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Background: For patients with breast cancer undergoing neoadjuvant chemotherapy (NACT), most of the existing prediction models of pathologic complete response (pCR) using clinicopathological features were based on standard statistical models like logistic regression, while models based on machine learning mostly utilized imaging data and/or gene expression data. This study aims to develop a robust and accessible machine learning model to predict pCR using clinicopathological features alone, which can be used to facilitate clinical decision-making in diverse settings., Methods: The model was developed and validated within the National Cancer Data Base (NCDB, 2018-2020) and an external cohort at the University of Chicago (2010-2020). We compared logistic regression and machine learning models, and examined whether incorporating quantitative clinicopathological features improved model performance. Decision curve analysis was conducted to assess the model's clinical utility., Results: We identified 56,209 NCDB patients receiving NACT (pCR rate: 34.0%). The machine learning model incorporating quantitative clinicopathological features showed the best discrimination performance among all the fitted models [area under the receiver operating characteristic curve (AUC): 0.785, 95% confidence interval (CI): 0.778-0.792], along with outstanding calibration performance. The model performed best among patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (AUC: 0.817, 95% CI: 0.802-0.832); and by adopting a 7% prediction threshold, the model achieved 90.5% sensitivity and 48.8% specificity, with decision curve analysis finding a 23.1% net reduction in chemotherapy use. In the external testing set of 584 patients (pCR rate: 33.4%), the model maintained robust performance both overall (AUC: 0.711, 95% CI: 0.668-0.753) and in the HR+/HER2- subgroup (AUC: 0.810, 95% CI: 0.742-0.878)., Conclusions: The study developed a machine learning model ( https://huolab.cri.uchicago.edu/sample-apps/pcrmodel ) to predict pCR in breast cancer patients undergoing NACT that demonstrated robust discrimination and calibration performance. The model performed particularly well among patients with HR+/HER2- breast cancer, having the potential to identify patients who are less likely to achieve pCR and can consider alternative treatment strategies over chemotherapy. The model can also serve as a robust baseline model that can be integrated with smaller datasets containing additional granular features in future research., (© 2024. The Author(s).)

Protein activity state, rather than protein or mRNA abundance, is a biologically regulated and relevant input to many processes in signaling, differentiation, development, and diseases such as cancer. While there are numerous methods to detect and quantify mRNA and protein abundance in biological samples, there are no general approaches to detect and quantify endogenous protein activity with single-cell resolution. Here, we report the development of a chemoproteomic platform, single-cell activity-dependent proximity ligation, which uses automated, microfluidics-based single-cell capture and nanoliter volume manipulations to convert the interactions of family-wide chemical activity probes with native protein targets into multiplexed, amplifiable oligonucleotide barcodes. We demonstrate accurate, reproducible, and multiplexed quantitation of a six-enzyme (Ag-6) panel with known ties to cancer cell aggressiveness directly in single cells. We further identified increased Ag-6 enzyme activity across breast cancer cell lines of increasing metastatic potential, as well as in primary patient-derived tumor cells and organoids from patients with breast cancer.

Purpose: Integrative medicine (IM) has received the American Society of Clinical Oncology's endorsement for managing cancer treatment-related side effects. Little is known about racial differences in familiarity, interest, and use of IM among patients with breast cancer., Methods: Patients with breast cancer enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort were surveyed regarding familiarity, interest, and use of acupuncture, massage, meditation, music therapy, and yoga. Familiarity and interest, measured by a 5-point Likert scale, was modeled using proportional odds. Use was self-reported, and modeled using binary logistic regression., Results: Of 1,300 respondents (71.4% White and 21.9% Black), Black patients were less likely than White patients to be familiar with acupuncture (aOR 0.60, 95% CI 0.41-0.87); there were no racial differences in familiarity with massage, meditation, music therapy, and yoga. While there were no differences in interest in acupuncture between Black and White patients (aOR 1.12, 95% CI 0.76-1.65), Black patients were more interested in massage (aOR 1.86, 95% CI 1.25-2.77), meditation (aOR 2.03, 95% CI 1.37-3.00), music therapy (aOR 2.68, 95% CI 1.80-3.99), and yoga (aOR 2.10, 95% CI 1.41-3.12). Black patients were less likely than White patients to have used acupuncture (aOR 0.49, 95% CI 0.29-0.84); but there were no racial differences in use of massage, meditation, music therapy, and yoga., Conclusion: Black patients expressed more interest in IM than their White counterparts; there were no racial differences in IM use, except lower acupuncture use among Black patients. A breast program focused on equity should provide access to these services for patients with breast cancer., (© 2024. The Author(s).)

Fluxes in human copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate. We herein apply an unbiased temporal evaluation of the signaling and whole genome transcriptional activities modulated by copper level fluctuations to identify potential copper sensor proteins responsible for driving these activities. We find that fluctuations in physiologically relevant copper levels modulate EGFR signal transduction and activation of the transcription factor CREB. Both intracellular and extracellular assays support Cu 1+  inhibition of the EGFR phosphatase PTPN2 (and potentially PTPN1)-via ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism. We additionally show i) copper supplementation drives weak transcriptional repression of the copper importer CTR1 and ii) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper stimulated EGFR/CREB signaling and CTR1 expression., (© 2024. The Author(s).)

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment., (©2024 American Association for Cancer Research.)

Background: Since the COVID-19 pandemic began, we have seen rapid growth in telemedicine use. However, telehealth care and services are not equally distributed, and not all patients with breast cancer have equal access across US regions. There are notable gaps in existing literature regarding the influence of neighborhood-level socioeconomic status on telemedicine use in patients with breast cancer and oncology services offered through telehealth versus in-person visits., Objective: We assessed the relationship between neighborhood socioeconomic disadvantage and telemedicine use among patients with breast cancer and examined differential provisions of oncology services between telehealth and in-person visits., Methods: Neighborhood socioeconomic disadvantage was measured using the Area Deprivation Index (ADI), with higher scores indicating greater disadvantages. Telemedicine and in-person visits were defined as having had a telehealth and in-person visit with a provider, respectively, in the past 12 months. Multivariable logistic regression was performed to examine the association between ADI and telemedicine use. The McNemar test was used to assess match-paired data on types of oncology services comparing telehealth and in-person visits., Results: The mean age of the patients with breast cancer (n=1163) was 61.8 (SD 12.0) years; 4.58% (52/1161) identified as Asian, 19.72% (229/1161) as Black, 3.01% (35/1161) as Hispanic, and 72.78% (845/1161) as White. Overall, 35.96% (416/1157) had a telemedicine visit in the past 12 months. Of these patients, 65% (266/409) had a videoconference visit only, 22.7% (93/409) had a telephone visit only, and 12.2% (50/409) had visits by both videoconference and telephone. Higher ADI scores were associated with a lower likelihood of telemedicine use (adjusted odds ratio [AOR] 0.89, 95% CI 0.82-0.97). Black (AOR 2.38, 95% CI 1.41-4.00) and Hispanic (AOR 2.65, 95% CI 1.07-6.58) patients had greater odds of telemedicine use than White patients. Compared to patients with high school or less education, those with an associate's degree (AOR 2.67, 95% CI 1.33-5.35), a bachelor's degree (AOR 2.75, 95% CI 1.38-5.48), or a graduate or professional degree (AOR 2.57, 95% CI 1.31-5.04) had higher odds of telemedicine use in the past 12 months. There were no significant differences in providing treatment consultation (45/405, 11.1% vs 55/405, 13.6%; P=.32) or cancer genetic counseling (11/405, 2.7% vs 19/405, 4.7%; P=.14) between telehealth and in-person visits. Of the telemedicine users, 95.8% (390/407) reported being somewhat to extremely satisfied, and 61.8% (254/411) were likely or very likely to continue using telemedicine., Conclusions: In this study of a multiethnic cohort of patients with breast cancer, our findings suggest that neighborhood-level socioeconomic disparities exist in telemedicine use and that telehealth visits could be used to provide treatment consultation and cancer genetic counseling. Oncology programs should address these disparities and needs to improve care delivery and achieve telehealth equity for their patient populations., (©Jincong Q Freeman, Fangyuan Zhao, Frederick M Howard, Rita Nanda, Olufunmilayo I Olopade, Dezheng Huo. Originally published in JMIR Cancer (https://cancer.jmir.org), 18.07.2024.)

