Breast Cancer Cases Research Articles

Risk factors of breast cancer among patients from a lower- and middle-income country: A case-control study from Nepal.

e12502 Background: Although breast cancer occurs overwhelmingly in high-income countries, there has been a recent increase in the incidence of breast cancer cases in low and middle-income countries. Reports from hospital-based registries showed that breast cancer is second most common cancer in Nepalese women. The study aimed to find the risk factors associated with breast cancer among breast cancer patients at a tertiary care hospital from Nepal. Methods: An Institutional-based 1:1 unmatched case-control study with a sample of 100 women was conducted at Patan Academy of Health Sciences, Patan Hospital, Kathmandu, Nepal, between May to October 2023. Women aged 20-84 years with histologically confirmed breast cancer within the last 4 years of the interview date were identified retrospectively as a study cases. Semi-structured questionnaire was used for data collection. Multivariate logistic regression model was used to calculate the adjusted odds ratio with 95%CI. Results: The significantly associated risk factors included age (41-50yrs: OR 5.03, >50 years: OR31.11), marital status (married: OR9.23), age at menarche (13-15 yrs: OR 3.79), and oral contraception use (OC user: OR 4.26). Conclusions: Emphasizing regular breast cancer screening programs above 40 years of age and adequate counselling and awareness about that risks and benefits of hormonal contraception among high-risk groups might help to mitigate the risk of breast cancer.

Expert consensus recommendations on the daily clinical use of pembrolizumab for early triple-negative breast cancer.

e12521 Background: Triple-negative breast cancer (TNBC) accounts for 10–15% of all breast cancer cases and is associated with poor outcomes. Neoadjuvant chemotherapy is the standard treatment for early TNBC (eTNBC) to achieve a pathologic complete response which is associated with long-term clinical outcomes and to guide adjuvant treatment for residual disease after definitive surgery. Pembrolizumab, a programmed death 1 (PD-1) inhibitor, is approved for the peri-operative treatment of stage II and III TNBC. The Hong Kong Breast Cancer Foundation (HKBCF) convened a multi-disciplinary consensus consisting of surgeons, and clinical and medical oncologists to discuss the implementation of immunotherapy in the peri-operative setting and provide expert guidance on topics lacking definitive evidence from the KEYNOTE-522 study in daily clinical routine. Methods: The panel included 7 breast surgeons, 6 clinical oncologists, and 3 medical oncologists representing the academic, public, and private settings in Hong Kong. A modified Delphi panel was conducted, testing the panel on 7 different topics and 45 statements relating to the peri-operative treatment of eTNBC. Evidence was graded according to GRADE. Statements were initially voted by online form on a 6-point Likert scale, and the results were discussed during a consensus meeting. Consensus to accept was considered at a median ≥5 and an IQR ≤1.75 and consensus to reject at median ≤2 and an IQR ≤1.75. Results: Key findings are that the panel considered 1) the uncommon subtype “oestrogen receptor (ER)-low” does not formally meet the definition of TNBC but should be treated as TNBC; 2) pembrolizumab as a viable addition in the peri-operative setting; 3) guideline-recommended NAC for cT1c disease may be considered; but 4) this does not necessarily mean immunotherapy should be added, though it may be considered case-by-case. Furthermore, the panel 5) agreed that pembrolizumab prescription does not need to be guided by PD-L1 expression, and 6) that for patients with residual disease after NAC plus pembrolizumab, the addition of capecitabine to pembrolizumab is acceptable, however, 7) was divided about the addition of a PARPi to pembrolizumab for patients with a germline BRCA1/2 mutation (g BRCA1/2m) and residual disease — guided by the lack of routine g BRCA1/2m testing in Hong Kong. Finally, the panel 8) proposed to recommend adhering to the KEYNOTE-522 weekly paclitaxel regimen with a subclause to consider 3-weekly regimen as an alternative for specific technical or logistical challenges. Conclusions: The KEYNOTE-522 study has provided robust evidence on the efficacy and safety of peri-operative pembrolizumab in eTNBC patients. However, several clinical questions remain unanswered, and until further evidence is available, the HKBCF recommendations provide expert guidance on the use of pembrolizumab for eTNBC patients in daily clinical practice.

Demographics and survival outcomes of stage IV male breast cancer: A retrospective analysis of SEER database.

