JNCI Cancer Spectrum

BackgroundThe tumor microenvironment (TME) significantly impacts breast cancer progression, with stromal and immune components influencing tumor behavior. The scavenger receptor SCARA5 is recognized as a tumor suppressor in various cancers, but its role in breast cancer remains uncertain. MethodsWe performed integrative transcriptomic analyses of bulk RNA-seq data from TCGA-BRCA, validated with GTEx, to investigate SCARA5 expression and its clinical significance. Differential expression, PAM50 subtype classification, PCA/t-SNE clustering, and ROC analyses were used to assess diagnostic potential. Functional enrichment (GO, KEGG, Reactome), PPI networks, and co-expression analyses explored pathways related to SCARA5. Single-cell transcriptomic datasets (TISCH2, Broad Portal) and spatial profiling (Human Protein Atlas) were employed to examine cellular and spatial localization. The prognostic importance was assessed using GEPIA2 survival analysis. ResultsSCARA5 was significantly downregulated in breast tumors, especially in Her2-enriched and Luminal B subtypes, with ROC curves confirming its diagnostic importance. Enrichment and PPI analyses linked SCARA5 to lipid metabolism, immune regulation, and scavenger receptor pathways. Co-expression studies showed associations with lipid metabolism genes (FABP4, ADIPOQ, CD36) and immune-related genes (CLEC3B, LYVE1). Single-cell data indicated SCARA5 expression was limited to fibroblasts, endothelial cells, and immune subsets, with rare expression in malignant epithelial cells. Spatial analysis confirmed stromal enrichment, mainly in areas rich in fibroblasts and endothelial cells. Survival analysis demonstrated worse outcomes in patients with HER2+ and Luminal B breast cancers who had low SCARA5 expression. ConclusionSCARA5 is a stromal-enriched gene with potential tumor-suppressive and immunometabolic regulatory roles in breast cancer. Its diagnostic and prognostic significance, especially in aggressive subtypes, highlights its potential as a biomarker and therapeutic target within the tumor stroma.

BackgroundThe ability to predict future risk of cancer development in non-malignant biopsies is poor. Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumor-promoting microenvironmental mechanism that secretes pro-inflammatory paracrine factors. With most work done in non-human models and the heterogenous nature of senescence the precise role of senescent cells in the development of cancer in humans is not well understood. Further, more than one million non-malignant breast biopsies are taken every year that could be a major source of risk-stratification for women. MethodsWe applied single cell deep learning senescence predictors based on nuclear morphology to histological images of 4,411 H&E-stained breast biopsies from healthy female donors. Senescence was predicted in the epithelial, stromal, and adipocyte compartments using predictor models trained on cells induced to senescence by ionizing radiation (IR), replicative exhaustion (RS), or antimycin A, Atv/R and doxorubicin (AAD) exposures. To benchmark our senescence-based prediction results we generated 5-year Gail scores, the current clinical gold standard for breast cancer risk prediction. FindingsWe found significant differences in adipocyte-specific IR and AAD senescence prediction for the 86 out of 4,411 healthy women who developed breast cancer an average 4.8 years after study entry. Risk models demonstrated that individuals in the upper median of scores for the adipocyte IR model had a higher risk (OR=1.71 [1.10-2.68], p=0.019), while the adipocyte AAD model revealed a reduced risk (OR=0.57 [0.36-0.88], p=0.013). Individuals with both adipocyte risk factors had an OR of 3.32 ([1.68-7.03], p<0.001). Alone, 5-year Gail scores yielded an OR of 2.70 ([1.22-6.54], p=0.019). When combining Gail scores with our adipocyte AAD risk model, we found that individuals with both of these risk predictors had an OR of 4.70 ([2.29-10.90], p<0.001). InterpretationAssessment of senescence with deep learning allows considerable prediction of future cancer risk from non-malignant breast biopsies, something that was previously impossible to do. Furthermore, our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols. FundingThis study was funded by the Novo Nordisk Foundation (#NNF17OC0027812), and by the National Institutes of Health (NIH) Common Fund SenNet program (U54AG075932).

