Constitutional BRCA1 and MGMT Methylation Are Significant Risk Factors for Triple-Negative Breast Cancer and High-Grade Serous Ovarian Cancer in Saudi Women.

Breast cancer (BC) and ovarian cancer (OC) are rapidly increasing in Saudi Arabia. BRCA1 and MGMT epimutations have been linked to a higher risk of these malignancies. The present research investigated the impact of these epimutations on the prevalence of BC and OC among Saudi women. DNA methylation was evaluated using methylation-specific PCR, whereas mRNA expression levels were assessed using qRT-PCR. We evaluated white blood cell (WBC)-BRCA1 methylation in 1958 Saudi women (908 BC patients, 223 OC patients, and 827 controls). MGMT methylation was determined in 1534 of the 1958 women (700 BC patients, 223 OC patients, and 611 controls). BRCA1 methylation was detected in 8.6% of the controls and 11% of the BC patients. This epimutation was linked to 13.8% of the early-onset BC patients (p = 0.003) and 20% of the triple-negative breast cancer (TNBC) patients (p = 0.0001). BRCA1 methylation was also detected in 14% of the OC patients (p = 0.011), 19.4% of patients aged <55 years (p = 0.0007), and 23.4% of high-grade serous ovarian cancer (HGSOC) patients. In contrast, the BRCA1 mutation was detected in 24% of the OC patients, 27.4% of patients aged ≥55 years, and 26.7% of the HGSOC patients. However, MGMT methylation was detected in 10% of the controls and 17.4% of the BC patients (p = 0.0003). This epimutation was linked to 26.4% of the late-onset BC patients (p = 0.0001) and 11% of the TNBC patients. MGMT methylation was also found in 15.2% of the OC patients (p = 0.034) and 19.1% of HGSOC patients (p = 0.054). Furthermore, 36% of the BRCA1-methylated patients and 34.5% of the MGMT-methylated patients had a family history of cancer, including breast and ovarian cancer. Notably, BRCA1 and MGMT mRNA levels were greater in the WBC RNA of the BC patients and cancer-free methylation carriers than in that of the OC patients. Our data indicate that BRCA1 and MGMT epimutations significantly contribute to the development of breast cancer and ovarian cancer in Saudi cancer patients. These blood-based biomarkers could help identify female patients at high risk of developing TNBC and HGSOC at an early age.

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies.

PURPOSE: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. METHODS: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. RESULTS: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). CONCLUSION: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

[Guidelines for clinical diagnosis and treatment of advanced triple negative breast cancer in China（2024 edition）].

Breast cancer ranks as the most common female malignancy worldwide. Data from GLOBOCAN 2020 showed that breast cancer surpassed lung cancer and become the leading malignancy globally which was a serious threat to women's health. Different from Caucasian, there is a lower prevalence of breast cancer in Chinese women. But the age-standardized incidence rate of breast cancer in China has reached to 39.1 per 100,000 in 2020, with 416,000 new cases, accounting for 18.4% of global breast cancer burden, due to multiple factors such as lifestyle and dietary habits changes in recent years[1]. The treatment and prevention of breast cancer are becoming increasingly a tuff task. In addition, triple-negative breast cancer (TNBC) is a subtype with higher malignancy and worse prognosis. Due to lack of specific therapeutic targets, less treatment progress has been made in recent years. There is even less progress in the therapy of advanced TNBC, but huge unmet needs exist for further therapeutic optimization. Echoing advocacy from The Society of Breast Cancer China Anti-Cancer Association; International Medical Exchange Society, Chinese Anti-Cancer Association; Breast Cancer Group, Branch of Oncologist, Chinese Medical Doctor Association, top experts from multidisciplinary departments of breast cancer in China have consensus on this "Guidelines for Clinical Diagnosis and Treatment of Advanced Triple-Negative Breast Cancer in China (2024 Edition)" according to the latest evidence based updates. We hope this pater can guide or optimize the precise therapeutic decision-making for advanced triple-negative breast cancer in China.

Treatment patterns, healthcare resource utilization and outcomes for early stage triple-negative breast cancer in Japan.