11142 Background: Male Breast Cancer (MBC) is a rare malignancy accounting for <1% of all breast cancer cases in the United States. It is often lately diagnosed due to lack of awareness leading to substantial morbidity and mortality. Previous studies revealed higher risk of death among males compared to females across all stages, but little known about the impact of Hormone Receptor (HR) and Human Epidermal growth factor Receptor 2(HER 2) statuses on prognosis and survival among MBC patients. So, we aim to study the survival outcomes of stage IV MBC patients using SEER (Surveillance, Epidemiology, and End Results) data. Methods: A retrospective analysis was conducted using a SEER database and identified stage IV MBC cases (Any T, Any N, M1) diagnosed between 2010-2015. The selection of these years is based on the reporting of HER2 status on SEER database starting from 2010 and to ensure a current period and a minimum of 5 years of follow-up. Patient demographics, tumor HR/HER 2 status and survival data were extracted and analyzed. Subgroup analyses were performed to show the correlation between HR/HER 2 status and survival. Results: The study included 144 patients. 59.7%(86/144) were above 60 years of age. Majority were Caucasians up to 68.1%(98/144) followed by African Americans 18.7% (27/144), Hispanics 6.9%(10/144) and Asians/Pacific Islanders 6.2%(9/144). Among the subtypes, the most common was HR+/HER2- consisting of 69.4%(100/144) followed by HR+/HER2+ 19.4%(28/144), HR-/HER2- 9.7%(14/144), HR-/HER2+ 1.4%(2/144). The median overall survival varied among different subtypes of breast cancer and was noted to be 31.5 months, 25 months, 4.5 months and 10 months among HR+/HER2-, HR+/HER2+, HR-/HER2- and HR-/HER2+ respectively (Table). In the comparison between HR+/HER2+ and HR-/HER2-, the risk of death differed significantly, as indicated by a hazard ratio of 0.26 (95% CI 0.12-0.56, p = 0.001), highlighting a poor survival of HR-/HER2-. Conclusions: This retrospective analysis provides valuable insights into the demographics and survival outcomes of stage IV MBC patients. Triple negative (HR-/HER2-) subtype continues to have poor outcomes in males as well, emphasizing the need to explore novel treatment strategies to improve outcomes for this unique patient population. Although, treatment regimens for MBC are extrapolated from women, the disparity in survival across all subtypes requires the need to get more men on breast cancer clinical trials when feasible. [Table: see text]

Study the Correlation of Zearalenone with Prevalence of Breast Cancer in Al-Najaf Province, Iraq

Abstract Background: This study aimed to investigate the concentration of ZAN in female breast cancer patients compared to a control group. Objectives: The objective of this study was to determine the concentration of ZAN and its association with breast cancer in female patients treated at the National Educational Oncology Hospital in the Al-Najaf Province. Materials and Methods: A total of 40 female breast cancer patients who were treated at the National Educational Oncology Hospital in the Al-Najaf Province between April and August 2022 were included in the study. Additionally, 20 healthy females served as the control group. High-performance liquid chromatography (HPLC) was used to quantitatively diagnose the ratio of ZAN in the 40 breast cancer cases with positive results. Serum samples were collected in sterile Eppendorf tubes and analyzed using HPLC to determine the concentration of ZAN. Relevant patient information, including age ranges, was recorded in data sheets. Results: The results revealed a significant increase (P < 0.05) in ZAN concentrations among the breast cancer patients compared to the control group. The concentrations of ZAN were measured at 0.345394 and 0.220381 ng/mL, respectively, indicating higher ZAN levels in the breast cancer patient group. Conclusion: This study provides evidence of a significant association between ZAN concentration and breast cancer in female patients treated at the National Educational Oncology Hospital in the Al-Najaf Province. These findings contribute to the understanding of the role of ZAN in breast cancer development. Further research is warranted to explore the mechanisms underlying this relationship and potentially develop targeted interventions.

Imaging the Male Breast: Gynecomastia, Male Breast Cancer, and Beyond.

The number of men undergoing breast imaging has increased in recent years, according to some reports. Most male breast concerns are related to benign causes, most commonly gynecomastia. The range of abnormalities typically encountered in the male breast is less broad than that encountered in women, given that lobule formation rarely occurs in men. Other benign causes of male breast palpable abnormalities with characteristic imaging findings include lipomas, sebaceous or epidermal inclusion cysts, and intramammary lymph nodes. Male breast cancer (MBC) is rare, representing up to 1% of breast cancer cases, but some data indicate that its incidence is increasing. MBC demonstrates some clinical features that overlap with those of gynecomastia, including a propensity for the subareolar breast. Men with breast cancer tend to present at a later stage than do women. MBC typically has similar imaging features to those of female breast cancer, often characterized by an irregular mass that may have associated calcifications. Occasionally, however, MBC has a benign-appearing imaging phenotype, with an oval shape and circumscribed margins, and therefore most solid breast masses in men require tissue diagnosis. Histopathologic evaluation may alternatively reveal other benign breast masses found in men, including papillomas, myofibroblastomas, and hemangiomas. Radiologists must be familiar with the breadth of male breast abnormalities to meet the rising challenge of caring for these patients. ©RSNA, 2024 Supplemental material is available for this article.

A randomized trial of dietary modification with exercise in women who are class 2 obese with non-metastatic breast cancer.

