Psychological distress and breast cancer : a bidirectional link

• Psychological distress is one of the six vital signs among patients with cancer. An increased risk of psychiatric disorders has also been reported among cancer patients, compared with the general population. On the other hand, psychological distress might also influence the initiation and progression of cancer. As breast cancer is the most common cancer, and females are more vulnerable to psychiatric disorders than men, we further investigated the bidirectional link between psychological distress and breast cancer. The potential mechanisms linking together psychological distress and breast cancer include inflammation, neuroendocrine pathways, behavioral factors, and reproductive and hormonal factors. In this thesis, we studied various response processes and consequences of psychological distress in relation to the risk, prognosis, and diagnostic workup of breast cancer, including stress coping ability, anti-inflammatory drug use, and genetic determinants of different stress pathways, to comprehensively investigate such a link. In Study I, we examined whether sense of coherence (SoC), as a measure of resilience to psychological distress, reduced the risk of breast cancer. We included all women who had answered the SoC-13 questionnaire when enrolled in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort, and identified incident cases of breast cancer after enrollment of these women through cross-linkages with Swedish national registers. We used the SoC score measured at enrollment as the main exposure because SoC is believed to be stable. We estimated the hazard ratio (HR) and 95% confidence interval (CI) of breast cancer in relation to SoC, based on Cox proportional hazards models, after adjustment for potential confounders. We found no evidence to support an association between SoC and risk of breast cancer (HR: 1.08; 95% CI: 0.90-1.29). In Study II, considering that inflammation is a critical component in both cancer development and stress response (especially chronic stress response), we assessed whether use of non-steroidal anti-inflammatory drugs (NSAIDs) reduced the risk of breast cancer. We used a nested case-control design within the general female population of Sweden as well as within the KARMA cohort. Conditional logistic regression models were used to estimate HRs and 95% CIs, adjusted for potential confounders. We did not find use of aspirin to be associated with the risk of breast cancer. However, use of non-aspirin NSAIDs was associated with a slightly increased risk of early-stage breast cancer (HR: 1.05; 95% CI: 1.02-1.08), a decreased risk of advanced-stage breast cancer (HR: 0.80; 95% CI: 0.73-0.88), and a decreased risk of breast cancer in general among women with dense breasts (HR: 0.72; 95% CI: 0.59-0.89). In study III, we aim to understand the potential genetic determinants of the link between psychological distress and breast cancer prognosis. We assessed whether somatic mutations and gene expression of the neuroendocrine pathways, namely the adrenergic, cholinergic, dopaminergic, glucocorticoid, and serotonergic pathways, which are directly involved in stress response, were associated with breast cancer prognosis. We used a matched extreme case-control design based on two cohorts of breast cancer patients from China, US, and other countries. Somatic mutations and gene expression data were derived from whole exome sequencing (WES) and RNA sequencing on tumor and paired normal breast tissues. Logistic regression was used to estimate the odds ratio of invasive disease-free survival (iDFS). A two-fold increase of somatic mutation burden in genes of the glucocorticoid pathway was associated with a 17% (95% CI: 2%-35%) elevated odds of reaching iDFS endpoints. This association might be regulated through differential gene expression of the glucocorticoid pathway in tumor tissue. In Study IV, we compared the risk of psychiatric disorders potentially related to psychological distress among cancer patients with or without pre-diagnostic use of NSAIDs. We conducted a cohort study including all cancer patients diagnosed during July 2006 to December 2013 in Sweden and followed them for an incident diagnosis of anxiety, depression, or stress-related disorders. Cox proportional hazards models were used to estimate the HR and 95% CI, adjusted for potential confounders. We found a reduced risk of anxiety, depression, and stress-related disorders among cancer patients with pre-diagnostic use of aspirin (HR: 0.88; 95% CI: 0.81-0.97) and contrastingly an increased risk of these psychiatric disorders among patients with pre-diagnostic use of non-aspirin NSAIDs (HR: 1.24; 95% CI: 1.15-1.32). A more prominent risk decreased in relation to aspirin use was found among females and patients with breast cancer. Taken together, the knowledge gained through this thesis work helps to improve our understanding on the role of psychological distress in the risk and prognosis of cancer and supports intervention of severe psychological distress subsequent to a cancer diagnosis. In the long run, such knowledge should also help pave the way for the development of innovative measures for the prevention of cancer and cancer-related morbidity and mortality.

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