Aim: There is limited information regarding the treatment and outcomes of early stage triple-negative breast cancer (esTNBC) in real-world settings in Japan. Materials & methods: Retrospective analyses of the Medical Data Vision database assessed treatment patterns, healthcare resource utilization (HCRU), patient characteristics, outcomes and prognostic factors among four groups (neoadjuvant therapy+surgery+adjuvant therapy; neoadjuvant therapy+surgery; surgery+adjuvant therapy; surgery only) of esTNBC patients. Results: Treatment patterns, HCRU and demographics varied among the four groups. HCRU was greater and prognosis tended to be worse in the neoadjuvant+surgery+adjuvant therapy group. Conclusion: Our results provide insights into the treatment practices, HCRU and prognosis of esTNBC in Japan. The treatment practices were heterogeneous, reflecting the decision-making process in Japan during the study period.

Triple-negative breast cancer (TNBC) is a cancer type that does not express three biomarkers (estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2), which results in a lack of targeted treatment strategies. Early stage TNBC (esTNBC) is mainly treated by anticancer drugs before (neoadjuvant) and/or after (adjuvant) surgery and adjuvant radiotherapy. New therapies including an immune checkpoint inhibitor which helps better immune system and a PARP inhibitor which helps repair DNA damage were approved for esTNBC in 2022 in Japan, and they are expected to change the treatment options for TNBC. However, there are limited data about the treatment patterns, healthcare resource utilization (HCRU) and outcomes for esTNBC in real-world clinical practice in Japan. Therefore, a hospital-based administrative database was analyzed to understand the treatment patterns for patients with esTNBC in Japan, the HCRU, treatment outcomes (overall survival and event free survival), and the associated factors. Patients received a large variety of treatments before and after surgery. Patients who received both neoadjuvant and adjuvant therapies tended to have more severe disease and required greater HCRU, and their outcomes were worse than patients who received neoadjuvant treatment only, adjuvant treatment only or neither neoadjuvant nor adjuvant treatment. Our findings will help us understand how new treatments will impact the treatment practices and patient outcomes in the future.

Lifetime alcohol consumption patterns and young-onset breast cancer by subtype among Non-Hispanic Black and White women in the Young Women's Health History Study.

PURPOSE: The role of alcohol in young-onset breast cancer (YOBC) is unclear. We examined associations between lifetime alcohol consumption and YOBC in the Young Women's Health History Study, a population-based case-control study of breast cancer among Non-Hispanic Black and White women < 50 years of age. METHODS: Breast cancer cases (n = 1,812) were diagnosed in the Metropolitan Detroit and Los Angeles County SEER registry areas, 2010-2015. Controls (n = 1,381) were identified through area-based sampling and were frequency-matched to cases by age, site, and race. Alcohol consumption and covariates were collected from in-person interviews. Weighted multivariable logistic regression was conducted to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for associations between alcohol consumption and YOBC overall and by subtype (Luminal A, Luminal B, HER2, or triple negative). RESULTS: Lifetime alcohol consumption was not associated with YOBC overall or with subtypes (all ptrend ≥ 0.13). Similarly, alcohol consumption in adolescence, young and middle adulthood was not associated with YOBC (all ptrend ≥ 0.09). An inverse association with triple-negative YOBC, however, was observed for younger age at alcohol use initiation (< 18 years vs. no consumption), aOR (95% CI) = 0.62 (0.42, 0.93). No evidence of statistical interaction by race or household poverty was observed. CONCLUSIONS: Our findings suggest alcohol consumption has a different association with YOBC than postmenopausal breast cancer-lifetime consumption was not linked to increased risk and younger age at alcohol use initiation was associated with a decreased risk of triple-negative YOBC. Future studies on alcohol consumption in YOBC subtypes are warranted.