e22542 Background: As overweight and obesity increases worldwide, associated risks of breast cancer parallel. A higher body mass index (BMI) has been linked with at least seventeen types of solid tumors, including 9% of all breast cancer cases. Weight gain post-diagnosis is associated with greater morbidity and may increase cancer recurrence risk by 30-40%. Exercise and diet modifications carry potential to lower risk of recurrence. Herein, we report a 6-month pilot study at Piedmont Fayette Hospital in women with nonmetastatic breast cancer with diet modification. Methods: Women with non-metastatic breast cancer, class 2 obesity were recruited to participate in a six-month pilot study at the Thomas F. Chapman Family Cancer Wellness Program at Piedmont Fayette Hospital. Following consent, participants were randomized into either: ARM 1- Dietary coaching including Caloric Counting/Food Tracking with Exercise Coaching ARM 2- Dietary coaching including Carbohydrate Cycling/Intermittent Fasting/Caloric Counting/Food Tracking with Exercise Coaching. The primary goal of this pilot study is to evaluate and compare the feasibility and preliminary efficacy of two weight loss interventions. Results: As of December 2023, 20 patients were enrolled in the dietary modification study. 11 patients completed 6 months of dietary modification. Of the 11 evaluable patients, 6 were randomized to arm 1 and 5 patients were randomized to arm two, table 1. There was not a substantial weight loss in arm 1 at 6 months. However, patients on arm 2 had a median 17-pound weight loss. Conclusions: Although this was a small pilot study performed at the community hospital, we were able to demonstrate dietary modification is feasible in women with nonmetastatic breast cancer and class II obesity. Furthermore, carbohydrate cycling, and intermittent fasting seemed to be a more effective method at weight loss over calorie restriction. We plan to further expand this pilot study to other Piedmont Wellness Centers. [Table: see text]

Joint effects of long-term exposure to multiple air pollutants and breast cancer risk.

10572 Background: Human exposure to air pollution involves complex mixtures of multiple correlated air pollutants. To date, very few studies have assessed the combined effect of exposure to multiple air pollutants on breast cancer risk. We assessed the joint effects of multiple air pollutants and breast cancer risk. Methods: The study was based on a case-control study nested within the French E3N cohort, involving 5222 incident breast cancer cases and 5222 matched controls. For each woman, the average of the mean annual concentration estimates for eight air pollutants ((benzo(a)pyrene, cadmium, dioxins, polychlorinated biphenyls (PCB153), nitrogen dioxide (NO2), particulate matters (PM2.5, PM10), ozone) was estimated from cohort inclusion (in 1990) to the index date. We used Bayesian Profile Regression, which groups individuals according to their exposure profile and risk levels, and assigns a risk to each of these clusters. Odds ratios (OR) and their 95% credible intervals (CrI) were estimated. Results: Overall, 21 clusters were identified. The cluster characterized by low exposures to all pollutants, except ozone was taken as reference. A significant increase in breast cancer risk compared to the reference cluster was observed for 3 clusters, with the OR of 1.61 (CrI: 1.13;2.26), OR (1.00; 1.88), and OR 1.38 (1.00; 1.88) respectively. These three clusters share quite similar exposure profiles characterized by women in urban settings with high exposure to most pollutants, particularly to NO2, PM and PCB153. Conclusions: Overall, there is evidence of a positive joint effect of high level exposures to air several pollutants, namely NO2, PM and PCB153 and increased risk of breast cancer.

Concordance between tissue (tumor DNA) and liquid (ctDNA) biopsy next-generation sequencing (NGS) data in detection of PIK3CA, AKT1, and PTEN alterations in breast cancer: A retrospective analysis.

e15033 Background: In the Phase 3 CAPItello-291 trial (NCT04305496), the addition of capivasertib (a potent, selective pan-AKT inhibitor) to fulvestrant significantly improved progression-free survival in patients with HR+/HER2− advanced breast cancer, especially in those with PIK3CA/AKT1/PTEN-altered tumors identified using tissue biopsy-based FoundationOneCDx. Given the growing utility of circulating tumor DNA (ctDNA) and interest in liquid biopsy-based tests to detect PIK3CA/AKT1/PTEN alterations, we performed a retrospective analytical comparison of FoundationOneCDx and blood-based FoundationOneLiquidCDx NGS data. Methods: We utilized the FoundationCORE database of breast cancer cases profiled during routine clinical care with FoundationOneCDx and/or FoundationOneLiquidCDx (covering the same genomic regions). Analytical comparison of all pathogenic PIK3CA/AKT1/PTEN alterations as well as alterations defined in the CAPItello-291 protocol (CAPItello-291 alterations) was performed in paired data from cases with both tissue and liquid biopsies, sampled within 90 days of each other. Subgroup analysis was conducted based on ctDNA tumor fraction (TF). Data from liquid biopsies were analyzed for co-occurring mutations. Results: CAPItello-291 alterations were detected in 44.9% of 35,730 tissue biopsies and 34.3% of 7056 liquid biopsies profiled from Jan 2017–Jun 2023. In paired NGS data (n=289), the overall positive percent agreement (PPA) for CAPItello-291 alterations across ctDNA TF subgroups was: TF ≥10% (n=99): 92.5%; TF 1–10% (n=66): 97.1%; TF <1% (n=124): 33.9%. The PPA for all PIK3CA/AKT1/PTEN short variants (base substitutions, indels) analyzed was: ctDNA TF ≥10%: PIK3CA, 93.9%; AKT1, 100%; PTEN, 100%, and ctDNA TF 1–10%: PIK3CA, 96.3%; AKT1, 100%; PTEN, 100%. For PTEN biallelic deletions, the PPA was 50% (2/4) in cases with ctDNA TF ≥10%. In liquid biopsies with CAPItello-291 alterations (n=2421), the most frequent co-occurring mutations were in TP53 (49.9%), ESR1 (31.2%), CDH1 (23.7%), NF1 (13.0%), RB1 (12.8%), CHEK2 (12.4%), ATM (11.9%), FGF3 (11.4%), FGF19 (11.0%), and FGF4 (10.5%). Mutations in BRCA1 (2.4%), BRCA2 (4.8%), and PALB2 (1.3%) were also observed. Conclusions: PPA between liquid and tissue biopsy NGS data for the detection of PIK3CA/AKT1/PTEN short variants was high in cases with ctDNA TF ≥1%. Liquid biopsies offer a minimally invasive approach for the detection of some CAPItello-291 alterations. However, limitations posed by ctDNA TF <1% and sample and variant types should be considered. Together, these data can help clinicians make informed decisions regarding suitable diagnostic tests to determine patient eligibility for breast cancer therapies.

