Susan Dent

AIMS: To characterize the influence of a cancer diagnosis on the use of preventive cardiovascular measures in patients with and without cardiovascular disease (CVD). METHODS: Data from the Behavioural Risk Factor Surveillance System Survey (spanning 2011 to 2022) 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. RESULTS: 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 versus 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% 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. CONCLUSIONS: 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.

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.

Taselisib is a potent β-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.

The field of cardio-oncology was born from the necessity for recognition and management of cardiovascular diseases among patients with cancer. This need for this specialty continues to grow as patients with cancer live longer as a result of lifesaving targeted and immunologic cancer therapies beyond the usual chemotherapy and/or radiation therapy. Often, potentially cardiotoxic anticancer treatment is necessary in patients with baseline cardiovascular disease. Moreover, patients may need to continue therapy in the setting of incident cancer therapy-associated cardiotoxicity. Herein, we present and discuss the concept of permissive cardiotoxicity as a novel term that represents an essential concept in the field of cardio-oncology and among practicing cardio-oncology specialists. It emphasizes a proactive rather than reactive approach to continuation of lifesaving cancer therapies in order to achieve the best oncologic outcome while mitigating associated and potentially off-target cardiotoxicities.

Cancer patients and survivors have elevated cardiovascular risk when compared with noncancer patients. Cardio-oncology has emerged as a new subspecialty to comanage and address cardiovascular complications in cancer patients such as heart failure, atherosclerotic cardiovascular disease (ASCVD), valvular heart disease, pericardial disease, and arrhythmias. Cardiac computed tomography (CT) can be helpful in identifying both clinical and subclinical ASCVD in cancer patients and survivors. Radiation therapy treatment planning CT scans and cancer staging/re-staging imaging studies can quantify calcium scores which can identify pre-existing subclinical ASCVD. Cardiac CT can be helpful in the evaluation of cardiac tumors and pericardial diseases, especially in patients who cannot tolerate or have a contraindication to cardiac magnetic resonance. In this review, we describe the optimal utilization of cardiac CT in cancer patients, including risk assessment for ASCVD and identification of cancer treatment-related cardiovascular toxicity.