This hypothesis-generating study aims to examine the extent to which computed tomography-assessed body composition phenotypes are associated with immune and PI3K/AKT signaling pathways in breast tumors. A total of 52 patients with newly diagnosed breast cancer were classified into four body composition types: adequate (lowest two tertiles of total adipose tissue [TAT]) and highest two tertiles of total skeletal muscle [TSM] areas); high adiposity (highest tertile of TAT and highest two tertiles of TSM); low muscle (lowest tertile of TSM and lowest two tertiles of TAT); and high adiposity with low muscle (highest tertile of TAT and lowest tertile of TSM). Immune and PI3K/AKT pathway proteins were profiled in tumor epithelium and the leukocyte-enriched stromal microenvironment using GeoMx (NanoString). Linear mixed models were used to compare log2-transformed protein levels. Compared with the normal type, the low muscle type was associated with higher expression of INPP4B (log2-fold change = 1.14, p = 0.0003, false discovery rate = 0.028). Other significant associations included low muscle type with increased CTLA4 and decreased pan-AKT expression in tumor epithelium, and high adiposity with increased CD3, CD8, CD20, and CD45RO expression in stroma (P<0.05; false discovery rate >0.2). With confirmation, body composition can be associated with signaling pathways in distinct components of breast tumors, highlighting the potential utility of body composition in informing tumor biology and therapy efficacies.

ImportanceMammographic density (MD) and pathogenic variants (PVs) in breast cancer susceptibility genes are major determinants of breast cancer risk, but their association and joint effects on breast cancer risk are unclear. ObjectiveTo investigate the association between the presence or absence of PVs in breast cancer susceptibility genes and MD measures, and their joint effects on breast cancer risk in an observational study; and to evaluate causality using Mendelian randomisation (MR) analyses. DesignCase-control analyses using data from the Breast Cancer Association Consortium (1991-2016). Sequencing and genotyping took place between 2009 and 2021. SettingMulticenter ParticipantsA total of 6,809 cases and 18,189 controls were included, from 15 studies, comprising women aged 19 to 92 years with mammograms taken at least one year before diagnosis. ExposureMD measures, including dense area (DA), non-dense area (NDA), percentage density (PD) and absolute difference in PD between left and right breasts (ADPD), and PVs in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C and RAD51D. Main outcomes and measuresBreast cancer risk overall, by oestrogen receptor expression-defined subtypes, and among BRCA1 and BRCA2 PV carriers. ResultsNo association was found between the overall burden of PVs and any MD measure. There was some evidence for a negative interaction between the burden of PVs in the eight genes and PD (OR=0.79,95%CIint=0.62,1.00, PLRT=0.047). This appears to be largely driven by a positive interaction with NDA. MR analyses indicated attenuated effects for BRCA1 (for PD, OR per standard deviation =1.02(95%CI:0.78,1.34) but not BRCA2 PV carriers (1.54,95%CI=1.08,2.24)). Conclusions and RelevanceThere was no evidence of association between PVs in breast cancer susceptibility genes and MD measures, but some suggestion that the association between MD and breast cancer risk may be weaker in PV carriers. Replication of these findings in further large datasets is required.

BackgroundGut microbiome is an emerging potentially modifiable contributor to breast health, including breast cancer (BCa). To advance prevention research in this area, we established a prospective biobanking cohort of cancer-free women. MethodsEligible women were [&ge;]40 years old, had no cancer history and no recent antibiotic use. Women were enrolled during screening mammography visits at three imaging centers in Florida (February 2021-June 2024), completed a BCa risk factor survey, and underwent body measurements. We collected digital mammograms and stool/urine/saliva samples. Optionally, women completed NIHs Diet History Questionnaire and a neighborhood stress questionnaire. Mammographic breast density (MBD) was assessed using established computerized approaches. ResultsWe recruited 733 cancer-free women (49% Caucasian, 21% African American, 26% Hispanic, and 4% from mixed/other races). The average age was 60 years (range 40-92); the majority (68.3%) were postmenopausal. BCa risk factor, neighborhood stress and diet questionnaires were completed by 97%, 65% and 58% of participants, respectively. Urine, saliva, and mammograms were available for all women; 83% also returned stool samples. ConclusionsWe have established a representative cohort of screen-aged women with comprehensive BCa risk factor data, biospecimen collection, and MBD. ImpactThis unique resource provides opportunity for future gut microbiome-focused BCa prevention research.

