Time Breast Research Articles

Abstract 6129: Emerging disparities in the clinical actionability landscape for patients with inferred African ancestry

Abstract The past decade has seen a surge in the approval and availability of precision oncology therapies targeting distinct genomic alterations. We sought to determine whether these advances have benefitted patients with cancer from various ancestral backgrounds equally over time. We therefore annotated all genomic alterations identified in a pan-cancer cohort of 55,970 solid tumor samples sequenced with the MSK-IMPACT clinical assay using incremental versions of the precision oncology knowledge base OncoKB and computed the fraction of samples with OncoKB Level 1 alterations (biomarkers included in the FDA drug label) per year based on the annual cumulative FDA-approved targeted therapies. In 2010, 4.4% of patients with inferred African ancestry (AFR), and 2.4% of patients with inferred non-Ashkenazi Jewish European ancestry (EUR) had Level 1 alterations, largely explained by differences in cancer type prevalence between these groups. However, by mid-2023, AFR had a significantly lower percent of Level 1 alterations (25.3%) compared to EUR (31.2%), and this difference remained significant after adjusting for cancer type and disease status (q-value = 2.6e-08). Next, we compared AFR versus EUR percentages of Level 1 alterations over time in breast and colorectal (CRC) patient samples, two cancers in which racial disparities of cancer incidence and outcomes are well-documented. We observed that prior to 2019, the fraction of breast cancer patient samples with a Level 1 alteration was similar among AFR (13%) and EUR (12.2%), primarily due to comparable rates of ERBB2 amplifications (12.4% in AFR, 11.7% in EUR). However, following the breast cancer-specific FDA approvals of alpelisib+fulvestrant for PIK3CA-mutant disease in 2019 and elacestrant for ESR1-mutant disease in 2023, a significant shift in Level 1 actionability was observed between EUR (45%) and AFR (34%) attributed in part to the paucity of PIK3CA (26.3% vs. 36.2% in EUR) and ESR1 (4.1% vs. 7.5% in EUR) oncogenic alterations in AFR. We further observed AFR with CRC to have lower prevalence of MSI-H (5.8% vs.10.7% in EUR), TMB (12.5% vs. 18.8% in EUR) and BRAF V600E (5.1% vs. 9% in EUR). Correspondingly, in 2023, 16.4% of AFR with CRC have Level 1 alterations compared to 25.4% of EUR. Moreover, while AFR have higher rates of KRAS mutations (57.2% vs. 42.6% in EUR), they have a lower prevalence of the standard care biomarker KRAS G12C (3.4% vs. 7% of KRAS-mutant CRC in EUR) further exacerbating the disparities in CRC clinical actionability. Taken together, here we demonstrate that a significant disparity exists in the clinical actionability landscape of AFR with cancer compared to EUR, largely due to differences in relative mutational frequencies of Level 1 genomic alterations. Citation Format: Kanika Arora, Sarah P. Suehnholz, Hongxin Zhang, Ritika Kundra, Subhiksha Nandakumar, Moriah Nissan, A. Rose Brannon, Chaitanya Bandlamudi, Marc Ladanyi, Alexander Drilon, David B. Solit, Nikolaus Schultz, Michael F. Berger, Debyani Chakravarty. Emerging disparities in the clinical actionability landscape for patients with inferred African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6129.

Overexpression of HMGB3 and its prognostic value in breast cancer.