Association of mammographic and sonographic findings with prognostic molecular factors and hormone receptor expression in malignant breast lesions.

The aim of this study was to determine whether mammographic and sonographic features of malignant breast lesions are correlated with tumor histologic grade, hormonal receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67 status. In this retrospective study, imaging and histopathological findings of 187 biopsy-proven breast cancer cases from November 2019 to February 2021 were reviewed. The Chi-square test was used to examine the potential correlation between mammographic and sonographic characteristics with histopathological features such as hormonal receptor, HER2 status, Ki-67 labeling index, and histological grade. We observed that microlobulated margin as well as oval/round morphology in mammograms correlate with triple-negative intrinsic subtype (P = 0.006 and P = 0.004). The presence of calcification in sonography was significantly higher in the luminal-B subtype (P = 0.002). Furthermore, ill-defined margins in mammography were significantly higher in amplified HER2 expression (P = 0.004) in the same manner as an oval/round shape in higher levels of Ki-67 (P = 0.030). Mammography and sonography features may reflect the biological behavior of various subtypes of breast cancer and can detect more aggressive breast cancers that can mimic benign or less malignant appearing lesions. These findings may be an excellent predictor for some subtypes like triple-negative breast cancer. Studying the range of these imaging characteristics may help in better understanding the prognosis, choosing a treatment strategy, and predicting response to treatment.

AI-assisted clinical summary and treatment planning for cancer care: A comparative study of human vs. AI-based approaches.

1523 Background: Understanding a patient's clinical narrative, timeline, and history is critical for accurate treatment decision-making. However, reviewing and summarizing complex records is time-consuming and error-prone. Recent advancements in artificial intelligence (AI), specifically large language models (LLM), offer paths to improve quality and efficiency. Methods: A study was conducted on 50 breast cancer cases from an academic medical institution, utilizing all medical records—clinic, pathology, and radiology reports—up until the point of the initial treatment decision. All cases were processed using three different approaches: AI-assisted; full-AI; and human-only. In the AI-assisted method, two oncology physician assistants (PAs) revised AI-generated summaries to create clinical summaries. The full-AI method had AI independently produce clinical summaries, while the human-only method had the PAs compile summaries without AI. Eight board-certified international oncology specialists blindly evaluated summaries for faithfulness, completeness, and succinctness using a 3-point scale, ranked their preferences, and tried to predict which summaries were full-AI. Rankings were assessed using a Friedman test followed by a Wilcoxon signed-rank test, and full-AI prediction was assessed using a two-sided one-sample binomial test. After summarization, a distinct AI system with access to clinical guidelines provided treatment plans. These plans were then evaluated by a board-certified oncologist with access to the original treatment decision. Results: The study found specialists favored AI-assisted, followed by full-AI, and then human-only summaries, with average ranks of 1.73, 1.93, 2.34 respectively (lower is better, p<0.001). The difference between full-AI and AI-assisted was not significant (p=0.11). Evaluation scores (mean±95%CI, higher is better) showed AI-assisted, full-AI, and human-only scored 2.35±0.13, 2.14±0.14, 2.17±0.14 for faithfulness; 2.28±0.12, 2.01±0.12, 1.93±0.14 for completeness; and 2.33±0.12, 2.21±0.12, 1.99±0.13 for succinctness. The average summarization time was 19.71, 1.17, 26.03 minutes. Full-AI identification accuracy was 0.28 (not different from chance 0.33, p=0.46). With AI-assisted summaries, the treatment plans were accurate in 45 cases (90%) and partially accurate in 5 cases (10%). In the 5 partially accurate cases, the system was accurate with the provided input data, but there were inaccuracies with the input data, including incorrect formats or missing data. Conclusions: Incorporating LLMs into the creation of medical summaries has shown improvements in both quality and efficiency, achieving up to 22.2x speed up with full-AI, indicating that AI-assisted summarization tools can potentially enhance care quality. AI-assisted summaries yield accurate treatment plans when the input data is accurate.