Purpose: We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort., Methods: This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs., Results: Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC., Conclusion: CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention., Competing Interests: Conflict of Interest Brent Mabey, Elisha Hughes, Matthew Kucera, Timothy Simmons, Brooke Hullinger, Sarah Ratzel, Susanne Wagner, Jerry S. Lanchbury, Katherine Johansen Taber, Thomas P. Slavin, and Alexander Gutin were employed by Myriad Genetics, Inc. at the time of the study and received salaries and stocks as compensation. Holly J. Pederson and Monique Gary have received consulting fees from Myriad Genetics, Inc. Charis Eng has ownership interests in MyLegacy/MyFHH/Family Care Path. Judy Garber has received research funding from Ambry Genetics and Invitae and has other relationships, or an immediate family member with relationships, with AACR, Diana Helis Henry Medical Foundation, James P. Wilmot Foundation, Adrianne Helis Malvin Medical Research Foundation, Breast Cancer Research Foundation, Facing our Risk of Cancer Empowered, Novartis, GTx, Aleta BioTherapeutics, H3 Biomedicine, and Kronos Bio. Ora Gordon has had a consulting or advisory role with GRAIL and Genetic Technologies, has received travel or accommodation expenses from GRAIL, and has received research funding from GRAIL. Jennifer R. Klemp has received consulting fees and speakers’ bureaus fees from AstraZeneca, has ownership interests in Cancer Survivorship Training, is employed by Caris Life Sciences, Inc, and has received a salary as compensation and consulting fees. Olufunmilayo I. Olopade has an ownership interest in 54Gene and Tempus, has an ownership interest and has received a salary from CancerIQ, and has other interests in Color Genomics, Healthy Life for All Foundation, and Roche/Genetech. Mark E. Robson has provided clinical trial services to AstraZeneca and Merck and has received consulting fees from and/or been on advisory boards for Change Healthcare, Intellisphere, MyMedEd, Physician’s Education Resources, and Research to Practice. Pat W. Whitworth has received consulting fees from or had contracted research with Agendia, Biotheranostics, Genomic Health, Impedimed, Myriad Genetics, Inc, Prelude, and Veracyte, and has an ownership interest in Medneon. All other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Given high costs of Oncotype DX (ODX) testing, widely used in recurrence risk assessment for early-stage breast cancer, studies have predicted ODX using quantitative clinicopathologic variables. However, such models have incorporated only small cohorts. Using a cohort of patients from the National Cancer Database (NCDB, n = 53,346), we trained machine learning models to predict low-risk (0-25) or high-risk (26-100) ODX using quantitative estrogen receptor (ER)/progesterone receptor (PR)/Ki-67 status, quantitative ER/PR status alone, and no quantitative features. Models were externally validated on a diverse cohort of 970 patients (median follow-up 55 months) for accuracy in ODX prediction and recurrence. Comparing the area under the receiver operating characteristic curve (AUROC) in a held-out set from NCDB, models incorporating quantitative ER/PR (AUROC 0.78, 95% CI 0.77-0.80) and ER/PR/Ki-67 (AUROC 0.81, 95% CI 0.80-0.83) outperformed the non-quantitative model (AUROC 0.70, 95% CI 0.68-0.72). These results were preserved in the validation cohort, where the ER/PR/Ki-67 model (AUROC 0.87, 95% CI 0.81-0.93, p = 0.009) and the ER/PR model (AUROC 0.86, 95% CI 0.80-0.92, p = 0.031) significantly outperformed the non-quantitative model (AUROC 0.80, 95% CI 0.73-0.87). Using a high-sensitivity rule-out threshold, the non-quantitative, quantitative ER/PR and ER/PR/Ki-67 models identified 35%, 30% and 43% of patients as low-risk in the validation cohort. Of these low-risk patients, fewer than 3% had a recurrence at 5 years. These models may help identify patients who can forgo genomic testing and initiate endocrine therapy alone. An online calculator is provided for further study., (© 2024. The Author(s).)

Splicing-based transcriptome-wide association studies (splicing-TWASs) of breast cancer have the potential to identify susceptibility genes. However, existing splicing-TWASs test the association of individual excised introns in breast tissue only and thus have limited power to detect susceptibility genes. In this study, we performed a multi-tissue joint splicing-TWAS that integrated splicing-TWAS signals of multiple excised introns in each gene across 11 tissues that are potentially relevant to breast cancer risk. We utilized summary statistics from a meta-analysis that combined genome-wide association study (GWAS) results of 424,650 women of European ancestry. Splicing-level prediction models were trained in GTEx (v.8) data. We identified 240 genes by the multi-tissue joint splicing-TWAS at the Bonferroni-corrected significance level; in the tissue-specific splicing-TWAS that combined TWAS signals of excised introns in genes in breast tissue only, we identified nine additional significant genes. Of these 249 genes, 88 genes in 62 loci have not been reported by previous TWASs, and 17 genes in seven loci are at least 1 Mb away from published GWAS index variants. By comparing the results of our splicing-TWASs with previous gene-expression-based TWASs that used the same summary statistics and expression prediction models trained in the same reference panel, we found that 110 genes in 70 loci that are identified only by the splicing-TWASs. Our results showed that for many genes, expression quantitative trait loci (eQTL) did not show a significant impact on breast cancer risk, whereas splicing quantitative trait loci (sQTL) showed a strong impact through intron excision events., Competing Interests: Declaration of interests O.I.O. reported receiving grants from Tempus (scientific advisory board) during the conduct of the study; being cofounder of CancerIQ, serving as a board of director member for 54gene, and receiving grants from Color Genomics (research support) and grants from Roche (clinical trial support for IIT) outside the submitted work. No other disclosures were reported., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Purpose: Black women experience the highest breast cancer mortality rate compared with women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry., Experimental Design: We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n = 182) and the University of Chicago (Chicago, IL; n = 161). We also analyzed RNA sequencing data from Nigeria (n = 84) and The Cancer Genome Atlas (TCGA) datasets (n = 863). Patient prognosis was analyzed using multiple datasets., Results: The VEGF-hypoxia signature was highest in the basal-like subtype compared with other subtypes, with greater expression in Black women compared with White women. In TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared with non-necrosis tumors (P < 0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation, and necrosis. T-cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in TCGA dataset. Finally, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (P < 0.0001) and SCAN-B datasets (P = 0.002)., Conclusions: These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora., (©2024 American Association for Cancer Research.)

