The prevalence and mortality of breast cancer is increasing in Asian countries, including India. With advances in medical technology leading to better detection and characterization of the disease, it has been possible to classify breast cancer into various subtypes using markers, which helps predict the risk of distant recurrence, response to therapy, and prognosis using a combination of molecular and clinical parameters. Breast cancer and its therapy, mainly surgery, systemic therapy (anticancer chemotherapy, hormonal therapy, targeted therapy, and immunotherapy), and radiation therapy, are associated with significant adverse influences on physical and mental health, quality of life, and the economic status of the patient and her family. The fear of recurrence and its devastating effects often leads to overtreatment, with a toxic cost to the patient financially and physically in cases in which this is not required. This article discusses some aspects of a breast cancer diagnosis and its impact on the various facets of the life of the patient and her family. It further elucidates the role of prognostic factors, the currently available biomarkers and prognostic signatures, and the importance of ethnically validating biomarkers and prognostic signatures.

https://ascopubs.org/doi/pdfdirect/10.1200/GO.20.00033

Overview of Breast Cancer and Implications of Overtreatment of Early-Stage Breast Cancer: An Indian Perspective.

Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (eg, M2 macrophages, regulatory T cells) and microvasculature Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM) Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality

/pdf/the-contribution-of-race-to-breast-tumor-microenvironment-uq4j3apef5.pdf

The Contribution of Race to Breast Tumor Microenvironment Composition and Disease Progression.

BACKGROUND Black women with breast cancer have lower survival rates and higher recurrence rates in comparison with white women. This study compared treatment and survival outcomes for black and white women at a highly specialized tertiary care cancer center. METHODS An institutional review board-approved, retrospective institutional database review was performed to identify all black women treated for invasive breast cancer between 2005 and 2010. Women with a prior history of breast cancer, stage IV cancer, or bilateral breast cancer were excluded. White women had similar exclusion criteria applied and were then matched to black women 1:1 by age and diagnosis year. Clinicopathologic and treatment variables were compared by race. Kaplan-Meier methodology was used to estimate overall survival (OS) and disease-free survival (DFS); a multivariable analysis was conducted with Cox regression models. RESULTS The study group consisted of 1332 women (666 black). The median tumor size was larger in black women (1.6 vs 1.3 cm; P < .001). Black women had more nodal disease (41.1% vs 32%; P < .001) and had tumors that were more frequently an estrogen receptor-negative (32.9% vs 15%; P < .001), progesterone receptor-negative (47.1% vs 30.2%; P < .001), or triple-negative (TN) subtype (24% vs 8.9%; P < .001) in comparison with white women. Black women also had inferior DFS and OS; race was not an independent prognostic indicator in the multivariable analysis. CONCLUSIONS Black women had more advanced disease and adverse prognostic indicators at diagnosis, but race was not an independent predictor of outcome. Black women were significantly more likely to have TN breast cancer. Further research is necessary to understand the differences in tumor biology associated with race.

Does race predict survival for women with invasive breast cancer

Among women diagnosed with stage I–IIIa, node-negative, hormone receptor (HR)-positive breast cancer (BC), Oncotype DX recurrence scores (ODX RS) inform chemotherapy treatment decisions. Differences in recurrence scores or testing may contribute to racial disparities in BC mortality among women with HR+ tumors. We identified 12,081 non-Hispanic White (NHW) and non-Hispanic Black (NHB) BC patients in Georgia (2010–2014), eligible to receive an ODX RS. Logistic regression was used to estimate the odds of chemotherapy receipt by race and ODX RS. Cox proportional hazard regression was used to calculate the hazard ratios (HRs) comparing BC mortality rates by race and recurrence score. Receipt of Oncotype testing was consistent between NHB and NHW women. Receipt of chemotherapy was generally comparable within strata of ODX RS—although NHB women with low scores were slightly more likely to receive chemotherapy (OR = 1.16, 95% CI 0.77, 1.75), and NHB women with high scores less likely to receive chemotherapy (OR = 0.77, 95% CI 0.48, 1.24), than NHW counterparts. NHB women with a low recurrence score had the largest hazard of BC mortality (HR = 2.47 95% CI 1.22, 4.99) compared to NHW women. Our data suggest that additional tumor heterogeneity, or other downstream treatment factors, not captured by ODX, may be drivers of racial disparities in HR+ BC.

