Risk Of Triple-negative Breast Cancer Research Articles

Epigenetic and Immune Mechanisms Linking Breastfeeding to Lower Breast Cancer Rates.

This review shows how mammary stem cells (MaSCs) influence breast development, breastfeeding, and breast cancer risk. MaSCs, which can differentiate into various cell types, are vital for breast tissue health, but also disease development in breast tissue. Research shows that breastfeeding affects MaSCs, offering protection against breast cancer through various mechanisms. Hormonal changes such as increased prolactin concentration, oxytocin secretion, lower progesterone levels, and reduced exposure to estrogen during lactation promote apoptosis in potential cancer cells, boost immune surveillance, and modulate inflammation. Key findings reveal that pregnancy at an earlier age and extended breastfeeding reduce MaSC numbers, lowering cancer risk. Additionally, breastfeeding induces various epigenetic changes, such as DNA methylation and histone modification, which provide long-term protection against the development of cancer. Components of breast milk, like alpha-lactalbumin and lactoferrin, contribute by promoting cancer cell apoptosis and inhibiting tumor growth. The dual benefits of breastfeeding are reduced breast cancer risk for mothers and immunological advantages for infants. Multicenter epidemiology research has focused particular attention on longer breastfeeding duration associated with a reduced risk of triple-negative breast cancer. This review offers comprehensive evidence that breastfeeding protects against breast cancer through various biological, hormonal, and molecular mechanisms, showing the importance of promoting breastfeeding as a natural cancer prevention method. This article reviews the role of mammary stem cells in breast development, lactation, and breast cancer.

High BMI Is Associated with Changes in Peritumor Breast Adipose Tissue That Increase the Invasive Activity of Triple-Negative Breast Cancer Cells

Breast cancer is the most common cancer in women with multiple risk factors including smoking, genetics, environmental factors, and obesity. Smoking and obesity are the top two risk factors for the development of breast cancer. The effect of obesity on adipose tissue mediates the pathogenesis of breast cancer in the context of obesity. Triple-negative breast cancer (TNBC) is a breast cancer subtype within which the cells lack estrogen, progesterone, and HER2 receptors. TNBC is the deadliest breast cancer subtype. The 5-year survival rates for patients with TNBC are 8–16% lower than the 5-year survival rates for patients with estrogen-receptor-positive breast tumors. In addition, TNBC patients have early relapse rates (3–5 years after diagnosis). Obesity is associated with an increased risk for TNBC, larger TNBC tumors, and increased breast cancer metastasis compared with lean women. Thus, novel therapeutic approaches are warranted to treat TNBC in the context of obesity. In this paper, we show that peritumor breast adipose-derived secretome (ADS) from patients with a high (>30) BMI is a stronger inducer of TNBC cell invasiveness and JAG1 expression than peritumor breast ADS from patients with low (<30) BMI. These findings indicate that patient BMI-associated changes in peritumor AT induce changes in peritumor ADS, which in turn acts on TNBC cells to stimulate JAG1 expression and cancer cell invasiveness.

Abstract A014: Racial and socioeconomic disparities in breast feeding and the impact of pregnancy-related medical conditions among a population-based sample of non-Hispanic Black and White women

Abstract Background: Breastfeeding has been associated with a reduced risk of breast cancer (BC), particularly with Triple Negative BC (TNBC). The risk of TNBC is higher among premenopausal women, Black/African American (AA) women, and poorer women. Notably there are significant disparities in breastfeeding, where non-Hispanic Black (NHB) women and poorer women are less likely to breastfeed in the United States. Studies have identified historical racial trauma, unsupportive work and hospital policies, breast milk formula advertising, and knowledge and beliefs about breast feeding as factors that contribute to breast feeding practices. However, there is a paucity of research on pregnancy related medical conditions (PMCs) that potentially impact initiation and duration of breastfeeding. The purpose of this study is to evaluate racial and socioeconomic differences in breastfeeding, and if PMCs impact breastfeeding practices in a population-based sample of non-Hispanic Black and White women. Method: Data are from the Young Women’s History and Health Study (YWHHS), a population- based case-control study of invasive BC among non-Hispanic Black (NHB) and non-Hispanic White (NHW) women aged 20-49 years residing in Metropolitan Detroit and Los Angeles County, 2010-2015. The analytic sample here includes the first pregnancy of control participants with singleton live births (n=675). Area-based control participants were sampled from the 2010 Census. Interviews assessed complete reproductive histories, including breastfeeding history (never, <6 months, and ≥6 months), PMCs experienced during pregnancy, self-reported race, and household financial struggles before age 13 years (to approximate childhood socioeconomic position (chSEP)). PMCs examined included: 1) premature birth, 2) diabetes or pre-diabetes related PMCs, 3) blood pressure-related PMCs, and 4) BMI ≥ 25 kg/m2 at age 18 years. Weighted percentages were evaluated with a chi-square test and considered significant at p < 0.05. Analyses were further stratified by race/ethnicity and chSEP. Result: NHB women were 2.4 times significantly more likely to never breastfeed than NHW women (W% =52.0 (NHB) and 21.3 (NHW), p=<0.0001). Similarly, women with lower compared to higher chSEP were 1.5 times significantly more likely to never breastfeed (W% = 42.7 (lower chSEP) and 28.5 (higher chSEP), p=0.003). Those with BMI ≥ 25 kg/m2 at age 18 years (p<0.001) alone, and with one or more PMCs (p=0.01) were also less likely to breastfeed. When stratified by race/ethnicity the pattern of breastfeeding did not differ significantly by any PMC within NHB and NHW women. When stratified by chSEP, however, BMI ≥ 25 kg/m2 at age 18 years (p = 0.004) and having one or more PMCs (p=0.03) were significantly associated with never breastfeeding among those with higher chSEP. Conclusion: NHB women and women with lower chSEP were substantially less likely to breastfeed. Additionally, BMI ≥ 25 kg/m2 at age 18 and PMCs were associated with lower frequency of breastfeeding overall and among those with higher chSEP. Citation Format: Meheret B. Gebreegziabher, Lydia R. Post, Chris C. Cho, Zhenzhen Zhang, Kelly A. Hirko, Dorothy R. Pathak, Ann S. Hamilton, Ann G. Schwartz, Ellen M. Velie. Racial and socioeconomic disparities in breast feeding and the impact of pregnancy-related medical conditions among a population-based sample of non-Hispanic Black and White women [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A014.