BackgroundCopper is an essential nutrient required for energy production, antioxidant defense, and connective tissue maturation, yet has emerged as a metabolic vulnerability in cancer. CTR1 (SLC31A1), the high-affinity copper importer, mediates cellular copper uptake, and its upregulation may signal increased copper demand in tumor cells. The dynamics of copper regulation across tumor growth, aggressiveness, and treatment resistance remain poorly defined in breast cancer. We investigated whether CTR1 expression and systemic copper changes reflect a coordinated tumor-systemic copper axis MethodsA retrospective dataset of 1632 breast cancer patients receiving neoadjuvant chemotherapy was analyzed to compare CTR1 gene expression between responders and non-responders across molecular subtypes and tumor grades. Findings were extended to a prospective neoadjuvant cohort in which paired pre-and post-treatment serum copper levels were measured. {Delta}Copper (post-pre change) was correlated with subtype, grade, response, and tumor size ResultsCTR1 expression was significantly higher in triple-negative breast cancer (TNBC) non-responders than responders (P = 0.0021), particularly in grade 3 tumors (P = 0.0035), with no difference in luminal subtypes. In the prospective cohort, {bigtriangleup}Copper was positive predominantly in TNBC and strongly grade-dependent: all grade 3 TNBCs exhibited copper elevation post-therapy, whereas all grade 2 TNBCs showed negative {bigtriangleup}Copper (P = 0.034). The only relapse in the cohort, a TNBC non-responder, exhibited persistently positive {bigtriangleup}Copper at follow-up and relapse, whereas non-responders from other subtypes showed near-zero or negative {bigtriangleup}Copper (P = 0.011). Baseline serum copper was higher in patients with smaller (clinical T1) versus larger (T2-T3) tumors (P = 0.033) ConclusionsParallel CTR1 upregulation in tumors and systemic copper elevation post-therapy suggest a coordinated copper mobilization program in high-grade TNBC. These integrated retrospective and prospective findings link copper transport to therapy response and tumor aggressiveness, highlighting copper biology as a potential therapeutic axis in breast cancer.

IntroductionThe mammogram risk score (MRS), an AI-driven texture feature derived from digital mammograms, strongly predicts breast cancer risk independently of breast density, though underlying mechanisms remain unclear. This study investigated relationships between established breast cancer risk factors, covering anthropometrics, reproductive factors, family history, and mammographic density metrics, and MRS. MethodsUsing data from the Nurses Health Study II (292 cases, 561 controls), we validated MRSs association with breast cancer using logistic regression and evaluated its relationships with risk factors through: linear regressions of MRS on observed risk factors and polygenic scores associated with risk factors, and Mendelian randomization (MR) analysis via two-stage least squares regression. We conducted two-sample MR of MRS using summary statistics from genome-wide association studies of risk factors. ResultsMRS was significantly associated with breast cancer risk before adjustment for BI-RADS density (OR=1.92 per SD increase in MRS; 95%CI:1.57-2.33; AUC=0.69) and after (OR=1.85; 95%CI:1.49-2.30). Early life body size and adult body mass index (BMI) were inversely associated with MRS, while history of benign breast disease and BI-RADS density showed positive associations; after adjusting for BI-RADS density, associations between MRS and the other three risk factors attenuated. Higher polygenic score for dense area was associated with increased MRS ({beta}=0.16 SD increase in MRS per SD increase in polygenic score; 95%CI: 0.06-0.25), as was percent density ({beta}=0.14; 95%CI:0.05-0.23). Two-sample MR identified associations between genetically predicted dense area ({beta}=0.83 SD increase in MRS per SD increase in dense area; 95%CI:0.39-1.27) and percent density ({beta}=1.14; 95%CI:0.55-1.74) with MRS. After adjusting for BI-RADS density and BMI, higher waist-to-hip ratio was significantly associated with increased MRS in polygenic score and two-sample MR analyses. No significant associations were observed with other risk factors. ConclusionWe validated MRSs association with breast cancer risk in cases diagnosed 0.5-10.1 years (median 2.6) after mammogram acquisition. Our findings reveal robust associations between breast density measures and MRS and suggest a potential impact of central obesity on MRS. Future larger-scale studies are crucial to validate these results and explore their potential to enhance our understanding of breast cancer etiology and refine risk prediction models.