/pdf/oncotype-dx-recurrence-score-implications-for-disparities-in-2r3b6ev036.pdf

Oncotype DX recurrence score implications for disparities in chemotherapy and breast cancer mortality in Georgia

Background General populations of black women have a higher risk of developing breast cancer negative for both estrogen receptor (ER) and progesterone receptor (PR) in comparison with white counterparts. Racial differences remain unknown in the risk of developing aggressive invasive breast cancer (IBC) that is characterized by negativity for both ER and PR (ER-PR-) or higher 21-gene recurrence scores after ductal carcinoma in situ (DCIS). Methods This study identified 163,892 women (10.5% black, 9.8% Asian, and 8.6% Hispanic) with incident DCIS between 1990 and 2015 from the Surveillance, Epidemiology, and End Results data sets. Cox proportional hazards regression was used to estimate hazards ratios (HRs) of subsequent IBC classified by the hormone receptor status and 21-gene recurrence scores. Results During a median follow-up of 90 months, 8333 women developed IBC. In comparison with white women, the adjusted HR of subsequent ER-PR- breast cancer was 1.86 (95% confidence interval [CI], 1.57-2.20) for black women (absolute 10-year difference, 2.2%) and 1.40 (95% CI, 1.14-1.71) for Asian women (absolute 10-year difference, 0.4%); this was stronger than the associations for ER+ and/or PR+ subtypes (Pheterogeneity = .0004). The 21-gene recurrence scores of subsequent early-stage, ER+ IBCs varied by race/ethnicity (Pheterogeneity = .057); black women were more likely than white women to have a recurrence score of 26 or higher (HR, 1.38; 95% CI, 1.00-1.92). No significant difference was observed in the risks of subsequent IBC subtypes for Hispanic women. Conclusions Black and Asian women with DCIS had higher risks of developing biologically aggressive IBC than white counterparts. This should be considered in treatment decisions for black and Asian patients with DCIS.

/pdf/race-and-risk-of-subsequent-aggressive-breast-cancer-2m8c464jkp.pdf

Race and risk of subsequent aggressive breast cancer following ductal carcinoma in situ

Background: Black race is associated with worse outcomes in localized hormone receptor (HR)-positive breast cancer in population-based and in clinical trial cohorts, whether using self-identified race (Albain et al. JNCI 2009 [PMID: 19584328; Sparano et al. JNCI 2012 [PMID: 22250182) or genetically-identified race (Schneider et al. J Precision Oncol 2017 [PMID: 29333527]). This disparity persists after adjustment for treatment delivery parameters (Hershman et al. JCO 2009 [PMID:19307504]). We evaluated clinicopathologic characteristics, treatment delivered and clinical outcomes in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity (Sparano et al. NEJM 2018 [PMID: 29860917]). Methods: The analysis included 9719 evaluable TAILORx participants. The association between clinical outcomes and race (white, black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined, including invasive disease-free survival (iDFS), distant relapse-free interval (DRFI), relapse-free interval (RFI), and overall survival (OS). Proportional hazards models were fit including age (5 categories), tumor size (>2 cm vs. Results: The study population included 8189 (84%) whites, 693 (7%) blacks, 405 (4%) Asians, and 432 (4%) with other/unknown race. Regarding ethnicity, 7635 (79%) were non-Hispanic, 889 (9%) Hispanic, and 1195 (12%) unknown. There was no significant difference in RS distribution (p=0.22) in blacks compared with whites, or in median (17 vs. 17) or mean RS (19.1 vs. 18.2). There was likewise no difference in Hispanic vs. non-Hispanic ethnicity for RS distribution (p=0.72) or median (17 vs. 17) or mean RS (18.5 vs. 18.0). Black race (39% vs. 30%) and Hispanic ethnicity (39% vs. 30%) were both associated with younger age ( Conclusions: In patients eligible and selected for participation in TAILORx, black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy. This adds to an emerging body of evidence suggesting a biologic basis or other factors contributing to racial disparities in HR-positive breast cancer that requires further evaluation. Citation Format: Albain K, Gray RJ, Sparano JA, Makower DF, Pritchard KI, Hayes DF, Geyer, Jr. CE, Dees EC, Goetz MP, Olson, Jr. JA, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge, Jr. GW. Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-07.

