Study may help oncologists tailor chemotherapy to patients based on their genetic make-up

Genetic variations in an individual’s ability to repair DNA damage may help predict survival in lung cancer patients treated with the common chemotherapy drugs cisplatin or carboplatin, a new study shows. The findings, if verified in larger studies, may help oncologists tailor chemotherapy to patients based on their genetic make-up. The study and an accompanying editorial will be published online June 1 in the Journal of Clinical Oncology (JCO).

“The concept of selecting a chemotherapy drug based on a patient’s genetic make-up is relatively new and very exciting,” said lead investigator Sarada Gurubhagavatula, MD, of Massachusetts General Hospital. “We hope that this type of research will one day enable doctors and patients to make more informed decisions about chemotherapy treatments.”

Study investigators evaluated genetic variations (also called polymorphisms) in two DNA repair genes – XPD and XRCC1 – in 103 patients diagnosed with stage III or IV non-small cell lung cancer who were treated with cisplatin or carboplatin.

The XPD and XRCC1 genes are involved in correcting mistakes that sometimes occur when DNA is copied in preparation for cell division. Researchers suspected that the inability to repair DNA damage may lead to more aggressive lung tumors that spread more rapidly to other organs, thereby decreasing survival.

By comparing combinations of variations in both genes, researchers found that more variations were associated with decreased median survival. Patients with a total of three variations in the XPD and XRCC1 genes survived a median of 6.8 months, while those with no variations survived a median of 20.4 months. Patients with two variations survived a median of 11 months, and those with one variation survived 16.6 months.

The presence of genetic variations independently predicted survival even after researchers took into account patients’ ability to carry out daily activities, their stage of disease, and the type of chemotherapy they received.

While other researchers have investigated the link between XPD and XRCC1 gene variations in patients with other cancers, particularly those with colorectal cancer, this is the first study to look at variations in these genes in patients with lung cancer.

Researchers noted that the retrospective nature of the study presented certain limitations. Because evaluation of clinical response and time to disease progression is often imprecise in the retrospective setting, the study focused on overall survival, the most objective outcome. However, they noted that future studies measuring clinical outcome and time to disease progression may be critical to further understand the mechanism by which DNA repair affects patient outcome.

An accompanying editorial by Heinz-Josef Lenz, MD, Associate Professor of Medicine and Preventive Medicine at the USC Norris Comprehensive Cancer Center discusses the application of polymorphisms in clinical oncology and the potential for including analyses of germline (inherited) polymorphisms known to have an effect on the efficacy and toxicity of certain common chemotherapeutic agents into clinical trials, and eventually into clinical practice.

“This paper is a good example of the potential future using these polymorphisms in the clinic but at the same time of the limitations and the need for a better functional understanding in our quest to elucidate the role of germline polymorphisms in clinical oncology,” said Dr. Lenz.

"XPD and XRCC1 Genetic Polymorphisms are Prognostic Factors in Advanced Non-Small Cell Lung Cancer Patients Treated with Platinum Chemotherapy.” Sarada Gurubhagavatula et al, Massachusetts General Hospital Cancer Center, Boston, MA.

The Journal of Clinical Oncology is the semi-monthly peer-reviewed journal of the American Society of Clinical Oncology (ASCO), the world’s leading professional society representing physicians who treat people with cancer.