INTRODUCTION
The relationship between mood and cancer has fascinated scientists since the time of the ancient Greeks. Over the last several decades, investigators have attempted to identify an association between depression and cancer survival, but these efforts have yielded mixed results. Although meta-analyses suggest that there may be an association between depression and survival (Satin et al., Reference Satin, Linden and Phillips2009; Pinquart & Duberstein, Reference Pinquart and Duberstein2010), the variability in individual study findings may be the result of different relationships according to cancer type and stage (Onitilo et al., Reference Onitilo, Nietert and Egede2006) and the lack of prior investigation into molecular determinants of prognosis such as tumor genotype.
We have consistently found that depression at the time of diagnosis predicts worse survival in patients with metastatic non-small cell lung cancer (NSCLC) (Pirl et al., Reference Pirl, Temel and Billings2008, Reference Pirl, Traeger and Greer2012). Our previous results suggest a median survival benefit of 3–5 months for patients who are not depressed, which is larger than the magnitude of benefit from chemotherapy treatment in this population. Depression, therefore, represents an important target for novel intervention strategies for affected patients with metastatic NSCLC. However, our previous work has demonstrated that improvement in depressive symptoms might not be associated with improved survival in this population (Pirl et al., Reference Pirl, Traeger and Greer2012). Additionally, we have found that depression at the time of the first oncology visit prior to a patient's knowledge of their genotype results may be associated with tumor epidermal growth factor receptor (EGFR) genotype (Pirl et al., Reference Pirl, Traeger and Greer2011). Patients whose tumors harbored EGFR mutations, which confer a better prognosis, were significantly less likely to have depression than patients with EGFR wild-type tumors.
Tumor genotyping in patients with newly diagnosed metastatic NSCLC has now become the standard of care, and initial treatment decisions are based on the results of EGFR mutation status (Azzoli et al., Reference Azzoli, Baker and Temin2009; Mok et al., Reference Mok, Wu and Thongprasert2009). Patients with EFGR mutated lung cancer have a vigorous response to EGFR inhibitors and have an approximate doubling in median survival with metastatic disease compared with those with wild-type tumors (Sequist et al., Reference Sequist, Joshi and Jänne2007b). Patients with tumors that harbor an EGFR mutation also appear to have better prognoses regardless of treatment (Eberhard et al., Reference Eberhard, Johnson and Amler2005; Fukuoka et al., Reference Fukuoka, Wu and Thongprasert2011).
We hypothesized that tumor EGFR genotype may account for the relationship between depression and survival in this population. We investigated this possible relationship in a cohort of patients with metastatic NSCLC, in which we had previously demonstrated as association between depression and worse survival.
METHOD
Sample
We used a different cohort of patients with newly diagnosed metastatic NSCLC than the one in which we previously demonstrated an association between depression and tumor EGFR genotypes (Pirl et al., Reference Pirl, Traeger and Greer2011). Between June 7, 2006 and July 15, 2009, 151 ambulatory patients within 8 weeks of diagnosis of metastatic NSCLC participated in a randomized controlled trial comparing early palliative care (EPC) integrated with standard oncology care with standard oncology care alone at the Massachusetts General Hospital (MGH). Full details of the trial are published elsewhere (Temel et al., Reference Temel, Greer and Muzikansky2010). Patients who presented to the outpatient thoracic oncology clinic were eligible to enroll if they had confirmed metastatic NSCLC, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, and the ability to read and respond to questions in English. Patients who were already receiving care from the palliative care service were not eligible to participate in the study. All medical oncologists in the clinic agreed to approach, recruit, and obtain consent from their patients. Enrolled patients were randomly assigned in a 1:1 fashion without stratification, 77 to EPC integrated with standard care and 74 to standard care alone. Before enrollment began, our Institutional Review Board approved the study protocol, and all participants provided written informed consent.
Depression
We assessed depression at enrollment with the Patient Health Questionnaire-9 (PHQ-9) (Spitzer et al., Reference Spitzer, Kroenke and Williams1999). The PHQ-9 is a nine item self-report instrument developed to screen for major depressive disorder in primary care settings using Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria. It can be scored continuously for a measure of symptom severity and categorically for presumed diagnoses of major depression syndrome (MDS). Individuals receive a diagnosis of MDS according to DSM-IV criteria if they endorse at least one of the first two items as occurring at least half the days and at least four of the other seven items as occurring at least half the days in the past 2 weeks. The PHQ-9 has been validated in samples of patients with cancer and used in clinical trials with this population (Ell et al., Reference Ell, Xie and Quon2008; Fann et al., Reference Fann, Berry and Wolpin2009).