Abstract GS4-07: Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial

Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER driven transcriptional activity. OP-1250 potently inactivates both wild-type ER and mutant forms of ER that confer ligand independent activity and resistance to standard of care endocrine therapies. OP-1250 inhibits estrogen-driven breast cancer cell growth and induces degradation of the ER. In preclinical models, OP-1250 is active in the presence of wild-type ER, mutant ER (ESR1 activating mutations), and brain metastasis. OP-1250 is being developed for ER+, HER2- metastatic breast cancer (MBC) patients (pts). We previously reported Phase 1a (dose escalation) results, here we present data from the Phase 1b expansion portion of the clinical trial. Methods: Following Phase 1a dose escalation of OP-1250 from 30 mg to 300 mg QD, a recommended phase 2 dose (RP2D) range was defined of 60 to 120 mg QD. Sixty pts are planned for Phase 1b enrollment, with 30 pts at each dose level (60 and 120 mg). In Phase 1b eligibility included measurable disease, 1–4 prior lines of hormonal therapy, and £1 prior line of chemotherapy in the advanced setting. Pts were monitored for adverse events (AE) and tumor assessments (RECIST 1.1) were conducted every two 28-day cycles. Results: As of May 13, 2022, 37 patients were assigned to either 60 mg or 120 mg dose levels. Pts were heavily pretreated: 62% had received 2 or more prior endocrine therapies in the advanced setting, 32% received chemotherapy, and 97% had received a prior CDK 4/6 inhibitor. More than half (57%) of pts who had ctDNA evaluated had an ESR1 mutation. At 60 mg and 120 mg, OP-1250 demonstrated high oral bioavailability and dose proportional exposure. The most common treatment emergent adverse events reported (≥10%) in Phase 1b in the 60 mg/120 mg cohorts were nausea (28%/21%), vomiting (17%/16%), fatigue (17%/5%) and headache (11%/ 11%). Adverse events were Grade 1/2, with the exception of two Grade 3 events at 60 mg (diarrhea and anemia); no Grade 3 events occurred at 120 mg. There were no dose reductions or discontinuations due to an AE. Across Phase 1b, among pts eligible for at least one post-baseline scan (n = 24), 1 confirmed PR (cPR) was observed at 60 mg and 1 uPR was observed at 120 mg. Data continues to mature and updated data will be presented. Conclusions: OP-1250 was well tolerated and showed promising safety and efficacy in Phase 1b pts treated at 60 mg and 120 mg daily. Based on safety and pharmacokinetic data, a RP2D will be selected. A Phase 2 evaluation will be initiated, and a Phase 3 monotherapy study is planned for 2023. Conflict of interest: Corporate-sponsored Research: Erika Hamilton: Abbvie, Acerta Pharma, Accutar Biotechnology, ADC Therapeutics, AKESOBIO Australia, Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, Black Diamond, Bliss BioPharmaceuticals, Boehringer Ingelheim, Cascadian Therapeutics, Clovis, Compugen, Cullen-Florentine, Curis, CytomX, Daiichi Sankyo, Dana Farber Cancer Inst, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, InvestisBio, Jacobio, Karyopharm, Leap Therapeutics, Lilly, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merck, Mersana, Merus, Millennium, Molecular Templates, Myraid Genetic Laboratories, Novartis, Nucana, Olema, OncoMed, Onconova Therapeutics, ORIC Pharmaceuticals, Orinove, Pfizer, Pharma Mar, Pieris Pharmaceuticals Pionyr, Immunotherapeutics, Plexxikon, Radius Health, Regeneron, Relay Therapeutics, Repertoire, Immune Medicine, Rgenix, Roche/Genentech, SeaGen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Vincerx Pharma, Zenith Epigenetics, Zymework Other Substantive Relationships: Erika Hamilton: Consulting Advisory Role (all to institution only): Arcus, Arvinas, AstraZeneca, Black Diamond, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Deciphera Pharmaceuticals, Eisai, Greenwich LifeSciences, H3 Biomedicine iTeosJanssen, Lilly, Loxo, Merck, Mersana, Novartis, Orum Therapeutics, Pfizer, Propella Therapeutics, Puma Biotechnology, Relay Therapeutics, Roche/Genentech, SeaGen, Silverback Therapeutics 

http://www.ejcancer.com/article/S0959804922008966/pdf

Phase 1b results from OP-1250-001, a dose escalation and dose expansion study of OP-1250, an oral CERAN, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer (NCT04505826)

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Abstract GS4-07: Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial

Phase 1b results from OP-1250-001, a dose escalation and dose expansion study of OP-1250, an oral CERAN, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer (NCT04505826)