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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.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.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.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.

African American (AA) families have the highest risk of prostate cancer. However, the genetic factors contributing to prostate cancer susceptibility in AA families remain poorly understood. We performed whole-exome sequencing of one affected and one unaffected brother in an AA family with hereditary prostate cancer. The novel non-synonymous variants discovered only in the affected individuals were further analyzed in all affected and unaffected men in 20 AA-PC families. Here, we report one rare recurrent ADPRHL1 germline mutation (c.A233T; p.D78V) in four of the 20 families affected by prostate cancer. The mutation co-segregates with prostate cancer in two families and presents in two affected men in the other two families, but was absent in 170 unrelated healthy AA men. Functional characterization of the mutation in benign prostate cells showed aberrant promotion of cell proliferation, whereas expression of the wild-type ADPRHL1 in prostate cancer cells suppressed cell proliferation and oncogenesis. Mechanistically, the ADPRHL1 mutant activates PARP1, leading to an increased H2O2 or cisplatin-induced DNA damage response for prostate cancer cell survival. Indeed, the PARP1 inhibitor, olaparib, suppresses prostate cancer cell survival induced by mutant ADPRHL1. Given that the expression levels of ADPRHL1 are significantly high in normal prostate tissues and reduce stepwise as Gleason scores increase in tumors, our findings provide genetic, biochemical, and clinicopathological evidence that ADPRHL1 is a tumor suppressor in prostate tissue. A loss of function mutation in ADPRHL1 induces prostate tumorigenesis and confers prostate cancer susceptibility in high-risk AA families.Implications:This study highlights a potential strategy for ADPRHL1 mutation detection in prostate cancer–risk assessment and a potential therapeutic application for individuals with prostate cancer in AA families.

Supplementary Table 1. Stage and HPV status by disease site among 150 cases. Supplementary Table 2. SolCD44/Total Protein test by HPV status and stage. Supplementary Table 3. Characteristics of hospital-based cases and controls and community controls. Supplementary Table 4. Prognostic Significance of CD44 and Total Protein Levels.

Supplementary Figure from A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families

Supplementary Table from A Recurrent ADPRHL1 Germline Mutation Activates PARP1 and Confers Prostate Cancer Risk in African American Families

Oral cavity and oropharyngeal cancer (oral cancer) is a deadly disease that is increasing in incidence. Worldwide 5-year survival is only 50% due to delayed intervention with more than half of the diagnoses at stage III and IV, whereas earlier detection (stage I and II) yields survival rates up to 80% to 90%. Salivary soluble CD44 (CD44), a tumor-initiating marker, and total protein levels may facilitate oral cancer risk assessment and early intervention. This study used a hospital-based design with 150 cases and 150 frequency-matched controls to determine whether CD44 and total protein levels in oral rinses were associated with oral cancer independent of age, gender, race, ethnicity, tobacco and alcohol use, and socioeconomic status (SES). High-risk subjects receiving oral cancer prevention interventions as part of a community-based program (n = 150) were followed over 1 year to determine marker specificity and variation. CD44 ≥5.33 ng/mL was highly associated with case status [adjusted OR 14.489; 95% confidence interval (CI), 5.973–35.145; P < .0001, vs. reference group CD44 Cancer Prev Res; 9(6); 445–55. ©2016 AACR.

Supplementary Table S1. Associations of Overall Breast Cancer Risk with 74 Breast Cancer Risk Variants in African Americans with Study-specific Results.

Supplementary Figure S1, Supplementary Figure S1. Regional plots of 3p24, 11q13, 12p11, 14q13, 16q12/TOX3, 16q12/FTO, 16q23, and 19p13.

Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2.Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations.Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23–32. ©2011 AACR.

Supplementary Materials from Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent

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Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016–26. ©2017 AACR.