Tumor Genotyping
All new patients diagnosed with metastatic NSCLC currently undergo tumor genotype testing as part of the routine initial assessment at the MGH thoracic oncology clinic. However, over the enrollment period of this prospective study, the proportion of our patient population with metastatic NSCLC who underwent testing steadily grew from ~ 10% in 2006 to ~ 50% in 2009.
Tumor biopsy specimens are required for genotyping. During the study interval, both direct sequencing of EGFR and multiplexed driver oncogene analysis with the SNaPshot platform were utilized (Dias-Santagata et al., Reference Dias-Santagata, Akhavanfard and David2010; Sequist et al., Reference Sequist, Heist and Shaw2011). Our clinical pathology department conducts genotype testing in a Clinical Laboratory Improvement Amendments (CLIA)-certified manner; results are typically available 3–4 weeks after requisition, and documented in the electronic health record. EGFR genotype status for patients with metastatic NSCLC was coded as EGFR mutation, EGFR wild-type, or unknown EGFR genotype (not tested).
Statistical Methods
We performed statistical analyses using SPSS, version 17.0. We had previously reported an association between depression and survival in this sample (Pirl et al., Reference Pirl, Traeger and Greer2012) and a series of models were tested to evaluate whether EGFR genotype could account for an association between depression and survival. First, we sought to demonstrate an association between depression and EGFR genotype using χ2 for differences in prevalence of MDS. We also used independent samples t tests to examine differences in depression symptom severity between those with known EGFR mutations and those with wild-type and unknown genotypes. Next, we tested Cox proportional hazards models to investigate associations of EGFR genotype with survival, adjusting for the following variables that can be associated with survival in this population (Paralkar et al., Reference Paralkar, Li and Langer2008; Stinchcombe & Socinski, Reference Stinchcombe and Socinski2009): ECOG performance status, age, sex, race, smoking, and marital status. Finally, we examined the extent to which EGFR genotype might account for this association by entering EGFR genotype into Cox proportional hazards models of depression predicting survival, adjusting for all covariates. An attenuation in the relationship between depression and survival (as observed by ≥10% reduction in the hazard ratio and/or conversion to a non-significant p-value for depression), would suggest that the association between depression and survival is confounded by EGFR genotype, and supports the hypothesis that EGFR genotype accounts for at least part of the relationship between depression and survival. We considered all p-values at the two-sided α level of 0.05 to be statistically significant.
RESULTS
Table 1 includes a summary of the study sample characteristics. Of the 151 participants, 150 completed the PHQ-9 at enrollment. Twenty-one patients (14.0%) met diagnostic criteria for MDS. Patients who met criteria for MDS did not differ significantly from those who were not depressed with respect to age, sex, ECOG performance status, smoking history, race, and marital status. Forty-four patients (29.3%) had genotyping performed, 17 (38.6%) of whom tested positive for EGFR mutations.
Table 1. Sample characteristics
MDS, major depressive syndrome; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor.
Depression and NSCLC EGFR Genotype
Whereas patients with wild-type EGFR tumors and unknown EGFR genotypes had similar rates of MDS, 4/27 (15%) and 17/105 (16%) respectively, no patients with EGFR mutated tumors (0/17) met criteria for MDS. However, the difference in prevalence among genotype groups did not reach statistical significance (p = 0.22). Patients harboring EGFR mutations had lower levels of depression than did those with wild type and unknown genotypes (4.12 [SD = 2.50] and 6.94 [SD = 5.26] respectively, p = 0.03). More specifically among patients with known EGFR genotype, those with EGFR mutations had significantly lower depression severity scores on the PHQ-9 than did those with EGFR wild-type tumors (4.12 [SD = 2.50] and 6.44 [SD = 5.10] respectively, p = 0.05).
