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.

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.

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.

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.

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.

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.

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.