Cardioprotective Potential of Sodium-Glucose Co-Transporter-2 Inhibitors in Cancer Patients Treated With Anthracyclines: An Observational Study.

Anthracyclines are pivotal in cancer treatment, yet their clinical utility is hindered by the risk of cardiotoxicity. Preclinical studies highlight the effectiveness of sodium-glucose co-transporter-2 inhibitors (SGLT2i) in mitigating anthracycline-induced cardiotoxicity. Nonetheless, the translation of these findings to clinical practice remains uncertain. This study aims to evaluate the safety and potential of SGLT2i for preventing cardiotoxicity in cancer patients, without pre-existing heart failure (HF), receiving anthracyclines therapy. Using the TriNetX Global Research Network, cancer patients without prior HF diagnosis, receiving anthracycline therapy were identified and classified into two groups based on SGLT2i usage. A 1:1 propensity score matching was used to control for baseline characteristics between the two groups. Patients were followed for 2 years. The primary endpoint was new-onset HF and secondary endpoints were HF exacerbation, new-onset arrhythmia, myocardial infarction, all-cause mortality, and all-cause hospitalization. Safety outcomes included acute renal failure and creatinine levels. A total of 79,074 patients were identified and 1,412 were included post-matching (706 in each group). They comprised 53% females, 62% White, with a mean age of 62.5 ± 11.4 years. Over the 2-year follow-up period, patients on SGLT2i had lower rates of new-onset HF (HR 0.147, 95% CI [0.073 - 0.294]) and arrhythmia (HR 0.397, 95% CI [0.227 - 0.692]) compared to those not on SGLT2i. The incidence of all-cause mortality, myocardial infarction, all-cause hospitalization, and safety outcomes were similar between both groups. In conclusion, amidst cancer patients receiving anthracycline therapy without preexisting HF, SGLT2i use demonstrates both safety and effectiveness in reducing anthracycline-induced cardiotoxicity, with a decreased incidence of new-onset HF, HF exacerbation, and arrhythmias.

Use of new and emerging cancer drugs: what the cardiologist needs to know.

The last decade has witnessed a paradigm shift in cancer therapy, from non-specific cytotoxic chemotherapies to agents targeting specific molecular mechanisms. Nonetheless, cardiovascular toxicity of cancer therapies remains an important concern. This is particularly relevant given the significant improvement in survival of solid and haematological cancers achieved in the last decades. Cardio-oncology is a subspecialty of medicine focusing on the identification and prevention of cancer therapy-related cardiovascular toxicity (CTR-CVT). This review will examine the new definition of CTR-CVT and guiding principles for baseline cardiovascular assessment and risk stratification before cancer therapy, providing take-home messages for non-specialized cardiologists.

Coverage for evidence-based cancer survivorship care services.

PURPOSE: The American Society of Clinical Oncology Cancer Survivorship Committee established a task force to determine which survivorship care services were being denied by public and private payers for coverage and reimbursement. METHODS: A quantitative survey instrument was developed to determine the clinical practice-reported rates of coverage denials for evidence-based cancer survivorship care services. Additionally, qualitative interviews were conducted to understand whether coverage denials were based on payer policies, cost-sharing, or prior authorization. RESULTS: Of 122 respondents from 50 states, respondents reported that coverage denials were common ("always," "most of the time," or "some of the time") for maintenance therapies, screening for new primary cancers or cancer recurrence. Respondents reported that denials in coverage for maintenance therapies were highest for immunotherapy (41.74%) and maintenance chemotherapy (40.17%). Coverage denials for new primary cancer screenings were highest for Hodgkin lymphoma survivors needing a PET/CT scan (49.04%) and breast cancer survivors at a high risk of recurrence who needed an MRI (63.46%), respectively. More than half of survey respondents reported denials for symptom management and supportive care services. Fertility services, dental services when indicated, and mental health services were denied "always" or "most of the time" 23.1%, 22.5%, and 12.8%, respectively. Respondents reported they often had a process in place to automatically appeal denials for evidence-based services. The denial process, however, resulted in greater stress for the patient and provider. CONCLUSION: Our study demonstrates that additional advocacy with payers is needed to ensure that reimbursement policies are consistent with evidence-based survivorship care services.

Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique.

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice.

SGLT2 Inhibitor Use and Risk of Clinical Events in Patients With Cancer Therapy-Related Cardiac Dysfunction.

BACKGROUND: Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart failure (HF). Sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF. OBJECTIVES: This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy-related cardiac dysfunction (CTRCD) or HF. METHODS: The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the TriNetX research network. Patients aged ≥18 years with a history of type 2 diabetes mellitus, cancer, and exposure to potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1, 2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period. RESULTS: The study cohort included 1,280 patients with CTRCD/HF (n = 640 per group; mean age: 67.6 years; 41.6% female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296 [95% CI: 0.22-0.40]; P = 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P = 0.003), acute kidney injury (OR: 0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839]; P = 0.012) were also less frequent in patients on SGLT2 inhibitors. CONCLUSIONS: SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF.

Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.

Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.

Developing a Clinical Cardio-Oncology Program and the Building Blocks for Success: JACC: CardioOncology How To.

•Cardio-oncology programs are necessary to provide optimal cardiovascular care to cancer patients and survivors.•Focus on developing a clear vision and mission-successful programs must be tailored to an organization's unique landscape.•Fostering partnerships with cardiologists and oncologists to provide high-quality patient-centered care is crucial.•Patience is essential-program development takes time, but success can be achieved.

Circulating Cardiovascular Biomarkers in Cancer Therapeutics-Related Cardiotoxicity: Review of Critical Challenges, Solutions, and Future Directions.

Cardiotoxicity is a growing concern in the oncology population. Transthoracic echocardiography and multigated acquisition scans have been used for surveillance but are relatively insensitive and resource intensive. Innovative imaging techniques are constrained by cost and availability. More sensitive, cost-effective cardiotoxicity surveillance strategies are needed. Circulating cardiovascular biomarkers could provide a sensitive, low-cost solution. Biomarkers such as troponins, natriuretic peptides (NPs), novel upstream signals of oxidative stress, inflammation, and fibrosis as well as panomic technologies have shown substantial promise, and guidelines recommend baseline measurement of troponins and NPs in all patients receiving potential cardiotoxins. Nonetheless, supporting evidence has been hampered by several limitations. Previous reviews have provided valuable perspectives on biomarkers in cancer populations, but important analytic aspects remain to be examined in depth. This review provides comprehensive assessment of critical challenges and solutions in this field, with focus on analytical issues relating to biomarker measurement and interpretation. Examination of evidence pertaining to common and serious forms of cardiotoxicity reveals that improved study designs incorporating larger, more diverse populations, registry-based approaches, and refinement of current definitions are key. Further efforts to harmonize biomarker methodologies including centralized biobanking and analyses, novel decision limits, and head-to-head comparisons are needed. Multimarker algorithms incorporating machine learning may allow rapid, personalized risk assessment. These improvements will not only augment the predictive value of circulating biomarkers in cardiotoxicity but may elucidate both direct and indirect relationships between cardiovascular disease and cancer, allowing biomarkers a greater role in the development and success of novel anticancer therapies.

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.

Cardiac Interventions in Patients With Active, Advanced Solid and Hematologic Malignancies: JACC: CardioOncology State-of-the-Art Review.