National trends in neoadjuvant chemotherapy utilization in patients with early-stage node-negative triple-negative breast cancer: the impact of the CREATE-X trial.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) allows for assessment of tumor pathological response and has survival implications. In 2017, the CREATE-X trial demonstrated survival benefit with adjuvant capecitabine in patients TNBC and residual disease after NAC. We aimed to assess national rates of NAC for cT1-2N0M0 TNBC before and after CREATE-X and examine factors associated with receiving NAC vs adjuvant chemotherapy (AC). METHODS: A retrospective cohort study of women with cT1-2N0M0 TNBC diagnosed from 2014 to 2019 in the National Cancer Database (NCDB) was performed. Variables were analyzed via ANOVA, Chi-squared, Fisher Exact tests, and a multivariate linear regression model was created. RESULTS: 55,633 women were included: 26.9% received NAC, 52.4% AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71 years, p < 0.01). NAC utilization significantly increased over time: 19.5% in 2014-15 (n = 3,465 of 17,777), 27.1% in 2016-17 (n = 5,140 of 18,985), and 33.6% in 2018-19 (n = 6,337 of 18,871, p < 0.001). On multivariate analysis, increased NAC was associated with younger age (< 50), non-Hispanic white race/ethnicity, lack of comorbidities, cT2 tumors, care at an academic or integrated-network cancer program, and diagnosis post-2017 (p < 0.05 for all). Patients with government-provided insurance were less likely to receive NAC (p < 0.01). Women who traveled > 60 miles for treatment were more likely to receive NAC (p < 0.01). CONCLUSION: From 2014 to 2019, NAC utilization increased for patients with cT1-2N0M0 TNBC. Racial, socioeconomic, and access disparities were observed in who received NAC vs AC and warrants interventions to ensure equitable care.

A Multiscale Spatiotemporal Epidemiological Analysis of Neighborhood Correlates of Triple-Negative Breast Cancer.

BACKGROUND: Women living in disadvantaged neighborhoods present with increased prevalence rates of triple-negative breast cancer (TNBC). This study takes a spatiotemporal epidemiological approach to understand the impact of socioenvironmental contextual factors on TNBC prevalence rates. METHODS: We analyzed 935 TNBC cases from a major cancer center registry, between 2005 and 2017, to explore spatial and space-time clusters of TNBC prevalence rates at the census tract and neighborhood scales. Spatial regression analysis was performed to examine relationships between nine socioenvironmental factors and TNBC prevalence rates at both ecological scales. RESULTS: We observed spatial clustering of high TNBC prevalence rates along a north-south corridor of Miami-Dade County along Interstate 95, a region containing several majority non-Hispanic Black neighborhoods. Among the ecologic measures, the percent of a region designated as a brownfield was associated with TNBC prevalence rates at the tract-level (ß = 4.27; SE = 1.08; P < 0.001) and neighborhood-level (ß = 8.61; SE = 2.20; P < 0.001). CONCLUSIONS: Our spatiotemporal analysis identified robust patterns of hot spots of TNBC prevalence rates in a corridor of several disadvantaged neighborhoods in the northern half of the county. These patterns of TNBC align with the literature regarding at-risk groups and neighborhood-level effects on TNBC; however, remain to be validated in a population-based sample. IMPACT: Spatial epidemiological approaches can help public health officials and cancer care providers improve place-specific screening, patient care, and understanding of socioenvironmental factors that may shape breast cancer subtype through gene-environment and epigenetic interactions.

Associations Between Neighborhood-Level Income and Triple-Negative Breast Cancer in a Majority-Minority Population.

BACKGROUND: Previous studies on disparities in triple-negative breast cancer (TNBC) focus on race/ethnicity, with few exploring the impact of contextual factors such as neighborhood-level income. This study evaluates the effect of neighborhood-level income on disparities in TNBC among a racially and ethnically diverse cohort, after accounting for granular individual-level risk factors of TNBC. PATIENTS AND METHODS: Patients with stage I-IV breast cancer from 2005 to 2017 were identified from our local tumor registry. The primary outcome was diagnosis of TNBC. Using 5-years estimates from the American Community Survey, we obtained median household income for each census tract which was categorized into quartiles. Mixed effects logistic regression was conducted and stratified by race and ethnicity, controlling for individual-level sociodemographic, comorbidities, and tumor characteristics. RESULTS: Among 5377 breast cancer registry patients, 16.5% were diagnosed with TNBC. The majority were Hispanic (50.1%) followed by non-Hispanic Black (NHB) (28.0%). After controlling for individual-level covariables including race and ethnicity, comorbidities, and tumor characteristics, women from low-income neighborhoods had increased odds of TNBC compared with other breast cancer subtypes, compared with those in high-income neighborhoods [odds ratio (OR) 1.33; 95% confidence interval (CI) 1.04, 1.70, p < 0.001]. In stratified analyses, NHB patients from low-income neighborhoods had two times the odds of TNBC diagnosis compared with those from high-income neighborhoods (OR 2.11; 95% CI 1.02, 4.37). CONCLUSION: We found that living in a low-income neighborhood is associated with an increased odds of TNBC independent of granular individual-level TNBC risk factors, particularly NHB race. More striking, NHB living in low-income neighborhoods had increased odds of TNBC compared with NHB living in high-income neighborhoods. Our results suggest potential unaccounted gene-environment and/or social (api)genomic interactions between neighborhood-level income and TNBC subtype development.

