EGFR Status May Explain Depression-Survival Link in NSCLC



ANAHEIM, CALIF. – Notable survival differences between depressed and nondepressed patients with non–small cell lung cancer may be attributable to EGFR-mutation status, according to a small but provocative study conducted by Dr. William Pirl of the cancer center at Massachusetts General Hospital in Boston.

The investigation arose from the observation by Dr. Pirl that NSCLC patients with EGFR (epidermal growth factor receptor) mutations were rarely referred for psychiatric evaluation of depression, which is a common comorbid diagnosis among cancer patients and one that is increasingly linked to decreased survival.

He wondered whether the 15% of lung cancer patients with EGFR mutations might be less susceptible to depression because they would know of their more optimistic prognosis, relative to other patients with the disease. Could their avoidance of depression relate to smoking status, since more patients with EGFR mutations are nonsmokers? Or is it possible that a biological explanation might underlie the relationship between depression and survival in NSCLC?

Results of his study of newly diagnosed NSCLC patients point to biology, although potential biological pathways are still under investigation, Dr. Pirl said in an interview following a presentation of his latest findings at the annual conference of the American Psychosocial Oncology Society.

In a previous study of 43 recently diagnosed NSCLC patients, he and associates found that patients who were depressed according to Hospital Anxiety and Depression Scale scores lived a median of 2.5 months, compared with median survival rates of 10.4 months in nondepressed patients (Psychosomatics 2008 May-June [doi:10.1176/appi.psy.49.3.218]).

To determine whether tumor genotypes played a role, Dr. Pirl’s team administered the MDS (Major Depression Rating Scale, which is a scale derived from the Hamilton Rating Scale for Depression and the Melancholia Scale, and aligned with DSM-IV criteria for major depressive disorder) and the PHQ-9 (Patient Health Questionnaire–9) to 148 patients with metastatic NSCLC prior to the processing of their genotype results. They found the following:

  • None of 16 patients with an EGFR mutation had depression, based on either instrument.
  • In all, 4 of 27 patients (15%) with wild-type mutations as well as 17 of 105 (16%) of those with unknown mutations met criteria for depression, according to the MDS.
  • Even more patients with wild-type mutations (9 of 27, or 33%) and unknown mutations (32 of 105, or 39%) met criteria for depression, according to the PHQ-9.

After 3 years, significantly more depressed patients than nondepressed patients had died (hazard ratio, 1.75; P = .03). Patients with an EGFR genotype also had a significant survival advantage over other patients in the study (P = .004).

"[If we put] genotype into the survival model, depression is no longer significantly associated with survival," reported Dr. Pirl, director of the hospital’s center of psychiatric oncology and behavioral sciences.

A study will soon be underway to explore plausible biological pathways linking EGFR, depression, and survival.

One candidate is tumor growth factor–alpha (TGF-alpha), a ligand of EGFR known to cause circadian rhythm dysfunction. Dr. Pirl noted in his talk that EGFR mutants do not produce TGF-alpha.

If replicated, the study could "raise larger questions about the biological pathways to depression and could possibly uncover a novel pathway in people with medical illnesses," he added in an interview.

Dr. Pirl’s coinvestigators included Dr. Jennifer S. Temel, a medical oncologist, and Joseph Greer, Ph.D., associate director of behavioral medicine at the hospital. They reported having no relevant financial disclosures.

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