Invasive cardiac interventions are recommended to treat ST-segment elevation myocardial infarction, non-ST-segment elevation acute coronary syndromes, multivessel coronary disease, severe symptomatic aortic stenosis, and cardiomyopathy. These recommendations are based on randomized controlled trials that historically included few individuals with active, advanced malignancies. Advanced malignancies represent a significant competing risk for mortality, and there is limited evidence to inform the risks and benefits of invasive cardiac interventions in affected patients. We review the benefit conferred by invasive cardiac interventions; the periprocedural considerations; the contemporary survival expectations of patients across several types of active, advanced malignancy; and the literature on cardiovascular interventions in these populations. Our objective is to develop a rational framework to guide clinical recommendations on the use of invasive cardiac interventions in patients with active, advanced cancer.

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.

Adverse Cardiovascular Events Associated With Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Metastatic Breast Cancer.

Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines (P=0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.

COVID-19 severity and cardiovascular outcomes in SARS-CoV-2-infected patients with cancer and cardiovascular disease.

Background: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited. Objectives: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF. Methods: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated. Results: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p<0.001). CVD/CVRF was associated with worse COVID-19 severity in patients who had not received recent cancer therapy, but not in those undergoing active cancer therapy (OR 1.51 [95% CI 1.31-1.74] vs. OR 1.04 [95% CI 0.90-1.20], pinteraction <0.001). Conclusions: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701).

The underutilization of preventive cardiovascular measures in patients with cancer: an analysis of the Behavioural Risk Factor Surveillance System, 2011-22.

AIMS: This study aimed to characterize the influence of a cancer diagnosis on the use of preventive cardiovascular measures in patients with and without cardiovascular disease (CVD). METHODS AND RESULTS: Data from the Behavioural Risk Factor Surveillance System Survey (spanning 2011-22) were used. Multivariable logistic regression models adjusted for potential confounders were applied to calculate average marginal effects (AME), the average difference in the probability of using a given therapy between patients with and without cancer. Outcomes of interest included the use of pharmacological therapies, physical activity, smoking cessation, and post-CVD rehabilitation. Among 5 012 721 respondents, 579 114 reported a history of CVD (coronary disease or stroke), and 842 221 reported a diagnosis of cancer. The association between cancer and the use of pharmacological therapies varied between those with vs. without CVD (P-value for interaction: <0.001). Among patients with CVD, a cancer diagnosis was associated with a lower use of blood pressure-lowering medications {AME: -1.46% [95% confidence interval (CI): -2.19% to -0.73%]}, lipid-lowering medications [AME: -2.34% (95% CI: -4.03% to -0.66%)], and aspirin [AME: -6.05% (95% CI: -8.88% to -3.23%)]. Among patients without CVD, there were no statistically significant differences between patients with and without cancer regarding pharmacological therapies. Additionally, cancer was associated with a significantly lower likelihood of engaging in physical activity in the overall cohort and in using post-CVD rehabilitation regimens, particularly post-stroke rehabilitation. CONCLUSION: Preventive pharmacological agents are underutilized in those with cancer and concomitant CVD, and physical activity is underutilized in patients with cancer in those with or without CVD. LAY SUMMARY: •This paper compared the use of preventive cardiovascular measures, both pharmaceutical and non-pharmaceutical, in patients with and without cancer.•In patients with cardiovascular disease and cancer, there is a lower use of preventive cardiovascular medications compared with those with cardiovascular disease but without cancer. This includes a lower utilization of blood pressure-lowering medications, cholesterol-lowering medications, and aspirin.•Patients with cancer reported lower levels of exercise but higher levels of smoking cessation compared with those without cancer.

Cancer Treatment-Related Cardiovascular Toxicity in Gynecologic Malignancies: JACC: CardioOncology State-of-the-Art Review.

Improvements in early detection and treatment of gynecologic malignancies have led to an increasing number of survivors who are at risk of long-term cardiac complications from cancer treatment. Multimodality therapies for gynecologic malignancies, including conventional chemotherapy, targeted therapeutics, and hormonal agents, place patients at risk of cancer therapy-related cardiovascular toxicity during and following treatment. Although the cardiotoxicity associated with some female predominant cancers (eg, breast cancer) have been well recognized, there has been less recognition of the potential adverse cardiovascular effects of anticancer therapies used to treat gynecologic malignancies. In this review, the authors provide a comprehensive overview of the cancer therapeutic agents used in gynecologic malignancies, associated cardiovascular toxicities, risk factors for cardiotoxicity, cardiac imaging, and prevention strategies.

Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-, PIK3CA-mutated breast cancers.

BACKGROUND: Mutations in the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, cause dysregulation of the PI3K pathway in 35-40% of patients with HR+/HER2- breast cancer. Preclinically, cancer cells harboring double or multiple PIK3CA mutations (mut) elicit hyperactivation of the PI3K pathway leading to enhanced sensitivity to p110α inhibitors. METHODS: To understand the role of multiple PIK3CAmut in predicting response to p110α inhibition, we estimated the clonality of multiple PIK3CAmut in circulating tumor DNA (ctDNA) from patients with HR+/HER2- metastatic breast cancer enrolled to a prospectively registered clinical trial of fulvestrant ± taselisib, and analyzed the subgroups against co-altered genes, pathways, and outcomes. RESULTS: ctDNA samples with clonal multiple PIK3CAmut had fewer co-alterations in receptor tyrosine kinase (RTK) or non-PIK3CA PI3K pathway genes compared to samples with subclonal multiple PIK3CAmut indicating a strong reliance on the PI3K pathway. This was validated in an independent cohort of breast cancer tumor specimens that underwent comprehensive genomic profiling. Furthermore, patients whose ctDNA harbored clonal multiple PIK3CAmut exhibited a significantly higher response rate and longer progression-free survival vs subclonal multiple PIK3CAmut. CONCLUSIONS: Our study establishes clonal multiple PIK3CAmut as an important molecular determinant of response to p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.

ER+, HER2- advanced breast cancer treated with taselisib and fulvestrant: genomic landscape and associated clinical outcomes.

Taselisib is a potent ß-sparing phosphatidylinositol 3-kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CAmut ctDNA treated with taselisib + fulvestrant, tumour protein p53 (TP53; encoding p53) and fibroblast growth factor receptor 1 (FGFR1) alterations were associated with shorter progression-free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CAmut ctDNA harbouring a neurofibromin 1 (NF1) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CAmut ctDNA. Altogether, we demonstrated the impact of genomic (co-)alterations on outcomes with one of the largest clinico-genomic datasets of ER+, HER2-, PIK3CAmut breast cancer patients treated with a PI3K inhibitor.

Cancer Therapy-Related Hypertension: A Scientific Statement From the American Heart Association.

Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease, and hypertension. One of the most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors. Adjunctive therapy, including corticosteroids, calcineurin inhibitors, and nonsteroidal anti-inflammatories, as well as anti-androgen hormone therapy for prostate cancer, may further increase blood pressure in these patients. Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment. The exact molecular mechanisms underlying hypertension are unclear, but recent discoveries indicate an important role for reduced nitric oxide generation, oxidative stress, endothelin-1, prostaglandins, endothelial dysfunction, increased sympathetic outflow, and microvascular rarefaction. In addition, genetic polymorphisms in vascular endothelial growth factor receptors are implicated in vascular endothelial growth factor inhibitor-induced hypertension. Diagnosis, management, and follow-up of cancer therapy-induced hypertension follow national hypertension guidelines because evidence-based clinical trials specifically addressing patients who develop hypertension as a result of cancer therapy are currently lacking. Rigorous baseline assessment of patients before therapy is started requires particular emphasis on assessing and treating cardiovascular risk factors. Hypertension management follows guidelines for the general population, although special attention should be given to rebound hypotension after termination of cancer therapy. Management of these complex patients requires collaborative care involving oncologists, cardiologists, hypertension specialists, primary care professionals, and pharmacists to ensure the optimal therapeutic effect from cancer treatment while minimizing competing cardiovascular toxicities.