Native American ancestry and breast cancer risk in Colombian and Mexican women: ruling out potential confounding through ancestry-informative markers.

BACKGROUND: Latin American and Hispanic women are less likely to develop breast cancer (BC) than women of European descent. Observational studies have found an inverse relationship between the individual proportion of Native American ancestry and BC risk. Here, we use ancestry-informative markers to rule out potential confounding of this relationship, estimating the confounder-free effect of Native American ancestry on BC risk. METHODS AND STUDY POPULATION: We used the informativeness for assignment measure to select robust instrumental variables for the individual proportion of Native American ancestry. We then conducted separate Mendelian randomization (MR) analyses based on 1401 Colombian women, most of them from the central Andean regions of Cundinamarca and Huila, and 1366 Mexican women from Mexico City, Monterrey and Veracruz, supplemented by sensitivity and stratified analyses. RESULTS: The proportion of Colombian Native American ancestry showed a putatively causal protective effect on BC risk (inverse variance-weighted odds ratio [OR] = 0.974 per 1% increase in ancestry proportion, 95% confidence interval [CI] 0.970-0.978, p = 3.1 × 10-40). The corresponding OR for Mexican Native American ancestry was 0.988 (95% CI 0.987-0.990, p = 1.4 × 10-44). Stratified analyses revealed a stronger association between Native American ancestry and familial BC (Colombian women: OR = 0.958, 95% CI 0.952-0.964; Mexican women: OR = 0.973, 95% CI 0.969-0.978), and stronger protective effects on oestrogen receptor (ER)-positive BC than on ER-negative and triple-negative BC. CONCLUSIONS: The present results point to an unconfounded protective effect of Native American ancestry on BC risk in both Colombian and Mexican women which appears to be stronger for familial and ER-positive BC. These findings provide a rationale for personalised prevention programmes that take genetic ancestry into account, as well as for future admixture mapping studies.

Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes.

PURPOSE: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. METHODS: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. RESULTS: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. CONCLUSIONS: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.

Contribution of constitutional BRCA1 promoter methylation to early-onset and familial breast cancer patients from Pakistan.

PURPOSE: Constitutional BRCA1 promoter methylation has been identified as a potential risk factor for breast cancer (BC) in the Caucasian population. However, this data is lacking for BC patients of Asian origin. Therefore, we assessed the contribution of constitutional BRCA1 promoter methylation in Pakistani BC patients. METHODS: A total of 385 BRCA1/2-negative index BC patients (197 early-onset BC (≤ 30 years), 152 familial BC, 17 familial BC and ovarian cancer, 19 male BC) and 107 healthy controls were screened for the constitutional BRCA1 promoter methylation by methylation-sensitive high-resolution melting assay. Overall, 131 patients displayed triple-negative BC (TNBC) and 254 non-TNBC phenotypes. The prevalence of BRCA1 promoter methylation was calculated based on clinicopathological characteristics using univariable and multivariable logistic regression models. RESULTS: Constitutional BRCA1 promoter methylation was identified in 19.5% (75/385) of BC patients and 13.1% (14/107) of controls. The frequency of methylation was higher in early-onset BC (23.4% vs. 13.1%, P = 0.035) and TNBC patients (29.0% vs. 13.1%, P = 0.004) compared to controls. Methylation was also more prevalent in patients with high-grade than low-grade tumors (21.7% vs. 12.2%, P = 0.034) and progesterone receptor (PR)-negative than PR-positive tumors (26.0% vs. 13.9%, P = 0.004). Constitutional BRCA1 promoter methylation remained independently associated with TNBC phenotype (odds ratio 1.99; 95% CI 1.12-3.54; P = 0.02) after adjusting for BC diagnosis age, tumor grade, ER, and PR status. CONCLUSION: Constitutional BRCA1 promoter methylation is associated with TNBC and can serve as a non-invasive blood-based biomarker for Pakistani TNBC patients.

