Evolutionary continuity and divergence of auditory dorsal and ventral pathways in primates revealed by ultra-high field diffusion MRI.

Auditory dorsal and ventral pathways in the human brain play important roles in supporting speech and language processing. However, the evolutionary root of the dual auditory pathways in the primate brain is unclear. By parcellating the auditory cortex of marmosets (a New World monkey species), macaques (an Old World monkey species), and humans using the same individual-based analysis method and tracking the pathways from the auditory cortex based on multi-shell diffusion-weighted MRI (dMRI), homologous auditory dorsal and ventral fiber tracks were identified in these primate species. The ventral pathway was found to be well conserved in all three primate species analyzed but extend to more anterior temporal regions in humans. In contrast, the dorsal pathway showed a divergence between monkey and human brains. First, frontal regions in the human brain have stronger connections to the higher-level auditory regions than to the lower-level auditory regions along the dorsal pathway, while frontal regions in the monkey brain show opposite connection patterns along the dorsal pathway. Second, the left lateralization of the dorsal pathway is only found in humans. Moreover, the connectivity strength of the dorsal pathway in marmosets is more similar to that of humans than macaques. These results demonstrate the continuity and divergence of the dual auditory pathways in the primate brains along the evolutionary path, suggesting that the putative neural networks supporting human speech and language processing might have emerged early in primate evolution.

Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer.

PURPOSE: The combination of fulvestrant with alpelisib, a PI3K inhibitor, improves progression-free survival in metastatic hormone receptor-positive, PIK3CA-mutant breast cancer. This study describes the incidence, risk factors, and treatment of alpelisib-associated hyperglycemia. METHODS: Patients with metastatic breast cancer who received alpelisib from 2013 to 2021 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Alpelisib prescription dates and patient/tumor characteristics were abstracted from medical records. Risk factors associated with hyperglycemia and alpelisib dose reduction/discontinuation were evaluated using Pearson's χ2 tests. RESULTS: Among 247 patients, baseline median body mass index was 25.4 kg/m2 and median hemoglobin A1c (HbA1c) was 5.5%. A total of 152 patients (61.5%) developed any-grade hyperglycemia and 72 patients (29.2%) developed grade 3-4 hyperglycemia; median time to onset was 16 days. A total of 100 patients (40.5%) received alpelisib on a clinical trial; rates of hyperglycemia were significantly higher in patients treated as standard care versus on a clinical trial (any-grade hyperglycemia 80.3% vs. 34.0%, grade 3-4 hyperglycemia 40.2% vs. 13.0%, p < .001). Baseline HbA1c was significantly associated with development of hyperglycemia (p < .001) and alpelisib dose reduction/discontinuation (p = .015). Among those who developed hyperglycemia, 101 (40.9%) received treatment, most commonly with metformin. A total of 49 patients (19.8%) were referred to an endocrinologist, which was associated with SGLT2 inhibitor prescription (p = .007). CONCLUSIONS: Rates of hyperglycemia among patients treated with alpelisib as standard care were significantly higher than patients treated on clinical trials. Elevated baseline HbA1c is associated with alpelisib-induced hyperglycemia and requiring dose modification. Optimization of glycemic status before alpelisib initiation should become routine practice.

HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer.

Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the "cluster" pattern of G-ITH, whereas the "mosaic" pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects.

Looking beyond carboplatin and paclitaxel for the treatment of advanced/recurrent endometrial cancer.

Endometrial cancer incidence and mortality are rising among all ethnic groups. Carboplatin plus paclitaxel is the established frontline treatment for advanced/recurrent disease; however, subsequent treatment with traditional cytotoxic chemotherapy is challenging. The molecular characterization of endometrial cancer has provided important insights into the biological drivers of carcinogenesis, which has allowed for the development of newer precision immunotherapies and targeted therapies, including pembrolizumab, dostarlimab, and lenvatinib. Until recently, platinum rechallenge was often considered at the time of recurrence, given the lack of other available therapeutic options; however, "platinum sensitivity" in endometrial cancer is subjective and largely based on expert opinion and/or practitioner experience. Small retrospective studies have tried to provide guidance on the utility of platinum rechallenge, but they are limited by variable patient characteristics and small sample sizes. The applicability of these retrospective studies to contemporary clinical practice is difficult in the setting of changing patient demographics, a better understanding of endometrial cancer drivers, and the recent approvals of immune checkpoint inhibitors and the combination of lenvatinib plus pembrolizumab in the second-line setting. The primary focus of this review is to distill the available data regarding platinum-doublet chemotherapy rechallenge and highlight recent pivotal developments in endometrial cancer treatment, as well as future directions.

