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.

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.

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.

Racial-Ethnic Comparison of Guideline-Adherent Gynecologic Cancer Care in an Equal-Access System.

OBJECTIVE: To compare receipt of National Comprehensive Cancer Network Guideline-adherent treatment for gynecologic cancers, inclusive of uterine, cervical, and ovarian cancer, between non-Hispanic White women and racial-ethnic minority women in the equal-access Military Health System. METHODS: We accessed MilCanEpi, which links data from the Department of Defense Central Cancer Registry and Military Health System Data Repository administrative claims data, to identify a cohort of women aged 18-79 years who were diagnosed with uterine, cervical, or ovarian cancer between January 1, 1998, and December 31, 2014. Information on tumor stage, grade, and histology was used to determine which treatment(s) (surgery, chemotherapy, radiotherapy) was indicated for each patient according to the National Comprehensive Cancer Network Guidelines during the period of the data (1998-2014). We compared non-Hispanic Black, Asian, and Hispanic women with non-Hispanic White women in their likelihood to receive guideline-adherent treatment using multivariable logistic regression models given as adjusted odds ratios (aORs) and 95% CIs. RESULTS: The study included 3,354 women diagnosed with a gynecologic cancer of whom 68.7% were non-Hispanic White, 15.6% Asian, 9.0% non-Hispanic Black, and 6.7% Hispanic. Overall, 77.8% of patients received guideline-adherent treatment (79.1% non-Hispanic White, 75.9% Asian, 69.3% non-Hispanic Black, and 80.5% Hispanic). Guideline-adherent treatment was similar in Asian compared with non-Hispanic White patients (aOR 1.18, 95% CI 0.84-1.48) or Hispanic compared with non-Hispanic White women (aOR 1.30, 95% CI 0.86-1.96). Non-Hispanic Black patients were marginally less likely to receive guideline-adherent treatment compared with non-Hispanic White women (aOR 0.73, 95% CI 0.53-1.00, P=.011) and significantly less likely to receive guideline-adherent treatment than either Asian (aOR 0.65, 95% CI 0.44-0.97) or Hispanic patients (aOR 0.56, 95% CI 0.34-0.92). CONCLUSION: Racial-ethnic differences in guideline-adherent care among patients in the equal-access Military Health System suggest factors other than access to care contributed to the observed disparities.

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.

Adjuvant radioactive iodine use among differentiated thyroid cancer patients in the military health system.

OBJECTIVE: Adjuvant radioactive iodine (RAI) for the treatment of differentiated thyroid cancer has been associated with better prognosis, but no consensus has been reached on the best practices for RAI. Limited data on RAI use and factors associated with the receipt of postoperative RAI in the general population are available and, to our knowledge, no data on RAI use among the U.S. Department of Defense (DoD) beneficiaries. METHODS: Among 3,002 beneficiaries with differentiated thyroid cancer, who underwent total/near-total thyroidectomy between 1998 and 2007, logistic regression identified factors associated with RAI and examined effect modification by age and tumor size. RESULTS: Fifty-two percent of patients received RAI. Receipt of RAI was more likely among beneficiaries who were diagnosed between 2004 and 2007, active duty members, had indirect care, and more advanced disease, and less likely among those affiliated with the Air Force or had unknown medical coverage. In addition, receipt of RAI significantly varied by tumor size among patients with regional lymph node metastasis. CONCLUSION: Among DoD beneficiaries, adjuvant RAI use was associated with clinical and nonclinical factors. Although evidence of effect modification between the recipient of RAI by tumor size was apparent, future research with a larger sample size is warranted to confirm results of this study.

Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterized by aggressive behavior and poor prognosis. While >50 % of patients with inherited BRCA1 mutations have TNBC, the prevalence of BRCA1 mutations in patients with TNBC remains unclear. Deciphering the relationship between BRCA1 and TNBC is critical to understanding the etiology of TNBC, leading to improved patient counseling and treatment. All female patients with TNBC enrolled in the Clinical Breast Care Project were identified. Genomic DNA was isolated from blood and the exonic regions of the BRCA1 gene were amplified and sequenced. Sequence data was analyzed and mutations identified using Sequencher 4.10.1. Of the 190 women with TNBC, genomic DNA was available for 182. Seventy percent of patients were considered high-risk for having a BRCA1 mutation based on the National Comprehensive Cancer Network criteria. Clinically relevant mutations were detected in 16 (9 %) patients ranging in age from 26 to 69 years at diagnosis. Six of these patients were diagnosed >50 years. The C61G mutation was found in three Caucasian women diagnosed >40 years, while six African-American women had mutations, including the 943ins10 West African founder mutation. Upon conclusion, causative BRCA1 mutations were detected in 9 % of TNBC patients, including patients without significant family histories and/or diagnosed at a later age. The mutation frequency in patients <60 years was 11.2-18.3 % in those patients with significant risk factors and 4.6 % in those without, while in patients >60 years, the mutation frequency was 3.5-7.7 % in patients with risk factors, 2.3 % in those without. Thus, evaluation of additional risk factors in both patients younger and older than 60 years should improve the identification of TNBC patients benefiting from genetic testing of BRCA1.

Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure.

PURPOSE: To investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. PATIENTS AND METHODS: Levels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. RESULTS: Nuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n = 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n = 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). CONCLUSION Nuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.

Double-blinded, placebo-controlled, prospective randomized trial evaluating the efficacy of paravertebral block with and without continuous paravertebral block analgesia in outpatient breast cancer surgery.

BACKGROUND: Paravertebral block (PVB) is an effective alternative to general anesthesia for breast cancer surgery. Continuous paravertebral block (CPVB) anesthesia may extend postoperative analgesia at home and improve quality of early postoperative recovery of breast cancer patients. PURPOSE: This double-blinded randomized trial was conducted to compare degree of pain, nausea, mood, level of symptom distress, and time to return to normal daily activity between PVB and PVB + CPVB in patients undergoing outpatient breast cancer surgery. PATIENTS AND METHODS: Between July 2003 and April 2008 we randomly assigned 94 (73 evaluable) patients in a 1:1:1 ratio with early breast cancer to single injection PVB followed by CPVB infusion of 0.1% or 0.2% ropivacaine vs placebo (saline) for 48 hours postoperatively for unilateral breast cancer surgery without reconstruction. The primary study endpoint was the degree of pain, nausea, mood state, level of symptom distress, and recovery time. RESULTS: Of the 468 patients assessed for eligibility, 94 consented and 21 with incomplete data or follow-up were excluded, leaving 73 subjects for analysis. There was no clinically significant difference in degree of postoperative pain, nausea, mood state, level of symptom distress, or return to normal activity among the three study groups. CONCLUSION: The current study does not support the routine use of continuous paravertebral catheter anesthesia in patients undergoing operative treatment for breast cancer.