Risk factors for the development of triple-negative breast cancer versus non-triple-negative breast cancer: a case-control study.

The risk factors for breast cancer have been defined in several studies but there is deficient data for specific subtypes. We report here the pathological characteristics of a breast cancer cohort and risk factors for patients with triple-negative disease. In this case-control study, a prospective breast cancer cohort was evaluated for demographic, reproductive, obesity-related and other risk factors using a validated questionnaire. Tumors were characterized for routine pathological characteristics and immunohistochemical markers of basal-like breast cancer. Patients with triple-negative breast cancer (TNBC) constituted cases and those with non-TNBC were controls. Odds ratios (OR) were calculated for each risk factor and independent associations were tested in an unconditional logistic regression analysis. Between 2011 and 2014, 1146 patients were recruited, of whom 912 [TNBC 266 (29.1%), non-TNBC 646 (70.9%)] with sufficient pathology material were analysed. Reproductive factors of parity, breastfeeding, age-at-menarche, age at first full-term pregnancy and oral contraceptive use were not significantly associated with TNBC. Higher body mass index (BMI > 24.9 vs ≤ 24.9, OR 0.89, 95%CI 0.63-1.24, p = 0.49) was not significantly associated while lesser waist circumference (> 80 cm vs ≤ 80 cm, OR 0.64, 95%CI 0.45-0.9, p = 0.012) and lower waist-to-hip ratio were significantly associated (> 0.85 vs ≤ 0.85, OR 0.72, 95%CI 0.51-1.0, p = 0.056), with TNBC. History of tobacco use was not significantly associated while lower socio-economic status was borderline associated with TNBC (socio-economic category > 5 versus ≤ 5, OR 0.73, 95%CI 0.50-1.06, p = 0.106). No factor was significant after adjustment for covariates. Central obesity seems to be preferentially associated with non-TNBC, and lower socio-economic status with TNBC in India, while most other conventional risk factors of breast cancer show no significant association with TNBC versus non-TNBC.

Translational Epidemiology: Genetic Ancestry in Breast Cancer: What Is the Role of Genetic Ancestry and Socioeconomic Status in Triple-Negative Breast Cancer?

Racial/ethnic and socioeconomic disparities seen in triple-negative breast cancer (TNBC) have prompted questions regarding the role of genetic ancestry in breast cancer (BC) subtype development, tumor biology, and ultimately prognosis. The causes of disparities in TNBC are influenced greatly by both sociopolitical factors and genetic ancestry, and now, the potential genomic underpinnings of social factors. To comprehensively understand disparities in TNBC, it is critical to take a translational epidemiologic approach that takes into account genomic and non-genomic factors. Understanding the interplay between genetic ancestry and social genomics and their proportional influence on outcomes can guide our priorities for screening, diagnosis, and interventions for this aggressive BC subtype.

Influence of advanced age on the prognosis of triple-negative breast cancer patients: A surveillance, epidemiology, and end results-based study.