Association between nonadherence to cardiovascular risk factor medications after breast cancer diagnosis and incidence of cardiac events.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death among patients with early-stage breast cancer (BC), but adherence to cardiovascular disease risk factor (CVD-RF) medications is reported to be poor in BC survivors. The objective of the current study was to determine the association between nonadherence to CVD-RF medications and cardiovascular events in BC survivors. METHODS: The authors included patients with stages I to III BC from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database who had Medicare part D coverage and who were taking at least 1 CVD-RF medication prior to their BC diagnosis (2008-2013). Logistic regression was performed to define factors associated with nonadherence. Cox regression was used to calculate the association between nonadherence and new cardiac events after treatment. RESULTS: Among 15,576 patients included in the current analysis, 4797 (30.8%) were nonadherent to at least 1 category after the initial BC treatment period. Black race, greater comorbidity burden, more advanced cancer stage, hormone receptor-negative status, and receipt of chemotherapy were found to be associated with nonadherence. Nonadherence after treatment demonstrated a trend toward an increased risk of a subsequent cardiac event (hazard ratio [HR], 1.15; 95% CI 1.00-1.33 [P = .06]). This effect size increased with nonadherence to a greater number of medications (P < .01). There was an increased risk of experiencing a cardiac event noted with becoming nonadherent to hypertension medications (HR, 1.33; 95% CI, 1.18-1.51 [P < .0001]), hyperlipidemia medications (HR, 1.21; 95% CI, 1.05-1.40 [P = .009]), and diabetes medications (HR, 1.31; 95% CI, 1.10-1.56 [P = .003]). CONCLUSIONS: Nonadherence to CVD-RF medications after treatment of BC is associated with an increased risk of a cardiac event. Improving outcomes and reducing morbidity after a diagnosis of BC requires attention to non-BC conditions.

Omega-3 fatty acid use for obese breast cancer patients with aromatase inhibitor-related arthralgia (SWOG S0927).

PURPOSE: Although aromatase inhibitors (AIs) prolong survival in post-menopausal breast cancer (BC) patients, AI-associated arthralgia can lead to discontinuation. Obese patients have higher rates of AI arthralgia than non-obese patients, but treatment options are limited. Omega-3 fatty acid (O3-FA) treatment for AI arthralgia has produced mixed results. METHODS: We performed an exploratory analysis of SWOG S0927, a multicenter randomized placebo-controlled trial of O3-FA use for AI arthralgia. Post-menopausal women with stage I-III BC taking an AI were randomized to 24 weeks of O3-FAs or placebo. Brief Pain Inventory (BPI) questionnaires and fasting serum were collected at baseline, 12, and 24 weeks. The BPI assessment included worst pain, average pain, and pain interference scores (range 0-10). RESULTS: Among the 249 participants, 139 had BMI < 30 kg/m2 (56%) and 110 had BMI ≥ 30 kg/m2 (44%). Among obese patients, O3-FA use was associated with significantly lower BPI worst pain scores at 24 weeks compared with placebo (4.36 vs. 5.70, p = 0.02), whereas among non-obese patients, there was no significant difference in scores between treatment arms (5.27 vs. 4.58, p = 0.28; interaction p = 0.05). Similarly, O3-FA use was associated with lower BPI average pain and pain interference scores at 24 weeks compared with placebo among obese patients, but no significant difference between treatment arms in non-obese patients (interaction p = 0.005 and p = 0.01, respectively). CONCLUSIONS: In obese BC patients, O3-FA use was associated with significantly reduced AI arthralgia compared to placebo.

Evaluation of a mobile behavior change program for weight loss in breast cancer survivors.