Predicting pathological response in early-stage triple-negative breast cancer: Exploring the role of BRCA gene mutations—A retrospective single-institution study.

e12656 Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, constituting approximately 15-20% of all breast cancer cases. While less than 10% of all breast cancer patients harbor BRCA1/2 mutations, ~20% of TNBC patients carry these mutations. Notably, at least one-third of BRCA1 carriers develop TNBC. This study aimed to investigate the association between BRCA mutation status and pathological response (PR) in early-stage TNBC patients, specifically, the impact of BRCA positivity on achieving pathological complete response (pCR), and identify other potential predictors of PR. Methods: We conducted a retrospective cohort study of patients with early-stage (Stage I-III) triple-negative breast cancer diagnosed and treated at our institution between January 2012 and June 2022, following Institutional Review Board (IRB) approval. Patients were identified from our Institutional Cancer Registry based on complete data availability (including other inclusion criteria) excluding patients who did not receive neoadjuvant chemotherapy. Data on demographics, tumor characteristics, treatment regimens, and pathological response (assessed according to [specified criteria]) were extracted from the charts. Results: Out of 228 patients diagnosed with early-stage triple-negative breast cancer, 54.6% had no genetic mutations, while 7.9%, 4.9%, and 8.4% harbored BRCA1, BRCA2, and other mutations, respectively. Notably, 23.4% did not receive genetic counseling or testing at our institution. Patients with BRCA2 mutations had a 100% pathological response rate, of which 57.14% had pCR, compared to 85.7% for BRCA1, of which 71.43% had pCR. Furthermore, 93.8% of patients with other genetic mutations had pathological response, of which 56.25% had pCR, as compared to 68.42% in non-mutated cases of which 26.7% had pCR ( P=0.038). Analysis of other variables revealed no significant impact of age, BMI, performance status, or neoadjuvant chemotherapy regimen on pathological response. Conclusions: This retrospective study suggests a trend towards higher complete pathological responses in early-stage triple-negative breast cancer patients with BRCA and other genetic mutations compared to those without. These findings were statistically significant, indicating a potential clinical trend that specific genetic mutations may be associated with improved response to neoadjuvant chemotherapy in early-stage triple-negative breast cancer. Further research is needed to confirm these findings and guide the development of personalized treatment strategies based on a patient's genetic profile. Additionally, our findings highlight the importance of genetic testing for all patients with early-stage triple-negative breast cancer, regardless of age or family history.

Genomic analysis of the tumor microenvironment in Asian and Native Hawaiian and Pacific Islander patients with triple negative breast cancer.

e12644 Background: Triple negative breast cancer (TNBC) accounts for approximately 10- 20% of breast cancer cases and has the worst overall survival and prognosis compared to other subtypes. Unlike other subtypes, patients with TNBC are responsive to neoadjuvant therapy. A higher percent of stromal tumor infiltrating lymophocytes (sTILs) in the tumor microenvironment of TNBC correlates with an improved prognosis. Previous studies demonstrate that Native Hawaiians and Pacific Islanders (NHPIs) and Asians have equivocal percent of sTILs. Yet NHPIs have a higher mortality rate at 24.9% compared to Asians at 11%. Our study aims to molecularly characterize the tumor microenvironment in a diverse population of patients with TNBC who received neoadjuvant therapy. Methods: Retrospective chart review was conducted on 12 Asians and 12 NHPI patients with early stage TNBC from 2015 to 2022 from a medical oncology clinic within the Hawai’i Pacific Health system. Patient data collected include age at diagnosis of breast cancer, histology, BMI, clinical stage, sTILs, residual cancer burden, neoadjuvant treatment, and pathologic complete response. Core biopsy samples were processed and analyzed using the nCounter Breast Cancer 360 Panel. Further analysis was obtained using the nSolver Advanced Analysis Module. Results: Patient characteristics are listed in the table. Most patients had the basal-like immunosuppressed TNBC subtype. Among differentially expressed genes between races, 31 genes were statistically significant. NHPIs expressed more IL12RB2 and MYC, and Asians expressed more FGFR4 and MLPH. Among responders compared to non-responders, 5 genes were statistically significant. Responders expressed more STC1 and PTGER3, and non-responders expressed more CRAYAB, TMPRSS2, and CHAD. Among old and young patients, 132 genes were statistically significant. Older patients expressed more FUT3 and CKMT1, and younger patients expressed more MMP7 and MIA. Conclusions: In this pilot study, the molecular and genetic differences suggest that the tumor microenvironment may play a role in treatment outcomes between NHPIs and Asians. Further analysis will be conducted to determine the differences in immune cell infiltration. [Table: see text]

DNA methylation-based biological age and time to relapse in triple negative breast cancer.