Introduction: Age at diagnosis has shown significant effect on the prognosis in breast cancer patients. However, whether age is an independent risk factor remains controversial. Furthermore, population-based estimates of age on the prognosis impact in triple-negative breast cancer are still lacking. The aim of this study was to analyze the influence of age and other factors on the prognosis and survival of triple-negative breast cancer patients. Materials and Methods: We used the surveillance, epidemiology, and end results program data from 2011 to 2014. A retrospective cohort study was conducted to investigate prognosis factors in triple-negative breast cancer. Patients were divided into two groups according to age at diagnosis: 75 + years (the elderly patients) and < 75 years (reference group). The clinicopathologic characteristics of different age groups were compared using Chi-square tests. Overall survival (OS) and breast cancer-specific survival were analyzed using the Kaplan-Meier method. Prognostic factors were compared using the Cox proportional hazards model. We also analyzed the difference of distant metastasis at initial diagnosis on every group. Results: A total of 21,429 triple-negative breast cancer patients were included in our study. The mean breast cancer-specific survival time of triple-negative breast cancer was 70.5 months for the reference group and 62.4 months for the elderly group. Survival analysis showed that the breast cancer-specific survival rate was 78.9% for the reference group and 67.4% for the elderly group. The mean OS time was 69.0 months for the reference group and 52.3 months for the elderly group. The 5-year OS of triple-negative breast cancer patients was 76.4% for the reference group and 51.3% for the elderly group. The prognosis of elderly patients is much poor than reference group. Univariate Cox regression analysis showed that age, race, marital status, histological grade, stage, T, N, M, surgery, radiotherapy, and chemotherapy were risk factors for triple-negative breast cancer (TNBC) (P < 0.05). Multivariate Cox regression analysis showed that age, race, marital status, histological grade, stage, T, N, M, surgery, radiotherapy, and chemotherapy were independent risk factors for TNBC (P < 0.05). Conclusions: Age is an independent risk factor for the prognosis of TNBC patients. Elderly triple-negative breast cancer patients displayed obvious lower 5-year survival rate compared to reference group, even though they have better grade stage, minor tumor, less lymph node metastasis. The lower rate of marital status, radiotherapy, chemotherapy, surgery, and higher rate of metastasis at diagnosis must contribute to their poor outcome.

Triple-negative breast cancer: epidemiology, molecular mechanisms, and modern vaccine-based treatment strategies.

Long-standing scarcity of efficacious treatments and tumor heterogeneity have contributed to triple-negative breast cancer (TNBC), a subtype with a poor prognosis and aggressive behavior that accounts for 10-15% of all new cases of breast cancer. TNBC is characterized by the absence of progesterone and estrogen receptor expression and lacks gene amplification or overexpression of HER2. Genomic sequencing has detected that the unique mutational profile of both the somatic and germline modifications in TNBC is staggeringly dissimilar from other breast tumor subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. Nevertheless, reports regarding the penetrance and risk of other susceptibility genes are relatively scarce. Recurring mutations (e.g., TP53 and PI3KCA mutations) occur together with rare mutations in TNBC, and the shared effects of genomic modifications drive its progression. Given the heterogeneity and complexity of this disease, a clinical understanding of the genomic modifications in TNBC can pave an innovative way toward its therapy. In this review, we summarized the most recent discoveries associated with the underlying biology of developmental signaling pathways in TNBC. We also summarize the recent advancements in genetics and epidemiology and discuss state-of-the-art vaccine-based therapeutic strategies for TNBC that will enable tailored therapeutics.

State Variation in Racial and Ethnic Disparities in Incidence of Triple-Negative Breast Cancer Among US Women.