Association between Toll-like receptor 2 rs4696483 and rs1898830 polymorphisms and the risk of triple-negative breast cancer

PurposeBreast cancer (BC) is heterogeneous in clinical manifestation, of which the triple-negative (TNBC) subtype is the most aggressive. This study examines the associations between Toll-Like Receptor (TLR)-2 polymorphisms and the susceptibility to BC and TNBC. MethodsGenotyping of TLR-2 rs1898830 and rs4696483 polymorphisms was done by real-time PCR in 488 women with BC (130 TNBC, 358 non-TNBC) and 476 cancer-free control women. ResultsThe minor allele frequency (MAF) of rs4696483 was significantly lower in BC cases compared to controls, and significantly lower frequencies of rs4696483 C/T and higher frequencies of rs1898830 G/G genotypes were seen in BC cases. Significantly higher MAF of rs4696483 and higher C/T and T/T rs4696483 genotypes frequencies were seen in TNBC than in non-TNBC cases. Considering the prevalent AC haplotype as a reference, 2-locus TLR-2 haplotype analysis did not identify any 2-locus TLR-2 haplotype associated with an altered risk of BC or TNBC. Positive associations of rs1898830 and rs4966483 were seen with the histological type in TNBC and negatively with distant metastasis and HR status in TNBC and non-TNBC rs1898830 carriers. In addition, rs4696483 was positively correlated with hormonotherapy and surgery in non-TNBC cases, while rs1898830 was negatively associated with hormonotherapy. Furthermore, rs1898830 was negatively and positively correlated with BMI in TNBC and TNBC cases, respectively, but positively with Ki-67 status. ConclusionsOur study highlights the association between TLR-2 genetic polymorphisms and BC and TNBC susceptibility, suggesting these variants' diagnostic/prognostic capacity in BC patients and patient subgroups.

Deciphering the Chemotherapeutic Role of the Aryl Hydrocarbon Receptor Antagonist Resveratrol against the High-Penetrance Genes of Triple-Negative Breast Cancer.

In addition to several other malignancies, the ligand-activated aryl hydrocarbon receptor (AhR) signaling pathway has been found to enhance the risk of triple-negative breast cancer (TNBC). Many natural compounds of pharmaceutical importance are identified as antagonistic exogenous ligands of AhR. The expressional lack of hormone receptors coupled with adverse prognosis leads to the absence of molecular-targeted therapy in TNBC. Hence, discovering low-cost therapeutic alternatives involving the identification of effective biomarkers is an urgent necessity. This study investigates the binding mechanism of resveratrol, a dietary exogenous AhR ligand against the high-penetrance genes in TNBC, viz., PALB2, TP53, PTEN, STK11, BRCA1, and BRCA2. Post-pharmacokinetic evaluation, molecular docking revealed the binding energy scores of resveratrol against the six TNBC high-penetrance receptors. The results obtained from docking were confirmed by molecular dynamics simulation including principal component analysis, calculation of total interaction energy, and free-energy landscape computation. PALB2 emerged as a promising therapeutic receptor of resveratrol. Furthermore, the PALB2-resveratrol binding dynamics were evaluated against olaparib, an FDA-approved standardized TNBC inhibitor. Our study reveals comparatively better chemistry of PALB2-resveratrol than PALB2-olaparib. Considering the current surge in the discovery of precision medicine in biomarker-based cancer therapeutics, this study proposes PALB2-resveratrol as a unique drug-receptor combination thus awaiting validation through in vitro studies.

Feasibility of risk assessment for breast cancer molecular subtypes

PurposeFew breast cancer risk assessment models account for the risk profiles of different tumor subtypes. This study evaluated whether a subtype-specific approach improves discrimination.MethodsAmong 3389 women who had a screening mammogram and were later diagnosed with invasive breast cancer we performed multinomial logistic regression with tumor subtype as the outcome and known breast cancer risk factors as predictors. Tumor subtypes were defined by expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) based on immunohistochemistry. Discrimination was assessed with the area under the receiver operating curve (AUC). Absolute risk of each subtype was estimated by proportioning Gail absolute risk estimates by the predicted probabilities for each subtype. We then compared risk factor distributions for women in the highest deciles of risk for each subtype.ResultsThere were 3,073 ER/PR+ HER2 − , 340 ER/PR +HER2 + , 126 ER/PR−ER2+, and 300 triple-negative breast cancers (TNBC). Discrimination differed by subtype; ER/PR−HER2+ (AUC: 0.64, 95% CI 0.59, 0.69) and TNBC (AUC: 0.64, 95% CI 0.61, 0.68) had better discrimination than ER/PR+HER2+ (AUC: 0.61, 95% CI 0.58, 0.64). Compared to other subtypes, patients at high absolute risk of TNBC were younger, mostly Black, had no family history of breast cancer, and higher BMI. Those at high absolute risk of HER2+ cancers were younger and had lower BMI.ConclusionOur study provides proof of concept that stratifying risk prediction for breast cancer subtypes may enable identification of patients with unique profiles conferring increased risk for tumor subtypes.

