Chemotherapy, Genetic Score Predict Breast Cancer VTE Risk

Polygenic score could help identify breast cancer patients at high risk of venous thromboembolism

medwireNews: The risk of venous thromboembolism (VTE) in breast cancer patients is predicted by use of chemotherapy and genetic susceptibility to thrombosis, Swedish research suggests.

VTE occurred in 276 of 4261 Stockholm women who were diagnosed with primary invasive breast cancer between 2001 and 2008 and followed-up for a median of 7.6 years. This gave a VTE rate of 8.6 per 1000 person–years, say Judith Brand, from the Karolinska Institutet in Stockholm, Sweden, and co-workers.

After adjusting for a raft of patient, tumour and treatment factors, receipt of chemotherapy was the strongest predictor of VTE, with a hazard ratio (HR) of 1.98.

And relative to those with a lower score, the adjusted HR was 1.90 for patients in the top 5% of a polygenic risk score based on nine genome-wide single nucleotide polymorphisms shown to be significantly associated with VTE, including the Factor V Leiden (FVL) susceptibility loci.

The polygenic risk score was significantly stronger in patients aged at least 60 years than in younger individuals, with HRs of 2.44 versus 1.31, the team writes in Clinical Cancer Research.

The 1-year cumulative incidence of VTE was 9.5% for patients who were using chemotherapy and were in the top 5% for the polygenic risk score versus 1.3% for patients with neither risk factor.

Again, further stratification suggested that the impact of the polygenic risk score increased with age, so that the 1-year cumulative incidence rose to 25.0% among patients aged 60 years or older who had a strong genetic susceptibility and were using chemotherapy.

“Because the vascular environment changes with age (i.e., increased vascular stiffness in older individuals), a stronger genetic effect at older age is considered plausible”, the researchers comment, adding that lifestyle and environmental exposures may also alter gene expression.

“Regardless of the mechanism involved, this finding suggests that a patient's age is an important parameter when considering genetic testing in patients with breast cancer, which requires evaluation in future risk stratification efforts.” 

The researchers also note that switching the polygenic risk score for confirmed homozygous or heterozygous carriage of FVL predicted similar rates of both relative and absolute VTE events in the breast cancer patients.

“Because the majority of patients in the highest 5% of the [polygenic risk score] were FVL carriers (93%), these results may suggest that a routinely available test is sufficient for identifying patients at highest risk”, the researchers write, but they recognise that the risk score has an additional benefit of allowing patients to be classified as low or intermediate risk.

While acknowledging that the absolute short-term risk of VTE in breast cancer patients undergoing chemotherapy is comparable to that of hospitalised and postoperative patients who would be routinely treated with thromboprophylaxis, the team concludes that further investigations are needed to determine the “joint effect of genetic markers and other clinical risk factors in VTE risk prediction, and to identify specific high-risk patients in which thromboprophylaxis is considered beneficial and safe.”

Reference

Brand JS, Hedayati E, Humphreys K, et al. Chemotherapy, genetic susceptibility, and risk of venous thromboembolism in breast cancer patients. Clin Cancer Res 2016; 22: 5249–5255, first published online 1 November. DOI: 10.1158/1078-0432.CCR-16-1110

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