Tests ID Breast Cancer Patients at Risk for Blood Clots

Veronica Hackethal, MD

November 04, 2016

A Swedish study has suggested that genetic testing could identify breast cancer patients at high risk for venous thromboembolism (VTE). Results were published online November 1 in Clinical Cancer Research.

The study is the first population-based evaluation of both individual and combined effects of chemotherapy and genetic susceptibility on VTE risk, say the authors.

"In our study, breast cancer patients receiving chemotherapy experienced a short-term increased risk of VTE, and this risk was further increased by high genetic susceptibility to VTE," first author Judith Brand, PhD, of the Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News via email.

Results also showed that this increased risk was particularly strong among older patients.

Cancer patients, especially those receiving chemotherapy, have an increased risk for VTE, a serious complication that carries significant morbidity and mortality, the researchers comment. VTE also increases healthcare costs and has long-term complications, such as recurrent thrombosis and decreased quality of life.

"As one of the most common cancers, breast cancer is a major contributor to the cancer-associated VTE burden and associated healthcare costs," Dr Brand pointed out.

The incidence of VTE varies among breast cancer patients. The incidence is particularly high just after diagnosis, during the period in which the patient is receiving chemotherapy. Heritability also plays a large role in VTE risk, with about 50% to 60% of cases thought to be linked to genetics.

Routine thromboprophylaxis is not recommended during chemotherapy because of the risk for bleeding and because of the relatively low incidence of VTE, which is around 1% to 2%, according to background information in the article. Identifying patients at high risk for VTE could help individualize treatment for those who might benefit from prophylaxis.

The study included 4261 Swedish women with primary invasive breast cancer diagnosed between 2001 and 2008 in Stockholm. Follow-up continued until 2012. Researchers evaluated VTE risk with respect to whether participants received chemotherapy and to genetic susceptibility. To determine genetic susceptibility, they used a polygenic risk score that included nine genes linked to VTE. Participants in the top 5% were considered to have high genetic susceptibility. The results were adjusted for patient, tumor, and treatment characteristics.

The study showed that participants who received chemotherapy had a nearly twofold increased risk for VTE (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.40 - 2.80), though risk was increased only during the first year after diagnosis.

Those with high genetic susceptibility had a nearly twofold increased risk for VTE [HR, 1.90; 95% CI, 1.24 - 2.91] compared to those with lower genetic scores.

For patients who received chemotherapy and had increased genetic risk, the 1-year cumulative incidence of VTE was 9.5%, compared to 1.3% for those without these risk factors (P < .001).

The effect of genetics was stronger in those aged 60 years and older (HR, 2.44; 95% CI, 1.37- 4.35) compared to those younger than 60 years (HR, 1.31; 95% CI, 0.67 - 2.55, p interaction = .04). For older participants with both risk factors, the 1-year cumulative incidence of VTE was 25%.

"Altogether, these results will inform future risk stratification efforts aimed at reducing the VTE burden in chemotherapy-treated breast cancer patients by targeted prevention of VTE in patients at highest risk," Dr Brand commented.

However, before genetic testing can be used in the clinical setting, research will be needed to evaluate the benefits and safety of thromboprophylaxis in high-risk patients, she added. Studies will also need to evaluate the sensitivity and specificity of genetic testing and whether it provides added value to other clinical and laboratory tests that evaluate VTE risk. One current risk model — the Khorana model — uses five clinical and laboratory measures but does not include genetic data.

One limitation of the current study is the small number of older patients, the researchers acknowledge. They also note that the results need to be confirmed in larger-scale trials.

Nevertheless, "[W]e emphasize the importance of considering age-dependent effects, as our study indicated a stronger genetic effect in older breast cancer patients," Dr Brand told Medscape Medical News.

One advantage of genetic markers, according to the authors, is that they might not change in response to inflammation, surgery, and clinical stage, as laboratory and clinical values may. Also, genetic testing has the potential to identify patients at high, intermediate, and low VTE risk, according to Dr Brand.

Role of Genetic Risk Factors

The study is "important" in highlighting the potential role of genetic risk factors for predicting VTE risk, according to Bengt Zöller, MD, PhD, of Lund University and Malmö University Hospital, in Sweden, who was approached for comment.

"Of special interest is the finding that genetic risk factors were important also among older patients. Usually the relative importance of genetic factors decreases with age in complex traits like VTE," Dr Zöller commented in an email to Medscape Medical News.

Dr Zöller also highlighted results suggesting that 93% of patients with the highest genetic risk scores had factor V Leiden (FVL) mutation, which causes resistance to activated protein C (APC-resistance). The FVL mutation accounts for about 20% of all VTE cases and may increase VTE risk by twofold in cancer patients, according to background information in the article.

These results suggest that "much of the clinical relevant effect of the genetic risk score was related to APC-resistance," according to Dr Zöller.

Tests for the FVL mutation are routinely available and may be adequate for identifying patients at highest risk for VTE, but such tests cannot differentiate varying levels of risk, the authors point out in the article.

"The present study is a step in the right direction for the introduction of screening for genetic risk factors of VTE in order to identify high-risk individuals who could benefit most for prophylaxis," Dr Zöller concluded. "I hope that this will not take another 20 years or more."

This study was funded by the Swedish Research Council, the Swedish Cancer Society, and the Swedish Research Council for Health, Working Life and Welfare (FORTE). The authors and Dr Bengt have disclosed no relevant financial relationships.

Clin Cancer Res. Published online November 1 2016. Abstract

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