Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (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 to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-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 breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

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.

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

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

The interrelationship between obesity and race in breast cancer prognosis: a prospective cohort study.

BACKGROUND: Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. METHODS: We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). RESULTS: 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m2). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52-6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06-4.51) and non-obese (HR = 2.11, 95% CI = 1.05-4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. CONCLUSIONS: Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between the Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors.

Immunogenicity Risk Assessment of Process-Related Impurities in An Engineered T Cell Receptor Cellular Product.

Cell therapies such as genetically modified T cells have emerged as a promising and viable treatment for hematologic cancers and are being aggressively pursued for a wide range of diseases and conditions that were previously difficult to treat or had no cure. The process development requires genetic modifications to T cells to express a receptor (engineered T cell receptor (eTCR)) of specific binding qualities to the desired target. Protein reagents utilized during the cell therapy manufacturing process, to facilitate these genetic modifications, are often present as process-related impurities at residual levels in the final drug product and can represent a potential immunogenicity risk upon infusion. This manuscript presents a framework for the qualification of an assay for assessing the immunogenicity risk of AA6 and Cas9 residuals. The same framework applies for other residuals; however, AAV6 and Cas9 were selected as they were residuals from the manufacturing of an engineered T cell receptor cellular product in development. The manuscript: 1) elucidates theoretical risks, 2) summarizes analytical data collected during process development, 3) describes the qualification of an in vitro human PBMC cytokine release assay to assess immunogenicity risk from cellular product associated process residuals; 4) identifies a multiplexed inflammatory innate and adaptive cytokine panel with pre-defined criteria using relevant positive controls; and 5) discusses qualification challenges and potential solutions for establishing meaningful thresholds. The assessment is not only relevant to establishing safe exposure levels of these residuals but also in guiding risk assessment and CMC strategy during the conduct of clinical trials.

Acute manganese toxicosis related to joint health supplement ingestion in two dogs.

Two unrelated dogs residing in the same house including an 11-year-old, female spayed, mixed breed dog and a 7-year-old, female spayed, mixed breed dog ingested approximately 75 capsules of a human joint health supplement (Ligaplex I; Standard Process, WI, USA). A total of 2,062 mg of manganese was ingested between both dogs. Dog 1 developed acute fulminant liver failure and a severe coagulopathy that led to hepatic fractures and exsanguination from hemoabdomen. The estimated maximum time from ingestion of the joint health supplement to death was 36 to 48 h. Histologic examination revealed severe periportal hepatic necrosis with mild evidence of preexisiting liver disease and renal tubular epithelial necrosis. Manganese concentrations in liver and kidney tissue were severely increased. Dog 2 developed a severe acute liver injury and was hospitalized for 6 days. Therapies provided during hospitalization included intravenous fluids, maropitant, pantoprazole, N-acetylcysteine, vitamin C, S-adenosylmethionine, and silybin. The dog was treated long-term with S-adenosylmethionine, silybin, ursodiol, and vitamin C. Clinical and biochemical resolution occurred on the recheck examination that took place on day 44. The veterinary literature is comprised of only 2 reports containing 3 dogs that describe acute manganese intoxication. Here, we provide a detailed description of 2 dogs that developed manganese-induced toxicosis after ingestion of a human joint health supplement.

Development and initial validation of the parental response to adolescents' emotions scale: A mixed methods approach.

An exploratory mixed methods design was used to explore age-appropriate characteristics of parental response to emotion (PRE) during adolescence in Chinese families and develop the parental response to adolescents' emotions scale (C-PRAES). Qualitative interviews with 21 parent-adolescent dyads were employed to explore characteristics of PRE in adolescence and generate item pools. Structural validity, criterion validity, measurement invariance across informants (adolescents vs. parents, mothers vs. fathers) and consistency reliability were examined in the quantitative phase (Nadolescent = 702, Nparent = 476). New age-appropriate strategies were generated from qualitative phase: Guidance in reappraisal, Allowing independent regulation, and Avoiding escalation of conflict. The formal version of the C-PRAES comprised items in two dimensions (supportive/non-supportive) and exhibited good validity, reliability, and measurement invariance.

The association of breast surgery ASPIRE: breast pain pathway rapid evaluation project - study protocol.