Post-diagnosis weight gain is common in early-stage breast cancer and is associated with increased risk of recurrence and mortality. Intentional weight loss is difficult to maintain, and digital lifestyle interventions may provide a scalable approach to address this challenge. In this prospective single-arm study (ClinicalTrials.gov NCT04753268; February 15, 2021), key eligibility criteria included: stage I-III breast cancer, body mass index (BMI) ≥ 27.5 kg/m2, and completion of cancer treatment ≥6 months before study enrollment. Participants were provided with a behavioral change mobile application (Noom®). The primary endpoint was a change in self-reported weight from baseline to 26 weeks. Secondary endpoints included engagement, changes in physical activity, dietary patterns, and patient-reported outcomes (PRO). In total, 31 patients were enrolled (mean age 56.8 ± 9.9, mean baseline BMI 33.5 kg/m2 ± 6.5). The mean weight change was -4.8 kg ( ± 4.4, P < 0.001), mean percent weight change was -5.6% ( ± 5.0%); 11/31 patients (35.5%) lost ≥5% of their initial weight. Metrics of digital application engagement associated with weight loss ≥5% included articles read (P = 0.012), weights logged (P = 0.006), food records logged (P = 0.001), messages sent (P = 0.001), and application open count (P = 0.014). Significant increases were seen in mean daily step count (P = 0.004), GPAQ scores (P = 0.002), and Body Image Scale scores (P < 0.001). Mean energy intake remained consistently in a calorie-restricted range of 1300-1400 kcal/day. In this study, breast cancer survivors were highly engaged with a behavioral change smartphone application which led to clinically significant weight loss, increased physical activity, maintenance of an energy-restricted diet, and improvements in body image.

Enhancing Early-Stage Breast Cancer Survivorship: Evidence-Based Strategies, Surveillance Testing, and Imaging Guidelines.

Addressing the challenges of survivorship necessitates a comprehensive, patient-centered approach, focusing on mitigating risk through lifestyle modification, identifying distant recurrence, and optimization of breast imaging. This article will discuss the current and emerging clinical strategies for the survivorship period, advocating a multidisciplinary and comprehensive approach. In this manner, early-stage breast cancer survivors are empowered to navigate their journey with enhanced knowledge, facilitating a transition to life beyond cancer.

Dose dense doxorubicin plus cyclophosphamide in a modified KEYNOTE522 regimen for triple negative breast cancer.

The KEYNOTE-522 (KN522) regimen for neoadjuvant treatment of triple negative breast cancer (TNBC) utilized q3week dosing for doxorubicin plus cyclophosphamide (AC); however, dose-dense AC (ddAC) has demonstrated superior overall survival (OS) compared to q3week AC in anthracycline and taxane-based regimens. We performed a retrospective analysis assessing the use of ddAC in KN522 and the impact of sequencing ddAC before or after carboplatin/paclitaxel (CbT) plus pembrolizumab on multiple outcomes. 128 patients with TNBC were included. Overall pathologic complete response (pCR) rate of 56%. Sequencing of ddAC vs CbT first showed no difference in pCR rate (ddAC 55% vs. CbT 58%, p = 0.77). However, ddAC first compared to CbT first correlated with a significant increase in the incidence of overall treatment delays (ddAC 70% vs. CbT 51%, p = 0.03), with cytopenias most frequent (ddAC 59% vs. CbT 31%, p = 0.001). ddAC in a modified KN522 regimen is safe, tolerable, and effective. Efficacy is comparable regardless of chemotherapy sequencing, but ddAC first is significantly associated with higher rates of treatment delays and cytopenias.

Zinc catalyzed and mediated asymmetric propargylation of trifluoromethyl ketones with a propargyl boronate.

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the N-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist BI 653048. A mechanism for the boron-zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones.

Development of a large scale asymmetric synthesis of the glucocorticoid agonist BI 653048 BS H3PO4.

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.

Asymmetric synthesis of sulfinamides using (-)-quinine as chiral auxiliary.

A process has been designed and demonstrated for the asymmetric synthesis of sulfinamides using quinine as auxiliary. A variety of chiral sulfinamides including N-alkyl sulfinamides with diverse structure were prepared in good yields and excellent enantioselectivity starting from easily available and inexpensive reagents. The auxiliary quinine could be recovered and recycled.

