Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.

BACKGROUND: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown. METHODS AND RESULTS: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis. CONCLUSIONS: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.

NSABP FB-10: a phase Ib/II trial evaluating ado-trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer.

BACKGROUND: We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients. METHODS: Forty-nine HER2-positive patients (determined locally) who progressed on-treatment with trastuzumab + pertuzumab were enrolled in this phase Ib/II study. Mutations and HER2 amplifications were assessed in ctDNA before (C1D1) and on-treatment (C2D1) with the Guardant360 assay. Archived tissue (TP0) and study entry biopsies (TP1) were assayed for whole transcriptome, HER2 copy number, and mutations, with Ampli-Seq, and centrally for HER2 with CLIA assays. Patient responses were assessed with RECIST v1.1, and Molecular Response with the Guardant360 Response algorithm. RESULTS: The ORR in phase II was 7/22 (32%), which included all patients who had at least one dose of study therapy. In phase I, the ORR was 12/19 (63%), which included only patients who were considered evaluable, having received their first scan at 6 weeks. Central confirmation of HER2-positivity was found in 83% (30/36) of the TP0 samples. HER2-amplified ctDNA was found at C1D1 in 48% (20/42) of samples. Patients with ctHER2-amp versus non-amplified HER2 ctDNA determined in C1D1 ctDNA had a longer median progression-free survival (PFS): 480 days versus 60 days (P = 0.015). Molecular Response scores were significantly associated with both PFS (HR 0.28, 0.09-0.90, P = 0.033) and best response (P = 0.037). All five of the patients with ctHER2-amp at C1D1 who had undetectable ctDNA after study therapy had an objective response. Patients whose ctHER2-amp decreased on-treatment had better outcomes than patients whose ctHER2-amp remained unchanged. HER2 RNA levels show a correlation to HER2 CLIA IHC status and were significantly higher in patients with clinically documented responses compared to patients with progressive disease (P = 0.03). CONCLUSIONS: The following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies. Clinical Trials registration NCT02236000.

Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

Management of Neuroendocrine Breast Carcinoma (NEBC): Review of Literature.

Extra pulmonary high-grade poorly differentiated neuroendocrine carcinomas (EP-NECs) are rare tumors that usually arise in the gastrointestinal and genitourinary tracts. Primary neuroendocrine carcinoma of the breast (NEBC) is extremely rare, representing less than 0.1% of all breast cancers and less than 1% of neuroendocrine neoplasms. Consequently, they can be misdiagnosed as other types of breast cancer, however, proper immunohistochemical (IHC) studies can assist with making the correct diagnosis. Management of NEBC can be challenging given the paucity of evidence-based literature and should not routinely follow the therapeutic guidelines of other breast cancers. In this article, we review the current literature regarding the management of NEBC.

Phase II Clinical Trial of Pembrolizumab and Chemotherapy Reveals Distinct Transcriptomic Profiles by Radiologic Response in Metastatic Triple-Negative Breast Cancer.

PURPOSE: A single arm, phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple-negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, overall survival (OS), and identify pathologic and transcriptomic correlates of response to therapy. PATIENTS AND METHODS: Patients with ≤2 prior therapies for metastatic disease were treated with CNP regardless of tumor programmed cell death-ligand 1 status. Core tissue biopsies were obtained prior to treatment initiation. ORR was assessed using a binomial distribution. Survival was analyzed via the Kaplan-Meier method. Bulk RNA sequencing was employed for correlative studies. RESULTS: Thirty patients were enrolled. The ORR was 48.0%: 2 (7%) complete responses (CR), 11 (41%) partial responses (PR), and 8 (30%) stable disease (SD). The median DOR for patients with CR or PR was 6.4 months [95% confidence interval (CI), 4-8.5 months]. For patients with CR, DOR was >24 months. Overall median PFS and OS were 5.8 (95% CI, 4.7-8.5 months) and 13.4 months (8.9-17.3 months), respectively. We identified unique transcriptomic landscapes associated with each RECIST category of radiographic treatment response. In CR and durable PR, IGHG1 expression was enriched. IGHG1high tumors were associated with improved OS (P = 0.045) and were concurrently enriched with B cells and follicular helper T cells, indicating IGHG1 as a promising marker for lymphocytic infiltration and robust response to chemo-immunotherapy. CONCLUSIONS: Pretreatment tissue sampling in mTNBC treated with CNP reveals transcriptomic signatures that may predict radiographic responses to chemo-immunotherapy.