Background: Breast pain accounts for 20-40% of new referrals to breast units in the UK and these patients have a very low risk of breast cancer. Patients have previously been assessed in resource-intensive, cancer-exclusion, one stop clinics, which are now failing to meet government targets due to excessive demand. UK Breast units are increasingly piloting Breast Pain-only Pathways (BPP) to assess these patients, and there is no consensus for the optimal pathway. The aim of this prospective multicentre study is to assess the safety and patient satisfaction of different BPPs to inform future BPP design and implementation. Methods: All UK breast units will be invited to join the ASPIRE study between January 2023 and December 2023. Units with a BPP are invited to submit their pathway for evaluation; and those without a BPP who see patients with breast pain-only in a one stop clinics setting are also invited to join the study to evaluate the traditional pathway model concurrently. Patient satisfaction assessments will be collected after their initial consultation and patient outcomes, including subsequent cancer diagnosis, will be followed up at 12 months to determine if they have cancer diagnosis after discharge to assess pathway safety.

Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

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.

Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand.

Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon usage conserved across antibody genes. One feature thereof is the hyperutilization of codons that lack genome-encoded Watson-Crick transfer RNAs (tRNAs), instead relying on the posttranscriptional tRNA modification inosine (I34), which expands the decoding capacity of specific tRNAs through wobbling. Antibody-secreting cells had increased I34 levels and were more reliant on I34 for protein production than naïve B cells. Furthermore, antibody I34-dependent codon usage may influence B cell passage through regulatory checkpoints. Our work elucidates the interface between the tRNA pool and protein production in the immune system and has implications for the design and selection of antibodies for vaccines and therapeutics.

Parent-adolescent Congruence and Discrepancy in Perceived Parental Emotion Socialization to Anger and Sadness: Using Response Surface Analysis to Examine the Links with Adolescent Depressive Symptoms.

Parents and adolescents often hold discrepant perceptions of parental emotion socialization, which reflect misunderstandings in parent-adolescent communication on emotions and have potential detrimental effects on mental health of adolescents. The present study investigated the associations between parent-adolescent congruence and discrepancy in parental emotion socialization perception to two specific negative emotions (anger and sadness) and depressive symptoms in Chinese adolescents. A total of 372 adolescents (48.4% female, Mage = 13.43, SDage = 0.49) and their parents (79.6% mother, Mage = 41.15, SDage = 5.46) participated in this study. Both parents and adolescents reported perceived parental emotion socialization to anger and sadness, and adolescents reported depressive symptoms. Data were analyzed using polynomial regression and response surface analyses. Both congruence and discrepancy in parent and adolescent's reports were associated with adolescent depressive symptoms. A higher level of adolescent depressive symptoms was associated with higher parent-adolescent congruence in supportive responses to anger, sadness, and nonsupportive responses to anger. A higher level of depressive symptoms was associated with inconsistent reporting of supportive responses to sadness and nonsupportive responses to anger (only when parents had a more positive view than adolescents). This study highlights the significance of evaluating parent-child communication process by assessing perceived emotion socialization from both parents and adolescents and analyzing the reporting congruence and discrepancy. It also suggests that enhancing effective communication regarding parental emotion socialization could be a promising target for adolescent mental health promotion programs.

The Interrelationship between Obesity and Race in Breast Cancer Prognosis: A Prospective Cohort Study.

Purpose: Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. Methods: We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). Results: 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m2). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52-6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06-4.51) and non-obese (HR = 2.11, 95% CI = 1.05-4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. Conclusion: Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors.

Configurational entropy is an intrinsic driver of tissue structural heterogeneity.

Tissues comprise ordered arrangements of cells that can be surprisingly disordered in their details. How the properties of single cells and their microenvironment contribute to the balance between order and disorder at the tissue-scale remains poorly understood. Here, we address this question using the self-organization of human mammary organoids as a model. We find that organoids behave like a dynamic structural ensemble at the steady state. We apply a maximum entropy formalism to derive the ensemble distribution from three measurable parameters - the degeneracy of structural states, interfacial energy, and tissue activity (the energy associated with positional fluctuations). We link these parameters with the molecular and microenvironmental factors that control them to precisely engineer the ensemble across multiple conditions. Our analysis reveals that the entropy associated with structural degeneracy sets a theoretical limit to tissue order and provides new insight for tissue engineering, development, and our understanding of disease progression.

The unhealthy-tasty intuition in dining out situations: the role of health inferences and taste expectations.