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Aim: Multiple genes and genetic variants may contribute to racial/ethnic disparities in obesity-associated breast cancer diagnosis and prognosis. Therefore, we evaluate whether racial/ethnic differences in polygenic risk score (PRS) contribute to obesity and inflammatory biomarker in breast cancer patients. Methods: In a tri-racial/ethnic population of 403 breast cancer patients, 21% African American (AA), 65% Hispanic White (HW), and 14% non-Hispanic White (NHW), we evaluated racial/ethnic differences in obesity PRS, the association between PRS and an inflammatory biomarker C-reactive protein (CRP), and its implication in bariatric surgery eligibility. The obesity PRS was constructed via a weighted risk allele model using 35 obesity-related single nucleotide polymorphisms (SNPs). SAS version 9.3 for Windows (SAS Institute, Cary, NC, USA) was used to perform the logistic regression analysis. Results: About 74% of our study population were overweight or obese. The mean ± SD of obesity PRS was 45.03 ± 10.66 for obese patients and 39.36 ± 8.81 for non-obese patients (P < 0.0001). AA patients had a significantly higher obesity PRS than HW and NHW (P < 0.0001). The obesity PRS significantly correlated with body mass index and CRP levels (P < 0.0001) and was associated with bariatric surgery eligibility (OR = 4.32, 95%CI: 1.89-9.87). Conclusion: In summary, multiple obesity-associated SNPs contribute to racial/ethnic disparities in obesity of breast cancer patients; the obesity PRS has application in identifying breast cancer patients with higher genetic risk for obesity who may benefit from more aggressive weight management, such as bariatric surgery to improve breast cancer clinical outcomes.

Background Nelfinavir (NFV), an HIV‐1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer. Methods Two dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse‐phase‐protein‐array analyses. Results NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose‐limiting toxicity, whereas no dose‐limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow‐up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT. Conclusions NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation., In a phase 1 clinical trial, nelfinavir, an HIV protease inhibitor, was determined to be safe and tolerable when added to standard chemoradiation therapy for locally advanced cervical cancer. Cervical tumor pAkt and pS6 protein levels decrease with nelfinavir treatment, and cell cycle and cancer‐associated pathways are further reduced with nelfinavir added to chemoradiation.

International audience; Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age

Purpose Genetic variations in DNA damage repair (DDR) genes may influence radiation therapy (RT)–induced acute normal tissue toxicity in patients with breast cancer. Identifying an individual or multiple single-nucleotide polymorphisms (SNPs) associated with RT–induced early adverse skin reactions (EASR) is critical for precision medicine in radiation oncology. Methods and Materials At the completion of RT, EASR was assessed using the Oncology Nursing Society scale (0-6) in 416 patients with breast cancer, and Oncology Nursing Society score ≥4 was considered RT-induced EASR. PLINK set-based tests and subsequent individual SNP association analyses were conducted to identify genes and SNPs associated with EASR among the 53 DDR genes and 1968 SNPs. A weighted polygenic risk score (PRS) model was constructed to ascertain the association between the joint effect of risk alleles and EASR. Results The study population consisted of 264 Hispanic whites, 86 blacks or African Americans, 55 non-Hispanic whites, and 11 others. A total of 115 patients (27.6%) developed EASR. Five genes (ATM, CHEK1, ERCC2, RAD51C, and TGFB1) were significantly associated with RT-induced EASR. Nine SNPs within these 5 genes were further identified: ATM rs61915066, CHEK1 rs11220184, RAD51C rs302877, rs405684, TBFB1 rs4803455, rs2241714, and ERCC2 rs60152947, rs10404465, rs1799786. In a multivariable-adjusted PRS model, patients in a higher quartile of PRS were more likely to develop EASR compared with patients in the lowest quartile (ORq2 vs.q1 = 1.94, 95% CI, 0.86-4.39; ORq3 vs.q1 = 3.46, 95% CI, 1.57-7.63; ORq4 vs.q1 = 8.64, 95% CI, 3.92-19.02; and Ptrend Conclusions We newly identified the associations between 9 SNPs in ATM, CHEK1, RAD51C, TGFB1, and ERCC2 and RT-induced EASR. PRS modeling showed its potential in identifying populations at risk. Multiple SNPs in DDR genes may jointly contribute to interindividual variation in RT-induced EASR. Validation in an independent external cohort is required to determine the clinical significance of these predictive biomarkers.