NSCLC EGFR Genotype and Survival
As expected, EGFR genotype was associated with survival. In unadjusted models, median survival was 16.8 months for patients with EGFR mutations, approximately twice the median survival of the other patients (8.2 months, log rank p = 0.01). Adjusting for age, sex, performance status, smoking history, race, and marital status, patients with EGFR mutations had superior survival (HR 0.44, 95% CI 0.23–0.88, p = 0.02).
Impact of EGFR Genotype on Relationship between Depression and Survival
The previously reported hazard ratio for depression and survival in this sample was HR 1.82 (95% CI 1.10–3.01, p = 0.02), adjusting for age, sex, performance status, smoking history, race, and marital status (Pirl et al., Reference Pirl, Traeger and Greer2012). When we entered tumor EGFR genotype into the model of MDS predicting survival, EGFR mutation remained significantly associated with survival (HR = 0.49, 95% CI 0.27–0.97, p = 0.002), but the relationship of MDS with survival was no longer significant (HR 1.61, 95% CI 0.97–2.68, p = 0.07). Additionally, the hazard ratio for MDS had a reduction of 11.0%, meeting our criteria for confounding and supporting the hypothesis that EGFR genotype at least partially explains the relationship between depression and survival.
DISCUSSION
Patients with metastatic NSCLC that harbors EGFR mutations have longer survival and appear to have less depression. These data raise the possibility that NSCLC genotype might explain a portion of the observed relationship between mood and survival in these patients. However, our data are not able to clarify the direction of the association between tumor genotype and depression, as we did not employ diagnostic psychiatric interviews to assess for past history of depression. It is possible that depression could contribute to the development of EGFR wild-type lung cancer and/or the converse. Although epidemiological studies have not clearly shown whether depression increases the risk for lung cancer (Knekt et al., Reference Knekt, Raitasalo and Heliovaara1996; Gross et al., Reference Gross, Gallo and Eaton2010), it is possible that depression might only factor into the likelihood of developing EGFR wild-type tumors. However, in clinical trials, agents that block activation of EGFR have been observed to improve mood and sleep, whereas platinum-based chemotherapies do not have this effect (Bezjak et al., Reference Bezjak, Tu and Seymour2006; Iurisci et al., Reference Iurisci, Rich and Levi2007; Su et al., Reference Su, Zhou, Zhou and Xu2010).
The finding that tumor genotype might partially account for the relationship between mood and cancer survival is consistent with our observation that improvement in depression among patients with metastatic NSCLC may not lead to improved survival (Pirl et al., Reference Pirl, Traeger and Greer2012). Although depression is treatable, this might suggest that the biology of lung cancer may ultimately be a stronger determinant of overall survival that is less modifiable once tumorogenesis has occurred. Nonetheless, we believe this study opens up a new area for further investigation that could have important clinical ramifications. Identifying the mechanism by which depression could be associated with tumor genotype has the potential to lead to novel concepts of targeted treatment for depression in this population.
The biologic mechanism underlying an association between EGFR genotype and depression could involve serum mediators that are general or specific. Levels of pro-inflammatory cytokines such as interleukin (IL)-6 have been associated with depression in patients with cancer (Musselman et al., Reference Musselman, Miller and Porter2001; Jehn et al., Reference Jehn, Kuehnhardt and Bartholomae2006; Lutgendorf et al., Reference Lutgendorf, Weinrib and Penedo2008; Miller et al., Reference Miller, Ancoli-Israel and Bower2008), and there could be differences, which vary by EGFR genotype, in the degree to which NSCLC evokes an inflammatory response in the body. The severity of cancer-related symptoms in patients with NSCLC during cancer treatment has been associated with inflammatory cytokines (Wang et al., Reference Wang, Shi and Williams2010), but their relationship to EGFR genotypes has yet to be studied.