Competing Interests: Declaration of interests CEC reports grants from Breast Cancer Now, Cancer Research UK (CRUK), Addenbrooke's Charitable Trust, and the National Institute for Health and Care Research (NIHR); participation in the Independent Data Monitoring Committees for the UK PivotalBoost trial (chair), the PROTIS phase III sinonasal proton versus IMRT trial (member), the TORPEdO Proton Beam Therapy trial (member); and a leadership role for the Lancet Breast Cancer Commission (chair). CHB reports grants and research support from AbbVie, Nektar Therapeutics, Pfizer, Polyphor, Amgen, Daiichi Sankyo, Sanofi, Exelixis, Regeneron, Novartis, Henlius, Shanghai Henlius Biotech, GSK, Janssen, OBI Pharma, Eli Lilly, Seagen, Checkpoint Therapeutics, Roche, Bristol Myers Squibb, MSD, Merck Serono, AstraZeneca, Novocure, Aveo Oncology, Takeda Pharmaceuticals, TRIO Pharmaceuticals, PharmaMar, Celgene, Myovant, PPD, Syneos Health, DOCS, Labcorp, ICON, IQVIA, Parexel, Nuvisan, PSI, and Medpace; ownership or stocks in Tummi and MEDSir; and participation in advisory boards and consulting activities for Boehringer Ingelheim, GSK, Novartis, Pfizer, Genentech, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Eli Lilly, Sanofi, and Daiichi Sankyo. DAC reports research grants and support from Exact Sciences and Novartis; consulting fees from Eli Lilly, Novartis, Seagen, Daiichi Sankyo, Erytech Pharma, Carnall Farrar, Sapience, and Sanofi; payment or honoraria for lectures and presentations from Exact Sciences, Gilead, Eli Lilly, and Pfizer; participation on data safety monitoring or advisory boards for Novartis, AstraZeneca, and Grail; unremunerated leadership roles for Make Seconds Count (chair of charity trustees) and the Breast International Group (chair of board of not-for-profit research organisation); and receipt of funding for analysis and medical writing for Eli Lilly and Novartis. FC reports payment or honoraria for lectures and presentations and support for attending meetings and travel from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead, GSK, IQVIA, Macrogenics, Medscape, MSD, Merus, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva Pharmaceuticals, and Touch Independent Medical Education; institutional financial support for clinical trials from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Fresenius, Genentech, Gilead, GSK, Ipsen, Incyte, Nektar Therapeutics, Nerviano, Novartis, Macrogenics, MediGene, MedImmune, MSD, Millenium, Pfizer, Pierre Fabre, Roche, Sanofi, Sonus, Tesaro, Tigris, Wilex, and Wyeth; a leadership role for the ABC Global Alliance and ABC Consensus Conference and Guidelines (president); and membership of ESMO, ESO, EORTC-BCG, IBCSG, SOLTI, ASCO, AACR, EACR, SIS, and ASPIC. WC reports honoraria from AstraZeneca, Pfizer, MSD, and Eisai. PAF reports a former role in the scientific advisory committee of Breast Cancer Trials Australia and New Zealand cooperative group (chair). RJ reports support from the Susan G Komen Foundation; grants from the National Institutes of Health (NIH), the Doris Duke Charitable Foundation, the Greenwall Foundation, and the American Cancer Society; serving as an expert witness for Kleinbard and Hawks Quindel Law; roles in the Board of Directors of ASCO (former member), ASTRO's Ethics Committee (chair), and the Women in Radiation Oncology Affinity Group (chair); membership on the Medical Advisory Board for Blue Cross Blue Shield Association; stock options for their advisory board role in Equity Quotient; and personal fees from the NIH, Doris Duke Charitable Foundation, and the Greenwall Foundation. FMK reports research grants from the ABC Global Alliance, Breast Cancer Now, Merck Serono WHO, MSD, Avon Cosmetics, the US Cancer Pain Relief Committee, and the Medical Research Council; consulting fees from Merck Serono and Instituto Tecnológico y de Estudios Superiores de Monterrey Mexico; and leadership roles for the Board of Directors of Women in Global Health (unpaid member), Tómatelo a Pecho (unpaid president and founder), the Mexican Health Foundation (unpaid Senior Economist), and the Board of Directors of the International Association for Hospice and Palliative Care (unpaid member). SAMcI reports grant funding from the NIHR, CRUK, and Breast Cancer Now; honoraria from Roche, MSD, AstraZeneca, Becton, Dickinson and Company; travel and conference support from Roche, Eli Lilly, and MSD; membership of advisory boards for Eli Lilly, MSD, Roche, and Novartis; and roles for the UK National Cancer Research Institute Breast Research Group (unpaid chair) and the Royal College of Surgeons Breast Surgical Specialty Lead (unpaid). K-AP reports clinical trial funding from AstraZeneca (paid to institution) and unremunerated previous participation in AstraZeneca advisory boards. LR reports grants from the European Commission Horizon 2020 and the German Research Foundation and a role in the International Association for Hospice and Palliative Care (Chair of Board of Directors). MKT reports grants from Addenbrooke's Charitable Trust and CRUK. FA reports grants from Novartis, Pfizer, AstraZeneca, Eli Lilly, Daiichi Sankyo, and Roche and consulting fees from MedImmune, Gilead, Relay Therapeutics, and Guardant Health. JEA reports speaker honoraria from AstraZeneca, Pfizer, Novartis, and Eisai and conference travel support from AstraZeneca. ISB reports participation in the Roche advisory board for ESMO. JMB reports research grants from Breast Cancer Now, AstraZeneca, MSD, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, Eli Lilly, Roche, CRUK, and the NIHR. MAF is funded by a Conquer Cancer Breast Cancer Research Foundation Career Development Award for Diversity and Inclusion supported by the Breast Cancer Research Foundation and reports financial support from the WeShare project. AF reports consultancy work for Oxford Immune Algorithmics; grants from Addenbrooke's Charitable Trust and the Ann McLaren Building Preclinical Imaging Suite of the University of Cambridge; and travel support from the University of Cambridge. DIR reports support from the University of Chicago Center for Global Health. DN reports research support from Cepheid; a grant from the US National Cancer Institute; and an unpaid leadership role with the WHO Global Breast Cancer Initiative. WER reports grants from the Cambia Health Foundation, the Robert Wood Johnson Foundation, and the Rita and Alex Hillman Foundation; and book royalties from Springer Publishing and Jones & Bartlett Learning. JR reports funding from the NIHR and support from AstraZeneca for attendance at a teaching event. DS reports a leadership role at the Jamaica Cancer Care and Research Institute (co-director). HS reports membership of the Breast Cancer Now Tissue Bank Advisory Board and voluntary patient membership of the Independent Cancer Patients' Voice charity; an honorarium from the CRUK Precision Grand Challenge; and support for travel expenses from Breast Cancer Now, CRUK, the Association of Breast Surgeons UK, and Breast International Group. IV-L reports grants from Resilience; consulting fees from Novartis, AstraZeneca, and Amgen; payment or honoraria for lectures and presentations from Novartis, Sandoz, Amgen, AstraZeneca, and Pfizer; and support for travel and attending meetings from Novartis. CV-G reports grants from AstraZeneca and Roche; consulting fees from Roche, Novartis, Pfizer, and Eli Lilly; honoraria from Roche, Myriad Genetics, and Novartis; and support for attending meetings and travel from Roche, MSD Oncology, and Pfizer. All other authors declare no competing interests.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations., (© 2024. The Author(s).)

Purpose: To examine the association between benign breast disease (BBD) and breast cancer (BC) in a heterogeneous population of African women., Methods: BC cases and controls were enrolled in three sub-Saharan African countries, Nigeria, Cameroon, and Uganda, between 1998 and 2018. Multivariable logistic regression was used to test the association between BBD and BC. Risk factors dually associated with BBD and BC were selected. Using a parametric mediation analysis model, we assessed if selected BC risk factors were mediated by BBD., Results: Of 6,274 participants, 55.6% (3,478) were breast cancer cases. 360 (5.7%) self-reported BBD. Fibroadenoma (46.8%) was the most commonly reported BBD. Women with a self-reported history of BBD had greater odds of developing BC than those without (adjusted odds ratio [aOR] 1.47, 95% CI 1.13-1.91). Biopsy-confirmed BBD was associated with BC (aOR 2.25, 95% CI 1.26-4.02). BBD did not significantly mediate the effects of any of the selected BC risk factors., Conclusions: In this study, BBD was associated with BC and did not significantly mediate the effects of selected BC risk factors., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Guidelines recommend the use of genomic assays such as OncotypeDx to aid in decisions regarding the use of chemotherapy for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. The RSClin prognostic tool integrates OncotypeDx and clinicopathologic features to predict distant recurrence and chemotherapy benefit, but further validation is needed before broad clinical adoption., Methods: This study included patients from the National Cancer Data Base (NCDB) who were diagnosed with stage I-III HR+/HER2- breast cancer from 2010 to 2020 and received adjuvant endocrine therapy with or without chemotherapy. RSClin-predicted chemotherapy benefit was stratified into low (<3% reduction in distant recurrence), intermediate (3%-5%), and high (>5%). Cox models were used to model mortality adjusted for age, comorbidity index, insurance, and race/ethnicity., Results: A total of 285,441 patients were identified for inclusion from the NCDB, with an average age of 60 years and a median follow-up of 58 months. Chemotherapy was associated with improved overall survival only for those predicted to have intermediate (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.60-0.79) and high benefit per RSClin (aHR, 0.66; 95% CI, 0.61-0.72). Consistent benefit was seen in the subset with a low OncotypeDx score (<26) and intermediate (aHR, 0.66; 95% CI, 0.53-0.82) or high (aHR, 0.71; 95% CI, 0.58-0.86) RSClin-predicted benefit. No survival benefit with chemotherapy was seen in patients with a high OncotypeDx score (≥26) and low benefit per RSClin (aHR, 1.70; 95% CI, 0.41-6.99)., Conclusions: RSClin may identify high-risk patients who benefit from treatment intensification more accurately than OncotypeDx, and further prospective study is needed., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs., Methods: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG)., Results: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16)., Conclusion: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined., Objective: To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation., Design, Setting, and Participants: In this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023., Exposures: Self-reported bilateral oophorectomy (with or without salpingectomy)., Main Outcomes and Measures: All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality., Results: There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy., Conclusions and Relevance: In this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