Background Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. Methods In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. Results The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43–15.16] in ProtecT, 7.07 [6.58–7.60] in African ancestry, 10.31 [9.58–11.11] in Asian ancestry, and 11.18 [10.34–12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11–0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15–0.22) and 0.26 (0.19–0.33), respectively. Conclusions We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Background: Adjuvant radiotherapy (RT) following surgery significantly improves breast cancer survival. However, some patients, particularly minorities, develop early adverse skin reactions (EASRs) or skin toxicities that negatively impact the quality of life (QOL). We assess RT-related EASRs and QOL using clinician-reported outcomes (CROs) and patient-reported outcomes (PROs) in a large multi-racial/ethnic breast cancer population. Methods: This prospective study recruited 1,000 breast cancer patients undergoing RT through the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base between 2011 and 2013. We used the Oncology Nursing Society (ONS) Skin Toxicity Criteria for CROs and Skindex-16 (SD-16) for PROs. Results: This study included 405 non-Hispanic whites (NHW), 277 black/African Americans (AA), 241 HW, 62 Asian/Pacific Islanders (ASPI), and 15 others. About 42% and 15% of patients developed RT-induced ONS grade 3+ and 4+ skin toxicities, respectively. RT-induced EASRs differed significantly by race/ethnicity at mid-RT, 1-month, and 2-month post-RT, but not at the end of RT. Total SD-16 scores differ by race/ethnicity at pre-RT, 1-month, and 6-month post-RT, but not at the end of RT. Overall, PROs have a moderate but significant correlation with CROs at the end of RT. Conclusion: RT-induced EASRs differed significantly by race/ethnicity. There was a moderate but significant correlation between PROs and CROs. However, PROs delineated a broader spectrum in capturing the impact of RT on patients’ QOL, which highlights the importance of integrating PROs in accessing RT-induced EASRs, particularly in minorities with worse RT-induced EASRs. Trial Registration: NCT01407770 (09/02/2011) Citation Format: James J. Urbanic, Edward G. Shaw, Cristiane Takita, Jean L. Wright, Edward H. Ip, Lingyi Lu, Luis Baez-Diaz, Doris R. Brown, Jon Strasser, Kathy Baglan, Mark Palmer, Anu Thakrar, Amarinthia E. Curtis, Glenn Lesser, Jennifer J. Hu. Radiotherapy-induced early adverse skin reactions: Comparative analysis of clinician- and patient-reported outcomes in a multi-racial/ethnic breast cancer population (WF-97609) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1900.

Background: Adjuvant radiotherapy (RT) following surgery significantly improves breast cancer survival. However, some patients, particularly minorities, develop acute skin toxicities that negatively impact their quality of life (QOL). The traditionally used measure of skin toxicities is clinician-reported outcomes (CROs), but recently there has been an increased interest in incorporating patient-reported outcomes (PROs). Therefore, our objective was to assess RT-related acute skin toxicities CROs and PROs in a large tri-racial/ethnic breast cancer population with 85% minorities. Methods: Patient demographics, treatment-, and clinical characteristics were prospectively collected for breast cancer patients who underwent breast-conserving surgery and planned to receive adjuvant RT from 2008 to 2014. 386 breast cancer patients with complete CROs and PROs were included in the final data analyses. The Common Terminology Criteria for Adverse Events (CTCAE, v. 3.0) was used for CROs and a skin-based QOL questionnaire was used for PROs. Concordance was assessed by calculating percent agreement and Cohen’s Kappa using McNemar’s test for significance. Results: The study population included 56 non-Hispanic whites (NHW), 81 black/African Americans (AA), and 249 Hispanic white (HW) breast cancer patients. Overall, the most commonly reported symptoms among patients were hyperpigmentation (n=179, 46%) and erythema (n=173, 45%). There were significant racial/ethnic differences in 4 patient-reported symptoms: warm to touch (p Conclusion: Multiple RT-induced skin-related symptoms differed significantly by race/ethnicity. However, CROs did not show racial/ethnic differences. There was a fair but significant agreement between PROs and CROs. A moderate level of concordance between PROs and CROs highlights the difficulty in assessing RT-related skin toxicities without a direct measure for which an improved skin assessment tool should be developed. PROs delineated a broader spectrum in capturing the impact of RT on patients’ QOL, which highlights the importance of integrating PROs in accessing RT-induced skin toxicities, particularly in minorities with worse RT-related skin symptoms that were not captured by CROs. Citation Format: Laura G. Acosta, Cristiane Takita, Isilinha M. Reis, Jean L. Wright, Wei Zhao, Jennifer J. Hu. Patient- and clinician-reported outcomes of radiotherapy-related acute skin toxicities in a tri-racial/ethnic breast cancer population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3052.