Evaluation of a polygenic risk score as a predictor of early onset triple-negative breast cancer in Black women.

10501 Background: Black women in the U.S. often develop early, biologically aggressive breast cancer (BC). Triple-negative breast cancer (TNBC) is a particularly aggressive type that occurs more frequently in Black than white women and often develops before recommended regular screening. More accurate risk prediction methods are urgently needed to identify young Black women with elevated risk of TNBC. Incorporating polygenic risk scores (PRS) into clinical models can substantially improve risk assessment, but most PRS have demonstrated poor performance among non-European ancestries. We previously described a multiple-ancestry PRS (MA-PRS), based on 56 ancestry-informative and 329 BC-associated single-nucleotide polymorphisms (SNPs), that predicts overall BC risk for diverse populations by characterizing genetic ancestry at each BC SNP and applying ancestry-specific SNP risks and frequencies. Here, we evaluated the extent to which MA-PRS improves upon clinical factors for the prediction of TNBC and early onset ( < 50 years) TNBC in a large, independent cohort of self-reported Black women. Methods: We examined clinical and genetic records from self-reported Black women referred for hereditary cancer testing from 8/22 - 9/23 and negative for pathogenic variants in BC-associated genes. The association of MA-PRS with TNBC was analyzed using multivariable logistic regression adjusted for personal and family cancer history, age and genetic ancestry. Analyses were conducted within the full cohort and the subpopulation of patients < 50 years old. Odds ratios (OR) are reported per standard deviation (SD) with 95% confidence intervals (CI). Results: We identified 14728 Black women who met study eligibility criteria. Nearly 70% (9895/14728) of patients were under the age of 50. In the full cohort, 629 (4.3%) patients were diagnosed with TNBC, and 173 (1.7%) were younger than 50 years old. MA-PRS significantly improved TNBC risk prediction over clinical factors in the full cohort and in the subpopulation of women under 50 (Table). The effect of MA-PRS on risk stratification was comparable to the 1.4 OR per SD reported in current literature for mammographic density, which is widely recognized as an important risk factor. Women in the top 5% of the MA-PRS distribution were at roughly 2-fold increased risk of TNBC (Table). Conclusions: MA-PRS substantially improved upon clinical factors for the prediction of TNBC and early-onset TNBC in a large cohort of Black women. MA-PRS appears to be equally as important for managing risk of early-onset TNBC as mammographic density for overall BC. Incorporation of MA-PRS into BC risk assessment has the potential to improve TNBC survival through more accurate identification of women at high risk. [Table: see text]

Abstract PO1-09-01: Patient Advocates, Oncologists & Research Scientists Collaborate to Address PostPartum Breast Cancer

Abstract The incidence of young women (YW=< 45) with aggressive breast cancer (BC) has been increasing and BC in younger women tends to be diagnosed in more advanced stages1. A group of advocates, oncologists and scientists have established an advocate-researcher dialogue to address this. A key finding we are highlighting and sharing with the community is that postpartum BC (PPBC) is a "free biomarker" for increased risk of metastatic disease. We report our efforts to understand the biologic underpinnings of PPBC, strategize to disseminate information, and accomplish our longterm goals to reduce BC incidence and mortality in YW. Interactions Between Childbirth & BC The interactions between the reproductive life phases and BC are complex. We are taught that having children and nursing them is protective against BC. What is complicated is the fact that after childbirth, women overall are at a 10-30% increased risk for getting early onset BC. For women < 30 at the time of their last baby, this increased risk converts to a protective effect about 10 years after childbirth, such that in later life they have a lower risk of getting BC in comparison to women who have not given birth. However for women who have children after 30, the risk remains increased for many decades. The peak window of time for YW to get BC is within 10 years after childbirth and diagnoses during this window are PPBC. The global trend of women delaying childbirth until they are older is one factor contributing to increased PPBC2. While lactation can be protective, this protection is seen most robustly against triple negative BC (TNBC). This protective effect is seen most strongly in women who nurse for about 6 months. In some who do not nurse, especially black women, risk for TNBC can be increased3. When women get diagnosed with PPBC several things are known4: The frequency of the different subtypes of BC (ER+,PR+,Her2+) is similar to BC diagnosed in YW overall, so most PPBC is ER+ Her2- While there is no difference in the % of women who will have Her2+ or TNBC among PPBC cases, more women with PPBC will have + lymph nodes at diagnosis Of women who get diagnosed with BC < 45, about half will occur in this PP window accounting for about 50% of all early onset BC Studies have shown that PPBC has a higher tendency towards developing metastatic disease in comparison to BC in women without children or in women diagnosed more than 10 years since last childbirth4. Research is ongoing to identify why this increased risk is occurring and how treatment can be tailored to eliminate this risk. Adherence to therapy and participation in clinical trials is crucial. Clinical trials should capture when a woman had her last child as a routine datapoint so PPBC can be researched more broadly. This datapoint - age of her youngest child when she was diagnosed - is essentially a "free biomarker" indicating risk for metastasis. Advocate-Researcher Outreach Efforts Production of a podcast episode "Rising Rates of BC & MBC in YW" on www.OurMBCLife.org produced by SHARE Cancer Support Discussion with other advocates and organizations to raise awareness Approach donors to increase funding for research in PPBC Summary BC in YW is increasing and YW with recent childbirth are at increased risk. Raising health awareness in a proactive, non-alarming manner is an important advocacy goal YW diagnosed within 10 years of a recent childbirth represent a unique subset of BC called PPBC Age of youngest child at time of diagnosis is an important free biomarker for risk and should be added to medical histories Increase funding is essential to determine why PPBC has different outcomes and how treatments can be tailored to ensure the wellness of our young mothers

