I-III breast cancer who had their initial diagnosis performed at Murtha Cancer Center at Walter Reed National Military Medical Center were identified. Differences in surgical interval (time between diagnosis and definitive breast surgery) and surgical procedures were evaluated using χ2 and Student t-tests while survival was analyzed using Kaplan-Meier survival estimates and log-rank tests. A P value < 0.05 was used to define significance. RESULTS: Surgical intervals did not differ significantly between populations with an average of 36.3 days in AAW and 33.9 days in EAW. Frequency of the percentage of women undergoing reexcision, mastectomy, and prophylactic removal of the contralateral breast did not differ significantly between populations. Likewise, frequency of sentinel lymph node biopsy and 5-year survival were not significantly different between AAW compared to EAW. DISCUSSION: Surgical intervals and procedures were similar between AAW and EAW treated within an equal-access MTF. These data demonstrate that the availability of quality surgical care to all patients with stage I-III breast cancer may eliminate survival disparities between AAW and EAW, emphasizing the importance of equalizing access to breast care.