Importance: Less than 5% of patients with cancer enroll in a clinical trial, partly due to financial and logistic burdens, especially among underserved populations. The COVID-19 pandemic marked a substantial shift in the adoption of decentralized trial operations by pharmaceutical companies., Objective: To assess the current global state of adoption of decentralized trial technologies, understand factors that may be driving or preventing adoption, and highlight aspirations and direction for industry to enable more patient-centric trials., Design, Setting, and Participants: The Bloomberg New Economy International Cancer Coalition, composed of patient advocacy, industry, government regulator, and academic medical center representatives, developed a survey directed to global biopharmaceutical companies of the coalition from October 1 through December 31, 2022, with a focus on registrational clinical trials. The data for this survey study were analyzed between January 1 and 31, 2023., Exposure: Adoption of decentralized clinical trial technologies., Main Outcomes and Measures: The survey measured (1) outcomes of different remote monitoring and data collection technologies on patient centricity, (2) adoption of these technologies in oncology and all therapeutic areas, and (3) barriers and facilitators to adoption using descriptive statistics., Results: All 8 invited coalition companies completed the survey, representing 33% of the oncology market by revenues in 2021. Across nearly all technologies, adoption in oncology trials lags that of all trials. In the current state, electronic diaries and electronic clinical outcome assessments are the most used technology, with a mean (SD) of 56% (19%) and 51% (29%) adoption for all trials and oncology trials, respectively, whereas visits within local physician networks is the least adopted at a mean (SD) of 12% (18%) and 7% (9%), respectively. Looking forward, the difference between the current and aspired adoption rate in 5 years for oncology is large, with respondents expecting a 40% or greater absolute adoption increase in 8 of the 11 technologies surveyed. Furthermore, digitally enabled recruitment, local imaging capabilities, and local physician networks were identified as technologies that could be most effective for improving patient centricity in the long term., Conclusions and Relevance: These findings may help to galvanize momentum toward greater adoption of enabling technologies to support a new paradigm of trials that are more accessible, less burdensome, and more inclusive.

Importance: Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined., Objective: To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not., Design, Setting, and Participants: Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023., Exposures: Entrance into an MRI surveillance program., Main Outcomes and Measures: Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis., Results: A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations., Conclusion and Relevance: Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

Introduction: Maturity-Onset Diabetes of the Young (MODY) is an unusual type of diabetes often missed in clinical practice, especially in Africa. Treatment decisions for MODY depend on a precise diagnosis, only made by genetic testing. We aimed to determine MODY knowledge among Nigerian healthcare professionals (HCPs), their perceptions, and barriers to the implementation of genetic testing in diabetes patients., Methods: A cross-sectional survey was conducted among doctors and nurses in three levels of public and private healthcare institutions in Ibadan, Nigeria, from December 2018 to June 2019. In all, 70% and 30% of a total 415 participants were recruited from public and private centers, respectively. HCPs were recruited in a 60:40% ratio, respectively. A 51-item instrument was used to assess MODY knowledge, perceptions of HCPs, and barriers to the implementation of genetic testing in diabetes patients., Results: In the survey, 43.4% self-rated their current MODY knowledge to be at least moderate. About 68%, 73% and 86%, respectively, correctly answered 3 of 5 questions on basic genetics' knowledge. However, only 1 of 7 MODY-specific questions was answered correctly by 72.7% of the respondents. The mean basic genetics and MODY-specific knowledge scores were 2.6/5 (SD=1.0) and 1.8/9 (SD=1.3), respectively. Multiple linear regression showed higher mean scores among those aged 30-49 years, those with degrees and fellowships (except PhD), and general practitioners; 360 (80.0%) perceived that genetic testing plays a central role in diabetes care. Barriers to genetic testing were lack of access to testing facilities, guidance on the use of and updates/educational materials on genetic testing (82.7%, 62.1% and 50.3%, respectively)., Conclusions: The level of MODY awareness and knowledge among Nigerian HCPs is unacceptably low with a lack of access to genetic testing facilities. These can hinder the implementation of precision diabetes medicine. Increased awareness, provision of decision support aids, and genetic testing facilities are urgently needed., Competing Interests: CONFLICTS OF INTEREST The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are used for patients with BRCA1/2 mutations, but patients with other mutations may benefit from PARPi treatment. Another mutation that is present in more cancers than BRCA1/2 is mutation to the TP53 gene. In 2D breast cancer cell lines, mutant p53 (mtp53) proteins tightly associate with replicating DNA and Poly (ADP-ribose) polymerase (PARP) protein. Combination drug treatment with the alkylating agent temozolomide and the PARPi talazoparib kills mtp53 expressing 2D grown breast cancer cell lines. We evaluated the sensitivity to the combination of temozolomide plus PARPi talazoparib treatment to breast and lung cancer patient-derived tumor organoids (PDTOs). The combination of the two drugs was synergistic for a cytotoxic response in PDTOs with mtp53 but not for PDTOs with wtp53. The combination of talazoparib and temozolomide induced more DNA double-strand breaks in mtp53 expressing organoids than in wild-type p53 expressing organoids as shown by increased γ-H2AX protein expression. Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Telemedicine has expanded rapidly during the COVID-19 pandemic. Data on telemedicine utilization are lacking, and racial/ethnic disparities in utilization and satisfaction are unknown among breast cancer patients. Methods: This was a longitudinal study, with two surveys conducted in 2020 and 2021, among patients enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort. Telemedicine utilization was modeled using mixed-effects logistic regression. Telemedicine satisfaction, assessed using a 5-point Likert scale, was modeled using mixed-effects proportional odds regression. Qualitative data on satisfaction were coded and analyzed using grounded theory. Results: Of 1,721 respondents, most (70.3%) were White, followed by 23.6% Black, 3.1% Asian, and 3.0% Hispanic. The median duration from breast cancer diagnosis to survey was 5.5 years (interquartile range: 2.7-9.4). In 2020, 59.2% reported telemedicine use; in 2021, 64.9% did, with a statistically significant increase ( p < 0.001). Black patients had greater odds of telemedicine use than White patients (adjusted odds ratio [AOR] = 1.55, 95% confidence interval [CI]: 1.17-2.05). In 2020, 90.3% reported somewhat-to-extreme satisfaction; in 2021, 91.2% did, with a statistically significant, although clinically small, increase ( p  = 0.038). There were no racial/ethnic differences in telemedicine satisfaction between Black (AOR = 1.05, 95% CI: 0.81-1.35), Asian (AOR = 0.63, 95% CI: 0.34-1.16), or Hispanic (AOR = 0.63, 95% CI: 0.33-1.21) and White patients. Major themes emerged from the respondents that explained their levels of satisfaction were convenience, safety, specialty dependence, and technical issues. Conclusions: Telemedicine utilization and satisfaction were high among breast cancer patients over time and across races/ethnicities. Telemedicine could have great potential in reducing barriers to care and promoting health equity for breast cancer patients. However, patients' perceived challenges in accessing high-quality virtual care should be addressed.