Insulin-Lowering Diets in Metastatic Cancer.

Hyperinsulinemia is an independent risk factor for cancer mortality. Insulin-lowering dietary strategies such as calorie restriction (CR), low-carbohydrate or ketogenic diets (KD), and intermittent fasting (IF) are aimed at reducing systemic stores of nutrients utilized by cancer cells, attenuating insulin-related growth signaling, and improving obesity-related metabolic parameters. In this narrative review, we searched the published literature for studies that tested various insulin-lowering diets in metastatic cancer in preclinical and clinical settings. A total of 23 studies were identified. Of these, 14 were preclinical studies of dietary strategies that demonstrated improvements in insulin levels, inhibition of metastasis, and/or reduction in metastatic disease burden in animal models. The remaining nine clinical studies tested carbohydrate restriction, KD, or IF strategies which appear to be safe and feasible in patients with metastatic cancer. These approaches have also been shown to improve serum insulin and other metabolic parameters. Though promising, the anti-cancer efficacy of these interventions, such as impact on tumor response, disease-specific-, and overall survival, have not yet been conclusively demonstrated. Studies that are adequately powered to evaluate whether insulin-lowering diets improve cancer outcomes are warranted.

Obesity and Breast Cancer Risk: The Oncogenic Implications of Metabolic Dysregulation.

CONTEXT: Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex. EVIDENCE ACQUISITION: Pubmed literature search using combinations of "obesity," "breast cancer risk," "diet," "exercise," "weight gain," "weight loss," "adipose tissue inflammation," "crown-like structure," "immune markers," "metformin," "gliflozins," "SGLT-2i," "GLP1-RA," and related terms. EVIDENCE SYNTHESIS: Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor-positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk. CONCLUSION: Incorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.

Enantioselective synthesis of diverse sulfinamides and sulfinylferrocenes from phenylglycine-derived chiral sulfinyl transfer agent.

A new chiral sulfinyl transfer auxiliary derived from readily available phenylglycine was developed. This auxiliary is utilized to synthesize a diverse array of alkyl- and arylsulfinamides and sulfinylferrocenes in high yields and excellent ee's. The desired products are produced in a one-pot sequence from the oxathiazolidine 2-oxide by two sequential nucleophilic additions that proceed in a stereospecific manner.

Sustained response to lenvatinib and pembrolizumab in two patients with KRAS-mutated endometrial mesonephric-like adenocarcinoma.

•Endometrial mesonephric-like adenocarcinoma (MLA) is a rare and aggressive subtype of epithelial endometrial cancer.•KRAS mutations are characteristic in patients with endometrial MLA.•We report two cases of KRAS-mutated endometrial MLA with excellent and durable responses to lenvatinib and pembrolizumab.•Tumors with KRAS mutations may be particularly sensitive to lenvatinib, but this warrants further study.

Low Subcutaneous Adiposity and Mortality in Esophageal Cancer.

BACKGROUND: Recent data suggest that subcutaneous adiposity represents an independent prognostic marker in cancer. We aimed to determine whether subcutaneous adiposity estimated by the subcutaneous adiposity tissue index (SATI) was associated with mortality in esophageal cancer. METHODS: We conducted a retrospective analysis of a prospectively enrolled cohort from 2009 to 2015 with esophageal cancer at two major cancer centers. CT scans for initial staging were used to quantify adiposity and skeletal muscle areas. Subjects were categorized as above or below median SATI using sex-specific values. Sarcopenia was defined using previously established skeletal muscle area cutoffs. Cox proportional hazards modeling was performed to determine associations between SATI and all-cause mortality. RESULTS: Of the original 167 patients, 78 met inclusion criteria and had CT images available. Mean age was 67 years, 81.8% had adenocarcinoma, and 58.9% had stage 3 or 4 disease. Median follow-up time was 29.5 months. Overall 5-year survival was 38.9% [95% confidence interval (CI), 26.8-50.7]. Lower body mass index, higher Charlson comorbidity score, and more advanced stage were independently associated with low SATI. Patients with low SATI had increased mortality (unadjusted HR 2.23; 95% CI, 1.20-4.12), even when adjusted for sarcopenia or for percent weight loss. In a multivariable model including age, histology, stage, and receipt of curative surgery, the association between low SATI and mortality was attenuated (adjusted HR 1.64; 95% CI, 0.81-3.34). CONCLUSIONS: Low subcutaneous adiposity as estimated by SATI may be associated with increased mortality in esophageal cancer. IMPACT: Interventions to reduce loss of subcutaneous fat may improve survival in esophageal cancer.