Validation of the PREDICT Prognostication Tool in US Patients With Breast Cancer.

BACKGROUND: PREDICT is an online prognostication tool derived from breast cancer registry information on approximately 6,000 women treated in the United Kingdom that estimates the postsurgical treatment benefit of surgery alone, chemotherapy, trastuzumab, endocrine therapy, and/or adjuvant bisphosphonates in early-stage breast cancer. Our aim was to validate the PREDICT algorithm in predicting 5- and 10-year overall survival (OS) probabilities using real-world outcomes among US patients with breast cancer. METHODS: A retrospective study was performed including women diagnosed with unilateral breast cancer in 2004 through 2012. Women with primary unilateral invasive breast cancer were included. Patients with bilateral or metastatic breast cancer, no breast surgery, or missing critical clinical information were excluded. Prognostic scores from PREDICT were calculated and external validity was approached by assessing statistical discrimination through area under time-dependent receiver-operator curves (AUC) and comparing the predicted survival to the observed OS in relevant subgroups. RESULTS: We included 708,652 women, with a median age of 58 years. Most patients were White (85.4%), non-Hispanic (88.4%), and diagnosed with estrogen receptor-positive breast cancer (79.6%). Approximately 50% of patients received adjuvant chemotherapy, 67% received adjuvant endocrine therapy, 60% underwent a partial mastectomy, and 59% had 1 to 5 axillary sentinel nodes removed. Median follow-up time was 97.7 months. The population's 5- and 10-year OS were 89.7% and 78.7%, respectively. Estimated 5- and 10-year median survival with PREDICT were 88.3% and 73.8%, and an AUC of 0.77 and 0.76, respectively. PREDICT performed most poorly in patients with high Charlson-Deyo comorbidity scores (2-3), where PREDICT overestimated OS. Sensitivity analysis by year of diagnosis and HER2 status showed similar results. CONCLUSIONS: In this prognostic study utilizing the National Cancer Database, the PREDICT tool accurately predicted 5- and 10-year OS in a contemporary and diverse population of US patients with nonmetastatic breast cancer.

Social Determinants of Health Data Improve the Prediction of Cardiac Outcomes in Females with Breast Cancer.

Cardiovascular disease is the leading cause of mortality among breast cancer (BC) patients aged 50 and above. Machine Learning (ML) models are increasingly utilized as prediction tools, and recent evidence suggests that incorporating social determinants of health (SDOH) data can enhance its performance. This study included females ≥ 18 years diagnosed with BC at any stage. The outcomes were the diagnosis and time-to-event of major adverse cardiovascular events (MACEs) within two years following a cancer diagnosis. Covariates encompassed demographics, risk factors, individual and neighborhood-level SDOH, tumor characteristics, and BC treatment. Race-specific and race-agnostic Extreme Gradient Boosting ML models with and without SDOH data were developed and compared based on their C-index. Among 4309 patients, 11.4% experienced a 2-year MACE. The race-agnostic models exhibited a C-index of 0.78 (95% CI 0.76-0.79) and 0.81 (95% CI 0.80-0.82) without and with SDOH data, respectively. In non-Hispanic Black women (NHB; n = 765), models without and with SDOH data achieved a C-index of 0.74 (95% CI 0.72-0.76) and 0.75 (95% CI 0.73-0.78), respectively. Among non-Hispanic White women (n = 3321), models without and with SDOH data yielded a C-index of 0.79 (95% CI 0.77-0.80) and 0.79 (95% CI 0.77-0.80), respectively. In summary, including SDOH data improves the predictive performance of ML models in forecasting 2-year MACE among BC females, particularly within NHB.

Estimating the overall survival benefit of adjuvant chemo-endocrine therapy in women over age 50 with pT1-2N0 early stage breast cancer and 21-gene recurrence score ≥26: A National Cancer Database analysis.