Background: Early adverse skin reactions (EASRs) are common side effects of postoperative adjuvant radiotherapy (RT) that significantly impact the quality of life (QOL) of breast cancer patients. This study used global metabolomics profiles of breast cancer populations to identify metabolic pathways and biomarkers that are significantly associated with RT-induced EASRs to identify potential targets for precision interventions. Methods: Using a frequency-matched study design, pre-RT urine samples from 60 female breast cancer patients receiving RT after breast-conserving surgery were metabolically profiled. Patients were recruited from the University of Miami Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital. Using MetaboAnalyst 3.0, we performed metabolomic data analysis, visualization, and interpretation on 84 candidate metabolites from a dataset of 478 total compounds. Student’s t-tests, correlation analyses, pathway enrichment, and topology analyses were conducted sequentially to identify metabolite biomarkers and pathways associated with RT-induced EASRs. Results: The study population consisted of 24 African American (40%), 18 non-Hispanic white (30%), 14 Hispanic white (24%), and 4 “other” (7%) patients with frequency matched by race/ethnicity and body mass index (BMI) categories (i.e., normal, overweight, and obesity) to have an equal number of high (n=30) and low (n=30) EASRs. Seven metabolic pathways were significantly associated with RT-induced EASRs, including alanine, aspartate, and glutamate metabolism; caffeine metabolism; pentose and glucuronate interconversions; glycine, serine, and threonine metabolism; beta-alanine metabolism; pantothenate and CoA biosynthesis; and glutathione metabolism. The alanine, aspartate, and glutamate metabolism pathway had the lowest false discovery rate (FDR)-adjusted p-value (p=0.0028) and the highest pathway impact value (0.60) of all enriched metabolic pathways. Thirteen metabolite biomarkers were significantly associated with RT-induced EASRs, including the principal compound of interest glutamate. Conclusions: In our study of breast cancer patients receiving adjuvant RT, alanine, aspartate, and glutamate metabolism had the highest impact value and significant FDR-adjusted p-value in predicting RT-induced EASRs. Our findings suggest that glutaminase inhibitors may have broader clinical applications in preventing RT-induced EASRs in addition to their potential enhancement of chemotherapy by triggering metabolic crises in tumor cells. Keywords: breast cancer, metabolomics, radiation therapy, and early adverse skin reactions. Citation Format: Alexandra N. McMahon, Cristiane Takita, Jean L. Wright, Eunkyung Lee, Joshua J. Kleinman, Isildinha M. Reis, Jennifer J. Hu. Metabolomics in radiotherapy-induced early adverse skin reactions in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2824.

African American (AA) families have the highest risk of prostate cancer. However, the genetic factors contributing to prostate cancer susceptibility in AA families remain poorly understood. We performed whole-exome sequencing of one affected and one unaffected brother in an AA family with hereditary prostate cancer. The novel non-synonymous variants discovered only in the affected individuals were further analyzed in all affected and unaffected men in 20 AA-PC families. Here, we report one rare recurrent ADPRHL1 germline mutation (c.A233T; p.D78V) in four of the 20 families affected by prostate cancer. The mutation co-segregates with prostate cancer in two families and presents in two affected men in the other two families, but was absent in 170 unrelated healthy AA men. Functional characterization of the mutation in benign prostate cells showed aberrant promotion of cell proliferation, whereas expression of the wild-type ADPRHL1 in prostate cancer cells suppressed cell proliferation and oncogenesis. Mechanistically, the ADPRHL1 mutant activates PARP1, leading to an increased H2O2 or cisplatin-induced DNA damage response for prostate cancer cell survival. Indeed, the PARP1 inhibitor, olaparib, suppresses prostate cancer cell survival induced by mutant ADPRHL1. Given that the expression levels of ADPRHL1 are significantly high in normal prostate tissues and reduce stepwise as Gleason scores increase in tumors, our findings provide genetic, biochemical, and clinicopathological evidence that ADPRHL1 is a tumor suppressor in prostate tissue. A loss of function mutation in ADPRHL1 induces prostate tumorigenesis and confers prostate cancer susceptibility in high-risk AA families. Implications: This study highlights a potential strategy for ADPRHL1 mutation detection in prostate cancer–risk assessment and a potential therapeutic application for individuals with prostate cancer in AA families.