BackgroundIn breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. MethodsA genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC. ResultsThe discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1x10-6, 33 variants associated with one or more TP53 phenotypes with P values <1x10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1x10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8x10-5 and 9.8x10-8, respectively) and TP53 GOF mutations (P value 8.4x10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons. ConclusionsWe found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.

PurposeTo comprehensively characterize the clinical and genomic landscapes of PIK3CA, AKT1, and PTEN alterations and examine their functional implications in AKT-driven breast cancer. Experimental DesignComprehensive genomic profiling of 51,767 breast tumors was performed with FoundationOne(R)CDx or FoundationOne(R). We examined the genomic landscape of PIK3CA, PTEN, and AKT1 alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data was used to functionally characterize clinical PTEN variants. ResultsThere were 29,157 total variants across PIK3CA, AKT1, and PTEN, including pathogenic variants and VUS. The most frequently altered gene was PIK3CA (37.4% of cases), followed by PTEN (13.5%), then AKT1 (5.4%). The most common alterations in each gene were PIK3CA H1047R (35.6% of PIK3CA-altered cases), E545K (19.7%), and E542K (11.7%); AKT1 E17K (69.7%); and PTEN homozygous copy number deletion (37.3%). PIK3CA alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), while AKT1 and PTEN alterations were balanced across ancestries. PIK3CA, AKT1, and PTEN pathogenic alterations were all mutually exclusive to each other. Using available DMS data on missense PTEN mutations, we found that 32.5% showed discordant effects on protein stability and phosphatase activity, underscoring the need for functional validation beyond predicted loss-of-function. ConclusionsHere we present the landscape of PIK3CA, AKT1, and PTEN alterations in the largest clinical cohort examined to date. The functional implications of lesser-known variants in each gene warrant further investigation by tools such as deep mutational scanning.

BackgroundEmerging work has demonstrated that histologically normal (non-tumor) tissue adjacent to breast tumor tissue shows evidence of molecular alterations related to tumorigenesis, referred to as field cancerization effects. Although changes in DNA methylation are known to occur early in breast carcinogenesis and the landscape of breast tumor DNA methylation is profoundly altered compared with normal tissue, there have been limited efforts to identify DNA methylation field cancerization effects in histologically normal breast tissue adjacent to tumor. MethodsMatched tumor, histologically normal tissue of the ipsilateral breast (ipsilateral-normal), and histologically normal tissue of the contralateral breast (contralateral-normal) were obtained from nine women undergoing bilateral mastectomy. Laser capture microdissection was used to select breast epithelial cells from normal tissues, and neoplastic cells from tumor specimens for genome-scale measures of DNA methylation with the Illumina HumanMethylationEPIC array. ResultsWe identified substantially more CpG loci that were differentially methylated between contralateral-normal breast and tumor tissue (63,271 CpG loci q < 0.01), than between ipsilateral-normal tissue and tumor (38,346 CpG loci q < 0.01). In addition, we identified differential methylation in ipsilateral-normal relative to contralateral-normal tissue (9,562 CpG loci p < 0.01). Hypomethylated loci in ipsilateral normal relative to contralateral were significantly enriched for breast cancer-relevant transcription factor binding sites including those for ESR1, FoxA1, and GATA3. Hypermethylated loci in ipsilateral-normal relative to contralateral-normal tissue were significantly enriched for CpG island shore regions. ConclusionsOur results indicate that early hypermethylation events in breast carcinogenesis are more likely to occur in the regions immediately surrounding CpG islands than CpG islands per se, reflecting a field effect of the tumor on surrounding histologically normal tissue. This work offers an opportunity to focus investigations of early DNA methylation alterations in breast carcinogenesis and potentially develop epigenetic biomarkers of disease risk.