BACKGROUND: Validation studies of the 21-gene recurrence score (RS) previously demonstrated that adjuvant chemotherapy plus endocrine therapy (CET) was associated with a significant survival benefit in women with node negative breast cancer (BC) and RS >31. However, the TAILORx trial, did not quantify the benefit of adjuvant CET in older women with node negative hormone receptor positive (HR+) BC with RS ≥26. We hypothesized that CET would be associated with improved overall survival (OS) compared to endocrine therapy (ET) in women >50 with HR+/HER2-node negative BC and RS ≥26. METHODS: The National Cancer Database (NCDB) was queried to identify women >50 with RS ≥26 ER+/HER2-BC pT1-2N0M0. Chi-square and logistic regression analysis determined the difference between ET and CET. OS was analyzed using a multivariable Cox model. RESULTS: We included 16,745 women-4740 (28.3%) received ET and 12,005 (71.7%) received CET. Women who received CET had: moderately (OR = 1.853, p < 0.001) or poorly/undifferentiated tumors (OR = 3.875, p < 0.001), pT2 (OR = 1.356, p < 0.001), or lymph-vascular invasion (OR = 1.206, p = 0.001). After accounting for demographic and oncologic factors, 5-year OS rates were significantly superior in women receiving CET vs. ET alone (95.4% vs. 92.0%, Hazard Ratio = 0.680, p < 0.001). CONCLUSIONS: We observed that CET was associated with a clinically and statistically significant higher OS compared to ET alone in women >50 years of age with RS ≥26 pT1 and pT2 N0M0 HR+/HER2-breast cancer, and which suggests that cytotoxic chemotherapy has an impact on reducing mortality that is independent of induction of premature ovarian failure.

Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases.

The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptor-gamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.

Radiomic predicts early response to CDK4/6 inhibitors in hormone receptor positive metastatic breast cancer.

The combination of Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is the standard of care for hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Currently, there are no robust biomarkers that can predict response to CDK4/6i, and it is not clear which patients benefit from this therapy. Since MBC patients with liver metastases have a poorer prognosis, developing predictive biomarkers that could identify patients likely to respond to CDK4/6i is clinically important. Here we show the ability of imaging texture biomarkers before and a few cycles after CDK4/6i therapy, to predict early response and overall survival (OS) on 73 MBC patients with known liver metastases who received palbociclib plus ET from two sites. The delta radiomic model was associated with OS in validation set (HR: 2.4; 95% CI, 1.06-5.6; P = 0.035; C-index = 0.77). Compared to RECIST response, delta radiomic features predicted response with area under the curve (AUC) = 0.72, 95% confidence interval (CI) 0.67-0.88. Our study revealed that radiomics features can predict a lack of response earlier than standard anatomic/RECIST 1.1 assessment and warrants further study and clinical validation.

Social Determinants of Health and Racial Disparities in Cardiac Events in Breast Cancer.

BACKGROUND: Racial disparities have been reported for breast cancer and cardiovascular disease (CVD) outcomes. The determinants of racial disparities in CVD outcomes are not yet fully understood. We aimed to examine the impact of individual and neighborhood-level social determinants of health (SDOH) on the racial disparities in major adverse cardiovascular events (MACE; consisting of heart failure, acute coronary syndrome, atrial fibrillation, and ischemic stroke) among female patients with breast cancer. METHODS: This 10-year longitudinal retrospective study was based on a cancer informatics platform with electronic medical record supplementation. We included women aged ≥18 years diagnosed with breast cancer. SDOH were obtained from LexisNexis, and consisted of the domains of social and community context, neighborhood and built environment, education access and quality, and economic stability. Race-agnostic (overall data with race as a feature) and race-specific machine learning models were developed to account for and rank the SDOH impact in 2-year MACE. RESULTS: We included 4,309 patients (765 non-Hispanic Black [NHB]; 3,321 non-Hispanic white). In the race-agnostic model (C-index, 0.79; 95% CI, 0.78-0.80), the 5 most important adverse SDOH variables were neighborhood median household income (SHapley Additive exPlanations [SHAP] score [SS], 0.07), neighborhood crime index (SS = 0.06), number of transportation properties in the household (SS = 0.05), neighborhood burglary index (SS = 0.04), and neighborhood median home values (SS = 0.03). Race was not significantly associated with MACE when adverse SDOH were included as covariates (adjusted subdistribution hazard ratio, 1.22; 95% CI, 0.91-1.64). NHB patients were more likely to have unfavorable SDOH conditions for 8 of the 10 most important SDOH variables for the MACE prediction. CONCLUSIONS: Neighborhood and built environment variables are the most important SDOH predictors for 2-year MACE, and NHB patients were more likely to have unfavorable SDOH conditions. This finding reinforces that race is a social construct.

Thirty-Day Unplanned Hospital Readmissions in Patients With Cancer and the Impact of Social Determinants of Health: A Machine Learning Approach.

