Cancer is now the second leading cause of death in the world according to the World Health Organization [WHO] (2020) estimates. In 2020, according to the Global Cancer Observatory (GCO) (2020c) nearly 10 million people died of cancer. Amongst all cancers, both sexes and all ages, breast cancer had the highest number of new cases, nearly 2.3 million (11.7%) in an estimated 19.3 million worldwide, and was fifth in number of deaths (6.9%) Global Cancer Observatory (GCO) (2020a). Lung cancer was second in number of new cases (11.4%) and the first in number of deaths, almost 1.8 million (18%) Global Cancer Observatory (GCO) (2020b).

Europe, considering the cancer statistics worldwide by region, has the second highest number in incidence, mortality and 5-year prevalence in all cancers, including breast and lung cancers [Global Cancer Observatory (GCO), 2020a,b, c]. Although Europe has only 9.7% of the world population, the estimated percentage of new cases was 22.8% (Sung et al., 2021). In Portugal Global Cancer Observatory (GCO) (2020d), the total estimated number of new cancers cases was 60,467, with a total number of 30,168 deaths from all cancers. Breast cancer is second to colorectum cancer with a number of 7,041 (11.6%) new cases, and lung cancer is fourth with 5,415 (9%) new cases. Breast cancer was the most common in females, all ages. Lung cancer was the third most frequent in males and in females, all ages.

The major cancer risk factors considered by World Health Organization [WHO] (2021) and widely investigated are the use of tobacco (Kim et al., 2014, 2018; Drope et al., 2018), alcohol intake (Oyesanmi et al., 2010; Bagnardi et al., 2015; Sun et al., 2020), unhealthy diet (WCRF, 2018; Morze et al., 2021; Tran et al., 2021), and lack of physical activity (Boyne et al., 2018; Chan et al., 2019; McTiernan et al., 2019). The WHO also considers air pollution and chronic infections as risk factors. Despite findings suggesting the association between psychological factors and development of cancer, mental health problems have not been recognized as risk factors of cancer. Even though the WHO states that “there is no health without mental health” (World Health Organization [WHO], 2018), highlighting the association of mental and physical health.

Psychological and emotional distress from exposure to adverse childhood experiences (ACEs), adverse life events, or traumatic stressors can cause psychological trauma and associated posttraumatic stress disorder (PTSD), pathological grief, and depression (Kessler et al., 2010; Trickey et al., 2012; Wang et al., 2018). Risk factors for the severity of impact of adverse/traumatic events include: prior trauma (Breslau et al., 1999; Hughes et al., 2017); gender (Tolin and Foa, 2006; Gallo et al., 2018); age (Willis et al., 2018); individual vulnerability (Bomyea et al., 2012); heredity factors (Koenen et al., 2002; Bomyea et al., 2012; Wang et al., 2018); family or social functioning and support (Boscarino, 1995; Trickey et al., 2012; Stevens and Jovanovic, 2019); and, social variables such as ethnic, demographic, and socioeconomic factors (Kosidou et al., 2011; Santini et al., 2021), among others. One or more of these risk factors can lead to psychopathology and physical disease.

Psychopathology can be triggered by psychological trauma, grief, and depression, causing alterations in neuropsychological functioning, cognitive processing, emotional regulation, and in adjustment, among other processes (Kessler et al., 2010; Bomyea et al., 2012; Carr et al., 2013; McKay et al., 2021). Psychological theories and underlining psychodynamic processes associated to traumatic events include alterations in cognitive, emotional, identity, personality, and relational (socioemotional) development. These alterations cause vulnerability, emotional instability, difficulties in self-regulation, alterations in adjustment, and poor social relationships (Bomyea et al., 2012; Carr et al., 2013). The psychological and interlinked physical symptoms associated to trauma, grief, and depression include: dysregulation of emotions and feelings (sadness, hopelessness, fear, anger, mistrust, and worry); progressive increase in anxiety, stress; depression; cognitive impairment; alterations in appetite; disturbance of sleep; psychomotor apathy/agitation; behavioral alterations; somatic symptoms; and functional impairment (Carr et al., 2013).

Physical disease has already been linked to the psychological factors of trauma, grief, and depression, and associated with higher rates of autoimmune disease, metabolic syndrome, coronary heart disease, respiratory disease, and some cancers (Boscarino, 2004; Miller et al., 2011; Hughes et al., 2017; Lopes et al., 2020; Santini et al., 2021). This risk is associated to the physiological alterations in neural, neuroendocrine, immune, and cardiovascular systems (Boscarino, 2004; Bomyea et al., 2012). Physiological functioning has been evaluated in studies of neurodevelopment and brain structure, in genetic and epigenetic research, among others.