Abstract PS07-09: Prenatal BRCA1 epimutations is a major cause of triple-negative breast cancer

Abstract Background: Low level normal cell BRCA1 epimutations have been associated with an increased risk of triple-negative breast cancer (TNBC). However, the fraction of TNBCs that may have BRCA1 epimutations as their underlying cause is unknown. Neither are the time of occurrence and the potential inheritance pattern of BRCA1 epimutations established. Methods: To address these questions, we analyzed BRCA1 methylation status in breast cancer tissue and matched white blood cells (WBC) from 411 patients with primary breast cancer, including 66 TNBCs. Samples were analyzed by a highly sensitive next-generation sequencing (NGS) assay on an Illumina MiSeq sequencer, allowing allele-resolved methylation assessment. Further, to assess the time of origin and the characteristics of normal cell BRCA1 methylation, we analyzed umbilical cord samples from 1260 newborn girls and 200 newborn boys.To assess potential Mendelian heritage, we analyzed BRCA1 methylation status in WBCs from 575 mothers and 531 fathers of newborn girls with (n = 102) and without (n = 473) WBC BRCA1 methylation. Results: We found concordant tumor and mosaic WBC BRCA1 epimutations in 10 out of 66 patients with TNBC and in four out of six patients with estrogen receptor (ER)-low expression (< 10%) of tumors (combined 14 out of 72; 19.4%, CI: 11.1-30.5). These exceeded the number of tumors harboring germline (n = 5) or somatic (n = 4) BRCA1 mutations. Notably, BRCA1 methylation and BRCA1 mutations were mutually exclusive. Contrasting the findings in TNBC and ER-low exprssion tumors, we found WBC and tumor BRCA1 methylation concordance in only three out of 221 patients with ER >10+% tumors and zero out of 116 patients with HER2 positive tumors. Intraindividually, BRCA1 epimutations affected the same allele in normal and tumor cells. Assessing BRCA1 methylation in umbilical cord WBCs from newborn girls, we found mosaic, predominantly monoallelic BRCA1 epimutations, with qualitative features similar to those in adults, in 113/1260 (9.0%) of individuals. We found no correlation between WBC BRCA1 methylation in newborns and methylation status in their mothers, fathers, or any parent. Notably, WBC BRCA1 methylation occurred at a significantly lower frequency in newborn boys ( 9/200; 4.5%) as compared to newborn girls (p = 0.038). Similarly, WBC BRCA1 methylation was found less common among fathers (16/531; 3.0%), as compared to mothers (46/575; 8.0%; p = 0.0003). Conclusions: Our findings suggest prenatal BRCA1 epimutations might be the underlying cause of around 20% of TNBC and low-ER expressing breast cancers. Such constitutional mosaic BRCA1 methylation likely arise through gender-related mechanisms in utero, independent of Mendelian inheritance. Citation Format: Per Lonning, Hans Petter Eikesdal, Elisabet Ognedal, Bjornar Gilje, Steinar Lundgren, Egil Blix, Helge Espelid, Jürgen Geisler, Stephanie Geisler, Emiel Janssen, Synnøve Yndestad, Laura Minsaas, Beryl Leirvaag, Reidun Lillestol, Stian Knappskog, Oleksii Nikolaienko. Prenatal BRCA1 epimutations is a major cause of triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-09.

Abstract PO2-28-04: Pregnancy-associated relapse of triple-negative breast cancer