PURPOSE: Develop a cancer-specific machine learning (ML) model that accurately predicts 30-day unplanned readmissions in patients with solid tumors. METHODS: The initial cohort included patients 18 years or older diagnosed with a solid tumor. Two distinct cohorts were generated: one with and one without detailed social determinants of health (SDOHs) data. For each cohort, data were temporally partitioned in 70% (training), 20% (validation), and 10% (testing). Tree-based ML models were developed and validated on each cohort. The metrics used to evaluate the model's performance were receiver operating characteristic curve (ROC), area under the ROC curve, precision, recall (R), accuracy, and area under the precision-recall curve. RESULTS: We included 13,717 patients in this study in two cohorts (5,059 without SDOH data and 8,658 with SDOH data). Unplanned 30-day readmission occurred in 21.3% of the cases overall. The five main non-SDOH factors most highly associated with an unplanned 30-day readmission (R, 0.74; IQR, 0.58-0.76) were: number of previous unplanned readmissions; higher Charlson comorbidity score; nonelective index admission; discharge to anywhere other than home, hospice, or nursing facility; and higher anion gap during the admission. Neighborhood crime index, neighborhood median home values, annual income, neighborhood median household income, and wealth index were the main five SDOH factors important for predicting a high risk for an unplanned hospital readmission (R, 0.66; IQR, 0.56-0.72). The models were not directly comparable. CONCLUSION: Key drivers of unplanned readmissions in patients with cancer are complex and involve both clinical factors and SDOH. We developed a cancer-specific ML model that with reasonable accuracy identified patients with cancer at high risk for an unplanned hospital readmission.

[Evidence of iSGLT2 in the treatment of chronic kidney disease]. / Evidencias de los iSGLT2 en el tratamiento de la enfermedad renal crónica.

The prevalence and incidence of chronic kidney disease (CKD) is constantly on the rise and it is foreseeable that in the coming decades it will be the main chronic disease in the developed world. CKD is also one of the main causes of cardiovascular morbidity and mortality, with cardiovascular diseases being the main etiology of CKD, so that one and the other feed back into what is known as the cardiorenal axis. Until five years ago, the only pharmacological treatment that had been shown to modify the course of the disease were inhibitors of the renin angiotensin system. However, in recent years, the development of inhibitors of the sodium glucose cotransporter type2 have led to a revolution in cardiovascular and renal protection, both in diabetic and non-diabetic patients, constituting, at present, the cornerstone in the CKD management.

Adjuvant chemotherapy is associated with an overall survival benefit regardless of age in ER+/HER2- breast cancer pts with 1-3 positive nodes and oncotype DX recurrence score 20 to 25: an NCDB analysis.

Background: The RxPONDER trial found that among breast cancer patients with estrogen receptor positive (ER+) breast cancer, 1-3 positive axillary nodes, and a recurrence score of ≤25, only pre-menopausal women benefitted from adjuvant chemoendocrine therapy; postmenopausal women with similar characteristic did not benefit from adjuvant chemotherapy. We aimed to replicate the RxPonder trial using a larger patient cohort with real world data to determine whether a RS threshold existed where adjuvant chemotherapy was beneficial regardless of age. Methods: The National Cancer Database (NCDB) was queried for women with ER+, human epidermal growth factor receptor 2 (HER2) negative breast cancer, 1-3 positive axillary nodes, and RS ≤25 who received endocrine (ET) only or chemo-endocrine therapy (CET). Cox regression interaction was explored between CET and age as a surrogate for menopausal status. Results: The final analytic cohort included 28,427 eligible women: 7,487 (26.3%) received adjuvant CET and 20,940 (73.7%) ET. In the entire cohort, RS had a normal distribution, with a median score of 14. After correcting for demographic and clinical variables, a threshold effect was observed with RS >20 being associated with a significantly inferior overall survival (OS) (P value range: < 0.001-0.019). In women with RS of 20-25, CET was associated with a significant improvement in OS compared to ET alone, regardless of age (age <=50: HR = 0.334, P=0.002; age>50: HR=0.521, P=0.019). Conclusion: Among women with ER+/HER2- breast cancer with 1-3 positive nodes, and a RS of 20-25-in contrast to the RxPONDER trial-we observed that CET was associated with an OS benefit in women regardless of age.

Survival in elderly patients with breast cancer with and without autoimmune disease.