Background: Cancers, with increasing incidence and mortality rates, constitute a leading public health problem in Nigeria. As the burden of cancer in Nigeria increases, research and quality service delivery remain critical strategies for improved cancer control across the continuum of care. This study contextualizes the challenges and gaps in oncology research and practice in Nigeria, and presents recommendations to address the gaps., Methods: This qualitative study was conducted among interprofessional and interdisciplinary stakeholders in oncology healthcare practice and research in academic settings, between July and September 2021. Key-informant interviews were held with six stakeholders and leaders in nursing, pharmacy, and medicine across the six geopolitical zones of Nigeria, and twenty-four in-depth interviews with early- or mid-career researchers or healthcare professionals involved in cancer prevention and treatment were conducted. The data were analyzed using a deductive thematic analysis approach and coded using the NVIVO 12 software., Results: Five sub-themes were identified as major challenges to oncology research, including poor funding, excessive workload, interprofessional rivalry, weak collaboration, and denial of cancer diagnosis by patients. Challenges identified for oncology practice were poor governance and financing, high costs of oncology treatments, poor public awareness of cancer, workforce shortage, and interprofessional conflicts. Recommended strategies for addressing these challenges were improved financing of oncology research and practice by government and relevant stakeholders, increasing interest of medical, nursing, and pharmaceutical students in oncology research through curricula-based approach and mentorship, increased oncology workforce, and improved intra- and inter-professional collaboration., Conclusion: These data highlight the challenges and barriers in oncology practice and research in Nigeria, and underscore the urgent need for increased investments in infrastructure to provide interdisciplinary and interprofessional research training for high-quality care. Only then can Nigeria effectively tackle the current and impending cancer burden in the country., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes., Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race., Design, Setting, and Participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022., Exposure: Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer., Main Outcomes and Measures: The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated., Results: The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor β signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only., Conclusions and Relevance: The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.

In the general population, physical activity has been associated with a lower risk of several cancers; however, the evidence for ovarian cancer is not clear. It is suggested that early-life physical activity may differentially impact risk. Whether this is true among women at high risk due to a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes has not been evaluated. Thus, we performed a matched case-control study to evaluate the association between adolescent and early-adulthood physical activity and ovarian cancer. BRCA mutation carriers who completed a research questionnaire on various exposures and incident disease and with data available on physical activity were eligible for inclusion. Self-reported activity at ages 12-13, 14-17, 18-22, 23-29, and 30-34 was used to calculate the average metabolic equivalent of task (MET)-hours/week for moderate, vigorous, and total physical activity during adolescence (ages 12-17) and early-adulthood (ages 18-34). Conditional logistic regression was used to estimate the OR and 95% confidence intervals (CI) of invasive ovarian cancer associated with physical activity. This study included 215 matched pairs (mean age = 57.3). There was no association between total physical activity during adolescence (ORhigh vs. low = 0.91; 95% CI: 0.61-1.36; Ptrend = 0.85), early-adulthood (ORhigh vs. low = 0.78; 95% CI: 0.51-1.20; Ptrend = 0.38) and overall (ORhigh vs. low = 0.81; 95% CI: 0.54-1.23; Ptrend = 0.56) and ovarian cancer. Findings were similar for moderate (Ptrend ≥ 0.25) and vigorous (Ptrend ≥ 0.57) activity. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, physical activity should continue to be encouraged to promote overall health., Significance: In this matched case-control study, we observed no association between physical activity during adolescence or early-adulthood and subsequent risk of ovarian cancer. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, being active remains important to promote overall health and well-being., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Requiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress., Objective: To assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing., Design, Setting, and Participants: Making Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US residents, and had access to the internet and a health care professional. Previous cancer genetic testing or counseling was exclusionary. In the family history cohort, participants had a personal or family history of breast or ovarian cancer. In the familial pathogenic variant (PV) cohort, participants reported 1 biological relative with a PV in an actionable cancer susceptibility gene. Data analysis was performed between December 13, 2020, and May 31, 2023., Intervention: Participants completed baseline questionnaires, watched an educational video, and were randomized to 1 of 4 arms: the control arm with pretest and/or posttest genetic counseling, or 1 of 3 study arms without pretest and posttest counseling. Genetic counseling was provided by phone appointments and testing was done using home-delivered saliva kits., Main Outcomes and Measures: The primary outcome was participant distress measured by the Impact of Event Scale 3 months after receiving the results. Secondary outcomes included completion of testing, anxiety, depression, and decisional regret., Results: A total of 3839 women (median age, 44 years [range 22-91 years]), most of whom were non-Hispanic White and college educated, were randomized, 3125 in the family history and 714 in the familial PV cohorts. In the primary analysis in the family history cohort, all experimental arms were noninferior for distress at 3 months. There were no statistically significant differences in anxiety, depression, or decisional regret at 3 months. The highest completion rates were seen in the 2 arms without pretest counseling., Conclusions and Relevance: In the MAGENTA clinical trial, omitting individualized pretest counseling for all participants and posttest counseling for those without PV during remote genetic testing was not inferior with regard to posttest distress, providing an alternative care model for genetic risk assessment., Trial Registration: ClinicalTrials.gov Identifier: NCT02993068.

With cancer incidence increasing worldwide, physicians with cancer research training are needed. The Scholars in Oncology-Associated Research (SOAR) cancer research education program was developed to train medical students in cancer research while exposing them to the breadth of clinical oncology. Due to the COVID-19 pandemic, SOAR transitioned from in-person in 2019 to virtual in 2020 and hybrid in 2021. This study investigates positive and negative aspects of the varying educational formats. A mixed-methods approach was used to evaluate the educational formats. Pre- and post-surveys were collected from participants to assess their understanding of cancer as a clinical and research discipline. Structured interviews were conducted across all three cohorts, and thematic analysis was used to generate themes. A total of 37 students participated in SOAR and completed surveys (2019 n = 11, 2020 n = 14, and 2021 n = 12), and 18 interviews were conducted. Understanding of oncology as a clinical (p < 0.01 for all) and research discipline (p < 0.01 for all) improved within all three cohorts. There was no difference between each cohort's improvement in research understanding (p = 0.6). There was no difference between each cohort's understanding of oncology-related disciplines as both clinical and research disciplines (p > 0.1 for all). Thematic analysis demonstrated that hybrid and in-person formats were favored over a completely virtual one. Our findings demonstrate that a medical student cancer research education program is effective using in-person or hybrid formats for research education, although virtual experiences may be suboptimal to learning about clinical oncology., (© 2023. The Author(s) under exclusive licence to American Association for Cancer Education.)

Purpose: Despite the disproportionately high risk of breast cancer among women of African heritage, little is known about the facilitators and barriers to implementing germline genetic testing and counseling (GT/C)., Methods: This scoping review followed guidelines recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. Published manuscripts from database inception through 2021 were sourced from PubMed, Cumulative Index to Nursing and Allied Health Literature via EBSCO, Embase, Cochrane Library, and Scopus. Search terms were used to retrieve articles addressing (1) African heritage, (2) breast cancer, and (3) GT or GC. The screening involved abstract and title review and full-text review. Data were extracted for all articles meeting the inclusion criteria., Results: A total of 154 studies were included. Most studies that took place were conducted in the United States (71.4%), and most first authors (76.9%) were from the United States. GT was conducted in 73 (49.7%) studies. BRCA1 / BRCA2 were the most commonly studied genes for germline mutations. GC was conducted in 49 studies (33.3%), and perspectives on GC were evaluated in 43 (29.3%). The use of racial/ethnic categories varied broadly, although African American was most common (40.1%). Racism was mentioned in three studies (2.0%)., Conclusion: There is a growing body of literature on GT/C for breast cancer in women of African heritage. Future studies on GT/C of African populations should consider increased clarity around racial/ethnic categorizations, continued community engagement, and intentional processes for informed consent.