Importance: There are few data on state variation in racial and ethnic disparities in incidence of triple-negative breast cancer (TNBC) in the US, limiting the ability to inform state-level health policy developments toward breast cancer equity. Objective: To quantify between and within racial and ethnic disparities in TNBC incidence rates (IRs) among US women across states. Design, Setting, and Participants: This cohort study using population-based cancer registry data included data for all women with TNBC diagnosed from January 1, 2015, to December 31, 2019, identified in the US Cancer Statistics Public Use Research Database. Data were analyzed from July through November 2022. Exposures: State and race and ethnicity (Hispanic, non-Hispanic American Indian or Alaska Native, non-Hispanic Asian or Pacific Islander, non-Hispanic Black, or non-Hispanic White) abstracted from medical records. Main Outcomes and Measures: The main outcomes were diagnosis of TNBC, age-standardized IR per 100 000 women, state-specific incidence rate ratios (IRRs) using the rate among White women in each state as a reference for between-population disparities, and state-specific IRRs using the race and ethnicity-specific national rate as a reference for within-population disparities. Results: The study included data for 133 579 women; 768 (0.6%) were American Indian or Alaska Native; 4969 (3.7%), Asian or Pacific Islander; 28 710 (21.5%), Black; 12 937 (9.7%), Hispanic; and 86 195 (64.5%), White. The TNBC IR was highest among Black women (25.2 per 100 000 women), followed by White (12.9 per 100 000 women), American Indian or Alaska Native (11.2 per 100 000 women), Hispanic (11.1 per 100 000 women), and Asian or Pacific Islander (9.0 per 100 000 women) women. Racial and ethnic group-specific and state-specific rates substantially varied, ranging from less than 7 per 100 000 women among Asian or Pacific Islander women in Oregon and Pennsylvania to greater than 29 per 100 000 women among Black women in Delaware, Missouri, Louisiana, and Mississippi. Compared with White women, IRRs were statistically significantly higher in 38 of 38 states among Black women, ranging from 1.38 (95% CI, 1.10-1.70; IR, 17.4 per 100 000 women) in Colorado to 2.32 (95% CI, 1.90-2.81; IR, 32.0 per 100 000 women) in Delaware; lower in 22 of 22 states among Asian or Pacific Islander women, varying from 0.50 (95% CI, 0.34-0.70; IR, 5.7 per 100 000 women) in Oregon to 0.82 (95% CI, 0.75-0.90; IR, 10.5 per 100 000 women) in New York; and did not differ among Hispanic and American Indian or Alaska Native women in 22 of 35 states and 5 of 8 states, respectively. State variations within each racial and ethnic population were smaller but still substantial. For example, among White women, compared with the national rate, IRRs varied from 0.72 (95% CI, 0.66-0.78; IR, 9.2 per 100 000 women) in Utah to 1.18 (95% CI, 1.11-1.25; IR, 15.2 per 100 000 women) in Iowa, 1.15 (95% CI, 1.07-1.24; IR, 14.8 per 100 000 women) in Mississippi, and 1.15 (95% CI, 1.07-1.24; IR, 14.8 per 100 000 women) in West Virginia. Conclusions and Relevance: In this cohort study, there were substantial state variations in racial and ethnic disparities in TNBC incidence, with Black women in Delaware, Missouri, Louisiana, and Mississippi having the highest rates among all states and racial and ethnic populations. The findings suggest that more research is needed to identify factors contributing to the substantial geographic variations in racial and ethnic disparities in TNBC incidence to develop effective preventive measures and that social determinants of health contribute to the geographic disparities in TNBC risk.

Neighborhood factors and triple negative breast cancer: The role of cumulative exposure to area-level risk factors.

BACKGROUND: Despite similar incidence rates among Black and White women, breast cancer mortality rates are 40% higher among Black women. More than half of the racial difference in breast cancer mortality can be attributed to triple negative breast cancer (TNBC), an aggressive subtype of invasive breast cancer that disproportionately affects Black women. Recent research has implicated neighborhood conditions in the etiology of TNBC. This study investigated the relationship between cumulative neighborhood-level exposures and TNBC risk. METHODS: This single-institution retrospective study was conducted on a cohort of 3316 breast cancer cases from New Castle County, Delaware (from 2012 to 2020), an area of the country with elevated TNBC rates. Cases were stratified into TNBC and "Non-TNBC" diagnosis and geocoded by residential address. Neighborhood exposures included census tract-level measures of unhealthy alcohol use, metabolic dysfunction, breastfeeding, and environmental hazards. An overall cumulative risk score was calculated based on tract-level exposures. RESULTS: Univariate analyses showed each tract-level exposure was associated with greater TNBC odds. In multivariate analyses that controlled for patient-level race and age, tract-level exposures were not associated with TNBC odds. However, in a second multivariate model that included patient-level variables and considered tract-level risk factors as a cumulative exposure risk score, each one unit increase in cumulative exposure was significantly associated with a 10% increase in TNBC odds. Higher cumulative exposure risk scores were found in census tracts with relatively high proportions of Black residents. CONCLUSIONS: Cumulative exposure to neighborhood-level risk factors that disproportionately affect Black communities was associated with greater TNBC risk.