BackgroundBreast cancer is comprised of distinct molecular subtypes. Studies have reported differences in risk factor associations with breast cancer subtypes, especially by tumor estrogen receptor (ER) status, but their consistency across racial and ethnic populations has not been comprehensively evaluated. MethodsWe conducted a qualitative, scoping literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis, extension for Scoping Reviews to investigate consistencies in associations between 18 breast cancer risk factors (reproductive, anthropometric, lifestyle, and medical history) and risk of ER-defined subtypes in women who self-identify as Asian, Black or African American, Hispanic or Latina, or White. We reviewed publications between January 1, 1990 and July 1, 2022. Etiologic heterogeneity evidence (convincing, suggestive, none, or inconclusive) was determined by expert consensus. ResultsPublications per risk factor ranged from 14 (benign breast disease history) to 66 (parity). Publications were most abundant for White women, followed by Asian, Black or African American, and Hispanic or Latina women. Etiologic heterogeneity evidence was strongest for parity, followed by age at first birth, post-menopausal BMI, oral contraceptive use, and estrogen-only and combined menopausal hormone therapy. Evidence was limited for other risk factors. Findings were consistent across racial and ethnic groups, although the strength of evidence varied. ConclusionThe literature supports etiologic heterogeneity by ER for some established risk factors that are consistent across race and ethnicity groups. However, in non-White populations evidence is limited. Larger, more comparable data in diverse populations is needed to better characterize breast cancer etiologic heterogeneity.

IMPORTANCEIn young-onset breast cancer, a diagnosis within 5-10 years of childbirth associates with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with breast cancer at younger ages, but the impact of childbirth on mortality is unknown. OBJECTIVEDetermine whether time between recent childbirth and breast cancer diagnosis impacts mortality among young-onset breast cancer patients with germline BRCA1/2 PVs. DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort study includes 903 women with germline BRCA1/2 PVs diagnosed with stage I-III breast cancer at [&le;]45 years of age, between 1950-2021 in the UK. MAIN OUTCOMES AND MEASURESThe primary outcome is all-cause mortality, censored at 20 years post-diagnosis. The primary exposure is time between most recent childbirth and breast cancer diagnosis, with recent childbirth defined as >0-<10 years post childbirth (n=419)], further delineated to >0-<5 years (n=228) and 5-<10 years (n=191). Mortality of nulliparous cases (n=224) was compared to the recent postpartum groups and the [&ge;]10 years postpartum (n=260) group. Cox proportional hazards regression analyses were adjusted for patient age, tumor stage, further stratified by tumor estrogen receptor (ER) and BRCA gene status. RESULTSFor all BRCA PV carriers, increased all-cause mortality was observed in women diagnosed >0-<10 years postpartum, compared to nulliparous and [&ge;]10 years groups, demonstrating the transient duration of postpartum risk. Risk of mortality was greater for ER-positive cases in the >0-<5 group [HR=2.35 (95% CI, 1.02-5.42)] and ER-negative cases in the 5-<10 group [HR=3.12 (95% CI, 1.22-7.97)] compared to the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5-<10 group was significantly increased, but only for BRCA1 carriers [HR=2.03 (95% CI, 1.15-3.58)]. CONCLUSIONS AND RELEVANCEYoung-onset breast cancer with germline BRCA PVs confers increased risk for all-cause mortality if diagnosed within 10 years of childbirth, with risk highest for ER+ cases at >0-<5 years postpartum, and for ER-cases at 5-<10 years postpartum. BRCA1 carriers are at highest risk for poor prognosis when diagnosed at 5-10 years postpartum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers. Key PointsO_ST_ABSQuestionC_ST_ABSIs a postpartum diagnosis an independent risk factor for mortality among young-onset breast cancer patients with germline BRCA1/2 PVs? FindingsA diagnosis <10 years postpartum associates with higher risk of mortality compared to nulliparous and [&ge;]10 years postpartum cases. Peak risk after childbirth varies for ER-positive (>0-<5 years) vs. ER-negative cases (5-<10 years). BRCA1 carriers had peak risk of mortality 5-10 years postpartum, with no associations observed for BRCA2 carriers. MeaningA breast cancer diagnosis within 10 years of childbirth independently associates with increased risk for mortality in patients with germline BRCA1/2 PVs, especially for carriers of BRCA1 PVs.