Abstract Introduction: Pregnancy Triple-negative breast cancer(TNMC) is the absence of ER PR and HER2 receptor expression. It constitutes about 15-20% of all breast cancers and is known to be the aggressive form with a high relapse rate (1). Interestingly, it usually affects women aged < 40 and has a low survival rate in African-American females. This case is a typical presentation of a 38-year-old young woman with PMH of T2NO right triple-negative breast cancer diagnosed in 2017 s/p right mastectomy with sentinel LN biopsy, received immunotherapy and chemotherapy, has been cancer-free for two years, and developed metastatic cancer during her pregnancy. In this case, we understand the diagnostic and therapeutic challenges of TNBC during pregnancy. Case: A 38-year-old African American woman, G0, T2NO triple negative invasive ductal carcinoma, underwent a right breast mastectomy and sentinel LN biopsy. She received treatment with (Anti-PD-L1 Antibody) concomitant with weekly paclitaxel and Doxorubicin/Cyclophosphamide (AC) chemotherapy. However, she had a residual 4cm tumor for which she was treated with adjuvant therapy with capecitabine for six months. A repeat Mammogram in 2019 showed no evidence of malignancy. In 2021, the patient was G2P2L1, admitted to the hospital after having a seizure. CT reported cystic/necrotic left parietal lesion mass effect with 8mm right-sided midline shift with metastasis to lungs and abdominal wall. She underwent L parietal craniectomy with resection of the tumor. At 32 weeks of gestation , chemotherapy with carboplatin and paclitaxel was given after her C-section and Gamma knife radiosurgery for metastatic lesions. She developed super refractory seizures, was induced into a coma with therapeutically anesthetic agents, and passed eventually. Discussion: Little literature exists on pregnancy-associated relapse of triple-negative breast cancer and its deterioration. Our patient was in remission for two years and was diagnosed with metastatic cancer during her second pregnancy. John et al., (2018) discussed an interesting association between breastfeeding, parity, and occurrence of TNBC, that there is a two-fold increased risk of developing TNBC with high parity(3 full-term pregnancies) and short-term breastfeeding (< 12 months) (2). Studies have also shown that cancers during or postpartum pregnancy are aggressive with more tumor burden and metastasize to the lungs, liver, and brain, which is consistent with our patient. (3) Conclusion: Pregnancy-associated breast cancer is diagnostically and therapeutically challenging during or in the postpartum period and with a high propensity of the triple-negative type. It requires a multidisciplinary team approach, awareness in the African American population, clinical suspicion of breast mass during pregnancy warrants imaging, and prolonged breastfeeding postpartum. Diagnosis is usually delayed due to pregnancy, and more research is needed on the diagnostic modalities during pregnancy for early treatment initiation. References Almansour NM. Triple-Negative Breast Cancer: A Brief Review About Epidemiology, Risk Factors, Signaling Pathways, Treatment and Role of Artificial Intelligence. Front Mol Biosci. 2022 Jan 25;9:836417. doi: 10.3389/fmolb.2022.836417. PMID: 35145999; PMCID: PMC8824427. John EM, Hines LM, Phipps AI, et al. Reproductive history, breast-feeding and risk of triple-negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) study. International Journal of Cancer. 2018;142(11):2273. doi:10.1002/ijc.31258 Amant F, Deckers S, Van Calsteren K, Loibl S, Halaska M, Brepoels L, et al. Breast cancer in pregnancy: recommendations of an international consensus meeting. Eur J Cancer (2010) 46(18):3158–68. 10.1016/j.ejca.2010.09.010 Citation Format: Vaidarshi Abbagoni. Pregnancy-associated relapse of triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-28-04.

Abstract PO5-10-03: A Translational Epidemiologic Approach to Understand Disparities in Triple Negative Breast Cancer: Integrating Germline Genomics, Genetic Ancestry, and Neighborhood Disadvantage

Abstract Background: Triple-negative breast cancer (TNBC) disproportionately affects women of West African ancestry and those living in neighborhood disadvantage (ND). However, these studies were limited in their ability to control for both ancestry and socioeconomic data. To overcome this limitation, we utilized the epidemiologic-genomic infrastructure of the Miami Breast Cancer Disparities (MBCD) study to evaluate the impact of ND on relative risk (RR) of TNBC, independent of West African ancestry. Methods: A prospective cohort of 502 women with breast cancer enrolled in the MBCD study from 2020-2022. Genetic ancestry, median neighborhood-level income quartiles (ND), germline genetic mutations, and tumor characteristics were assessed. Multinomial logistic regression was used to determine the RR between West African ancestry and TNBC (compared to ER+/HER2- and HER2+ disease) after controlling for access to care measures which might impact TNBC distributions and known TNBC risk factors (e.g., age, ND, BRCA 1 mutation, obesity, screening mammography). Results: Of the 502 women, 333 (66.33%) had ER+/HER2- disease, 67 (13.35%) had ER+/HER2+ disease, 22 (4.38%) had ER-/HER2+ disease, and 80 (15.94%) had TNBC. On univariable analysis, the highest West African quartile (RR 3.58 95%CI 1.72-7.42, p< 0.001), a BRCA 1 mutation (RR 7.89 95%CI 2.25-27.64, p=0.001) were associated with a higher RR of TNBC. Conversely, decreasing ND was associated with a lower RR of TNBC (RR 0.42 95%CI 0.21-0.83, p=0.013). On covariate adjusted multivariable analysis, decreasing ND (RR 0.45 95%CI 0.22-0.99, p=0.047) and a BRCA 1 mutation (RR 12.68 95%CI 3.19-50.35, p< 0.0001) were both significantly associated with TNBC compared to ER+/HER2- and HER2+ disease. Conclusions: To our knowledge, this prospective study is the first to evaluate the combined impact of genetic ancestry, germline genomics, and social factors on RR of TNBC. We discovered that ND and BRCA 1 mutations are independent predictors of TNBC, even after accounting for known TNBC risk factors (e.g., West African ancestry). These findings suggest a potential association between ND and TNBC, thus emphasizing the importance of a translational epidemiologic approach to understand TNBC disparities that considers both genomic and non-genomic factors. Table. Adjusted Multinomial Logistic Regression of Patient Genetic Ancestry, Sociodemographic and Tumor Characteristics Predictors of Breast Cancer Subtype Citation Format: Neha Goel, Alexandra Hernandez, Susan Kesmodel, Erin Kobetz, Nipun Merchant, Timothy Rebbeck. A Translational Epidemiologic Approach to Understand Disparities in Triple Negative Breast Cancer: Integrating Germline Genomics, Genetic Ancestry, and Neighborhood Disadvantage [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-10-03.

