(205) Real-World Retrospective Review: Investigating Cardiac Toxicity in Breast Cancer Patients Undergoing Capecitabine Therapy with and without DPYD Mutations - A Cardio-Oncology and Pharmacogenomic Study

Poster Abstract:

Background:

The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme in the metabolism of fluoropyrimidines like capecitabine. Individuals with reduced DPD activity are at an increased risk of developing potentially fatal toxicities, including severe myelosuppression, mucositis, and neurotoxicity.

The FDA has issued warnings about capecitabine use in patients with DPD deficiency. Additionally, CPIC suggests dose modifications or alternative treatments for intermediate or poor metabolizers. However, a discrepancy exists amongst oncology society guidelines. ASCO and NCCN currently do not recommend pre-emptive testing, while European entities like ESMO support genetic testing prior to treatment.

While some DPYD variants have well-established associations with reduced DPD activity and increased toxicity, others are classified as 'probable reduced-function' or 'unclear' due to limited evidence. Additionally, while toxicities like myelosuppression are well-characterized, associations between DPYD status and cardiotoxicity remain less clear. The most common clinical manifestation of fluoropyrimidine-associated cardiotoxicity is angina, but other cardiac events including myocardial infarction, arrhythmias, and heart failure have been reported in 3-9% of patients.

Given capecitabine's widespread use and potential cardiac risks, personalized treatment strategies are needed. Understanding the relationship between DPYD variants and capecitabine-induced cardiotoxicity is warranted for better informed treatment decisions and patient safety.

Objectives:

The primary objective is to compare the incidence of cardiac events in capecitabine-treated breast cancer patients with and without DPYD variants. The secondary objective is to identify additional predictive factors in the development of capecitabine-induced cardiotoxicity.

Methods:

This IRB approved retrospective study evaluated all UPMC breast cancer patients treated with capecitabine between January 1, 2016 and August 31, 2021. Patients were identified via a comprehensive data pull using ICD9/10 codes for a breast cancer diagnosis, filtering for those treated with capecitabine after diagnosis and those with available tissue or blood samples via coordination with the University of Pittsburgh Biospecimen Core. DPYD genotyping was performed by the UPMC Genome Center using the Pharmacoscan array.

Eligible patients (N=142) with complete clinical and genetic data were reviewed. Pre-specified oncology and cardiology terms were used to filter through chart notes, problem list entries, and ICD9/10 codes to identify cardiac events during and after therapy. Reviewers were blinded to genotype.

Patients with cardiac events underwent independent review by a cardio-oncologist and cardiology fellow to determine capecitabine attributability and were graded according to the corresponding cardiac condition in CTCAE Version 5.0. Descriptive statistics and non-parametric tests will be used for statistical analysis.

Results /

Discussion:

Pending

References (must also be included in final poster):

References:

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