Background: Ovarian cancer is the leading cause of death from all gynaecological malignancies. Only few biomarkers of epithelial ovarian cancer (EOC) prognosis have been studied so far among Nigerian patients., Objective: To determine the pattern of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) expression in patients with EOC seen in Nigeria., Materials and Methods: This was a retrospective multicentre study of 102 cases of epithelial ovarian cancers. Relevant clinical information was obtained from hospital-based records in the 3 participating centres. Tissue microarrays were constructed using representative tumour tissue and the ER, PR and HER2 immunohistochemical staining was carried out at the University of Chicago, United States of America., Results: Serous carcinomas predominated (71% of cases). ER positivity was observed in 31.4%, PR positivity in 21.5% and HER2/neu in 16.7% of tumours. Fifty-two percent of tumours were triple negative. Serous tumours were significantly associated with ER positivity (p=0.001). Mean patient age for EOC was 52.6 ± 13.1 years. There were no statistically significant associations between hormone receptor status and histological grade, FIGO staging or survival., Conclusion: Serous tumours were significantly associated with ER expression while non-serous tumours tended to be triple negative., (© 2023 Ajani MA et al.)

Introduction: comprehensive cancer risk assessment services are lacking in most sub-Saharan African countries and the use of accurate family history (FH) information could serve as a cheap strategy for risk evaluation. The aim of this study is to determine the proportion of women unaware of family history of cancer among female relatives and associated socio-demographic characteristics., Methods: using case-control data on breast cancer among 4294 women in Nigeria, Uganda and Cameroon, we investigated the proportion of women unaware of family history of cancer among their female relatives. The association between participants' response to their awareness of female relatives' cancer history and socio-demographic characteristics was analysed according to case-control status, family side and distance of relation. Results: the proportion of women unaware if any relative had cancer was 33%, and was significantly higher among controls (43.2%) compared to 23.9% among cases (p<0.001) (Adjusted Odds Ratio (OR) = 2.51, 95% CI = 2.14 - 2.95). Age, education and marital status remained significantly associated with being unaware of FH among controls on multiple regression., Conclusion: about a third of women interviewed did not know about cancer history in at least one of their female relatives. Efforts aimed at improving cancer awareness in sub-Saharan Africa (SSA) are needed. Our findings could be useful for future studies of cancer risk assessment in SSA., Competing Interests: The authors declare no competing interests., (Copyright: Babatunde Adedokun et al.)

Background: Although investigators have shown associations between socioeconomic status (SES) and outcomes in breast cancer, there is a paucity of such data for invasive lobular carcinoma (ILC), the second most common type of breast cancer. Herein we evaluated the relationship between SES with tumor features and outcomes in stage I to III patients with ILC., Methods: We analyzed a prospectively maintained institutional ILC database and utilized the area deprivation index (ADI) to determine neighborhood adversity, an indicator of SES. We used Cox proportional hazards models in Stata 17.0 to evaluate relationships between ADI quintile (Q), race, body mass index (BMI), clinicopathologic features, treatment type, and event-free survival (EFS)., Results: Of 804 patients with ILC, 21.4% lived in neighborhoods classified as ADI Q1 (least resource-deprived) and 19.7% in Q5 (most resource-deprived). Higher deprivation was significantly associated with larger tumor size (3.6 cm in Q5 vs. 3.1 cm in Q1), increased presence of lymphovascular invasion (8.9% in Q5 vs. 6.7% in Q1), and decreased use of adjuvant endocrine therapy (67.1% in Q5 vs. 73.6% in Q1). On multivariable analysis, tumor size, receptor subtypes, and omission of adjuvant endocrine therapy were associated with reduced EFS., Conclusions: These data show that patients with ILC and higher ADI experience more aggressive tumors and differences in treatment. More data evaluating the complex relationships between these factors is needed to optimize outcomes for patients with ILC, regardless of SES., Impact: ADI is associated with differences in patients with ILC., (©2023 The Authors; Published by the American Association for Cancer Research.)

Purpose: To externally evaluate a mammography-based deep learning (DL) model (Mirai) in a high-risk racially diverse population and compare its performance with other mammographic measures., Materials and Methods: A total of 6435 screening mammograms in 2096 female patients (median age, 56.4 years ± 11.2 [SD]) enrolled in a hospital-based case-control study from 2006 to 2020 were retrospectively evaluated. Pathologically confirmed breast cancer was the primary outcome. Mirai scores were the primary predictors. Breast density and Breast Imaging Reporting and Data System (BI-RADS) assessment categories were comparative predictors. Performance was evaluated using area under the receiver operating characteristic curve (AUC) and concordance index analyses., Results: Mirai achieved 1- and 5-year AUCs of 0.71 (95% CI: 0.68, 0.74) and 0.65 (95% CI: 0.64, 0.67), respectively. One-year AUCs for nondense versus dense breasts were 0.72 versus 0.58 ( P = .10). There was no evidence of a difference in near-term discrimination performance between BI-RADS and Mirai (1-year AUC, 0.73 vs 0.68; P = .34). For longer-term prediction (2-5 years), Mirai outperformed BI-RADS assessment (5-year AUC, 0.63 vs 0.54; P < .001). Using only images of the unaffected breast reduced the discriminatory performance of the DL model ( P < .001 at all time points), suggesting that its predictions are likely dependent on the detection of ipsilateral premalignant patterns., Conclusion: A mammography DL model showed good performance in a high-risk external dataset enriched for African American patients, benign breast disease, and BRCA mutation carriers, and study findings suggest that the model performance is likely driven by the detection of precancerous changes. Keywords: Breast, Cancer, Computer Applications, Convolutional Neural Network, Deep Learning Algorithms, Informatics, Epidemiology, Machine Learning, Mammography, Oncology, Radiomics Supplemental material is available for this article . © RSNA, 2023See also commentary by Kontos and Kalpathy-Cramer in this issue., Competing Interests: Disclosures of conflicts of interest: O.J.O. No relevant relationships. A.E.W. No relevant relationships. F.M.H. Funding from American Society of Clinical Oncology/Breast Cancer Research Foundation Young Investigator Award (2022YIA-6675470300), Department of Defense (DoD) Breakthrough Level 2 Award (BC211095P1), American Cancer Society Institutional Research Grant, National Institutes of Health (NIH)/National Cancer Institute (NCI) (K12CA139160), and Cancer Research Foundation Young Investigator Award. F.Z. No relevant relationships. T.F.Y. No relevant relationships. Y.Z. No relevant relationships. A.T.P. Funding from NIH/National Institute of Dental and Craniofacial Research (R56-DE030958), NIH/NCI (U01-CA243075), DoD Breakthrough Cancer Research program (BC211095), Horizon (2021-SC1-BHC), Stand Up to Cancer–Fanconi Anemia Research Fund–Farrah Fawcett Foundation, NCI/Department of Energy Innovative Methodologies and New Data for Predictive Oncology Model Evaluation (IMPROVE) project IAA; grants or contracts from AbbVie and Kura Oncology; honorarium from AbbVie; advisory board for Prelude, Elevar Therapeutics, Privo, and Ayala. M.L. No relevant relationships. B.S.A. No relevant relationships. K.K. No relevant relationships. G.S.K. No relevant relationships. O.I.O. Funding from the Susan & Richard Kiphart Family Foundation; leadership role with American Cancer Society and MacArthur Foundation; stock or stock options with CancerIq, Tempus, and Healthwell; receipt of equipment or services from Genentech/Roche, Cepheid, and Color Genomics. H.A. No relevant relationships. D.H. No relevant relationships., (© 2023 by the Radiological Society of North America, Inc.)