e13126 Background: Triple negative breast cancer (TNBC) represents 15% of all breast cancer cases and is one of the most aggressive forms of breast cancer with a poorer prognosis. Due to the lack of receptors, TNBC is not amendable to hormonal or anti-HER2 therapies and current gene expression arrays have limited clinical utility in TNBC. The identification of biomarkers associated with TNBC may aid in elucidating the underlying biological mechanisms of this disease and may also have implications for risk stratification, diagnosis, and prognosis of TNBC. The purpose of this study was to investigate the association between markers of biological aging and time to relapse in TNBC. Methods: DNA methylation and clinical data from a publicly available dataset (GSE141441) were used in this analysis. Breast tissue specimens in female TNBC patients who received (n=56) and who did not receive (n=110) chemotherapy underwent DNA methylation profiling using the Illumina Infinium HumanMethylation450K BeadChip. Five DNA methylation-based biological age metrics were calculated: intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and DunedinPACE (Pace of Aging Calculated from the Epigenome). Multiple linear and quantile regression analyses were performed to examine the association between the aging metrics and time to TNBC relapse. Interaction and stratified analyses by Ki-67 was additionally performed. Results: After adjusting for chronological age, GrimAA ( P=0.024) and DunedinPACE ( P=0.019) were negatively associated with time to relapse among patients who did not receive chemotherapy. Specifically, a 1-year increase in GrimAA and 1 unit increase in the pace of aging were associated with a 1.77-month and a 53.62-month shorter relapse of TNBC, respectively. Additionally, Ki-67 significantly modified the association between IEAA ( P=0.023) and DunedinPACE ( P=0.035) among patients who received chemotherapy with a 2.75- and a 42.17-month shorter relapse of TNBC among those with a Ki-67 index greater than 50% per unit increase in IEAA and DunedinPACE, respectively. Conclusions: We observed DNA methylation markers of biological age were associated with time to relapse in TNBC patients and these associations were modified by Ki-67. These biomarkers may have prognostic utility in TNBC relapse and potentially, may aid in oncological precision medicine efforts for personalized treatment regimens and surveillance. [Table: see text]

Male breast cancer survival in Mexico between 2007 and 2016: A retrospective cohort.

1116 Background: Male breast cancer represents around 1% of all breast cancers worldwide. Due to its rarity, it is more likely to be diagnosed at advanced stages than in women, and survival rates tend to be lower than in female patients. Information about survival in male breast cancer in low- and middle-income countries (LMIC) is scarce. Methods: We conducted a retrospective cohort study cross-linking nationwide reimbursement claims for breast cancer cases between 2007 and 2016 treated within the Seguro Popular health financing scheme to a national mortality registry in Mexico. Age, municipality of residence, clinical stage, and year of treatment initiation were described. Facilities were classified according to location, total breast cancer patient volume, and type of funding. We estimated 5-year overall survival (OS) with 95% confidence intervals (95% CI) through the Kaplan Meier method and used the log-rank test to compare differences between patient groups. Patients with in situ disease and missing data for clinical stage were excluded from survival analyses. Results: We identified 268,703 claims representing 60,846 patients, from which 328 were male (0.53%). Median age was 56 years (IQR 48-67). At treatment initiation, 20.7% of patients had early disease, 46.3% had locally advanced (LA) disease and 15.5% metastatic disease; clinical stage information was missing in 16% of patients Most patients (86.6%) were treated at public facilities, and 40.5% were treated at high volume facilities. With a median follow-up of 4.1 years, five-year OS in the whole cohort was 64.3% (CI 95% 58.1-71.2). In patients with early-stage disease, 5-year OS was 78.7% (95% CI 67.0-92.4), in LA disease 66.3% (95% CI 58.4-75.3) and in metastatic disease 39.7% (95% CI 27.5-57.5) (p <0.001). Patients with LA disease treated at a private facility had improved 5-year OS (88.9%) compared to those who were treated at a public facility (62.8%) (p=0.033). We did not find any other significant differences in survival according to patient or facility characteristics, including patient volume. Conclusions: These results represent the largest cohort to describe survival in men with breast cancer in Latin America. We found a larger proportion of men diagnosed with metastatic disease than described in women in Mexico, and lower than expected survival in patients with early-stage and LA disease.

Inhibition of AR and DNA-PK for radio-sensitization of AR-driven cancers.

e12593 Background: Breast cancer (BC) is the most diagnosed cancer globally with over 2.2 million new cases and 680,000 deaths annually. Radiotherapy (RT) is essential for curative BC treatment; however, 20% of BC cases are radio-resistant, with the underlying mechanisms remaining poorly understood. Previous studies in prostate cancer (PCa) have shown that androgen receptor (AR) promotes radio-resistance (RT-resistance) through transcriptional regulation and increased DNA repair capacity, including through upregulation of DNA repair proteins DNA-PK and PARP1. Although AR is expressed in 60% of BCs, the implications of AR in BC RT-resistance are not yet fully characterized. We hypothesized that AR may drive RT-resistance in BC through a similar AR-DNA repair loop. Methods: To characterize the repertoire of cofactors that cooperate with AR on the TF complex, we exposed a BC cell line to RT and performed rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) proteomics. We identified several candidate proteins that interact with AR to further investigate as targets for RT-sensitization. Survival analyses in BC and PCa cell lines were performed to identify RT-sensitizing agents. Molecular mechanisms of RT-sensitization were assessed using ATAC-seq and RNA-seq analyses. Results: Using RIME, we identified several DNA repair proteins including DNA-PK, PARP-1, and XRCC5 as differentially recruited to chromatin-bound AR. This suggests a cooperative role and provides potential druggable targets to improve RT-sensitivity. Based on these results, we also performed a survival analysis in AR-driven BC and PCa cell lines and showed that inhibition of either AR or DNA-PK led to RT-sensitization, and dual inhibition provided an additive effect. We sought to characterize the molecular mechanisms driving the RT-sensitizing effects of AR and DNA-PK inhibition and performed ATAC-seq and RNA-seq on treated and untreated cells. Combining enzalutamide with a DNA-PK inhibitor altered expression of several pathways implicated in RT-sensitization, although these pathways were largely distinct in BC and PCa. Further, we identified distinct genes that may be responsible for this phenotype in AR-driven BC. Additionally, we found a larger effect in chromatin rearrangement after treatment in PCa than BC. Conclusions: Identifying mechanisms of RT-resistance in hormone-driven cancers is essential to develop therapeutic strategies and improve patient outcomes. This study provides key evidence for AR-driven RT-resistance in BC and PCa, and identifies DNA-PK inhibition as a potential drug target. Distinct mechanisms appear to be driving this phenotype across BC and PCa, in our models. Understanding the cooperation of DNA repair and hormone signaling pathways will help support the use of DNA-damaging agents for hormone-driven cancers, and potentially inform rational design of novel drug-RT combinations.