BACKGROUND: Patients with certain autoimmune conditions are at a reduced risk of developing breast cancer compared to the general population. Despite this, little is known about outcomes in patients with breast cancer who have a concurrent autoimmune diagnosis. METHODS: This study compared differences in outcomes between women with breast cancer who had or did not have an autoimmune diagnosis. The SEER-Medicare databases (2007-2014) were used to identify patients with breast cancer and diagnosis codes were used to identify those with an autoimmune disorder. RESULTS: The studied autoimmune diseases had a prevalence of 27% among the 137,324 patients with breast cancer. Autoimmune disease was associated with significantly longer overall survival (OS) and significantly lower cancer-specific mortality (CSM) among stage IV breast cancer patients (p < 0.0001). After controlling for the effects of age, race, chronic kideny disease, chemotherapy, and radiation therapy autoimmune disease was still predictive of improved OS (HR: 1.45, 95% CI: 1.35-1.55, p < 0.0001) and CSM (HR: 1.40, 95% CI: 1.29-1.5, p < 0.0001). By contrast, in patients with stage I-III breast cancer, the presence of an autoimmune diagnosis was associated with a lower OS (p < 0.0001, p < 0.0001, and p = 0.026, respectively), compared to patients without autoimmune disease. CONCLUSIONS: We found a higher prevalence of rheumatoid arthritis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus in patients with breast cancer compared to age matched cohorts in the general population. The presence of an autoimmune diagnosis was associated with a lower OS in stages I-III breast cancer and improved OS and CSM in patients with stage IV disease. These results suggest that anti-tumor immunity plays an important role in late stage breast cancer and could potentially be exploited to improve the effectiveness of immunotherapy.

Allostatic load and cardiovascular outcomes in males with prostate cancer.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in men with prostate cancer (PC). Accumulated stress plays an important role in CVD development. The cumulative burden of chronic stress and life events can be measured using allostatic load (AL). METHODS: The initial cohort included males aged 18 years and older diagnosed with PC (2005-2019). AL was modeled as an ordinal variable (0-11). Fine-Gray competing risk regressions measured the impact of precancer diagnosis AL and postdiagnosis AL in 2-year major cardiac events (MACE). The effect of AL changes over time on MACE development was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after PC diagnosis). RESULTS: We included 5261 PC patients of which 6.6% had a 2-year MACE. For every 1-point increase in AL before and within 60 days after PC diagnosis, the risk of MACE increased 25% (adjusted hazard ratio [aHR] =1.25, 95% confidence interval [CI] = 1.18 to 1.33) and 27% (aHR = 1.27, 95% CI = 1.20 to 1.35), respectively. Using AL as a time-varying exposure, the risk of MACE increased 19% (aHR = 1.19, 95% CI = 1.11 to 1.27), 22% (aHR = 1.22, 95% CI = 1.14 to 1.33), 28% (aHR = 1.28, 95% CI = 1.23 to 1.33), and 31% (aHR = 1.31, 95% CI = 1.27 to 1.35) for every 1-point increase in AL before, 2 months after, 6 months after, and 1 year after PC diagnosis, respectively. CONCLUSION: AL and its changes over time are associated with MACE in PC patients, suggesting a role of a biological measure of stress as a marker of CVD risk among men with PC.

Racial disparities in breast cancer treatment patterns and treatment related adverse events.

The main objective of this work was to perform a comprehensive analysis and provide a race-stratified epidemiological report accounting for differences in treatment patterns and treatment related adverse events in Non-Hispanic women with breast cancer (BC). The cohort included women ≥ 18 years diagnosed with in-situ, early-stage, and late-stage BC (2005-2022). Treatment patterns included: surgery, breast radiation, chemotherapy, endocrine therapy, or biologic therapy. Treatment related adverse events were: chemotherapy complications, cardiovascular toxicities, immune-related adverse events, psychological affectations, or cognitive decline/dementia. The influence of race on the outcomes was measured via Cox proportional-hazards models. We included 17,454 patients (82% non-Hispanic Whites [NHW]). Most of the patients had a Charlson Comorbidity Score between 1 and 2 (68%), and TNM stage I (44.5%). Surgery was performed in 51.5% of the cases, while 30.6% received radiotherapy, 26.4% received chemotherapy, 3.1% received immunotherapy, and 41.2% received endocrine therapy. Non-Hispanic Blacks (NHB) had a lower probability of undergoing breast cancer surgery (aHR = 0.92, 95% CI 0.87-0.97) and of being prescribed endocrine therapy (aHR = 0.83, 95% CI 0.79-0.89), but a higher probability of receiving adjuvant radiotherapy (aHR = 1.40, 95% CI 1.29-1.52). Moreover, NHBs had lower risk of being diagnosed with psychological issues (aHR = 0.71, 95% CI 0.63-0.80) but a higher risk for cognitive decline/dementia (aHR = 1.30, 95% CI 1.08-1.56). In conclusion, NHB women diagnosed with BC were less likely than NHW to undergo curative intent surgery or receive endocrine therapy, and had a higher risk of cognitive decline/dementia after cancer treatment. Public policy measures are urgently needed which equalize access to quality healthcare for all patients and that promote a learning healthcare system which can improve cancer outcomes.