Abstract PO2-17-12: Phase I Trial of alpha-lactalbumin vaccine in high risk operable triple negative breast cancer (TNBC) and patients at high genetic risk for TNBC

Abstract Background: Triple-negative breast cancer (TNBC) has a poor prognosis and may be associated with germline mutations. α-Lactalbumin (aLA) is expressed in lactating breasts but not at other times or in other tissues. Expression of aLA is found in 70% of TNBC (PMID: 27322324) so could be an immunologic target for TNBC based on the “retired protein hypothesis” (PMID: 31926646). In pre-clinical studies, vaccination with aLA provided protection from development of autochthonous tumors in transgenic murine models of breast cancer and inhibited growth of established 4T1 transplantable breast tumors in BALB/c mice (PMID: 20512124). Methods: To determine the safety and immunogenicity of aLA, patients with early stage TNBC are being entered in a Phase I trial of aLA with GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Subjects receive 3 vaccinations given once every 2 weeks. Events of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 are considered dose-limiting toxicities (DLTs). Results: CTCAE toxicity by dose level is summarized below. All DLTs were injection site reactions, with ulceration and need for incisional drainage representing the grade 3 events. Seven (7) of 10 patients assayed to date have met protocol specified definitions of an immune response based on ELISpot assays to determine frequencies of T cells producing IFNγ and IL-17 in response to recombinant aLA. Assays for an additional 6 patients will be available in September 2023. Conclusion: Dose level ≤ 2 appears to be the maximum tolerated dose. Based on immune response, additional intermediate dose levels may be studied. An additional cohort of patients receiving concurrent anti-PD1 treatment is being accrued. Accrual of patients with BRCA1/2 or PALB2 mutations planning to undergo prophylactic mastectomy is beginning in order to define the toxicity and immunologic effects in this group and to determine whether inflammatory changes from occult lactational foci will be produced. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593) Table 1 Worst Toxicity by Dose Level Citation Format: Justin Johnson, Emily Rhoades, Holly Levengood, Halle Moore, Megan Kruse, Erin Roesch, Jame Abraham, Brenna Elliott, Rachel Swartz, Holly Pederson, Elena Haury, Azka Ali, Tiffany Onger, Andrew Sciallis, Zahraa Al-Hilli, Wei Wei, Thaddeus Stappenbeck, George Budd. Phase I Trial of alpha-lactalbumin vaccine in high risk operable triple negative breast cancer (TNBC) and patients at high genetic risk for TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-12.

Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction.

We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

Abstract 6119: Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks target treatments. It has been reported that African-American women have a higher incidence of TNBC and are diagnosed at an earlier age than women of European ancestry. This disparity may be attributed to both genetic and non-genetic risk factors that are associated with the African ancestry. In this study, we investigated whether genotype-derived African ancestry might be related to an elevated risk of TNBC, with adjustments for several known genetic and non-genetic risk factors. Included in the study are self-reported Black breast cancer patients diagnosed with TNBC (n =2,292) or estrogen receptor (ER)-positive cancer (n =7,863) and 9,324 controls included in the African-ancestry Breast Cancer Genetics (AABCG) Consortium. We estimated the global ancestry by Admixture and the local ancestry by FLARE, using reference of the European- and African-ancestry samples from the 1000 Genome Project. Odds ratios (OR) and 95% confidence interval (CI) per ten percent increase of the global African ancestry proportion were estimated using logistic regressions comparing TNBC with controls (case-control analyses) or with ER-positive cases (case-case analyses), adjusted for age. Similar analyses were conducted for the local African ancestry proportion at each of the 12 genomic regions that were identified in AABCG in relation to TNBC risk. Results for each participating study were meta-analyzed using fixed or random effect models. We further adjusted for non-genetic risk factors including body mass index (BMI), number of live births, breastfeeding, and menopausal status. A polygenic risk score (PRS) was constructed using 13 independent risk variants at the 12 TNBC risk loci. The PRS was additionally adjusted to investigate whether these risk variants mediated the association of African ancestry with TNBC risk. No significant association was observed between TNBC risk and global African ancestry proportion (OR: 1.03, 95% CI: 0.98-1.08) in case-control comparisons. Compared with ER-positive cases, however, TNBC cases had a higher global African ancestry, resulted in an OR of 1.09 (95% CI: 1.04, 1.13, P =5.35×10-5). A similar association was observed with additional adjustment for non-genetic risk factors, with an OR of 1.08 (95% CI: 1.03, 1.12, P =0.003). Similar patterns were also found for local ancestry proportion at six of the 12 TNBC risk loci (P &amp;lt;0.05). Further adjustment for the PRS attenuated the association between global ancestry and a TNBC diagnosis in case-case comparisons (OR: 1.05, 95% CI: 1.01, 1.10, P =0.013). Our study suggests that women with a higher African ancestry are more likely to be diagnosed with a TNBC than ER-positive breast cancer and genetic factors identified to date partially explain this association. Citation Format: Guochong Jia, Lili Liu, Julie R. Palmer, Christopher A. Haiman, Wei Zheng. Association of genetic African ancestry and triple-negative breast cancer risk: Findings from the African-ancestry breast cancer genetics consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6119.