High mobility group protein B3 (HMGB3) is abundantly expressed in a number of malignancies, contributing to tumor cell growth and predicting poor outcomes. More research on the connection between HMGB3 and breast cancer is needed. The prognostic significance of HMGB3 in breast cancer was examined and validated in this study. Using The Cancer Genome Atlas (TCGA) database RNA sequencing and clinical data, we investigated the associations between HMGB3 expression and tumor mutations, prognosis, and immune infiltration in breast cancer. The Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), breast cancer gene-expression miner (bc-GenExMiner), UALCAN, OncoLnc, cBio Cancer Genomics Portal (cBioPortal), and LinkedOmics databases were applied to examine the levels of expression, mutation, coexpression, and immune correlation of HMGB3 in breast cancer. cBioPortal and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) were used for coexpression and enrichment analyses, respectively. Experimental tests and a separate cohort of breast cancer patients in our center were used for validation. To determine independent risk factors affecting breast carcinoma prognosis, multivariate Cox regression analysis was performed. The Kaplan-Meier method was applied to analyze the connection between HMGB3 expression and overall survival time in breast cancer. Pan-cancer investigation using the GEPIA and UALCAN databases revealed a high level of HMGB3 expression in different malignancies, including breast cancer. HMGB3 might be a potential diagnostic biomarker, according to the receiver operating characteristic (ROC) curve (AUC=0.932). And immunohistochemistry confirmed higher HMGB3 protein expression in breast cancer tissues in clinical samples. Experimental tests also showed that breast cancer cells have higher expression of HMGB3, and knockdown of HMGB3 can promote the proliferation of breast cancer cells and increase sensitivity to chemotherapy. Human epidermal growth factor receptor 2 (HER2), Nottingham Prognostic Index (NPI), basal-like status, nodal status (N+), triple-negative status, and Scarff-Bloom-Richardson (SBR) grade all showed positive correlations with HMGB3 expression. Conversely, HMGB3 expression was negatively associated with the expression of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer. Breast cancer patients with high HMGB3 expression had poor overall survival, which was validated by an analysis of a separate cohort of breast cancer patients in our center. Cox regression analysis identified high HMGB3 expression as an independently associated risk factor for breast carcinoma. The amount of immunological infiltration was substantially linked with the high expression of HMGB3. The chromosome centromeric region, ATPase activity, and the cell cycle are critical areas where HMGB3 is involved, according to enrichment analysis. Therefore, we suspected that HMGB3 might be a potential biomarker for detecting and treating breast carcinoma. Breast cancer tissues had higher HMGB3 expression than normal breast tissues. HMGB3 overexpression may serve as an indicator for poor breast cancer outcomes.

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated—for the first time to our knowledge—associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10−6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10−9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Empirical validation of the Operative Entrustability Assessment using resident performance in autologous breast reconstruction and hand surgery

BackgroundIn 2013, we developed the Operative Entrustability Assessment (OEA) to facilitate evaluation and documentation of resident operative skills. This web-based tool provides real-time, transparent feedback to residents on operative performance. This study evaluated the construct validity of the OEA, assessing its association with operative time. MethodsWe used simple and multiple linear regression to estimate associations between OEA scores and operative time in selected procedures performed. ResultsOEAs were completed for 93 autologous breast reconstructions and 185 hand procedures. Self-assessed OEA was associated with shorter operative time in breast (p = 0.008) and hand (p = 0.036) cases. Evaluator OEA was associated with shorter operative time in breast (p = 0.018), but not hand cases (p = 0.377). Post-graduate year was not associated. ConclusionsThe OEA demonstrates construct validity: increasing scores are associated with shorter operative time and are better predictors of operative time than post-graduate year, making it an option for documenting competence prior to graduation.

Empirical Validation of the Operative Entrustability Assessment Using Resident Performance in Autologous Breast Reconstruction and Hand Surgery

Abstract Background In 2013, we developed the Operative Entrustability Assessment (OEA) to facilitate evaluation and documentation of resident operative skills. This web-based tool provides real-time, transparent feedback to residents on operative performance. This study evaluated the construct validity of the OEA, assessing its association with operative time. Methods We used simple and multiple linear regression to estimate associations between OEA scores and operative time in selected procedures performed. Results OEAs were completed for 93 autologous breast reconstructions and 185 hand procedures. Self-assessed OEA was associated with shorter operative time in breast (p = 0.008) and hand (p = 0.036) cases. Evaluator OEA was associated with shorter operative time in breast (p = 0.018), but not hand cases (p = 0.377). Post-graduate year was not associated. Conclusions The OEA demonstrates construct validity: increasing scores are associated with shorter operative time and are better predictors of operative time than post-graduate year, making it an option for documenting competence prior to graduation.

The timing of breast and axillary surgery after neoadjuvant chemotherapy for breast cancer.

Neoadjuvant chemotherapy (NAC) has traditionally been used in locally advanced and inflammatory breast cancer, allowing for a reduction in disease volume and therefore optimizing surgical resection of disease in the breast. NAC impacts both the tumor in the breast and the lymph nodes and may allow for the option of breast-conserving surgery and avoiding an axillary dissection. The aim of this review is to discuss the considerations and timing of surgical treatment of the breast and the axilla following NAC in patients with breast cancer.