Reorganizing a Medicine Residency Program in Response to the COVID-19 Pandemic in New York.

The COVID-19 pandemic has been particularly severe in New York City, resulting in a rapid influx of patients into New York-Presbyterian Hospital/Columbia University Irving Medical Center. The challenges precipitated by this pandemic have required urgent changes to existing models of care. Internal medicine residents are at the forefront of caring for patients with COVID-19, including the critically ill. This article describes the exigent restructuring of the New York-Presbyterian Hospital/Columbia University Internal Medicine Residency Program. Patient care and educational models were fundamentally reconceptualized, which required a transition away from traditional hierarchical team structures and a significant expansion in the program's capacity and flexibility to care for large numbers of patients with disproportionately high levels of critical illness. These changes were made while the residency program maintained the priorities of patient care and safety, resident safety and well-being, open communication, and education. The process of adapting the residency program to the demands of the pandemic was iterative given the unprecedented nature of this crisis. The goal of this article is to share the experiences and lessons learned from this crisis, communicate the solutions that were designed, and inform others who may be facing the prospect of creating similar disaster response measures.

On the racemization of chiral imidazolines.

Racemization of chiral imidazolines with base has been studied for the first time following an unexpected finding in the synthesis of chiral imidazoline ligands. Amine bases do not cause racemization. Strong inorganic bases can induce racemization, yet this occurs only when the nitrogen is unsubstituted, in agreement with a symmetry-allowed thermal disrotatory ring opening and closure from a diazapentadienyl anion. Surprisingly, even with electron-withdrawing N-substituents, no racemization is observed. Conditions which allow for the racemization-free manipulations of this important compound class have been defined and developed.

Association of Cardiovascular Risk Factors With Cardiac Events and Survival Outcomes Among Patients With Breast Cancer Enrolled in SWOG Clinical Trials.

Background Cardiovascular disease is the primary cause of death among patients with breast cancer. However, the association of cardiovascular-disease risk factors (CVD-RFs) with long-term survival and cardiac events is not well studied. Methods We examined SWOG (formerly the Southwest Oncology Group) breast cancer trials from 1999 to 2011. We identified baseline diabetes, hypertension, hypercholesterolemia, and coronary artery disease by linking trial records to Medicare claims. The primary outcome was overall survival. Patients with both baseline and follow-up claims were examined for cardiac events. Cox regression was used to assess the association between CVD-RFs and outcomes. Results We identified 1,460 participants older than 66 years of age from five trials; 842 were eligible for survival outcomes analysis. At baseline, median age was 70 years, and median follow-up was 6 years. Hypertension (73%) and hypercholesterolemia (57%) were the most prevalent conditions; 87% of patients had one or more CVD-RF. There was no association between any of the individual CVD-RFs and overall survival except for hypercholesterolemia, which was associated with improved overall survival (hazard ratio [HR], 0.73; 95% CI, 0.57 to 0.93; P = .01). With each additional CVD-RF, there was an increased risk of death (HR, 1.23; 95% CI, 1.08 to 1.40; P = .002), worse progression-free survival (HR, 1.12; 95% CI, 1.00 to 1.25; P = .05), and marginally worse cancer-free survival (HR, 1.15; 95% CI, 0.99 to 1.34; P = .07). The relationship between baseline CVD-RFs and cardiac events was analyzed in 736 patients. A strong linear association between the number of CVD-RFs and cardiac event was observed (HR per CVD-RF, 1.41; 95% CI, 1.17 to 1.69; P < .001). Conclusion Among participants in clinical trials, each additional baseline CVD-RF was associated with an increased risk of cardiac events and death. Efforts to improve control of modifiable CVD-RFs are needed, especially among those with multiple risk factors.