Another hypothesis for a mechanism that is more specific to NSCLC involves differences in the production of transforming growth factor (TGF)-α by tumors with different EGFR genotypes. TGF-α is a ligand of EGFR that is produced by several types of cancers (breast, prostate, colorectal, and lung) (Normanno et al., Reference Normanno, DeLuca and Bianco2006). TGF-α can stimulate EGFR and lead to the development, growth, and proliferation of tumors (Borrell-Pages et al., Reference Borrell-Pages, Rojo and Albanell2003; Normanno et al., Reference Normanno, DeLuca and Bianco2006). TGF-α can also bind to EGFR in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is the master pacemaker, to disrupt circadian rhythms (Kramer et al., Reference Kramer, Yang and Snodgrass2001; Vadigepalli et al., Reference Vadigepalli, Hao and Miller2006; Rich Reference Rich2007). In animal models, the administration of exogenous TGF-α results in circadian rhythm disturbances and what could be described as depressive behaviors (decreased activity and decreased eating) (Snodgrass–Belt et al., Reference Snodgrass-Belt, Gilbert and Davis2005; Gilbert & Davis, Reference Gilbert and Davis2009). In patients with colorectal cancer, serum levels of TGF-α have been associated with decreased sleep–wake rhythm amplitude (Rich et al., Reference Rich, Innominato and Boerner2005). Interestingly, EGFR mutant NSCLC is associated with lower serum levels of TGF-α and has undetectable in vitro extracellular levels of TGF-α (Tracy et al. Reference Tracy, Mukohara and Hansen2004; Fukuyama et al., Reference Fukuyama, Ichiki and Yamada2007; Volante et al., Reference Volante, Saviozzi and Rapa2007; Masago et al., Reference Masago, Fujita and Hatachi2008; Yonesaka et al., Reference Yonesaka, Zejnullahu and Lindeman2008).
Clinically, understanding the biology of an association between depression and EGFR wild-type NSCLC could contribute significantly to efforts to prevent and treat lung cancer. If depression is identified as a risk factor for developing EGFR wild-type NSCLC, depression screening should be incorporated into the lung cancer screening programs for smokers and high-risk individuals, which are being developed nationally in response to the results of the National Lung Screening Trial (National Lung Screening Trial Research Team, Reference Aberle and Adams2011). Similar to smoking cessation efforts, treating depression in this population could potentially reduce their risk of developing EGFR wild-type NSCLC. Additionally, depression might help further differentiate EGFR wild-type tumors into categories with different responses to anticancer treatments based on biologic factors that are clinically manifesting as depression. Because many patients with NSCLC have tumors without known mutations directing them toward targeted treatments, the presence of depression could assist in the personalization of cancer treatments among these individuals.
Conclusions drawn from these analyses have several limitations. First and foremost, the findings are from a post-hoc unplanned analysis of a clinical trial. Depression was not the primary outcome of the clinical trial and was assessed with a self-report instrument, the PHQ-9, instead of using diagnostic interviews. Additionally, we did not have full EGFR genotype data on all tumors. Over the course of the clinical trial, EGFR genotyping emerged as an integral component of clinical oncology practice, but was initially offered to only a minority of patients with NSCLC thought most likely to harbor the mutation. However, among the 44 patients who underwent genotyping in our study, the rate of EGFR mutations was 11%, consistent with the population estimates in North America (Sequist et al., Reference Sequist, Bell and Lynch2007a).
Another limitation to the study is that the association between EGFR genotype and depression was not as strong as that in our prior study in a different sample of patients with metastatic NSCLC. This could be because of the difference in timing of the assessment of depression between the two studies. In our original report, depression was assessed at the first oncology visit, before the results of genotyping were known (Pirl et al., Reference Pirl, Traeger and Greer2011). In the current analysis, trial participants could be within 8 weeks of their metastatic NSCLC diagnosis, and some may have had knowledge of their EGFR genotype status at the time of the depression assessment. The current sample also includes patients who were prescribed antidepressants, which we excluded from the prior analysis to avoid any potential preventative effects an antidepressant may have had on developing depression at the time of diagnosis. Nonetheless, we would expect that these differences would further obscure the findings; however, we still observed a significant association between NSCLC EGFR genotype and level of depressive symptoms.
Overall, our research suggests that tumor genotype should be considered in studies of depression and survival. If associations really do exist, elucidating the underlying mechanism of an association between depression and NSCLC EGFR genotype could lead to the development of more informed trials of interventions, not just for depression, but for cancer as well. In addition to determining the direction of an association between depression and EGFR wild-type NSCLC, potential serum mediators of the relationship, such as TGF-α and pro-inflammatory cytokines, need to be explored. Psychosocial and quality of life research that includes data on cancer genotypes has the potential to identify novel pathways from cancer biology to cancer-related symptoms, which may ultimately have the power to bring cancer symptom management into the era of personalized medicine.