Illness perceptions within 6months of cancer diagnosis are an independent prospective predictor of health-related quality of life 15months post-diagnosis.

Studies have found that illness perceptions explain significant variance in health outcomes in numerous diseases. However, most of the research is cross-sectional and non-oncological. We examined, for the first time in breast, colorectal and prostate cancer patients, if cognitive and emotional illness perceptions near diagnosis predict future multidimensional health-related quality of life (HRQoL). UK-based patients (N = 334) completed the illness perception questionnaire-revised within 6 months post-diagnosis and the quality of life in adult cancer survivors scale 15 months post-diagnosis. Sociodemographic and clinical data were obtained from medical records. Hierarchical multiple regression analyses were conducted. The sociodemographic and clinical factors collectively significantly predicted 8/12 HRQoL domains, although for 5/8 accounted for <10% of the variance. For all 12 HRQoL domains, illness perceptions collectively explained significant substantial additional variance (∆R(2) range: 5.6-27.9%), and a single illness perception questionnaire-revised dimension was the best individual predictor of 9/12 HRQoL domains. The consequences dimension independently predicted 7/12 HRQoL domains; patients who believed their cancer would have a more serious negative impact on their life reported poorer future HRQoL. The emotional representations and identity dimensions also predicted multiple HRQoL domains. Future research should focus on realising the potential of illness perceptions as a modifiable target for and mediating mechanism of interventions to improve patients' HRQoL.

Younger pubertal age is associated with allergy and other atopic conditions in girls.

Early menarche is linked to higher incidence of adult asthma, suggesting that earlier puberty may influence type 2 immune response characteristics of allergic diseases. We examined the hypothesis that timing of breast and pubic hair development, which precede menarche, is associated with increased childhood atopic conditions. Girls were enrolled at 6-8 yr of age (2004-2007) in the Breast Cancer and the Environment Research Program Puberty Study and were followed through 2011. Pubertal stages were assessed and atopic conditions were queried annually. Associations of age at pubertal stage 2 for breast or pubic hair development with atopic conditions were assessed using prevalence ratios (PR) or odds ratios (OR) and 95% confidence intervals (CI) from log-binomial regression and generalized estimating equation models, controlling for body mass index and other covariates. A total of 1055 girls with medical and pubertal stage data were included. Asthma (ever vs. never) was associated with younger pubarche (≤10 vs. >10 yr, PR = 1.15, CI: 1.04-1.28 adjusted for race/ethnicity and site; PR = 1.13, CI: 1.01-1.25 further adjusted for BMI), but not thelarche. In longitudinal models, risk of developing allergies increased with younger age at pubarche (adjusted OR = 1.60, CI: 1.10-2.34; ≤10 vs. >10 yr). Risks were highest among black girls with earlier pubarche (n = 248/326); for allergies, their fully adjusted OR was 2.35, CI: 1.06-5.19 for pubarche ≤10 vs. >10 yr. Atopic conditions during childhood are associated with younger age at pubarche, independent of obesity, and these relationships may vary by racial/ethnic groups.

Middle-segment preserving subtotal pancreatectomy for treating multifocal lesions in pancreas

Middle-segment preserving subtotal pancreatectomy for treating multifocal lesions in pancreas

Characterization of the Correlation Between Ages at Entry Into Breast and Pubic Hair Development

PurposeThe timing of breast and pubic hair development in girls are related, but the degree of correlation has not been well characterized. Periodic observations also are complicated by interval censoring.MethodsData used were from the Avon Longitudinal Study of Parents and Children. Mean age at entry into breast and pubic hair development was determined by the use of parametric survival analysis. The bivariate normal cumulative distribution function was evaluated over the region containing the paired event times; the likelihood was maximized with respect to the correlation coefficient ρ.ResultsAmong 3938 participants, estimated mean ages at entry into Tanner stage 2 for breast and pubic hair development were 10.19 and 10.95, respectively. The likelihood was maximized at ρ = 0.503 to 0.506. This value remained relatively constant among subgroups, although some heterogeneity was observed by maternal and child body mass index and birth order.ConclusionsThe timing of breast and of pubic hair development is moderately correlated and remain so when it is stratified by characteristics associated with puberty.