Evidence of alterations in brain structure, activity, and connectivity have been pinpointed in the neurobiological research associated to trauma in childhood. Neurobiological and neuro-imaging studies showed functional alterations and structural alterations with volume changes in the prefrontal cortex (PFC) and hippocampus (Cassiers et al., 2018). Studies also showed functional alterations in emotion processing in the anterior cingulate cortex, amygdala, and hippocampus, and alterations in executive functions in the PFC and basal ganglia (Fox et al., 2010; Miller et al., 2011; Luby et al., 2017; Cassiers et al., 2018). The cortico-amygdala neural circuitry regulates vigilance and responses to threatening stimuli, while the cortico-basal ganglia circuitry regulates reward processing. The neural reward system is important in many psychological and behavioral processes, such as learning, social bonding, addiction, among others. It is also involved in grief, linked to the psychological and physiological regulatory role played by attachment figures in this system (Kakarala et al., 2020). Another important neurobiological process associated to trauma and depression implicates the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, resulting in increased levels of cortisol and pro-inflammatory cytokines (Nusslock and Miller, 2016; Cassiers et al., 2018; Wang et al., 2018; Majd et al., 2020). Neurobiological studies identified various alterations in mechanisms that play a key role in the regulation of inflammation, including the sensitization of immune cells that initiate and sustain inflammation, the alteration in the sensitivity of monocytes to inhibition by glucocorticoids, the declining suppression of cytokine production by cortisol, among other processes linking the nervous, endocrine, and immune systems, that may lead to a chronic pro-inflammatory state (Danese and McEwen, 2012; Nusslock and Miller, 2016). Inflammation, which plays an essential role as the pathogenic link influencing all the systems, is considered the “common soil” of the multifactorial diseases and is known to play an important role in cancer development (Mantovani et al., 2008; Miller et al., 2011; Scrivo et al., 2011; Danese and McEwen, 2012).

Genetic and epigenetic studies associated to trauma showed changes in specific genes that regulate neural circuits. Some of these genes regulate function in the serotonin, catecholamines, and glucocorticoids systems, which are also implicated in depression (Bomyea et al., 2012; Majd et al., 2020). Genetic research focusing on epigenetic factors has, among other investigation, linked changes in DNA methylation (DNAm) (hypermethylation and hypomethylation) to pathways for development of disease in the different systems (Bomyea et al., 2012; Ridout et al., 2018; Lang et al., 2020; Czamara et al., 2021; Parade et al., 2021). Czamara et al. (2021) demonstrated that the effects of the interaction of genotype and exposure to childhood adversity had the highest influence on DNAm variability. The systematic review by Lang et al. (2020) explored studies with other markers of biological changes to ACEs, namely inflammatory markers such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), epigenetic modification by methylation [methylation of glucocorticoid receptor (GR) gene – NR3C1, methylation of the brain-derived neurotrophic factor (BDNF), methylation of the serotonin signaling genes], microRNA 124-3, interferon gamma (IFN-γ), corticotrophin releasing hormone (CRH), telomere length, and structural changes using functional MRI brain imaging. The inflammatory cytokines TNF-α and IL-6, were also identified in depression and are key endogenous factors in cancer-related inflammation (Mantovani et al., 2008; Majd et al., 2020).

The association between psychological factors, such as depression, anxiety, stress or personality, and cancer has been studied for a long time with controversial results (Nakaya et al., 2010; Lemogne et al., 2013a; Lin et al., 2013; Jia et al., 2017; Afrisham et al., 2019; Bahri et al., 2019; Abate et al., 2020). The psychological factors of trauma and grief have been less studied.

In the association of adverse life events/trauma, Bahri et al. (2019) in the systematic review and meta-analysis of cohort studies published in 2019 found that stressful life events “slightly increase the risk” of breast cancer with a pooled risk ratio (RR) of 1.11 [95% confidence interval (CI) = 1.03–1.19]. Lin et al. (2013) found a 1.5-fold greater risk for “striking life events” with odds ratio (OR) of 1.51 (95% CI = 1.15–1.97) and a 2.0-fold greater risk for “severe striking life events” with OR of 2.07 (1.06–4.03). The meta-analysis by Duijts et al. (2003) showed no association between adverse life events and breast cancer, except for the event of the death of a spouse with a moderate risk (OR = 1.77, 95% CI = 1.31–2.40) for breast cancer.