IntroductionMetastatic breast cancer (MBC) remains an incurable disease with a 5-year overall survival rate below 25%. Metastases often emerge from subclinical, disseminated tumor cells that persist despite systemic therapy of primary disease - referred to as minimal residual disease (MRD). Detecting MRD is critical for identifying patients at high risk of recurrence and enabling timely intervention. MethodsIn this study, we developed MammaTrace, a plasma-only cell-free DNA (cfDNA) methylation-based MRD assay, informed by differentially methylated regions (DMRs) identified in MBC using whole genome bisulfite sequencing. MammaTrace was evaluated in an independent longitudinal cohort of early-stage breast cancer patients treated with curative intent. ResultsMammaTrace achieved a sensitivity of 91% and specificity of 83%, with a median follow-up of 12.4 months. A positive MammaTrace score, indicative of MRD, preceded clinical or radiologic recurrence by a median of 457 days, providing a substantial lead time for therapeutic intervention to prevent progression to metastatic disease. ConclusionsMammaTrace enables detection of minimal residual disease in breast cancer patients, offering a substantial lead time before clinical recurrence. This approach may improve risk stratification and guide early therapeutic strategies to delay or prevent metastatic progression.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSThe causality of the association between physical activity and risk of breast and endometrial cancers is uncertain because available evidence is based exclusively on observational studies, which are potentially susceptible to confounding and reverse causation. ObjectiveTo investigate whether increased physical activity is causally associated with decreased risk of breast and endometrial cancers, using a two-sample Mendelian randomization study design. Design, Setting, and ParticipantsGenome-wide association studies of physical activity, breast cancer, and endometrial cancer, published up to April 31, 2019, were identified using PubMed and the GWAS catalog. Twelve single nucleotide polymorphisms (SNP) known at P < 5 x 10-8 to be associated with accelerometer-assessed or self-reported physical activity served as instrumental variables. Genetic summary data from four large consortia provided SNP-outcome associations [Breast Cancer Association Consortium; Discovery, Biology and Risk of Inherited Variants in Breast Cancer Consortium; Endometrial Cancer Association Consortium]. Main Outcomes and MeasuresThe primary outcomes were risk of breast cancer and risk of endometrial cancer. Secondary outcomes were estrogen receptor positive (ER+) and ER-breast cancers. Odds ratios (ORs) and 95% confidence intervals (CIs) per mean acceleration in milli-gravities of accelerometer-assessed physical activity and per one standard deviation (1-SD) increase in metabolic-equivalent (MET)-minutes/week of self-reported moderate-to-vigorous physical activity were computed using the inverse variance weighted method. A series of sensitivity analyses addressed the potential impact of heterogeneity, pleiotropy, and outliers. ResultsSummary data were available for 122,977 breast cancers and 12,270 endometrial cancers. Genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of breast and endometrial cancers. The associations (ORs [95% CI] per 1-SD increase in mean acceleration) were 0.88 (0.85-0.91) for breast cancer and 0.90 (0.83-0.97) for endometrial cancer. In addition, genetic predisposition to increased accelerometer-assessed physical activity was associated with lower risk of ER+ breast cancer. We found no evidence for an association between genetic predisposition to self-reported physical activity and risk of total breast cancer, breast cancer subtypes, or endometrial cancer. Conclusion and RelevanceThis first Mendelian randomization study shows that objectively-assessed physical activity plays a causal role in protecting against breast and endometrial cancers.

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

Recurrence scores based on a 21-gene assay are clinically useful for predicting prognosis and chemotherapy benefit in postmenopausal node-positive breast cancer patients, but its performance in premenopausal patients is inconsistent. Here, we evaluated Ataraxis Breast RISK (ATX), an AI test that predicts recurrence risk, and compared it with the genomic assay. ATX identified high risk patients misclassified as low risk by the genomic assay and therefore may refine selection of patients for adjuvant chemotherapy.

BackgroundBreast cancer is multifactorial. Focusing on limited risk factors may miss high-risk individuals. MethodsWe assessed the performance and overlap of various risk factors in identifying high-risk individuals for invasive breast cancer (BrCa) and ductal carcinoma in situ (DCIS) in 161,849 European-ancestry and 18,549 Asian-ancestry women. Discriminatory ability was evaluated using the area under the receiver operating characteristic curve (AUC). High-risk criteria included: 5-year absolute risk [&ge;]1{middle dot}66% by the Gail model [GAILbinary]; first-degree family history of breast cancer [FHbinary]; 5-year absolute risk [&ge;]1{middle dot}66% by a 313-variants polygenic risk score [PRSbinary]; and carriers of pathogenic variants in breast cancer predisposition genes [PTVbinary]. FindingsThe 5-year absolute risk by PRS outperformed the Gail model in predicting BrCa (Europeansvs controls: AUCPRS=0{middle dot}635 [0{middle dot}632-0{middle dot}638] vs AUCGail=0{middle dot}492 [0{middle dot}489-0{middle dot}495]; Asiansvs controls: AUCPRS=0{middle dot}564 [0{middle dot}556-0{middle dot}573] vs AUCGail=0{middle dot}506 [0{middle dot}497-0{middle dot}514]). PRSbinary and GAILbinary identified more high-risk European than Asia individuals. High-risk proportions were higher among BrCa (16-26%) and DCIS (20-33%) compared to controls (9-15%) among young Europeans and all Asians. Fewer than 7% of BrCa, 10% of DCIS, and 3% of controls were classified as high-risk by multiple risk classifiers. Overlap between PRSbinary and PTVbinary was minimal (<0{middle dot}65% Europeans, <0{middle dot}15% Asians) compared to the proportion at high risk using PTVbinary alone (Europeans: 4{middle dot}6%, Asians: 4{middle dot}4%) and PRSbinary alone (Europeans: 13{middle dot}9%, Asians: 8{middle dot}5%). PRSbinary and FHbinary uniquely identified 5-6% and 9-11% of young BrCa, respectively. InterpretationThe incomplete overlap between high-risk individuals identified by PRSbinary, GAILbinary, FHbinary, and PTVbinary highlights the need for a comprehensive approach to breast cancer risk prediction. SIGNIFICANCEThis study shows that different ways of predicting breast cancer risk do not always flag the same people, suggesting that combining multiple risk factors could improve early detection and screening.

For older patients with competing comorbidities, optimizing oncologic therapies is of paramount importance. Circulating tumor DNA (ctDNA) is a validated prognostic factor across solid tumors and may provide a strategy to identify patients for whom safe de-escalation of certain therapies is possible. In this prospective, hybrid-decentralized trial (n = 43 patients; NCT05914792) that integrated clinical outcomes, patient- and caregiver-reported outcomes, and correlative tissue analysis, the primary objective was to determine if ctDNA levels were associated with tumor progression in older patients who opted to forgo breast cancer surgery in favor of primary endocrine therapy (pET). ctDNA levels were highly concordant with imaging findings, and a lack of ctDNA clearance at 6 months was associated with tumor progression. In a competing risk regression adjusted for patient age, tumor stage, tumor grade, and tumor Ki-67, pre-treatment ctDNA positivity was associated with a significant risk of tumor progression (HR 30, 95% CI 4.4-209; p = 0.0005). No patients with pre-treatment ctDNA negativity experienced tumor progression. In correlative analyses examining ctDNA-positive tumors progressing on pET, we identified populations of CD11+ T cell-interacting macrophages that upregulate CD109 and CD89 and secrete immunosuppressive chemokines to create a favorable environment for cancer epithelial cell proliferation. These findings suggest that ctDNA may be a surveillance modality for older patients who receive pET, warranting future evaluation in a randomized setting. STATEMENT OF SIGNIFICANCEClinical management of older women with breast cancer can be challenging, and some women may opt to forego surgery through shared decision making with their physicians. Use of ctDNA for these patients may identify those at an increased risk for progression as well as those with endocrine-sensitive tumors who are good candidates for surgical de-escalation.

BackgroundUPF intake is associated with obesity. Despite obesity being a risk factor for postmenopausal breast cancer, evidence for an association between UPF and breast cancer is limited. Our objective was to assess the association between UPF intake and postmenopausal breast cancer risk in the NIH-AARP Diet and Health Study. MethodsParticipants reported dietary intake via a food frequency questionnaire at baseline in 1995-1996 and were followed through 2018. Food items were disaggregated into food codes and assigned Nova classification via database linkage. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for quintiles of UPF (g/1000 kcal/day) and postmenopausal breast cancer risk overall, by estrogen receptor (ER) status, and type (invasive or ductal carcinoma in situ (DCIS)), with and without adjustment for body mass index (BMI). ResultsAmong 181,460 postmenopausal women, 14,484 were diagnosed with breast cancer over a median 21 years of follow-up. Median (IQR) UPF intake was 284.6 (191.1-466.6) g/1000 kcal/day. No associations between UPF intake and postmenopausal breast cancer overall (HRQ5vs.Q1=0.98, 95% CI=0.93-1.03; Ptrend=0.32), by ER status (ER+: HRQ5vs.Q1=1.01, 95% CI=0.94-1.09; Ptrend=0.95; ER-: HRQ5 vs. Q1=1.02, 95% CI=0.87-1.20; Ptrend=0.58), or by type (invasive: HRQ5vs.Q1=0.98, 95% CI=0.92-1.04; Ptrend=0.14; DCIS HRQ5vs.Q1=1.00, 95% CI=0.87-1.13; Ptrend=0.26) were observed. Following BMI adjustment, inverse trends for overall (Ptrend=0.03) and invasive (Ptrend=0.01) breast cancer were observed. ConclusionUPF intake was not associated with postmenopausal breast cancer in the NIH-AARP cohort. Inverse trends observed after adjusting for BMI are likely spurious, owing to over-adjustment bias.

IntroductionWomen with recent parity are at increased short-term breast cancer (BC) risk and face a worse prognosis. The effect of parity on response to neoadjuvant chemotherapy (NAC) is unstudied, and the influence of inherited susceptibility on parity-related short-term risk remains unclear. MethodsWe conducted a retrospective case-cohort study among women aged [&le;]50 with non-metastatic BC diagnosed between 2010 and 2020 who underwent genetic testing and were treated at Northwestern Medicine. Associations between NAC response and recency of parity were evaluated using multivariate logistic regression, stratified by tumor biologic subtypes. Relationships between germline mutations, recency of parity, and BC were explored via multi-state modeling and linear regression. ResultsAmong 1,080 eligible women, 231 received NAC. Treatment response was poorer in parous women with triple negative tumors compared to nullipara, regardless of the recency of parity (P<0.03). Among 122 women (11.3%) with detectable pathogenic mutations, adjusted analyses with both modeling approaches revealed no indications that BRCA1/2 carriers had an increased hazard of BC diagnosis in the decade following recent parity, compared to nulliparous mutation carriers. For BRCA2 and PALB2 carriers, breast cancer diagnosis occurred less frequently in the post-partum intervals. ConclusionWe observed a poor response to NAC in parous TNBC patients compared to nullipara; effects of immunotherapy-based regimens deserve evaluation in the context of parity. Post-partum BC occurrence is not increased in BRCA1/2 carriers; effects of rarer susceptibility genes may differ. These important effects of parity on BC in young women and those at genetic risk warrant larger prospective studies.