Adjuvant Therapy in Breast Cancer Patients With Microscopic Residual Disease.

INTRODUCTION: Surgical resection is the gold standard for early-stage breast cancer. Positive surgical margins are associated with poor outcome. Endocrine therapy (ET) is recommended as primary systemic treatment for hormone receptor positive (HR+) breast cancer after surgery. We hypothesized that chemoenocrine therapy (CET) would not be associated with improved survival relative to ET for patients with positive margins. MATERIALS AND METHODS: The National Cancer Database was queried for pathologic stage I HR + HER2-breast cancer patients treated with partial mastectomy and adjuvant whole-breast irradiation between 2004 and 2017. The adjuvant treatment approaches to positive surgical margins were investigated and compared. Overall survival was compared between systemic treatment groups using multivariable cox proportional hazards regression. RESULTS: Among 228,453 patients, a positive surgical margin (microscopic residual disease, R1) was identified in 3561 (1.6%) patients. Compared with complete resections, positive margin was associated with inferior overall survival (hazard ratio [HR] = 1.276, P = 0.003). Among the R1 patients, 78.7% received ET only, 11.7% received CET, 1.2% received chemotherapy only, and 8.5% received no systemic therapy. After controlling for patient, facility, and tumor characteristics, ET provided greatest survival benefit (relative to no therapy, HR = 0.378, P < 0.001) followed by CET (HR = 0.446, P = 0.020). Compared with ET alone, CET is not associated with additional overall survival benefit (HR = 1.179, P = 0.595). CONCLUSIONS: CET appeared not to be associated with an improved overall survival in early stage HR + HER2-breast cancer with microscopic residual disease relative to ET. Positive surgical margins therefore are probably not a relevant clinical factor for adjuvant chemotherapy decision-making.

Histological Manifestations of Diabetic Kidney Disease and its Relationship with Insulin Resistance.

Histological manifestations of diabetic kidney disease (DKD) include mesangiolysis, mesangial matrix expansion, mesangial cell proliferation, thickening of the glomerular basement membrane, podocyte loss, foot process effacement, and hyalinosis of the glomerular arterioles, interstitial fibrosis, and tubular atrophy. Glomerulomegaly is a typical finding. Histological features of DKD may occur in the absence of clinical manifestations, having been documented in patients with normal urinary albumin excretion and normal glomerular filtration rate. Furthermore, the histological picture progresses over time, while clinical data may remain normal. Conversely, histological lesions of DKD improve with metabolic normalization following effective pancreas transplantation. Insulin resistance has been associated with the clinical manifestations of DKD (nephromegaly, glomerular hyperfiltration, albuminuria, and kidney failure). Likewise, insulin resistance may underlie the histological manifestations of DKD. Morphological changes of DKD are absent in newly diagnosed type 1 diabetes patients (with no insulin resistance) but appear afterward when insulin resistance develops. In contrast, structural lesions of DKD are typically present before the clinical diagnosis of type 2 diabetes. Several heterogeneous conditions that share the occurrence of insulin resistance, such as aging, obesity, acromegaly, lipodystrophy, cystic fibrosis, insulin receptor dysfunction, and Alström syndrome, also share both clinical and structural manifestations of kidney disease, including glomerulomegaly and other features of DKD, focal segmental glomerulosclerosis, and C3 glomerulopathy, which might be ascribed to the reduction in the synthesis of factor H binding sites (such as heparan sulfate) that leads to uncontrolled complement activation. Alström syndrome patients show systemic interstitial fibrosis markedly similar to that present in diabetes.