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Mass General Researchers Link Poor Lung Cancer Survival to Mutations in Two Genes

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Patients with lung cancer who have a certain gene mutation are more likely to respond to the chemotherapeutic agents cisplatin or carboplatin, according to research conducted at the Massachusetts General Hospital.

Results of this retrospective study may help oncologists better select patients for these commonly prescribed drugs. “We hope that this type of research will one day enable doctors and patients to make more informed decisions about chemotherapy treatments,” study author Sarada Gurubhagavatula said in a statement.

To arrive at their results, Gurubhagavatula and colleagues studied polymorphisms in a pair of 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.

Researchers believe that these genes, which are involved in correcting mistakes that can occur when DNA is copied in preparation for cell division, “may lead to more aggressive lung tumors” that metastasize to other organs, decreasing mortality.

The genes are not only linked to non-small-cell lung cancer. Other researchers have investigated the link between polymorphisms in the XPD and XRCC1 genes in patients with colorectal cancer. However, Gurubhagavatula’s study is believed to be the first study to look at variations in these genes in patients with lung cancer.

Comparing combinations of polymorphisms in both genes, the team found that more variations were associated with decreased median survival. Specifically, patients with a three polymorphisms in the genes survived a median of 6.8 months, while those with no polymorphisms survived a median of 20.4 months. Patients with two polymorphisms survived a median of 11 months, and those with one variation survived 16.6 months, the researchers found.

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

However, the researchers noted that the nature of the study “presented certain limitations.” Because evaluating clinical response and time-to-disease-progression “is often imprecise in the retrospective setting, the study focused on overall survival, the most objective outcome,” the researchers conceded. Yet 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.”

The results appear online in the June 1 Journal of Clinical Oncology.

In an accompanying editorial, Heinz-Josef Lenz, an associate professor of medicine and preventive medicine at the USC Norris Comprehensive Cancer Center, called the study “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.”

—KL

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