Background Inflammatory biomarker C-reactive protein (CRP) is associated with breast cancer risk and survival. We examined whether CRP levels before radiotherapy (pre-RT), after RT (post-RT), and RT-induced change impact breast cancer progression-free survival (PFS). Methods Plasma high-sensitivity CRP was measured, and patients were followed for up to 13 years after RT. PFS was calculated from the date of diagnosis to the date of disease progression or the last date of follow-up. Univariable and multivariable Cox proportional hazards regression models were used to evaluate the associations between CRP and PFS adjusted for other patient/clinical variables. Results In 469 patients (64 non-Hispanic Whites, 303 Hispanic Whites, and 102 African Americans), post-RT CRP levels were significantly higher in patients with progression compared to progression-free patients (mean±SD: 12.2±15.4 mg/L vs. 7.3±11.5, p=0.011). In univariable analyses, worse PFS was significantly associated with post-RT CRP ≥5.1 mg/L (hazard ratio [HR]: 2.67; 95% confidence interval [95% CI]: 1.65-4.30) and CRP change ≥2.3 mg/L (HR: 3.55; 95% CI: 2.25-5.64). In multivariable models, post-RT CRP ≥5.1 mg/L was associated with worse PFS in all (HR: 2.10; 95% CI: 1.29-3.42) or patients with tumor stage III (HR: 2.93, 95% CI: 1.20-7.18). CRP change ≥2.3 mg/L was associated with worse PFS in all (HR: 2.38; 95% CI: 1.45-3.92) or patients with tumor stage III (HR: 2.41, 95% CI: 1.09-5.33). Conclusions Our data suggest that an RT-induced hyper-inflammatory response may contribute to worse breast cancer PFS. Future larger studies are warranted to validate our findings and guide follow-up surveillance and targeted interventions.

IntroductionProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P, GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.

Background We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Materials and methods Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. Results CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. Conclusion We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Background: Somatic driver mutations in TP53 are associated with triple negative breast cancer (TNBC) and poorer outcomes. Breast cancers arising in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than non-Hispanic White (NHW) women. Missense driver mutations in TP53 are known to have different functional effects including loss-of function (LOF) or gain-of-function (GOF) activity. A subset of variants exhibit dominant negative (DNE) activity over wildtype TP53 or other TP53 family members. Methods: To determine if there were differences in TP53 mutation type by race or TNBC status we identified published and unpublished datasets with somatic mutation data, race, age, and hormone receptor status. Mutations were classified as LOF, GOF or CpG Island hotspot by published literature or type of mutation (e.g. frameshift and nonsense mutations were considered to be LOF). We used Fisher’s Exact test to assess for significant differences.Results: We identified 96 independent breast cancer studies with race and somatic TP53 mutation status available. The study comprised data from a total of 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. Of the total TP53 mutations, 939 (31.7%) were GOF, 1739 (58.7%) were LOF, and the remaining 286 (9.6%) were not able to be classified. With respect to DNE activity, 1246 (42%) showed activity, 1190 (40.1%) showed no activity, and 528 (17.8%) were unknown status. The distribution of TP53 mutation type was similar by race and ethnicity. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% in AA individuals (p=0.04). Mutations lacking DNE activity were positively associated with TNBC (OR=1.37, p=0.03) and estrogen receptor (ER) negative status (OR=1.38; p=0.005). Conclusions: In summary, ER negative and TNBC breast tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts are needed to further elucidate some of these findings.

Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of cancer death in Americans. With more than 3 million breast cancer survivors in the US, a number that is projected to increase, it is important to identify targets for precision intervention to improve breast cancer prognosis. With the rapid advancement of technology for metabolomics, the results from several recent studies have shown that metabolomics may have applications in breast cancer diagnosis and subtype analysis, characterization of heterogeneity of breast cancer, and prognosis. In the current study, we performed a global urinary metabolomic analysis of 120 breast cancer patients: 60 progression-free (PF) cases as the reference group and 60 with progressive disease (PD: recurrence, second primary, metastasis, or death). The urine samples were collected immediately after radiotherapy. Using UPLC-MS/MS and GC-MS, Metabolon Inc. identified a robust set of 1,742 biochemicals (1,258 known and 484 unknown structure). The most notable differences between PF and PD patients involved multiple pathways and metabolites include: carbohydrate metabolism (e.g., glucose, sedoheptulose, and N6-carboxymethyllysine), branch-chain amino acid metabolism (e.g., alpha-hydroxyisocaproate and beta-hydroxyisovalerylglycine), phosphatidylcholine metabolism (e.g., 1-palmitoyl-2-oleoyl-GPC (16:0/18:1) and 1-palmitoyl-2-linoleoyl-GPC (16:0/18:2)), arginine metabolism (e.g., dimethylarginine, N-acetylcitrulline, and homocitrulline), oxidative stress-related metabolites (e.g., cysteine-glutathione disulfide, gamma-glutamylisoleucine, and gamma-glutamylthreonine), androgenic steroids (Dehydroepiandrosterone sulfate (DHEA-S) and 16a-hydroxy DHEA 3-sulfate), and nucleotide metabolism. Some of these identified metabolomic differences may serve as potential predictive biomarkers of breast cancer prognosis. In summary, with increasing interest in targeting tumor metabolism in precision medicine and our pilot data suggesting multiple metabolic pathways in predicting breast cancer prognosis, future research is warranted to validate our findings and identify metabolomic targets for precision interventions. Citation Format: Jennifer J. Hu, Cristiane Takita, Isildinha M. Reis, George Yang, Wei Zhao, Eunkyung Lee. Metabolomics pathways and biomarkers in predicting breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2328.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p, A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Genotypic data were obtained from PRACTICAL consortium for 6,253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with performance of PHS46+African. A calibration factor (CF) was formulated using estimated Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our dataset with 1000 Genomes, we identified statistically significant associations between continental and calibration groupings. In conclusion, we identified PCs within 8q24 SNP window that were strongly associated with performance of PHS46+African. Further research to improve clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry

In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.

International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

IntroductionPolygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population.Material and MethodsAnonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach.ResultsThree SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53).ConclusionsWe identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans and Asians. A strategy of building on established statistical models might benefit ancestral groups generally under-represented in genome-wide association studies.

Background Polygenic risk scores (PRSs) have been demonstrated to identify women of European, Asian, and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry. Methods We assembled genotype data for women of African ancestry, including 9241 case subjects and 10 193 control subjects. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve. We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry and estimated lifetime absolute risk of BC in African Americans by PRS category. Results For overall BC, the odds ratio per SD of the 313-variant PRS (PRS313) was 1.27 (95% confidence interval [CI] = 1.23 to 1.31), with an area under the receiver operating characteristic curve of 0.571 (95% CI = 0.562 to 0.579). Compared with women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI = 1.38-fold to 1.72-fold). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction. Conclusion The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared with that reported in European, Asian, and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.