Abstract 5551: Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment

Abstract Several mutations have been identified that are associated with an increased risk of triple-negative breast cancer (TNBC), including those that are deleterious in the BRCA gene. TNBC is associated with the worst prognosis and the highest incidence of brain metastasis (30%) among all subtypes of BC. Despite objective responses to poly (ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-mutated TNBC, benefits are transitory. Furthermore, our understanding of the effect of PARP inhibitors (PARPi) in treating breast cancer brain metastasis (BCBM) and modulating its tumor microenvironment (TME) is still lacking. To this end, we analyzed the brain TME of BRCA-mutated BCBM in the absence or presence of treatment with PARPi. Interestingly, we found that the immune TME of the brain hinder the antitumor activity of PARPi by upregulating multiple immunosuppressive molecules, including PD-L1. Furthermore, we found that BCBM overexpress P-selectin through its interaction with the tumor-associated microglia, bone marrow-derived macrophages and endothelial cells in the TME. Thus, we designed a novel nanoparticle (NP) targeting P-selectin to serve as a brain-penetrant delivery system for the treatment of BCBM. In order to target BRCA-mutated BCBM, we harnessed our novel P-selectin-targeted NPs to entrap PARPi and other immune modulators that we found to exert synergistic activity when combined. To evaluate the antitumor activity of our P-selectin-targeted NPs, we established 3-dimensional (3D) ex vivo and in vivo BRCA-mutated BCBM models. Importantly, we saw favorable effects of the P-selectin-targeted NPs in comparison to the combination of the free drugs, suggesting that out targeted-NPs overcome the TME-mediated resistance to PARPi through the modulation of the immunosuppressive microenvironment of the brain. Citation Format: Rami Khoury, Ron Kleiner, Eilam Yeini, Daniel Rodriguez Ajamil, Sahar Israeli Dangoor, Tamer Sanalla, Iris Barshack, Roni Satchi-Fainaro. Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5551.

Abstract 3510: A radiogenomic approach for triple-negative breast cancer risk stratification

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive disease that accounts for 15-20% of all breast cancers. Expressions of ER, PR and HER2 receptors are lacking in this disease, and thus targeted therapies are not effective. TNBC has a shorter relapse-free survival, higher metastasis rate and decreased overall survival compared with other breast cancers. However, when undergoing standard treatment, some patients respond well, while others have poor outcome, suggesting TNBC heterogeneity. Early stratification of patients with long versus short survival could identify the subgroup of patients who would not benefit from exposure to toxicity of chemotherapy treatment. Here, we developed a non-invasive radiogenomic approach for TNBC risk stratification. Methods: A transcriptomic-based prognostic gene signature was previously developed using the TCGA-BRCA cohort (n=860). Briefly, LASSO Cox regression model analysis with the ‘glmnet’ R package was used to identify the transcriptomic signature gene-set consisting of 50 genes. We tested this signature to prognosticate overall survival in a Stanford cohort (n=63) and a previously published SCANB cohort (n=604). The patients were stratified into high- and low-risk groups based on the median risk-score. Next, we developed a machine learning model that identified a radiomic feature set to predict the prognostic transcriptomic risk-groups. Radiomic features were extracted from pre-treatment breast MRI. Radiomics features were extracted using PyRadiomics. The model utilized Decision Tree Classifier and LeaveOneOut method was used for cross-validation. Results: The transcriptomic signature low-risk group was significantly associated with improved overall survival in the two TNBC cohorts, with hazard ratios of 0.11 [95% CI: 0.01-0.88] for the Stanford cohort and 0.71 [95% CI: 0.52-0.97] for the SCANB cohort (log-rank p-values p=0.012 and p=0.032, respectively). Including this transcriptomic signature in a multivariate analysis, which adjusted for clinical features (patient age, grade, stage and Ki67%), the transcriptomic prognostic signature remained a significant prognostic factor (p&amp;lt;0.05). The radiomic feature set (consisting of 20 features) predicted the high- and low-risk transcriptomic groups with a mean accuracy of 72.2% and a mean AUROC of 71%. The precision, F1 and recall scores were 67%, 74% and 82%, respectively. In an independent dataset consisting of 116 Stanford TNBC patients, we used this model to predict risk groups based on the MRI radiomics features, and evaluated the prognostic effects of predicted risk groups. The overall survival of the predicted high-risk group was significantly poorer than the predicted low-risk group (p=0.013). Conclusions: We present a prognostic model that can non-invasively stratify TNBC patients for low versus high mortality risk using radiomic features derived from pre-treatment patient MRI data. Citation Format: Humaira Noor, Yuanning Zheng, Adam Mantz, Ryle Zhou, Andrew Kozlov, Wendy B. DeMartini, Shu-tian Chen, Satoko Okamoto, Debra Ikeda, Sarah Mattonen, Sandy Napel, Melinda L. Telli, George Sledge, Allison Kurian, Mina Satoyoshi, Olivier Gevaert, Haruka Itakura. A radiogenomic approach for triple-negative breast cancer risk stratification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3510.

The unique risk factor profile of triple-negative breast cancer: a comprehensive meta-analysis.

Triple-negative breast cancer (TNBC) has a poor prognosis compared with other breast cancer subtypes. This systematic review and meta-analysis examines whether known risk factors for breast cancer are also associated with TNBC in adult women. EMBASE, Medline, SCOPUS, and gray literature were queried with no limit on the date or language of publication. The exposures of interest included parity, breastfeeding, duration of breastfeeding, age at menarche, age at first live birth, oral contraceptive (OC) use, duration of OC use, use of menopausal hormone therapy (MHT), family history, body mass index (BMI), alcohol use, smoking, and breast density. The main outcome of interest was TNBC. Study quality was determined using the Newcastle-Ottawa scale for case control studies and cohort studies. We estimated weighted odds ratios from random effects models to study the exposure-outcome associations. Protocol was registered under the number: PROSPERO 2021 CRD42021254594. Thirty-three studies were included. Family history, longer duration of OC use, and higher breast density were significantly associated with increased risk for TNBC, whereas later age at menarche, later age at first birth, and breastfeeding were protective against TNBC. Parity, MHT, alcohol, smoking, and BMI were not significantly associated with TNBC overall, but higher parity was associated with higher risk among Black women. Our findings highlight that TNBC has a distinct risk factor profile compared with overall breast cancer. This can be the foundational work in identification of actionable TNBC risk factors to improve prevention and early detection of these poor prognosis breast tumors.