Introduction: Increasing obesity rates around the globe have challenged policymakers to find strategies to prompt healthier eating habits. While unhealthy eating takes place in many different contexts, dining out is a context where individuals often choose an unhealthy option despite the availability of healthier alternatives. One possible explanation for this behavior is the unhealthy-tasty intuition, which refers to the belief that unhealthy food is tastier than healthy food. Nevertheless, many policymakers and restaurant managers follow the - in this context - counterintuitive approach of using health claims to nudge people towards more healthy eating choices or habits. Methods: The current research employs an online experiment with 137 participants and investigates how health claims and sensory claims impact on the purchase intention of healthy options for desserts. Furthermore, it explores how health inferences and taste expectations mediate the intention to purchase. Results and discussion: Findings from the online experiment confirm that health claims prompt positive health inferences, while also stimulating unfavorable taste expectations, resulting in a lower intention to purchase. Surprisingly, we found no effect of a sensory claim on taste expectations. The findings of our experiment contradict the unhealthy-tasty intuition by revealing a significant positive correlation between taste expectations and health inferences. While both health inferences and taste expectations impact positively on purchasing intentions for the health-claim condition, the indirect effect of taste expectations was stronger than the indirect effect of health inferences.

Efficacy of perioperative 2% dorzolamide ophthalmic solution for reduction of postoperative ocular hypertension in dogs following routine phacoemulsification surgery: A prospective clinical trial.

OBJECTIVE: To evaluate the efficacy of 2% dorzolamide ophthalmic solution for reduction of postoperative ocular hypertension (POH) following routine phacoemulsification surgery in dogs. ANIMALS STUDIED: Thirty one dogs (53 eyes) with naturally occurring cataracts undergoing routine phacoemulsification surgery. PROCEDURE(S): A prospective, double-masked, randomized, placebo-controlled study design was utilized. Dogs received 2% dorzolamide ophthalmic solution or saline 1 h prior to surgery then three times daily for 21 days postoperatively in the operated eye(s). Intraocular pressure (IOP) was recorded 1 h prior to surgery and 3 h, 7 h, 22 h, 1 week and 3 weeks postoperatively. Statistical analyses were performed using chi-squared and Mann-Whitney U test with a significance level of p < .05. RESULTS: Postoperative ocular hypertension (IOP ≥25 mmHg, <24 h after surgery) occurred in 28/53 (52.8%) eyes. There was significant reduction in the incidence of POH for eyes receiving dorzolamide (10/26 (38.4%) eyes) versus eyes receiving placebo (18/27 (66.7%) eyes) (p = .0384). Animals were followed for a median of 163 days after surgery. Thirty-seven (37/53 (69.8%)) eyes were visual at final examination and 3/53 (5.7%) globes were enucleated postoperatively. At last follow-up, there was no difference in visual status (p = .9280), need for topical IOP lowering medication (p = .8319) or incidence of glaucoma (p = .5880) based on treatment group. CONCLUSIONS: Perioperative administration of topical 2% dorzolamide reduced the incidence of POH after phacoemulsification in the dogs studied. However, this was not associated with differences in visual outcome, incidence of glaucoma or need for IOP-lowering medications.

Osteopathia striata with cranial sclerosis causing a compressive optic neuropathy.

BACKGROUND: Osteopathia striata combined with cranial sclerosis (OS-CS) is an inherited skeletal dysplasia that manifests with macrocephaly, orofacial abnormalities, thickened craniofacial bones, and vertically oriented radiodensities of the long bones. CASE REPORT: Here, we present a severe case of OS-CS in a 4-year-old girl causing optic neuropathy as shown by radiographic evidence, ophthalmic findings, and histopathology. Previous genetic testing in this patient revealed a de novo heterozygous mutation in AMER1 (c.1057C>T, p.Arg353Ter). Although the patient had a pre-existing, appropriately functioning, ventriculoperitoneal (VP) shunt, a subsequent MRI of the brain and orbits showed narrowing of the bilateral optic nerve canals secondary to osseous thickening causing bilateral optic nerve atrophy, worse on the left. The patient underwent staged bilateral orbital osteotomies, optic canal decompression, and bilateral frontal craniotomy, and at 11 months postoperatively, her vision remained stable. Conclusions: While up to 50% of the patients with OS-CS may experience hearing loss due to cranial nerve compression, we present a case of severe visual loss secondary to OS-CS-associated optic nerve compression.

Precision fMRI reveals that the language-selective network supports both phrase-structure building and lexical access during language production.

A fronto-temporal brain network has long been implicated in language comprehension. However, this network's role in language production remains debated. In particular, it remains unclear whether all or only some language regions contribute to production, and which aspects of production these regions support. Across 3 functional magnetic resonance imaging experiments that rely on robust individual-subject analyses, we characterize the language network's response to high-level production demands. We report 3 novel results. First, sentence production, spoken or typed, elicits a strong response throughout the language network. Second, the language network responds to both phrase-structure building and lexical access demands, although the response to phrase-structure building is stronger and more spatially extensive, present in every language region. Finally, contra some proposals, we find no evidence of brain regions-within or outside the language network-that selectively support phrase-structure building in production relative to comprehension. Instead, all language regions respond more strongly during production than comprehension, suggesting that production incurs a greater cost for the language network. Together, these results align with the idea that language comprehension and production draw on the same knowledge representations, which are stored in a distributed manner within the language-selective network and are used to both interpret and generate linguistic utterances.