Genome-wide association studies (GWASs) have identified more than 200 genomic loci for breast cancer risk, but specific causal genes in most of these loci have not been identified. In fact, transcriptome-wide association studies (TWASs) of breast cancer performed using gene expression prediction models trained in breast tissue have yet to clearly identify most target genes. To identify candidate genes, we performed a GWAS analysis in a breast cancer dataset from UK Biobank (UKB) and combined the results with the GWAS results of the Breast Cancer Association Consortium (BCAC) by a meta-analysis. Using the summary statistics from the meta-analysis, we performed a joint TWAS analysis that combined TWAS signals from multiple tissues. We used expression prediction models trained in 11 tissues that are potentially relevant to breast cancer from the Genotype-Tissue Expression (GTEx) data. In the GWAS analysis, we identified eight loci distinct from those reported previously. In the TWAS analysis, we identified 309 genes at 108 genomic loci to be significantly associated with breast cancer at the Bonferroni threshold. Of these, 17 genes were located in eight regions that were at least 1 Mb away from published GWAS hits. The remaining TWAS-significant genes were located in 100 known genomic loci from previous GWASs of breast cancer. We found that 21 genes located in known GWAS loci remained statistically significant after conditioning on previous GWAS index variants. Our study provides insights into breast cancer genetics through mapping candidate target genes in a large proportion of known GWAS loci and discovering multiple new loci., Competing Interests: Declaration of interests O.I.O. reported receiving grants from Tempus (scientific advisory board) during the study, being cofounder of CancerIQ, serving as a member of the board of directors for 54gene, and receiving grants from Color Genomics (research support) and from Roche (clinical trial support for IIT) outside the submitted work., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways., Methods: De-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression., Results: After applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e-05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e-03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e-162), HSPA1A (logFC = - 2.73, P = 2.43e-49), ATRX (logFC = - 1.93, P = 5.89e-83), and NUTM2F (logFC = 2.28, P = 3.22e-196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2&#95;UP.V1&#95;UP (P = 3.95e-06), LTE2&#95;UP.V1&#95;UP (P = 2.90e-05), HALLMARK&#95;FATTY&#95;ACID&#95;METABOLISM (P = 0.0073), and HALLMARK&#95;ANDROGEN&#95;RESPONSE (P = 0.0074)., Conclusions: We observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations., (© 2023. The Author(s).)

Gene expression-based recurrence assays are strongly recommended to guide the use of chemotherapy in hormone receptor-positive, HER2-negative breast cancer, but such testing is expensive, can contribute to delays in care, and may not be available in low-resource settings. Here, we describe the training and independent validation of a deep learning model that predicts recurrence assay result and risk of recurrence using both digital histology and clinical risk factors. We demonstrate that this approach outperforms an established clinical nomogram (area under the receiver operating characteristic curve of 0.83 versus 0.76 in an external validation cohort, p = 0.0005) and can identify a subset of patients with excellent prognoses who may not need further genomic testing., (© 2023. The Author(s).)

Importance: Given conflicting results regarding the prognosis of erb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-low breast cancer, a large-scale, nationally applicable comparison of ERBB2-low vs ERBB2-negative breast cancer is needed., Objective: To investigate whether ERBB2-low breast cancer is a clinically distinct subtype in terms of epidemiological characteristics, prognosis, and response to neoadjuvant chemotherapy., Design/participants/setting: This retrospective cohort study was conducted using the National Cancer Database, including 1 136 016 patients in the US diagnosed with invasive breast cancer from January 1, 2010, to December 31, 2019, who had ERBB2-negative disease and had immunohistochemistry results available. ERBB2-low tumors were classified as having an immunohistochemistry score of 1+, or 2+ with a negative in situ hybridization test. Data were analyzed from November 1, 2021, through November 30, 2022., Exposures: Standard therapy according to routine clinical practice., Main Outcomes and Measures: The primary outcomes were overall survival (OS), reported as adjusted hazard ratios (aHRs), and pathologic complete response, reported as adjusted odds ratios (aORs), for ERBB2-negative vs ERBB2-low breast cancer, controlling for age, sex, race and ethnicity, Charlson-Deyo Comorbidity Index score, treatment facility type, tumor grade, tumor histology, hormone receptor status, and cancer stage., Results: The study identified 1 136 016 patients (mean [SD] age, 62.4 [13.1] years; 99.1% female; 78.6% non-Hispanic White), of whom 392 246 (34.5%) were diagnosed with ERBB2-negative and 743 770 (65.5%) with ERBB2-low breast cancer. The mean (SD) age of the ERBB2-negative group was 62.1 (13.2) years and 62.5 (13.0) years for the ERBB2-low group. Higher estrogen receptor expression was associated with increased rates of ERBB2-low disease (aOR, 1.15 per 10% increase). Compared with non-Hispanic White patients, of whom 66.1% were diagnosed with ERBB2-low breast cancer, fewer non-Hispanic Black (62.8%) and Hispanic (61.0%) patients had ERBB2-low disease, although in non-Hispanic Black patients this was mediated by differences in rates of triple-negative disease and other confounders. A slightly lower rate of pathologic complete response was seen in patients with ERBB2-low disease vs patients with ERBB2-negative disease on multivariable analysis (aOR, 0.89; 95% CI, 0.86-0.92; P < .001). ERBB2-low status was also associated with small improvements in OS for stage III (aHR, 0.92; 95% CI, 0.89-0.96; P < .001) and stage IV (aHR, 0.91; 95% CI, 0.87-0.96; P < .001) triple-negative breast cancer, although this amounted to only a 2.0% (stage III) and 0.4% (stage IV) increase in 5-year OS., Conclusions and Relevance: This large-scale retrospective cohort analysis found minimal prognostic differences between ERBB2-low and ERBB2-negative breast cancer. These findings suggest that, moving forward, outcomes in ERBB2-low breast cancer will be driven by ERBB2-directed antibody-drug conjugates, rather than intrinsic differences in biological characteristics associated with low-level ERBB2 expression. These findings do not support the classification of ERBB2-low breast cancer as a unique disease entity.

Background: The purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant., Methods: Participants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow-up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow-up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan-Meier method., Results: There were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk-reducing mastectomy and bilateral salpingo-oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%., Conclusion: Women with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately., (© 2022 American Cancer Society.)

Importance: With the increasing delivery of neoadjuvant chemotherapy (NACT) for patients with breast cancer in the US, it is important to know whether there is differential response to NACT by race and ethnicity and the potential long-term outcomes., Objective: To examine whether there were any racial and ethnic differences in pathologic complete response (pCR) rate following NACT and, if so, whether they varied by molecular subtype and were associated with survival., Design, Setting, and Participants: A retrospective cohort study was conducted including patients with stage I to III breast cancer diagnosed between January 2010 and December 2017 who underwent surgery and received NACT; median follow-up was 5.8 years, and data analysis was conducted from August 2021 to January 2023. Data were obtained from the National Cancer Data Base, a nationwide, facility-based, oncology data set that captures approximately 70% of all newly diagnosed cases of breast cancer in the US., Main Outcomes and Measures: Pathologic complete response, defined as ypT0/Tis ypN0, was modeled using logistic regression. Racial and ethnic differences in survival were analyzed using a Weibull accelerated failure time model. Mediation analysis was conducted to measure whether racial and ethnic differences in the pCR rate affect survival., Results: The study included 107 207 patients (106 587 [99.4%] women), with a mean (SD) age of 53.4 (12.1) years. A total of 5009 patients were Asian or Pacific Islander, 18 417 were non-Hispanic Black, 9724 were Hispanic, and 74 057 were non-Hispanic White. There were significant racial and ethnic differences in pCR rates, but the differences were subtype-specific. In hormone receptor-negative (HR-)/erb-b2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-positive (ERBB2+) subtype, Asian and Pacific Islander patients achieved the highest pCR rate (56.8%), followed by Hispanic (55.2%) and non-Hispanic White (52.3%) patients with the lowest pCR rate seen in Black patients (44.8%). In triple-negative breast cancer, Black patients had a lower pCR rate (27.3%) than other racial and ethnic groups (all >30%). In HR+/ERBB2- subtype, Black patients had a higher pCR rate (11.3%) than other racial/ethnic groups (all ≤10%). In mediation analysis, racial and ethnic differences in achieving pCR after NACT could explain approximately 20% to 53% of the subtype-specific survival differences across racial and ethnic groups., Conclusions and Relevance: In this cohort study of patients with breast cancer receiving NACT, Black patients had a lower pCR rate for triple-negative and HR-/ERBB2+ breast cancer but a higher pCR rate for HR+/ERBB2- diseases, whereas Asian and Pacific Islander patients had a higher pCR rate for HR-/ERBB2+ diseases. Tumor grade and ERBB2 copy number could account for some of these within-subtype disparities, but further studies are warranted. Inability to achieve a pCR can mediate in part, but not entirely, the worse survival outcomes experienced by Black patients.