Blacks experience disproportionate head and neck cancer (HNC) recurrence and mortality compared to Whites. Overall, vitamin D status is inversely associated to HNC pointing to a potential protective linkage. Although hypovitaminosis D in Blacks is well documented it has not been investigated in Black HNC patients. Thus, we conducted a prospective pilot study accessing vitamin D status in newly diagnosed HNC patients stratified by race and conducted in vitro studies to investigate mechanisms associated with potential cancer inhibitory effects of vitamin D. Outcome measures included circulating levels of vitamin D, related nutrients, and risk factor characterization as well as dietary and supplemental estimates. Vitamin D-based in vitro assays utilized proteome and microRNA (miR) profiling. Nineteen patients were enrolled, mean circulating vitamin D levels were significantly reduced in Black compared to White HNC patients, 27.3 and 20.0 ng/mL, respectively. Whites also supplemented vitamin D more frequently than Blacks who had non-significantly higher vitamin D from dietary sources. Vitamin D treatment of HNC cell lines revealed five significantly altered miRs regulating genes targeting multiple pathways in cancer based on enrichment analysis (i.e., negative regulation of cell proliferation, angiogenesis, chemokine, MAPK, and WNT signaling). Vitamin D further altered proteins involved in cancer progression, metastasis and survival supporting a potential role for vitamin D in targeted cancer prevention.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Background: Although preclinical data suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance, results from randomized clinical trials have failed to identify a subgroup of patients that derive a substantial benefit. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib can increase the anti-tumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Methods: In this randomized, open-label, phase 2 study, 167 postmenopausal women with newly diagnosed, operable, ER-positive, HER2-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to two-weeks of preoperative treatment with anastrozole 1 mg once daily or the combination of anastrozole 1mg with pictilisib 260 mg once daily. The primary endpoint was inhibition of tumor cell proliferation, as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses included targeted NGS of a comprehensive cancer panel of >400 genes (Ampliseq Comprehensive Cancer panel), copy number variation analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling (NanoString nCounter platform). Results:There was significantly greater geometric mean Ki67 suppression of 82.5% (90% CI, 78.3%-85.8%) for the combination vs 70.7% (61.0%-78.0%) for anastrozole [geometric mean ratio (combination/ anastrozole) 0.60 (0.58-0.85);p=0.01]. Higher baseline Ki67, Luminal B status and/or negative PR status were associated with increased benefit from adding pictilisib. A significant interaction was observed between PIK3CA mutation subtypes [helical domain mutations (HD), kinase domain mutations (KD), wildtype (WT)] and mean Ki67 suppression; the combination/anastrozole geometric mean ratio of Ki67 suppression was 0.48 (0.27-0.84; p=0.02) for patients with HD mutations and 0.63 (0.39–1.0; p=0.05) for patients with PIK3Ca WT, compared to 1.17 (0.57–2.41; p=0.64) for patients with KD mutations. This was largely due to patients with HD mutations showing a particularly poor response to anastrozole alone [mean Ki67 suppression 53.9% (9.5%-76.5%)], that was reversed by the addition of pictilisib [mean Ki-67 suppression 78.1% (71.0%-83.4%)]. On the other hand, patients with KD mutations responded well to anastrozole alone [mean Ki-67 suppression 77.7% (57.0%-88.4%)] and showed no benefit from the addition of pictilisib [mean Ki-67 suppression 73.9% (59.8%-83.0%)]. There was no significant difference in induction of apoptosis between treatment groups. Comprehensive pre- and post-treatment biomarkers analyses will be presented. Conclusions: Adding pictilisib to anastrozole significantly increases the anti-proliferative response to preoperative treatment with anastrozole. A significant interaction was observed between PIK3CA mutation subtypes, with patients with helical domain mutations showing a particularly poor response to anastrozole alone that was reversed by the addition of pictilisib. Citation Format: Schmid P, Pinder S, Wheatley D, Zummit C, Macaskill EJ, Hu J, Price R, Bundred N, Hadad S, Shia A, Sarker S-J, Lim L, Mousa K, O'Brien C, Wilson TR, Lackner MR, Gendreau S, Gazinska P, Korbie D, Trau M, Mainwaring P, Thompson A, Purushotham A. Interaction of PIK3CA mutation subclasses with response to preoperative treatment with the PI3K inhibitor pictilisib in patients with estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-02.

Purpose This study examined an inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), in radiotherapy (RT)-induced early adverse skin reactions or toxicities in breast cancer. Patients and Methods Between 2011 and 2013, 1,000 patients with breast cancer who underwent RT were evaluated prospectively for skin toxicities through the National Cancer Institute–funded Wake Forest University Community Clinical Oncology Program Research Base. Pre- and post-RT plasma hsCRP levels and Oncology Nursing Society skin toxicity criteria (0 to 6) were used to assess RT-induced skin toxicities. Multivariable logistic regression analyses were applied to ascertain the associations between hsCRP and RT-induced skin toxicities after adjusting for potential confounders. Results The study comprised 623 white, 280 African American, 64 Asian/Pacific Islander, and 33 other race patients; 24% of the patients were Hispanic, and 47% were obese. Approximately 42% and 15% of patients developed RT-induced grade 3+ and 4+ skin toxicities, respectively. The hsCRP levels differed significantly by race and body mass index but not by ethnicity. In multivariable analysis, grade 4+ skin toxicity was significantly associated with obesity (odds ratio [OR], 2.17; 95% CI, 1.41 to 3.34], post-RT hsCRP ≥ 4.11 mg/L (OR, 1.61; 95% CI, 1.07 to 2.44), and both factors combined (OR, 3.65; 95% CI, 2.18 to 6.14). Above-median post-RT hsCRP (OR, 1.93; 95% CI, 1.03 to 3.63), and change in hsCRP (OR, 2.80; 95% CI, 1.42 to 5.54) were significantly associated with grade 4+ skin toxicity in nonobese patients. Conclusion This large prospective study is the first to our knowledge of hsCRP as an inflammatory biomarker in RT-induced skin toxicities in breast cancer. We demonstrate that nonobese patients with elevated RT-related change in hsCRP levels have a significantly increased risk of grade 4+ skin toxicity. The outcomes may help to predict RT responses and guide decision making.