Employing semi-quantitative methods to classify breast cancer markers (ER, PR, HER2, Ki67) expression, using the RT-qPCR based APIS Breast Cancer Subtyping Kit.

e13091 Background: Accurate determination of breast cancer (BC) biomarker status is crucial for guiding patient management decisions. Histopathologists commonly use semi-quantitative scoring systems to convert subjective observations of immunohistochemistry (IHC) marker expression into quantitative data, allowing a more detailed categorisation of marker status. The APIS Breast Cancer Subtyping Kit (BCSK) is an in vitro diagnostic test, detecting the relative expression of seven mRNA target genes ( ESR1, PGR, ERBB2, MKI67, CCNA2, PCNA, and KIF23) from invasive BC tissue. The APIS BCSK reports a positive/negative result for each biomarker alongside a molecular classification. Here, we demonstrate that by implementing additional RNA expression cut-off values, it is possible to generate a semi-quantitative result by further stratifying target expression into negative, low, medium, and high status using the APIS BCSK. Methods: 368 formalin-fixed paraffin-embedded (FFPE) samples of BC cases were used, obtained by core needle biopsy or resection. IHC scores were correlated with copy numbers as determined by an independently validated digital PCR (dPCR) assay and were used to set copy number cut-off values corresponding to IHC classification. The generated dPCR cut-off values were used to evaluate the corresponding ∆Ct values (RNA expression results derived from the APIS BCSK). For each target, three ΔCt cut-offs were established, facilitating classification into negative, low, medium, and high expression. Results: The semi-quantitative approach successfully classified target expression levels ( ESR1, PGR, ERBB2, MKI67). Overlap in ΔCt values was observed in central IHC categories for all targets, likely due to tumor heterogeneity and differing measurement methods for IHC and RT-qPCR. Despite these discrepancies, the derived cut-off values define a semi-quantitative scale for each target (Table). Conclusions: This study has established a methodology that utilises target copy number values and IHC protein quantification to establish ΔCt cut-off points. For each target we have defined four distinct groups as negative, low, medium, and high expression. This approach provides a semi-quantitative scale for evaluating each target with the APIS BCSK and serves as a valuable tool for classifying and understanding target expression levels. [Table: see text]

Deciphering the global landscape of breast cancer in 38 OECD countries from 1990-2019: A benchmarking global analysis.

1046 Background: Breast Cancer (BC) stands as the primary contributor to disability and the second leading cause of death among countries belonging to the Organization for Economic Cooperation and Development (OECD). A comprehensive cross-country analysis of BC is crucial to monitor the growing burden. Methods: Employing the global burden of disease framework, we have calculated the incidence, prevalence, mortality, disability-adjusted life years (DALYs), and years of life lost (YLL) attributed to BC, categorized by age, gender, year, and geographical location across the 38 OECD member countries. Results: The total number of BC cases has witnessed a notable increase, rising from 5.5 million (95%UI: 5.1-6) in 1990 to 9 million (8.2-9.8) in 2019. BC-related deaths have also risen from 172,148 (164,284-176,147) in 1990 to 214,458 (195,692-226,347) in 2019, while DALYs have increased from 4.6 (4.5-4.8) in 1990 to 5.1 (4.8-5.5) in 2019. The annual percentage change (APC) in incidence has surged by 59% (44-75%) from 1990 to 2019. The highest APC in age-standardized incidence rates was observed in South Korea at 150% (99-205), while the most substantial decrease was recorded in Switzerland at 3%. Regarding death rates, Japan saw an 11% increase, Costa Rica 10%, Mexico 9%, South Korea 8%, and Turkey 4%, whereas the remaining countries witnessed a decrease from 1990 to 2019. In terms of DALY rates, Mexico and Japan experienced a 10% increase, South Korea 5%, Turkey 3%, with the rest showing a decrease from 1990 to 2019. Males bore a higher burden compared to females, with an APC in total incidence of 109% versus 58%, deaths at 73% versus 24%, and DALYs at 57% versus 10% from 1990 to 2019. The highest overall burden was observed in the 70+ age group, while the <70 and <20 age groups exhibited a decreasing trend. The total number of deaths is projected to continue increasing. Conclusions: In 2019, BC accounted for 6.64% of all cancer-related deaths and 7.9% of DALYs among women. Based on these findings, low-resource countries should consider reallocating funding to combat this burden, and public health policymakers need to prioritize surveillance and early screening efforts.