Prognostic disparities in young patients based on breast cancer subtype: A population-based study from the SEER database.

Triple-negative breast cancer (TNBC) is associated with younger age and worse long-term survival. However, the characteristics and prognosis of different subtypes of breast cancer (BC) in young (<40 years) patients have not yet been elucidated. The present population-based study explored the clinical and pathological characteristics of young TNBC patients and investigated their long-term survival. We enrolled patients from the Surveillance, Epidemiology, and End Results database younger than 40 years of age with primary BC. Cases were defined as patients with TNBC (hormone receptor [HR]-/human epidermal growth factor receptor 2 [HER2]-), and controls were patients with other subtypes of BC (HR-/HER2+, HR+/HER2-, and HR+/HER2+). Demographic, pathological, and radiotherapy, chemotherapy, and surgery data were extracted and the overall survival was the primary endpoint. We enrolled 14,234 young patients with BC in the present study, of whom 2798 (19.7%) had TNBC and 11,436 (80.3%) had another BC subtype. A higher proportion of TNBC patients than non-TNBC patients had a more advanced tumor-node-metastasis stage (II-IV 80.5% vs 73.1%, P < .001), and smaller proportions underwent radiotherapy (50.0% vs 53.3%, P = .002) and surgery (91.8% vs 92.9%, P < .001). TNBC was associated with significantly lower 5-year survival rates than other subtypes among patients with regional node positivity (0, 1-3, 4-9, ≥10: 54.2% vs 57.7%, 44.2% vs 55.9%, 31.0% vs 52.0%, and 27.7% vs 38.8%, P < .001) and those with different lymph node ratios (low, intermediate, high: 50.9% vs 56.0%, 34.6% vs 53.6%, and 24.8% vs 44.8%, P < .001). Our research is the first to investigate the relevant characteristics of young TNBC patients in comparison with those of young non-TNBC patients based on the surveillance, epidemiology, and end results database. We found that young TNBC patients have a higher pathological stage and worse long-term survival than young patients with other BC subtypes. These findings have implications in identifying young patients with TNBC for aggressive therapy and further investigations should be performed to explore new multimodal treatments for such patients.

Disparities in stage at diagnosis among breast cancer molecular subtypes in China.

BACKGROUND: Disease stage at diagnosis and molecular subtypes are the main determinants of breast cancer treatment strategies and prognosis. We aimed at examining the disparities and factors associated with the stage at diagnosis among the molecular subtypes in breast cancer patients in China. METHODS: We identified patients with first primary breast cancer diagnosed between January 1, 2016, and December 31, 2017, from 23 hospitals in 12 provinces in China. We analyzed the proportion of non-early-stage (stages II-IV) breast cancer cases based on the family history of breast cancer, body mass index (BMI), insurance status, and molecular subtypes. Multivariable analyses were used to estimate the factors associated with non-early-stage diagnosis among the molecular subtypes. We further compared these estimates with that in the United States using the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 9398 Chinese were identified with first primary invasive breast cancer. Of the 8767 patients with known stages, the human epidermal growth factor receptor 2 (HER2)-enriched subtype had the highest proportion of stages II-IV (76.6%) patients, followed by triple-negative breast cancer (73.2%), luminal B (69.9%), and luminal A (62.3%). The percentage of non-early-stage patients was higher in women with overweight or obesity than in those with a body mass index (BMI) <25 kg/m2 (adjusted odds ratio [OR] 1.3, 95% confidence interval (CI) 1.1-1.4). Patients with a family history of breast cancer had a higher likelihood of early-stage (adjusted OR 0.7, 0.5-0.8) breast cancer. Patients with rural insurance had a substantially higher risk of non-early-stage disease than those with urban insurance (adjusted OR 1.8, 1.4-2.2). Regarding the subtype, being overweight/obese only increased the risk of non-early-stage in luminal A breast cancer. Compared with the United States, China had a higher proportion of non-early-stage breast cancer for all subtypes, with the largest gap in luminal A (adjusted OR 2.2, 95% CI 2.0-2.4). CONCLUSION: The wide disparities in stage at breast cancer diagnosis imply that China urgently needs to improve early breast cancer diagnosis and health equity.