Research and experimental verification on the mechanisms of cellular senescence in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high heterogeneity, poor prognosis, and a low 10-year survival rate of less than 50%. Although cellular senescence displays extensive effects on cancer, the comprehensions of cellular senescence-related characteristics in TNBC patients remains obscure. Single-cell RNA sequencing (scRNA-seq) data were analyzed by Seurat package. Scores for cellular senescence-related pathways were computed by single-sample gene set enrichment analysis (ssGSEA). Subsequently, unsupervised consensus clustering was performed for molecular cluster identification. Immune scores of patients in The Cancer Genome Atlas (TCGA) dataset and associated immune cell scores were calculated using Estimation of STromal and Immune cells in MAlignantTumours using Expression data (ESTIMATE) and Microenvironment Cell Populations-counter (MCP-counter), Tumor Immune Estimation Resource (TIMER) and Estimating the Proportion of Immune and Cancer cells (EPIC) methods, respectively. Immunotherapy scores were assessed using TIDE. Furthermore, feature genes were identified by univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses; these were used to construct a risk model. Additionally, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and transwell assay were conducted for in vitro validation of hub genes. TNBC was classified into three subtypes based on cellular senescence-related pathways as clusters 1, 2, and 3. Specifically, cluster 1 showed the best prognosis, followed by cluster 2 and cluster 3. The levels of gene expression in cluster 2 were the lowest, whereas these were the highest in cluster 3. Moreover, clusters 1 and 3 showed a high degree of immune infiltration. TIDE scores were higher for cluster 3, suggesting that immune escape was more likely in patients with the cluster 3 subtype who were less likely to benefit from immunotherapy. Next, the TNBC risk model was constructed and validated. RT-qPCR revealed that prognostic risk genes (MMP28, ACP5 and KRT6A) were up-regulated while protective genes (CT83) were down-regulated in TNBC cell lines, validating the results of the bioinformatics analysis. Meanwhile, cellular experiments revealed that ACP5 could promote the migration and invasion abilities in two TNBC cell lines. Finally, we evaluated the validity of prognostic models for assessing TME characteristics and TNBC chemotherapy response. In conclusion, these findings help to assess the efficacy of targeted therapies in patients with different molecular subtypes, have practical applications for subtype-specific treatment of TNBC patients, and provide information on prognostic factors, as well as guidance for the revelation of the molecular mechanisms by which senescence-associated genes influence TNBC progression.

Abstract B083: The associations of breast density, hormone use, family history, reproductive and lifestyle factors with triple negative breast cancer: a systematic review and meta-analysis

Abstract Background: Triple negative breast cancer (TNBC) has poor prognosis compared to other breast cancer subtypes. Objectives: This systematic review and meta-analysis examines whether established breast cancer risk factors are associated with TNBC in adult females.Data Sources: Studies were searched on EMBASE, Medline, SCOPUS and grey literature with no limit on the date of publication. The search string included MeSH terms of the exposures of interest and TNBC. References of included studies were also searched. Study Selection: The exposures of interest included parity, breastfeeding, duration of breastfeeding, age at menarche, age at first live birth, oral contraceptive (OCP) use, duration of OCP use, use of hormone replacement therapy (HRT), family history, body mass index (BMI), alcohol use, smoking and breast density. Studies that compared exposures of interest between women diagnosed with TNBC versus cancer-free women.Main outcomes and Measures: The main outcome of interest was TNBC. The effect measures, weighted odds ratios, were estimated from random effects models. Sensitivity analyses stratified by menopausal status and using the leave one out meta-analysis (LOOM) method were performed.Data Extraction and Synthesis: Data extraction and synthesis was performed as per PRISMA guidelines. Four reviewers independently screened the search results in a blinded manner and conflicts were resolved by discussion. Study quality was determined using the Newcastle-Ottawa scale for case control studies and cohort studies. Data extraction was performed independently by four reviewers and one reviewer checked 30% of work of each other reviewer. Odds ratios were extracted and data were meta-analyzed using a random effects model. Results: Thirty-three studies were included. Family history, longer duration of oral contraceptive use, and higher breast density were significantly associated with increased risk for TNBC, and later age at menarche and breastfeeding were protective against TNBC. Later age at first birth was protective against TNBC. Parity, HRT, alcohol, smoking, and BMI were not significantly associated with risk for TNBC. Conclusion: These findings further clarify differences in etiology between ER/PR+HER2- and TNBC, highlighting the need to identify additional actionable risk factors for TNBC to improve prevention and early detection of these poor prognosis breast tumors. Citation Format: Nitya Kumar, Sarah Ehsan, Shahana Banerjee, Claudia Fernandez Perez, Isabelle Lhuilier, Jilian Neuner, Tara-Friebel Klinger, Bindhu Nair, Sara Anjum Niinuma, Shivangi Nampoothiri, Anne Marie McCarthy. The associations of breast density, hormone use, family history, reproductive and lifestyle factors with triple negative breast cancer: a systematic review and meta-analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B083.

Germline testing of BRCA1, BRCA2, PALB2 and CHEK2 c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing of ATM, RAD51C and RAD51D in over 400

BackgroundThe identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated...