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Background: It has been suggested that the association between body mass index and breast cancer risk differs between Asian women and Western women. We aimed to assess the associations between body mass index and breast cancer incidence in East Asian women., Methods: Pooled analyses were performed using individual participant data of 319,189 women from 13 cohort studies in Japan, Korea, and China. Participants' height and weight were obtained by measurement or self-reports at cohort baseline. Breast cancer was defined as code C50.0-C50.9 according to the International Classification. Using a Cox proportional hazards model, hazard ratios of breast cancer were estimated for each body mass index category, with the reference group set as the group with a body mass index of 21 to < 23 kg/m 2 . The hazard ratio for a 5 kg/m 2 increase in body mass index was also calculated., Results: During a mean 16.6 years of follow-up, 4819 women developed breast cancer. Similar to Westerners, a steady increase in breast cancer risk with increasing body mass index was observed in postmenopausal women, but the slope of the risk increase appeared to slow at a body mass index of 26-28 kg/m 2 . In premenopausal women, the inverse association seen in Westerners was not observed. The risk of developing breast cancer after 50 years of age increased slightly with increasing body mass index, which was more pronounced in the older birth cohort. There was no significant association between body mass index and the risk of developing breast cancer before 50 years of age, but the risk estimates changed from positive to negative as the birth cohort got younger., Conclusions: In East Asia, the role of body mass index in breast cancer in premenopausal women may be changing along with the increase in obesity and breast cancer. The increased risk of postmenopausal breast cancer with a higher body mass index was as robust as that of Western women., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in accordance with the Declaration of Helsinki. Each participating study was approved by the relevant institutional ethical review boards. The protocol for the ACC analysis was approved by the institutional review board of the National Cancer Center, Japan. The requirement for consent from several cohort studies was waived due to the justification for lack of consent at the time of the survey, the difficulty in obtaining new consent, and the public necessity of the research. Consent for publication All authors reviewed and approved the final version for submission. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Shoulder dysfunction is one of the most bothersome questions for breast cancer survivors. Studies show that mirror therapy can improve shoulder function in patients with a limited shoulder range of motion and shoulder pain. Here, this article reports the results of a randomized controlled trial investigating the effects of the mirror therapy on shoulder function in patients with breast cancer following surgical treatments., Methods: Totally, 79 participants were divided to two groups receiving active range-of-motion upper limb exercise based on the mirror therapy or active range-of-motion upper limb exercise respectively for 8 weeks. Shoulder range of motion, Constant-Murley Score, Disabilities of Arm, Shoulder, and Hand Questionnaire, Tampa Scale of Kinesiophobia, Visual analog scale, and grip strength were measured at baseline (T0), 2 weeks (T1), 4 weeks (T2), and 8 weeks (T3). The effects of the intervention on shoulder function were analyzed in generalized estimation equation, from group, time, and the interactions between group and time based on the data from participants who completed at least one post-baseline observation RESULTS: At least one post-baseline observation was performed by 69 participants (n=34 mirror group, n=35 control group). 28(82.35%) participants in the mirror group adhered to the exercise compared to 30(85.71%) in the control group. Generalized estimation equation model showed group had main effects on forward flexion (Waldχ²=6.476, P=0.011), with the Cohen's d=0.54. The effects of the group on abduction, Constant-Murley Score, and Disabilities of Arm, Shoulder, and Hand Questionnaire were significant when fix the effects of the time. At 8 weeks, participants in the mirror group showed an improvement in abduction compared to the control group (P=0.005), the Cohen's d was 0.70. At 8 weeks, participants in the mirror group had a higher Constant-Murley Score than control group (P=0.009), with Cohen's effect size value of d=0.64. The mirror group showed a greater improvement on the Disability of Arm, Shoulder, and Hand Questionnaire than control group at 2 weeks, 4 weeks, and 8 weeks (P≤0.032), but with a weak effect size value of all (r≤0.32). Group had main effects on Tampa Scale of Kinesiophobia (Waldχ²=6.631, P=0.010), with the Cohen's effect size value of d=0.56., Conclusions: Mirror therapy improved shoulder flexion, abduction, shoulder function in daily life, and arm function and symptom of the affected shoulder in patients with breast cancer following surgical treatment, while decreasing fear of movement/(re)injury. Mirror configuration needs to be improved in further research to increase its feasibility., Implications for Cancer Survivors: Breast cancer survivors can try mirror therapy as a practical and effective method in shoulder rehabilitation for a promotion on effects., Trial Registration: ClinicalTrial.gov Identifier: ChiCTR2000033080., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. 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. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency., Significance: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Background: Little research has focused on the relationship between gut microbiome and chemotherapy-induced toxicity., Methods: This prospective study involves 301 patients with breast cancer who had prechemotherapy stool samples collected. Gut microbiome was sequenced by shotgun metagenomics; associations with chemotherapy-induced toxicities during first-line treatment by gut microbial diversity, composition, and metabolic pathways with severe (i.e., grade ≥3) hematological and gastrointestinal toxicities were evaluated via multivariable logistic regression., Results: High prechemotherapy α-diversity was associated with a significantly reduced risk of both severe hematological toxicity (odds ratio [OR] = 0.94; 95% CI, 0.89-0.99; p = .048) and neutropenia (OR = 0.94; 95% CI, 0.89-0.99; p = .016). A high abundance of phylum Synergistota, class Synergistia, and order Synergistales were significantly associated with a reduced risk of severe neutropenia; conversely, enrichment of phylum Firmicutes C, class Negativicutes, phylum Firmicutes I, and class Bacilli A, order Paenibacillales were significantly associated with an increased risk of severe neutropenia (p range: 0.012-2.32 × 10 -3 ; false discovery rate <0.1). Significant positive associations were also observed between severe nausea/vomiting and high Chao1 indexes, β-diversity (p < .05), 20 species belonging to the family Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae (p value range: 6.14 × 10 -3 to 1.33 × 10 -5 ; false discovery rate <0.1), and three metabolic pathways involved in reductive tricarboxylic acid cycle I and cycle II, and an incomplete reductive tricarboxylic acid cycle (p < .01). Conversely, a high abundance of species Odoribacter laneus and the pathway related to the L-proline biosynthesis II were inversely associated with severe nausea/vomiting., Conclusions: Our study suggests that gut microbiota may be a potential preventive target to reduce chemotherapy-induced toxicity., (© 2024 American Cancer Society.)

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).)

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: 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.)

Purpose: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer., Methods: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity., Results: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( P nonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; P het = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity., Conclusion: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

With a growing body of evidence establishing circular RNAs (circRNAs) are widely exploited in eukaryotic cells and have a significant contribution in the occurrence and development of many complex human diseases. Disease-associated circRNAs can serve as clinical diagnostic biomarkers and therapeutic targets, providing novel ideas for biopharmaceutical research. However, available computation methods for predicting circRNA-disease associations (CDAs) do not sufficiently consider the contextual information of biological network nodes, making their performance limited. In this work, we propose a multi-hop attention graph neural network-based approach MAGCDA to infer potential CDAs. Specifically, we first construct a multi-source attribute heterogeneous network of circRNAs and diseases, then use a multi-hop strategy of graph nodes to deeply aggregate node context information through attention diffusion, thus enhancing topological structure information and mining data hidden features, and finally use random forest to accurately infer potential CDAs. In the four gold standard data sets, MAGCDA achieved prediction accuracy of 92.58%, 91.42%, 83.46% and 91.12%, respectively. MAGCDA has also presented prominent achievements in ablation experiments and in comparisons with other models. Additionally, 18 and 17 potential circRNAs in top 20 predicted scores for MAGCDA prediction scores were confirmed in case studies of the complex diseases breast cancer and Almozheimer's disease, respectively. These results suggest that MAGCDA can be a practical tool to explore potential disease-associated circRNAs and provide a theoretical basis for disease diagnosis and treatment.

Growing studies reveal that Circular RNAs (circRNAs) are broadly engaged in physiological processes of cell proliferation, differentiation, aging, apoptosis, and are closely associated with the pathogenesis of numerous diseases. Clarification of the correlation among diseases and circRNAs is of great clinical importance to provide new therapeutic strategies for complex diseases. However, previous circRNA-disease association prediction methods rely excessively on the graph network, and the model performance is dramatically reduced when noisy connections occur in the graph structure. To address this problem, this paper proposes an unsupervised deep graph structure learning method GSLCDA to predict potential CDAs. Concretely, we first integrate circRNA and disease multi-source data to constitute the CDA heterogeneous network. Then the network topology is learned using the graph structure, and the original graph is enhanced in an unsupervised manner by maximize the inter information of the learned and original graphs to uncover their essential features. Finally, graph space sensitive k-nearest neighbor (KNN) algorithm is employed to search for latent CDAs. In the benchmark dataset, GSLCDA obtained 92.67% accuracy with 0.9279 AUC. GSLCDA also exhibits exceptional performance on independent datasets. Furthermore, 14, 12 and 14 of the top 16 circRNAs with the most points GSLCDA prediction scores were confirmed in the relevant literature in the breast cancer, colorectal cancer and lung cancer case studies, respectively. Such results demonstrated that GSLCDA can validly reveal underlying CDA and offer new perspectives for the diagnosis and therapy of complex human diseases.

Purpose: Gut microbiota play an important role in human health, including cancer. Cancer and its treatment, in turn, may alter the gut microbiome. To understand this complex relationship, we profiled the gut microbiome of 356 Vietnamese patients with breast cancer., Materials and Methods: Stool samples were collected before chemotherapy, with 162 pre- and 194 postsurgery. The gut microbiome was measured by shotgun metagenomic sequencing. Associations of gut microbial diversity, taxa abundance, and gut microbiome health index (GMHI) with sociodemographic, clinical factors, and tumor characteristics were evaluated., Results: Postsurgery samples were associated with significantly lower α- and β-diversities ( P < .001) and showed significant differences in the abundance of 15% of 2,864 investigated taxa (false discovery rate [FDR] <0.1) compared with presurgery samples. An unhealthy gut microbiome was prevalent among patients with breast cancer, with a mean GMHI of -0.79 and -2.81 in pre- and postsurgery stool samples, respectively. In an analysis of 162 presurgery stool samples, diagnosis delay was significantly associated with lower α-diversity, variation in β-diversity, an increased abundance of species Enorma massiliensis , and a decreased abundance of Faecalicoccus pleomorphus . High intake of fiber was significantly associated with lower α-diversity and a higher abundance of species belonging to Bifidobacterium , Prevotella , and Bacteroides gena (FDR < 0.1). We did not find that cancer stage and subtype, menopausal status, comorbidity, antibiotic use during 3 months before stool collection, or physical activity was significantly associated with α- and β-diversities or GMHI although a few significant differences were observed in taxa abundance., Conclusion: Our study revealed that diagnosis delay, high fiber intake, and breast cancer surgery, which is always followed by antibiotic prophylaxis in Vietnam, led to a less diverse and unhealthy gut microbiome among patients with breast cancer.

Background: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts., Methods: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts., Results: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26])., Conclusion: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts., (© 2024. The Author(s).)

Purpose: The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis., Experimental Design: A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR., Results: HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISRhigh, but not proliferative ISRlow DCCs. HC4 blocked expansion of established micro-metastasis that contained ISRhigh slow-cycling cells. Single-cell gene expression profiling and imaging revealed that a significant proportion of solitary DCCs in lungs were indeed dormant and displayed an unresolved ER stress as revealed by high expression of a PERK-regulated signature. In human breast cancer metastasis biopsies, GADD34 expression (PERK-regulated gene) and quiescence were positively correlated. HC4 effectively eradicated dormant bone marrow DCCs, which usually persist after rounds of therapies. Importantly, treatment with CDK4/6 inhibitors (to force a quiescent state) followed by HC4 further reduced metastatic burden. In HNSCC and HER2+ cancers HC4 caused cell death in dormant DCCs. In HER2+ tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF., Conclusions: Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISRhigh DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested "persister" cells that escape anti-proliferative therapies., (©2023 American Association for Cancer Research.)

Background: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women., Methods: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel., Results: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28)., Conclusions: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women., Competing Interests: Competing interests: BCAC conflict of interest: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. JV is one ofthe inventors of diagnosis and treatment of ERCC3-mutant cancer. AWK has a research funding for his institution from Myriad Genetics for an unrelated project (funding dates 2017–2019). UM has research collaborations with Mercy BioAnalytics, RNA Guardian, Dana Farber and iLOF (Intelligent Lab on Fiber). RAM is a consultant for Pharmavite., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483 R ∧ rs1473473 D ∧ rs3729931 D : OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation., (© 2023. The Author(s).)

Background: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer., Methods: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs., Results: Assuming a 1 × 10 -5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (OR int  = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (OR int  = 0.91, 95% CI 0.88-0.94)., Conclusions: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Disseminated cancer cells (DCCs) in secondary organs can remain dormant for years to decades before reactivating into overt metastasis. Microenvironmental signals leading to cancer cell chromatin remodeling and transcriptional reprogramming appear to control onset and escape from dormancy. Here, we reveal that the therapeutic combination of the DNA methylation inhibitor 5-azacytidine (AZA) and the retinoic acid receptor ligands all-trans retinoic acid (atRA) or AM80, an RARα-specific agonist, promotes stable dormancy in cancer cells. Treatment of head and neck squamous cell carcinoma (HNSCC) or breast cancer cells with AZA+atRA induces a SMAD2/3/4-dependent transcriptional program that restores transforming growth factor β (TGF-β)-signaling and anti-proliferative function. Significantly, either combination, AZA+atRA or AZA+AM80, strongly suppresses HNSCC lung metastasis formation by inducing and maintaining solitary DCCs in a SMAD4 + /NR2F1 + non-proliferative state. Notably, SMAD4 knockdown is sufficient to drive resistance to AZA+atRA-induced dormancy. We conclude that therapeutic doses of AZA and RAR agonists may induce and/or maintain dormancy and significantly limit metastasis development., Competing Interests: Declaration of interests J.A.A.-G. is a scientific co-founder of, scientific advisory board member at, and equity owner in HiberCell and receives financial compensation as a consultant for HiberCell, a Mount Sinai spin-off company focused on therapeutics that prevent or delay cancer recurrence., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified around 200 loci associated with breast cancer risk. However, protein targets for these loci remain largely unknown. Identifying protein targets and biomarkers can improve the understanding of cancer biology and etiology and identify high-risk individuals for cancer prevention. In this study, we investigated genetically predicted levels of 1142 circulating proteins with breast cancer risk in 133 384 cases and 113 789 controls of European ancestry included in the Breast Cancer Association Consortium (BCAC). We identified 22 blood protein biomarkers associated with the risk of overall breast cancer at a false discovery rate (FDR) <0.05, including nine proteins encoded by genes located at least 500 kb away from previously reported risk variants for breast cancer. Analyses focusing on 124 encoding genes located at GWAS-identified breast cancer risk loci found 20 proteins associated with overall breast cancer risk and one protein associated with triple-negative breast cancer risk at FDR <0.05. Adjustment for the GWAS-identified risk variants significantly attenuated the association for 13 of these proteins, suggesting that these proteins may be the targets of these GWAS-identified risk loci. The identified proteins are involved in various biological processes, including glutathione conjugation, STAT5 signaling and NF-κB signaling pathways. Our study identified novel protein targets and risk biomarkers for breast cancer risk., (© 2023 UICC.)

Purpose: Physical activity (PA) is associated with many health benefits. While PA has been associated with reduced mortality after breast cancer diagnosis in many studies, few studies have examined the role of PA in breast cancer survival among underserved and minority populations, including Black women. We investigated PA in association with mortality among Black predominantly low-income breast cancer survivors in the Southern Community Cohort Study (SCCS)., Methods: Study participants were women diagnosed with incident breast cancer (n = 949) in the SCCS, which is a prospective cohort study of predominantly low-income adults aged 40-79 years recruited from 12 Southeastern states between 2002 and 2009. Participants completed a detailed baseline questionnaire, with annual follow-up for mortality via registry linkages. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of pre-diagnosis PA (measured via a validated questionnaire) with all-cause and breast cancer-specific mortality., Results: Breast cancer survivors had a mean age of 61.1 years and most (79.3%) had a household income of < $25,000. In adjusted models, higher levels of total PA (MET-hours/day) were inversely associated with all-cause mortality with HRs (95% CIs): 0.79 (0.59-1.06), 0.66 (0.49-0.90), and 0.60 (0.43-0.84), for Q2, Q3, and Q4 (reference: Q1), respectively, p trend  ≤ 0.01. A similar inverse association was found for breast cancer-specific mortality., Conclusion: Higher levels of pre-diagnosis PA were associated with improved survival among low-income Black breast cancer survivors. Resources to reduce barriers to PA participation and increase support for education and intervention efforts to promote PA among Black women are needed., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes., Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry., Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10 -6 ) and AC058822.1 (P = 1.47 × 10 -4 ), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C., Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10 -5 ), demonstrating the importance of diversifying study cohorts., (© 2023. The Author(s).)

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1 , BRCA2 and other high-risk genes with known penetrance.

Background: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear., Methods: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided., Results: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like., Conclusions: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10 -8 and a Bonferroni-corrected p < 4.6 × 10 -6 , respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Few studies have investigated the association between high-sensitivity C-reactive protein (hsCRP) level and site-specific cancer mortality. In this study, we aimed to examine the associations of hsCRP with overall and site-specific cancer mortality among South Koreans using data on the Health Examinees (HEXA) Study cohort (41,070 men and 81,011 women aged ≥40 years). We obtained mortality information from the National Statistical Office of Korea, which provided the dates and causes of all deaths occurring through December 31, 2015, by linking mortality data with each participant's unique national identifier. Cox proportional hazards and restricted cubic spline models were used to assess the association between hsCRP and cancer mortality with adjustment for covariates. An analysis of site-specific cancer mortality was focused on 5 major cancers (lung, liver, gastric, colorectal, and breast/prostate). Median hsCRP levels were 0.77 mg/L and 0.59 mg/L for men and women, respectively. A dose-response association between hsCRP and overall cancer mortality was observed in men but disappeared in women after exclusion of deaths occurring in the first 1 or 2 years of follow-up. Elevated hsCRP levels increased the risks of lung, liver, and gastric cancer mortality in men, but the risks of colorectal and breast cancer mortality were not increased. The dose-response association between hsCRP and cancer mortality was observed differently depending on site-specific cancer mortality by sex., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework., Methods: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis., Results: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (n total  = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 × 10 -4 ) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, P heterogeneity  < 0.005)., Conclusions: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics., Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (n snps =5) or sedentary time (n snps =6), or accelerometer-measured (n snps =1) or self-reported (n snps =5) vigorous physical activity., Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger)., Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women., Competing Interests: Competing interests: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received honoraria from Roche, Novartis and Pfizer. AWK declares research funding to her institution from Myriad Genetics for an unrelated project (funding dates 2017-2019). SL declares grants and honoraria paid to her institution from Amgen, Novartis, Pfizer, Roche, and, outside the submitted work, grants and/or honoraria paid to her institution from AbbVie, Celgene, Seattle Genetics, PrIME/Medscape, Daiichi-Sankyo, Lilly, Samsung, BMS, Puma, Immunomedics, AstraZeneca, Pierre Fabre, Merck, GlaxoSmithKlein, EirGenix, and Bayer, and personal fees from Chugai; SL also has a patent EP14153692.0 pending. UM declares stock ownership in Abcodia Ltd. RAM has been a consultant for Pharmavite. No other authors have conflicts to declare., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry., Methods: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined., Results: We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18)., Conclusions: No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk., (© 2022. The Author(s).)

Many risk factors have been identified for breast cancer. The potential causality for some of them remains uncertain, and few studies have comprehensively investigated these associations by molecular subtypes. We performed a two-sample Mendelian randomization (MR) study to evaluate potential causal associations of 23 known and suspected risk factors and biomarkers with breast cancer risk overall and by molecular subtypes using data from the Breast Cancer Association Consortium. The inverse-variance weighted method was used to estimate odds ratios (OR) and 95% confidence interval (CI) for association of each trait with breast cancer risk. Significant associations with breast cancer risk were found for 15 traits, including age at menarche, age at menopause, body mass index, waist-to-hip ratio, height, physical activity, cigarette smoking, sleep duration, and morning-preference chronotype, and six blood biomarkers (estrogens, insulin-like growth factor-1, sex hormone-binding globulin [SHBG], telomere length, HDL-cholesterol and fasting insulin). Noticeably, an increased circulating SHBG was associated with a reduced risk of estrogen receptor (ER)-positive cancer (OR = 0.83, 95% CI: 0.73-0.94), but an elevated risk of ER-negative (OR = 1.12, 95% CI: 0.93-1.36) and triple negative cancer (OR = 1.19, 95% CI: 0.92-1.54) (P heterogeneity  = 0.01). Fasting insulin was most strongly associated with an increased risk of HER2-negative cancer (OR = 1.94, 95% CI: 1.18-3.20), but a reduced risk of HER2-enriched cancer (OR = 0.46, 95% CI: 0.26-0.81) (P heterogeneity  = 0.006). Results from sensitivity analyses using MR-Egger and MR-PRESSO were generally consistent. Our study provides strong evidence supporting potential causal associations of several risk factors for breast cancer and suggests potential heterogeneous associations of SHBG and fasting insulin levels with subtypes of breast cancer., (© 2022 UICC.)

Purpose: Studies conducted primarily among European ancestry women reported 12 breast cancer predisposition genes. However, etiologic roles of these genes in breast cancer among African ancestry women have been less well-investigated., Methods: We conducted a case-control study in African American women, which included 1117 breast cancer cases and 2169 cancer-free controls, and a pooled analysis, which included 7096 cases and 8040 controls of African descent. Odds ratios of associations with breast cancer risk were estimated., Results: Using sequence data, we identified 61 pathogenic variants in 12 breast cancer predisposition genes, including 11 pathogenic variants not yet reported in previous studies. Pooled analysis showed statistically significant associations of breast cancer risk with pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D (all P < .05). The associations with BRCA1, PALB2, and RAD51D were stronger for estrogen receptor (ER)-negative than for ER-positive breast cancer (P heterogeneity < .05), whereas the association with CHEK2 was stronger for ER-positive than for ER-negative breast cancer., Conclusion: Our study confirmed previously identified associations of breast cancer risk with BRCA1, BRCA2, PALB2, ATM, TP53, NF1, and CHEK2 and provided new evidence to extend the associations of breast cancer risk with RAD51C and RAD51D, which was identified previously in European ancestry populations, to African ancestry women., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: Cognitive decline is one of the main side effects of breast cancer patients after relevant treatment, but there is a lack of clear measures for prevention and management without definite mechanism. Moreover, postoperative patients also have a need for limb rehabilitation. Whether the cognitive benefits of Baduanjin exercise can improve the overall well-being of breast cancer patients remains unknown., Methods: This randomized controlled trial was conducted on 70 patients with breast cancer receiving chemotherapy who were randomly assigned and allocated to (1:1) a supervised Baduanjin intervention group (5 times/week, 30 min each time) or a control group for 3 months. The effects of Baduanjin exercise intervention were evaluated by outcome measures including subjective cognitive function, symptoms (fatigue, depression, and anxiety), and health-related quality of life at pre-intervention (T0), 4 weeks (T1), 8 weeks (T2), and 12 weeks (T3). The collected data were analyzed by using an intention-to-treat principle and linear mixed-effects modeling., Results: Participants in the Baduanjin intervention group had a significantly greater improvement in terms of FACT-Cog (F = 14.511; p < 0.001), PCI (F = 15.789; p < 0.001), PCA (F = 6.261; p = 0.015), and FACT-B scores (F = 8.900; p = 0.004) compared with the control group over the time. The exercise-cognition relationship was significantly mediated through the reduction of fatigue (indirect effect: β = 0.132; 95% CI 0.046 to 0.237) and the improvement of anxiety (indirect effect: β =  - 0.075; 95% CI - 0.165 to -0.004)., Conclusions: This pilot study revealed the benefits of Baduanjin exercise for subjective cognition and health-related quality of life of Chinese breast cancer patients receiving chemotherapy and outlined the underlying mediating mechanism of exercise-cognition. The findings provided insights into the development of public health initiatives to promote brain health and improve quality of life among breast cancer patients., Trial Registration Number: ChiCTR 2,000,033,152., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Evidence on associations between dietary intake and risk of breast cancer subtypes is limited and inconsistent. We evaluated associations of fruit, vegetable, meat, and fish consumption with risk of breast cancer overall and by molecular subtype in the Vietnamese Breast Cancer Study (VBCS)., Method: VBCS includes 476 incident breast cancer cases and 454 age-matched controls. Dietary habits over the past 5 years were assessed by in-person interviews using a validated food frequency questionnaire. Associations of food groups with breast cancer were evaluated via logistic regression for overall and molecular subtype with adjustment for age, education, income, family history of cancer, menopausal status, body mass index, exercise, total energy intake, and other potential dietary confounders. Odds ratio (OR) was used to approximate relative risk., Results: High fruit intake was inversely associated with breast cancer risk, with adjusted ORs [95% confidence intervals (CI)] of 0.67 (95% CI, 0.47-0.95) and 0.41 (95% CI, 0.27-0.61) for second and third tertiles versus first tertile, respectively (Ptrend < 0.001). This association was stronger for triple-negative than other subtypes (Pheterogeneity < 0.001). High intake of freshwater fish was inversely associated with overall breast cancer (ORT3vsT1 = 0.63; 95% CI, 0.42-0.95; Ptrend = 0.03). An inverse association was observed between HER2-enriched subtype and red and organ meat intake (ORT3vsT1 = 0.40; 95% CI, 0.17-0.93; Ptrend = 0.04; Pheterogeneity = 0.50)., Conclusions: High intakes of fruit and freshwater fish were associated with reduced breast cancer risk; association for the former was stronger for triple-negative subtype., Impact: Our findings suggest high intakes of fruit and freshwater fish may reduce breast cancer risk among Vietnamese women., (©2022 American Association for Cancer Research.)

Background: Oncotype DX recurrence score (ODX RS) is a prognostic biomarker for early-stage, node-negative, estrogen receptor-positive (ER+) breast cancer. Whether test uptake, associated factors, and the test's prognostic values differ by race/ethnicity is unknown., Methods: From the National Cancer Database, 2010-2014, we identified 227,259 early-stage ER+, node-negative breast cancer cases. Logistic regression was used to examine ODX RS uptake and associated factors among non-Hispanic White (White), non-Hispanic Black (Black), Hispanic, and Asian American patients. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for overall mortality with ODX RS by race/ethnicity., Results: White patients were more likely to receive an ODX RS test compared with Black, Hispanic, and Asian American patients (36.7%, 32.8%, 31.6%, and 35.5%, respectively; P < 0.001). Disparities persisted after adjustments for demographics, clinical characteristics, and access-to-care, with rate ratios of 0.87 (95% CI, 0.85-0.88), 0.82 (95% CI, 0.80-0.85), and 0.89 (95% CI, 0.87-0.92), respectively, for Black, Hispanic, and Asian American compared with White patients. Black patients had higher proportions of high-risk scores (≥26) compared with White, Hispanic, and Asian American patients (19.1%, 14.0%, 14.2%, and 15.6%, respectively; P < 0.0001). ODX RS was predictive for total mortality across all races/ethnicities, particularly younger patients (<50). No significant race/ethnicity interactions were observed., Conclusions: Although ODX RS uptake and risk distribution varied by race/ethnicity, ODX RS was prognostic for mortality across groups., Impact: These findings emphasize the importance of developing strategies to increase ODX RS uptake among racial/ethnic minorities and call for more investigations on potential racial/ethnic differences in breast cancer biology. See related commentary by Wang et al., p. 704., (©2022 American Association for Cancer Research.)

Purpose: To evaluate the association between obesity and the relative prevalence of tumor subtypes among Black women with breast cancer (BC)., Methods: We conducted a pooled case-only analysis of 1,793 Black women with invasive BC recruited through three existing studies in the southeastern US. Multivariable case-only polytomous logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between obesity, measured by pre-diagnostic body mass index (BMI), and human epidermal growth factor receptor 2 + (HER2 +) and triple negative BC (TNBC) subtype relative to hormone receptor (HR) + /HER2- status (referent)., Results: Among 359 premenopausal women, 55.4% of cases were HR + /HER2 -, 20.1% were HER2 + , and 24.5% were TNBC; corresponding percentages among 1,434 postmenopausal women were 59.3%, 17.0%, and 23.6%. Approximately, 50-60% of both pre- and postmenopausal women were obese (BMI > 30 kg/m 2 ), regardless of BC subtype. We did not observe a significant association between obesity and BC subtype. Among postmenopausal women, class I obesity (BMI 35 + kg/m 2 ) was not associated with the development of HER2 + BC (OR 0.69; 95% CI 0.42-1.14) or TNBC (OR 0.93; 95% CI 0.60-1.45) relative to HR + /HER2- tumors. Corresponding estimates among premenopausal women were 1.03 (95% CI 0.43-2.48) and 1.13 (95% CI 0.48-2.64)., Conclusion: In this large study of Black women with BC, there was no evidence of heterogeneity of BMI by BC subtype., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this., Methods: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test., Results: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (P GXE =4.44×10 -6 )., Conclusion: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk., Impact: Our study suggests a limited role of gene-environment interactions in breast cancer risk., Competing Interests: Conflict of interest disclosure statement: The authors declare no potential conflicts of interest.

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs., (© 2021. The Author(s).)

Importance: Polygenic risk scores (PRSs) have shown promise in breast cancer risk prediction; however, limited studies have been conducted among Asian women., Objective: To develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors., Design, Setting, and Participants: This diagnostic study included women of Asian ancestry from the Asia Breast Cancer Consortium. PRSs were developed using data from genomewide association studies (GWASs) of breast cancer conducted among 123 041 women with Asian ancestry (including 18 650 women with breast cancer) using 3 approaches: (1) reported PRS for women with European ancestry; (2) breast cancer-associated single-nucleotide variations (SNVs) identified by fine-mapping of GWAS-identified risk loci; and (3) genomewide risk prediction algorithms. A nongenetic risk score (NGRS) was built, including 7 well-established nongenetic risk factors, using data of 416 case participants and 1558 control participants from a prospective cohort study. PRSs were initially validated in an independent data set including 1426 case participants and 1323 control participants and further evaluated, along with the NGRS, in the second data set including 368 case participants and 736 control participants nested within a prospective cohort study., Main Outcomes and Measures: Logistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% CIs and area under the receiver operating characteristic curve (AUC)., Results: A total of 126 894 women of Asian ancestry were included; 20 444 (16.1%) had breast cancer. The mean (SD) age ranged from 49.1 (10.8) to 54.4 (10.4) years for case participants and 50.6 (9.5) to 54.0 (7.4) years for control participants among studies that provided demographic characteristics. In the prospective cohort, a PRS with 111 SNVs developed using the fine-mapping approach (PRS111) showed a prediction performance comparable with a genomewide PRS that included more than 855 000 SNVs. The OR per SD increase of PRS111 score was 1.67 (95% CI, 1.46-1.92), with an AUC of 0.639 (95% CI, 0.604-0.674). The NGRS had a limited predictive ability (AUC, 0.565; 95% CI, 0.529-0.601). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and NGRS were at a 3.84-fold (95% CI, 2.30-6.46) and 2.10-fold (95% CI, 1.22-3.62) higher risk of breast cancer, respectively. The prediction model including both PRS111 and NGRS achieved the highest prediction accuracy (AUC, 0.648; 95% CI, 0.613-0.682)., Conclusions and Relevance: In this study, PRSs derived using breast cancer risk-associated SNVs had similar predictive performance in Asian and European women. Including nongenetic risk factors in models further improved prediction accuracy. These findings support the utility of these models in developing personalized screening and prevention strategies.

MicroRNAs (miRNA) have been shown to be associated with tumor diagnosis, prognosis, and therapeutic response. MiR-328-3p plays a significant role in breast cancer growth; however, its actual function and how it modulates specific biological functions is poorly understood. Here, miR-328-3p was significantly downregulated in breast cancer, especially in patients with metastasis. Mitochondrial carnitine palmitoyl transferase 1a (CPT1A) is a downstream target gene in the miR-328-3p-regulated pathway. Furthermore, the miR-328-3p/CPT1A/fatty acid β-oxidation/stemness axis was shown responsible for breast cancer metastasis. Collectively, this study revealed that miR-328-3p is a potential therapeutic target for the treatment of breast cancer patients with metastasis, and also a model for the miRNA-fatty acid β-oxidation-stemness axis, which may assist inunderstanding the cancer stem cell signaling functions of miRNA., (© 2021. The Author(s).)

Purpose: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups., Methods: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases)., Results: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk., Conclusion: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. All rights reserved.)

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

High nut consumption is associated with reduced total and certain cause-specific mortality in general populations. However, its association with cancer outcomes among long-term breast cancer survivors remains unknown. We examined the associations of nut consumption (including peanuts and tree nuts), assessed at 5-year postdiagnosis, with overall survival (OS) and disease-free survival (DFS) among 3449 long-term breast cancer survivors from the Shanghai Breast Cancer Survival Study, applying Cox regression analysis. During a median follow-up of 8.27 years post dietary assessment, there were 374 deaths, including 252 breast cancer deaths. Among 3274 survivors without previous recurrence at the dietary assessment, 209 developed breast cancer-specific events, that is, recurrence, metastasis or breast cancer mortality. At 5-year post dietary assessment (ie, 10-year postdiagnosis), regular nut consumers had higher OS (93.7% vs 89.0%) and DFS (94.1% vs 86.2%) rates. After multivariable adjustment, nut consumption was positively associated with OS (P trend  = .022) and DFS (P trend  = .003) following a dose-response pattern, with hazard ratios (95% confidence interval) of 0.72 (0.52-1.05) for OS and 0.48 (0.31-0.73) for DFS, for participants with greater than median nut intake compared with nonconsumers. The associations did not vary by nut type. Stratified analyses showed that the associations were more evident among participants with a higher total energy intake for OS (P interaction  = .02) and among participants with early stage (I-II) breast cancers for DFS (P interaction  = .04). The nut-DFS associations were not modified by estrogen receptor/progesterone receptor status or other known prognostic factors. In conclusion, nut consumption was associated with better survival, particularly DFS, among long-term breast cancer survivors., (© 2021 UICC.)

We have previously identified a genetic variant, rs34331122 in the 22q11.21 locus, as being associated with breast cancer risk in a genome-wide association study. This novel variant is located in the intronic region of the T-box transcription factor 1 (TBX1) gene. Cis-expression quantitative trait loci analysis showed that expression of TBX1 was regulated by the rs34331122 variant. In the current study, we investigated biological functions and potential molecular mechanisms of TBX1 in breast cancer. We found that TBX1 expression was significantly higher in breast cancer tumor tissues than adjacent normal breast tissues and increased with tumor stage (P < 0.05). We further knocked-down TBX1 gene expression in three breast cancer cell lines, MDA-MB-231, MCF-7 and T47D, using small interfering RNAs and examined consequential changes on cell oncogenicity and gene expression. TBX1 knock-down significantly inhibited breast cancer cell proliferation, colony formation, migration and invasion. RNA sequencing and flow cytometry analysis revealed that TBX1 knock-down in breast cancer cells induced cell cycle arrest in the G1 phase through disrupting expression of genes involved in the cell cycle pathway. Furthermore, survival analysis using the online Kaplan-Meier Plotter suggested that higher TBX1 expression was associated with worse outcomes in breast cancer patients, especially for estrogen receptor-positive breast cancer, with HRs (95% CIs) for overall survival (OS) and distant metastasis free survival (DMFS) of 1.5 (1.05-2.15) and 1.55 (1.10-2.18), respectively. In conclusion, our results suggest that the TBX1 gene may act as a putative oncogene of breast cancer through regulating expressions of cell cycle-related genes., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance., (© 2022. The Author(s).)

Background: The history of gestational diabetes mellitus (GDM) has been associated with breast cancer risk in some studies, particularly in young women, but results of cohort studies are conflicting., Methods: We pooled data from 257 290 young (age <55 years) women from five cohorts. We used multivariable Cox proportional-hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GDM history and risk of breast cancer, overall and by oestrogen receptor (ER) status, before age 55 years, adjusted for established breast cancer risk factors., Results: Five percent of women reported a history of GDM and 6842 women reported an incident breast-cancer diagnosis (median follow-up = 16 years; maximum = 24 years). Compared with parous women without GDM, women with a history of GDM were not at increased risk of young-onset breast cancer overall (HR = 0.90; 95% CI: 0.78, 1.03) or by ER status (HR = 0.96; 95% CI: 0.79, 1.16 for ER-positive; HR = 1.07; 95% CI: 0.78, 1.47 for ER-negative). Compared with nulliparous women, parous women with a history of GDM had a lower risk of breast cancer overall (HR = 0.79; 95% CI: 0.68, 0.91) and of ER-positive (HR = 0.82; 95% CI: 0.66, 1.02) but not ER-negative (HR = 1.09; 95% CI: 0.76, 1.54) invasive breast cancer. These results were consistent with the HRs comparing parous women without GDM to nulliparous women., Conclusions: Results of this analysis do not support the hypothesis that GDM is a risk factor for breast cancer in young women. Our findings suggest that the well-established protective effect of parity on risk of ER-positive breast cancer persists even for pregnancies complicated by GDM., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear., Methods: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes., Results: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions., Conclusion: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction., (© 2021. The Author(s).)

Objectives: Though menstrual and reproductive factors have been associated with the risk of breast cancer in many populations, very few studies have been conducted among Vietnamese women. This study aimed to assess the association between menstrual and reproductive factors and the risk of breast cancer in Vietnamese women., Methods: A retrospective case-control study of 490 breast cancer cases and 468 controls was conducted in Northern Vietnam. Unconditional logistic regression models adjusting for confounders were used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the associations of menstrual and reproductive factors with the risk of breast cancer; overall and by cancer subtype., Results: Among breast cancer patients, the luminal B subtype was the most frequent (48.6%), followed by HER2-overexpressing (24.5%), luminal A (16.7%), and triple-negative breast cancer (TNBC; 10.2%). Among menopausal women, menopausal age at 50 years or older (OR = 1.71, 95% CI: 1.15-2.57 vs. <50 y) was associated with an increased risk of breast cancer. Earlier age at menarche (<13 y) was associated with a significantly increased risk of breast cancer (OR = 2.66, 95% CI: 1.08-7.51) among premenopausal women only and the luminal A subtype of breast cancer (OR = 3.06, 95% CI: 1.04-8.16). Having more than two children was associated with a reduced risk of premenopausal (OR = .42, 95%CI: .21-.83), luminal B (OR = .43, 95% CI: .24-.79), and TNBC (OR = .34, 95% CI: .14-.89). Later menopause was positively associated with the risk of breast cancer with HER2 overexpression (OR = 2.19, 95% CI: 1.14-4.23)., Conclusion: Associations of menstrual and reproductive factors with breast cancer among Vietnamese women, particularly for among premenopausal women and for the luminal A subtype, are generally consistent with those reported from other countries. These findings suggest that changes in menstrual and reproductive patterns among young Vietnamese women may contribute to the recent rising incidence of breast cancer in Vietnam.

Background: The clinicopathological significance of spatial tumor-infiltrating lymphocytes (TILs) subpopulations is not well studied due to lack of high-throughput scalable methodology for studies with large human sample sizes., Objective: Establishing a cyclic fluorescent multiplex immunohistochemistry (mIHC/IF) method coupled with computer-assisted high-throughput quantitative analysis to evaluate associations of six TIL markers (CD3, CD8, CD20, CD56, FOXP3, and PD-L1) with clinicopathological factors of breast cancer., Methods: Our 5-plex mIHC/IF staining was shown to be reliable and highly sensitive for labeling three biomarkers per tissue section. Through repetitive cycles of 5-plex mIHC/IF staining, more than 12 biomarkers could be detected per single tissue section. Using open-source software CellProfiler, the measurement pipelines were successfully developed for high-throughput multiplex evaluation of intratumoral and stromal TILs., Results: In analyses of 188 breast cancer samples from the Nashville Breast Health Study, high-grade tumors showed significantly increased intratumoral CD3+CD8+ cytotoxic T lymphocyte density (P= 0.0008, false discovery rate (FDR) adjusted P= 0.0168) and intratumoral PD-L1 expression (P= 0.0061, FDR adjusted P= 0.0602) compared with low-grade tumors., Conclusions: The high- and low-grade breast cancers exhibit differential immune responses which may have clinical significance. The multiplexed imaging quantification strategies established in this study are reliable, cost-efficient and applicable in regular laboratory settings for high-throughput tissue biomarker studies, especially retrospective and population-based studies using archived paraffin tissues.

Background: Shoulder function complications are common after treatment for breast cancer. Quite a few survivors still report a limited shoulder range of motion, even though the free range-of-motion upper limb exercise is helpful to restore shoulder function. Mirror therapy (MT) is a classical and effective rehabilitation technique to recover motor and sensory function for the limbs; in addition, studies have reported that MT has an influence on patients with shoulder functional dysfunction including increasing shoulder range of motion, improving shoulder function scores, and decreasing pain scores. Here, we describe a protocol of a randomized controlled trial to explore if free range-of-motion upper limb exercise based on MT has efficacy on shoulder function in survivors after surgery of breast cancer., Methods/design: This is a prospective, single-blind, two-arm randomized controlled trial. An estimated 70 participants will be randomly allocated to (1) the MT group or (2) the control group. The participants in the control group receive free range-of-motion upper limb exercise, and participants in the MT group will engage in free range-of-motion upper limb exercise based on MT. The intervention will start on the first day after surgery and be completed at 8 weeks after surgery. The primary outcome in this protocol is shoulder range of motion (ROM), while the Constant-Murley Score (CMS); Disability of the Arm, Shoulder, and Hand Questionnaire (DASH); Tampa Scale of Kinesiophobia (13-item TSK); visual analog scale (VAS); grip strength; arm circumference; and lymphedema are the secondary outcomes. Assessment will be conducted before allocation (baseline) and at 2 weeks, 4 weeks, and 8 weeks after surgery., Discussion: Based on the results that MT has an influence on shoulder function immediately after intervention in patients without nerve injury, this randomized controlled trial is to observe the efficacy of MT on shoulder function after a long-term intervention in breast cancer survivors. We look forward to the innovation of this study for both breast cancer rehabilitation and MT., Trial Registration: Chinese Clinical Trial Registry ( ChiCTR ) ChiCTR2000033080. Registered on 19 May 2020., (© 2021. The Author(s).)

Purpose: There is an urgent need to understand the biological factors contributing to the racial survival disparity among women with hormone receptor-positive (HR+), HER2- breast cancer. In this study, we examined the impact of PAM50 subtype on 10-year mortality rate in women with HR+, HER2- breast cancer by race., Methods: Women with localized, HR+, HER2- breast cancer diagnosed between 2002 and 2012 from two population-based cohorts were evaluated. Archival tumors were obtained and classified by PAM50 into four molecular subtypes (i.e., luminal A, luminal B, HER2-enriched, and basal-like). The molecular subtypes within HR+, HER2- breast cancers and corresponding 10-year mortality rate were compared between Black and Non-Hispanic White (NHW) women using Cox proportional hazard ratios and survival analysis, adjusting for covariates., Results: In this study, 318 women with localized, HR+, HER2- breast cancer were included-227 Black (71%) and 91 NHW (29%). Young Black women (age ≤ 50) had the highest proportion of HR+, non-luminal A tumors (47%), compared to young NHW (10%), older Black women (31%), and older NHW (30%). Overall, women with HR+, non-luminal A subtypes had a higher 10-year mortality rate compared to HR+, luminal A subtypes after adjustment for age, stage, and income (HR 4.21 for Blacks, 95% CI 1.74-10.18 and HR 3.44 for NHW, 95% CI 1.31-9.03). Among HR+, non-luminal A subtypes there was, however, no significant racial difference in 10-yr mortality observed (Black vs. NHW: HR 1.23, 95% CI 0.58-2.58)., Conclusion: Molecular subtype classification highlights racial disparities in PAM50 subtype distribution among women with HR+, HER2- breast cancer. Among women with HR+, HER2- breast cancer, racial survival disparities are ameliorated after adjusting for molecular subtype., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)