Clinicopathological features and prognosis for pregnancy-associated breast cancer: A matched case-control study.

e12573 Background: Pregnancy-Associated Breast Cancer (PABC) is defined as breast cancer diagnosed during pregnancy or within 1 year postpartum. Studies indicate that PABC tends to have poorer prognostic characteristics and often worse outcomes compared to non-PABC. The primary goal of this study is to examine disease characteristics associated with PABC versus non-PABC in the United Arab Emirates (UAE), where breast cancer is characterized by a younger age and more advanced stage compared to North America and Europe. Additionally, the UAE has a younger mean age for first-time mothers and a similar age for all mothers compared to North America and Europe. Methods: Patients with PABC were selected from BC cases of women ≤40 years treated at Tawam Hospital, the largest tertiary cancer center in the UAE between January 2003 – December 2020. Each PABC patient was matched to two non-PABC patients (controls) according to cancer stage, age, and year of diagnosis. The Fisher's exact and Kruskal-Wallis tests were used to compare both study groups. Results: 66 women with PABC were identified, with a median age at diagnosis of 33.0 (interquartile range [IQR]: 30.0-37.0) years. Most presented with stage II (45.5%) or stage III (39.4%) disease and underwent mastectomy and axillary lymph node dissection. Invasive ductal carcinoma was the most frequent histological type in both groups (86.4% for PABC and 85.6% for non-PABC). PABC was associated with higher grade 3 disease compared with non- PABC (53% vs 51.5% p= 0.009). More women with PABC received neoadjuvant chemotherapy (NACT) and radiation therapy (RT) compared with non-PABC (48.5% vs 3%, p <0.001 and 80.3% vs 65.9%, p= 0.046, respectively). There were no statistically significant differences with regards to tumor size, nodal involvement, underlying histologic subtype, ER/PR expression or HER-2 status, rates of breast-conserving surgery and adjuvant chemotherapy receipt between the two groups. The median progression-free survival (PFS) was 3.2 years (IQR: 1.9-7.1) in PABC and 3.4 years (IQR: 1.2-6.2) in non-PABC group (P=0.306). The median overall survival (OS) was 4.5 years in the PABC (IQR: 2.4-7.9) versus 4.5 years (IQR: 1.9-7.9) in the non-PABC group (P = 0.786). Conclusions: PABC in women ≤40 years appears to be associated with grade III tumors and NACT and RT receipt compared to non-PABC. However, there were no significant difference in PSF and OS between PABC and non-PABC. Further analysis is underway to evaluate the prognostic factors and their effect on survival.

Once-daily upadacitinib versus placebo in adults with extensive non-segmental vitiligo: a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study

Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18-65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6mg (UPA6), upadacitinib 11mg (UPA11), upadacitinib 22mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24-52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n=49), UPA11 (n=47), UPA22 (n=43), or PBO (n=46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was-7.60 (95% CI-22.18 to 6.97; p=0.3037) for UPA6,-21.27 (95% CI-36.02 to-6.52; p=0.0051) for UPA11, and-19.60 (95% CI-35.04 to-4.16; p=0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was-7.45 (95% CI-16.86 to 1.96; p=0.1198) for UPA6,-10.84 (95% CI-20.37 to-1.32; p=0.0259) for UPA11 and-14.27 (95% CI-24.24 to-4.30; p=0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n=1)] and non-fatal ischemic stroke [UPA11 (n=1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. AbbVie Inc.

Evaluation of sarcopenia-associated survival in breast cancer with computed tomography-based pectoral muscle area measurements

Objective: Breast cancer is the most common and deadly female cancer. In breast cancer cases, survival is closely related to muscle mass, which is one of the components of body composition. Our aim was to investigate the usefulness of computed-tomography (CT)- based pectoral muscle measurements in detecting sarcopenia in patients with non-metastatic breast cancer and the relationship of these measurements with survival. Patients and Methods: Our study included 62 adult female breast cancer cases diagnosed with breast cancer between January 2012 and January 2018 and without metastasis in positron emission tomography/CT (PET/CT) examination obtained for pre-treatment staging. To evaluate sarcopenia, skeletal muscle index (SMI) and pectoral muscle index (PMI) were calculated by measuring pectoral muscle area and skeletal muscle area at L3 vertebra level on PET/CT images. Results: Deceased patients were significantly older (Median=73.90, IQR=27.04) than surviving patients (Median=54.60, IQR=13.37, p=0.025) and were diagnosed with cancer later in life (Median=63.92 IQR=30.16’ vs. Median=47.51 IQR=15.0, p=0.030). When the threshold of 31 cm2/m2 was selected, there was a statistically significant difference in survival between sarcopenic and non-sarcopenic groups (p=0.031). Conclusion: In conclusion, the presence of sarcopenia in female breast cancer cases is a parameter that affects survival and can be measured using radiological imaging methods. In addition to the measurements accepted in the literature regarding sarcopenia, pectoral muscle measurements can be chosen as an alternative method in the diagnosis of sarcopenia.