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Abstract 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, 95% CI 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

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.

Abstract 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 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.

Abstract 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.

Abstract 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

Abstract Background There is a male predominance of acute myeloid leukemia (AML) incidence, but survival data are conflicting. The objective of this study is to carry out a comprehensive analysis of sex differences in AML, and to investigate the impact of sex disparities in survival. Methods The cohort included patients ≥18 years diagnosed with AML (2010–2022). Demographics, treatment patterns, treatment adverse events, and survival were analyzed. The population was described and compared by sex, and sex‐based risks and associations were obtained via Cox proportional‐hazards regression. Results In total, 1020 AML patients were analyzed (57.4% males), with lower risk of death for females (aHR = 0.41, 95% CI 0.26–0.66). Among females, BMT (aHR = 0.51, 95% CI 0.27–0.97), hospitalization record (aHR = 0.65, 95%CI 0.45–0.93), and higher appointment completion rates (aHR = 0.98, 95% CI 0.98–0.98) were associated with lower risk of death. Overall, and similarly in males, higher age at diagnosis (aHR = 1.03, 95% CI 1.02–1.04) and a TP53 mutation (aHR = 2.24, 95% CI 1.69–2.97) were associated with higher risk of death. Conclusion Sex differences exist in both AML incidence and overall survival. Treatment and health care factors should be addressed by caregivers and public policies developed to reduce mortality rates and mitigate existing sex differences.

Abstract 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.

BackgroundThe 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.MethodsThe 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.ResultsThe 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=0.521, P=0.019).ConclusionAmong 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.

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.

Abstract The METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

Introduction: Lung cancer is the leading cause of cancer-related death and the second most often diagnosed malignancy worldwide. Males have higher incidence of lung cancer and higher mortality. It is hypothesized that the sex differences in survival are primarily driven by a better response of females to treatment. The primary objective of this work is to analyze and describe outcome differences between males and females diagnosed with having lung cancer. Methods: Data were obtained from a large hybrid academic-community practice institution and validated with Surveillance, Epidemiology, and End Results (SEER). The initial cohort included patients aged more than or equal to 18 years diagnosed with having primary malignant lung cancer. Patients were excluded from the analysis if they had an unknown diagnosis date, were missing sex, or had prior history of cancer. Chi-square, t test, and Kruskal-Wallis tests were used to compare characteristics of males and females. Risks were estimated by logistic and Cox regressions. Results: A total of 8909 patients from our institution and 725,018 in SEER were analyzed. Male-to-female ratio was 1.0. Females were more likely to undergo surgery and less likely to be treated with immunotherapy. Females had higher rates of documented psychological affections, depression, anxiety, urinary tract infection, hypothyroidism, and hyperthyroidism, while displaying lower rates of acute kidney injury, myocardial infarction, and myocarditis. Paired multivariable models revealed a lower risk of death for females in SEER (hazard ratio for females = 0.84, confidence interval: 0.69–1.02, p = 0.08) and equal risks in our institution (hazard ratio for females = 0.84, confidence interval: 0.69–1.02, p = 0.08). Conclusions: Female sex was associated with higher surgical rates, lower immunotherapy use rates, higher rates of endocrinologic complications after immunotherapy use, and higher rates of psychological disorders.

En este ensayo nos proponemos identificar y explicar la importancia que tienen algunos mitos que son presupuestos en el derecho (entendido en su doble acepción: 1) como orden normativo e instituciones jurídicas, así como 2) ciencia o jurisprudencia) y el Estado modernos, los cuales fueron resultado de un proceso de larga duración que ocurrió entre los siglos XVI y XIX, tiempo en el que centramos nuestra atención. El objetivo es contribuir al esclarecimiento de los procesos constitutivos del orden establecido en el siglo XIX, conocido como Estado de derecho.

For many years, the medical treatment of breast cancer was reliant solely on cytotoxic chemotherapy. However, over the past twenty years, treatment has evolved to a more target-directed approach. We now employ tailored therapy based on the presence or absence of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2). We expect this trend to continue, as agents that use novel approaches to target HER2, as well as targeting different portions of the HER signaling pathway, are in various stages of development. Notably, pertuzumab, a humanized monoclonal antibody that binds to a different domain of the extracellular portion of the HER2 receptor than trastuzumab, was recently approved for use, as was lapatinib, a small-molecule tyrosine kinase inhibitor. Patients with triple negative breast cancer, particularly those with the BRCA mutation, have more limited treatment options and carry a worse prognosis than those who are hormone receptor positive. However, recent data has shown that PARP inhibitors may have significant anti-tumor effect in those with this subtype of breast cancer. Novel agents that inhibit mTOR, PI3K, the insulin-like growth factor, heat shock protein 90, and histone deacetylase have shown promise in phase I-III trials and offer exciting new possibilities for the treatment of this often fatal disease. As we are presented with an ever increasing number of treatment options, the timing and combinations of therapeutic agents used becomes ever more complex in the age of personalized care, but we are hopeful that ultimately this will lead to improved patient outcomes.

Vinay Gudena, Alberto J Montero, Stefan GlückDivision of Hematology/Oncology, Braman Family Breast Cancer Institute, UMSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USAAbstract: Incremental advances over the last two decades in the treatment of stage IV metastatic breast cancer (MBC) have resulted in significantly prolonging the average life expectancy. In 2008, the estimated 5-year relative survival rate for MBC is 27% which compares favorably to rates in stage IV lung (3%) and pancreatic cancers (1%). Despite these advances, MBC remains an incurable disease, often associated with many symptoms and a decreased quality of life (QoL). Therefore, therapy goals in the treatment of MBC include prolonging both progression-free survival and overall survival rates, while at the same time improving QoL by palliation of symptoms. Therefore, systemic chemotherapy ideally should not induce unnecessary toxicities. Once chemotherapy is indicated, a number of drugs and regimens are available but only a few offer both palliation of symptoms (responses to therapy) and overall survival benefit. The addition of novel biologic compounds to chemotherapy has been shown in phase III trials to improve all the above mentioned clinical outcomes in MBC. This review will discuss data supporting the use of gemcitabine/taxane combinations in the treatment of MBC.Keywords: metastatic breast cancer, gemcitabine, taxanes

Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration-approved immune checkpoint inhibitors-pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)-demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.