Spontaneous bleeding in COVID-19: A retrospective experience of an Italian COVID-19 hospital.

Background: Haemorrhages in coronavirus disease 2019 (COVID-19) patients require proper knowledge and management. Objectives: To highlight the characteristics of haemorrhages in patients with COVID-19 infection. Method: A retrospective study examined CT scans performed over a 13-month period in patients hospitalised with COVID-19 infection to determine those who developed spontaneous bleeding. The authors also investigated correlations between the bleeding events and the patients' characteristics. Results: Haemorrhages occurred in 2.22% (31/1396) of patients hospitalised with COVID-19 infection (7.88%, 19/241 in the intensive care unit). Bleeding, major in most cases, occurred in anticoagulated patients, especially males with multiple comorbidities, aged between 60 and 79 years and mainly appeared in a single anatomical region (especially retroperitoneal), with the most voluminous in the chest wall. The complication was diagnosed on average 16.7 days after admission and occurred predominantly in critically ill patients undergoing invasive ventilation and pronation-supination cycles. In just under half of the cases, the haematomas were active, and in these cases, mainly with a single contrast blush and with earlier onset after the start of anticoagulation than in non-active bleeding. Major bleeding was also earlier in the presence of multiple morbidity. The vast majority of patients were treated conservatively and survived. Conclusion: At COVID-19 hospital centres, it is advisable that there is knowledge of such a complication for which CT imaging is essential for diagnosis and proper management. Although some authors have expressed doubts about anticoagulant treatment in patients with COVID-19, the bleeding complication in this study did not significantly affect the outcome. Contribution: Spontaneous haemorrhage did not significantly affect the outcome in this series.

Demystifying borderline personality disorder in primary care.

Borderline personality disorder (BPD) is a common mental health diagnosis observed in the primary care population and is associated with a variety of psychological and physical symptoms. BPD is a challenging disorder to recognize due to the limitations of accurate diagnosis and identification in primary care settings. It is also difficult to treat due to its complexity (e.g., interpersonal difficulties and patterns of unsafe behaviors, perceived stigma) and healthcare professionals often feel overwhelmed when treating this population. The aim of this article is to describe the impact of BPD in primary care, review current state of knowledge, and provide practical, evidence-based treatment approaches for these patients within this setting. Due to the lack of evidence-based pharmacological treatments, emphasis is placed on describing the framework for treatment, identifying psychotherapeutic opportunities, and managing responses to difficult clinical scenarios. Furthermore, we discuss BPD treatment as it relates to populations of special interest, including individuals facing societal discrimination and adolescents. Through this review, we aim to highlight gaps in current knowledge around managing BPD in primary care and provide direction for future study.

Smoking and Radiation-induced Skin Injury: Analysis of a Multiracial, Multiethnic Prospective Clinical Trial.

INTRODUCTION: Smoking during breast radiotherapy (RT) may be associated with radiation-induced skin injury (RISI). We aimed to determine if a urinary biomarker of tobacco smoke exposure is associated with increased rates of RISI during and after breast RT. PATIENTS AND METHODS: Women with Stage 0-IIIA breast cancer treated with breast-conserving surgery or mastectomy followed by RT to the breast or chest wall with or without regional nodal irradiation were prospectively enrolled on a multicenter study assessing acute/late RISI. 980 patients with urinary cotinine (UCot) measurements (baseline and end-RT) were categorized into three groups. Acute and late RISI was assessed using the ONS Acute Skin Reaction scale and the LENT-SOMA Criteria. RESULTS: Late Grade 2+ and Grade 3+ RISI occurred in 18.2% and 1.9% of patients, respectively-primarily fibrosis, pain, edema, and hyperpigmentation. Grade 2+ late RISI was associated with UCot group (P= 006). Multivariable analysis identified UCot-based light smoker/secondhand smoke exposure (HR 1.79, P= .10) and smoking (HR 1.60, p = .06) as non-significantly associated with an increased risk of late RISI. Hypofractionated breast RT was associated with decreased risk of late RISI (HR 0.51, P=.03). UCot was not associated with acute RISI, multivariable analysis identified race, obesity, RT site/fractionation, and bra size to be associated with acute RISI. CONCLUSIONS: Tobacco exposure during breast RT may be associated with an increased risk of late RISI without an effect on acute toxicity. Smoking cessation should be encouraged prior to radiotherapy to minimize these and other ill effects of smoking.