Importance: Among patients with breast cancer, inconsistent findings have been published on racial disparities in achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT)., Objective: To investigate whether racial disparities exist in achieving pCR and what factors contribute to them., Design, Setting, and Participants: Within the ongoing Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), which consists of a prospectively ascertained cohort of patients with breast cancer, 690 patients with stage I to III breast cancer receiving NACT were identified for this single-institution study at the University of Chicago Medicine. Patients diagnosed between 2002 and 2020 (median follow-up: 5.4 years) were included; next-generation sequencing data on tumor-normal tissue pairs were available from 186 ChiMEC patients, including both primary and residual tumor samples. Statistical analysis was performed from September 2021 to September 2022., Exposures: Demographic, biological, and treatment factors that could contribute to disparities in achieving pCR., Main Outcomes and Measures: pCR was defined as the absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ., Results: The study included 690 patients with breast cancer, with a mean (SD) age of 50.1 (12.8) years. Among the 355 White patients, 130 (36.6%) achieved pCR compared to 77 of the 269 Black patients (28.6%; P = .04). Not achieving pCR was associated with significantly worse overall survival (adjusted hazard ratio, 6.10; 95% CI, 2.80-13.32). Black patients had significantly lower odds of achieving pCR compared with White patients in the hormone receptor-negative/ERBB2+ subtype (adjusted odds ratio, 0.30; 95% CI, 0.11-0.81). Compared with White patients with ERBB2+ disease, Black patients were more likely to have MAPK pathway alterations (30.0% [6 of 20] vs 4.6% [1 of 22]; P = .04), a potential mechanism of anti-ERBB2 therapy resistance. Tumor mutational burden and somatic alterations in several genes (eg, FGF4, FGF3, CCND1, MCL1, FAT1, ERCC3, PTEN) were significantly different between the primary and residual tumors., Conclusions and Relevance: In this cohort study of patients with breast cancer, racial disparities in response to NACT were associated with disparities in survival and varied across different breast cancer subtypes. This study highlights the potential benefits of better understanding the biology of primary and residual tumors.

Background: Breast cancer survivors face long-term sequelae compared to the general population, suggesting altered metabolic profiles after breast cancer. We used metabolomics approaches to investigate the metabolic differences between breast cancer patients and women in the general population, aiming to elaborate metabolic changes among breast cancer patients and identify potential targets for clinical interventions to mitigate long-term sequelae., Methods: Serum samples were retrieved from 125 breast cancer cases recruited from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), and 125 healthy controls selected from Chicago Multiethnic Prevention and Surveillance Study (COMPASS). We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) combined with fold change to select metabolic features associated with breast cancer. Pathway analyses were conducted using Mummichog to identify differentially enriched metabolic pathways among cancer patients. As potential confounders we included age, marital status, tobacco smoking, alcohol drinking, type 2 diabetes, and area deprivation index in our model. Random effects of residence for intercept was also included in the model. We further conducted subgroup analysis by treatment timing (chemotherapy/radiotherapy/surgery), lymph node status, and cancer stages., Results: The entire study participants were African American. The average ages were 57.1 for cases and 58.0 for controls. We extracted 15,829 features in total, among which 507 features were eventually selected by our criteria. Pathway enrichment analysis of these 507 features identified three differentially enriched metabolic pathways related to prostaglandin, leukotriene, and glycerophospholipid. The three pathways demonstrated inconsistent patterns. Metabolic features in the prostaglandin and leukotriene pathways exhibited increased abundances among cancer patients. In contrast, metabolic intensity in the glycerolphospholipid pathway was deregulated among cancer patients. Subgroup analysis yielded consistent results. However, changes in these pathways were strengthened when only using cases with positive lymph nodes, and attenuated when only using cases with stage I disease., Conclusion: Breast cancer in African American women is associated with increase in serum metabolites involved in prostaglandin and leukotriene pathways, but with decrease in serum metabolites in glycerolphospholipid pathway. Positive lymph nodes and advanced cancer stage may strengthen changes in these pathways., (© 2023. The Author(s).)

Prolonged survival of patients with stage IV breast cancer could change the role of radiotherapy for local control of breast primary, but its survival benefit remains unclear. Our aim is to investigate the survival benefit of radiotherapy in de novo stage IV breast cancer. Stage IV breast cancer patients who received breast surgery and have survived 12 months after diagnosis (landmark analysis) were included in the study from 2010 to 2015 of the National Cancer DataBase. Multivariable Cox models and a propensity score matching were used to control for confounding effects. Of 11,850 patients, 3629 (30.6%) underwent postoperative radiotherapy to breast or chest wall and 8221 (69.4%) did not. In multivariable analysis adjusting for multiple prognostic variables, postoperative radiotherapy was significantly associated with better survival (hazard ratio [HR] 0.74, 95% confidence interval [95%CI] 0.69-0.80; P < 0.001). Radiotherapy was associated with improved survival in patients with bone (P < 0.001) or lung metastasis (P = 0.014), but not in patients with liver (P = 0.549) or brain metastasis (P = 0.407). Radiotherapy was also associated with improved survival in patients with one (P < 0.001) or two metastatic sites (P = 0.028), but not in patients with three or more metastatic sites (P = 0.916). The survival impact of radiotherapy did not differ among subtypes. The results of survival analysis in the propensity score-matched sub-cohort were precisely consistent with those of multivariable analysis. These real-world data show that postoperative radiotherapy might improve overall survival for de novo Stage IV breast cancer with bone or lung metastasis, regardless of subtypes., (© 2023. The Author(s).)

The hallmark signatures based on gene expression capture core cancer processes. Through a pan-cancer analysis, we describe the overview of hallmark signatures across tumor types/subtypes and reveal significant relationships between these signatures and genetic alterations. TP53 mutation exerts diverse changes, including increased proliferation and glycolysis, which are closely mimicked by widespread copy-number alterations. Hallmark signature and copy-number clustering identify a cluster of squamous tumors and basal-like breast and bladder cancers with elevated proliferation signatures, frequent TP53 mutation, and high aneuploidy. In these basal-like/squamous TP53 -mutated tumors, a specific and consistent spectrum of copy-number alterations is preferentially selected prior to whole-genome duplication. Within Trp53- null breast cancer mouse models, these copy-number alterations spontaneously occur and recapitulate the hallmark signature changes observed in the human condition. Together, our analysis reveals intertumor and intratumor heterogeneity of the hallmark signatures, uncovering an oncogenic program induced by TP53 mutation and select aneuploidy events to drive a worsened prognosis., Significance: Our data demonstrate that TP53 mutation and a resultant selected pattern of aneuploidies cause an aggressive transcriptional program including upregulation of glycolysis signature with prognostic implications. Importantly, basal-like breast cancer demonstrates genetic and/or phenotypic changes closely related to squamous tumors including 5q deletion that reveal alterations that could offer therapeutic options across tumor types regardless of tissue of origin., (© 2023 The Authors; Published by the American Association for Cancer Research.)