No published systematic reviews or meta-analysis on the association of grief and cancer risk were found.

In relation to the association of depression and cancer risk, the meta-analysis by McGee et al. (1994) concluded with “a small, but marginally statistically significant association between depression and the later development of cancer”. Oerlemans et al. (2007) confirmed this result on overall cancer with a summary RR of 1.19 (95% CI = 1.06–1.32) and found, in the analysis of studies with a follow-up of 10 or more years, that the risk between depression and subsequent breast cancer increased to a significant RR of 2.50 (1.06–5.91). On the other hand, Sun et al. (2015) found no significant association between depression and breast cancer. In more recent systematic reviews, Jia et al. (2017), found a significant association with overall cancer risk (RR = 1.15, 95% CI = 1.09–1.22), with liver cancer (RR = 1.20, 95% CI = 1.01–1.43), and lung cancer (RR = 1.33, 95% CI = 1.04–1.72). Wang et al. (2020) found, associated to clinically diagnosed depression a significantly increased risk of cancer incidence (adjusted RR = 1.13, 95% CI = 1.06–1.19). In terms of specific cancer sites, significant associations to lung cancer were observed (RR = 1.41, 95% CI = 1.17–1.69).

Results of the studies are inconsistent, and one explanation is that the epidemiological data comes from retrospective case-control studies open to recall bias (McGee et al., 1994). Important explanations included heterogeneity between studies due to demographics, study design, population studied, and assessment measures among other limitations (Wang et al., 2020).

The present systematic review aimed to study the connection between psychological factors and the risk of breast and lung cancer. The psychological factors of trauma, grief, and depression were studied. These factors may be present without a formal clinical diagnosis, and cause suffering, functional limitations, and morbidity. To study the association between psychological factors and the risk of breast and lung cancer, six research questions were defined as follows: is there a consensual association between (1) psychological trauma and breast cancer risk? (2) grief and breast cancer risk? (3) depression and breast cancer risk? (4) psychological trauma and lung cancer risk? (5) grief and lung cancer risk? and (6) depression and lung cancer risk?

Only studies in which the study variables were obtained before diagnosis of breast or lung cancer were included.

The systematic review protocol was registered with the International prospective register of systematic reviews (PROSPERO) and published without review on October 16, 2020 with registration number CRD42020209161.

The current systematic review was conducted using PRISMA statement guidelines for systematic reviews (Moher et al., 2009) and followed the recommendations of the Cochrane Collaboration for systematic reviews (Higgins et al., 2020).

The systematic review recognized 26 studies, 25 cohort and one case-control, that investigated the incidence of breast and lung cancer in people with history of adverse life events or trauma, grief, and depression at baseline. These 26 studies included a total of 2,554,762 participants (943,056 males), range 115 (Ollonen et al., 2005) to 1,220,697 (Chang et al., 2015). They were conducted between 1988 and 2020 (Figure 3) in Canada (n = 1), Denmark (n = 2), Finland (n = 4), France (n = 2), Iran (n = 1), South Korea (n = 1), Netherlands (n = 1), Taiwan (n = 2), United Kingdom (n = 2), and United States (n = 10). The follow-up time of these studies ranged from 1 (Kaster et al., 2019) to 36 years (Goldacre et al., 2007). Studies reported the cancer effect size of breast (n = 17), lung (n = 2), or both cancers (n = 7), after adjusted covariates.

The psychological factors were accessed through clinical interviews, clinical diagnoses based on ICD or DSM and self-report measures, namely the Beck Depression Inventory (BDI), Burnam eight-item scale, Centre of Epidemiologic Studies-Scale (CES-D), Cynical Distrust 10-item Scale, Diagnostic Interview Survey (DIS), Edinburgh Depression Scale (EDS), 36-item version of General Health Questionnaire (GHQ), Holmes and Rahe Scale, Life Events Scale in the Epidemiological Risk Factor (ERF), Mental Health Inventory-5 (MHI-5), Minnesota Multiphasic Inventory (MMPI), Modify Coping with Loss Scale, Modify Haan Coping and Stress Inventory (FI), Montegomery-Asberg Depression Rating Scale (MADRS), short-form of the Present State Examination (PSE), and Quick Inventory of Depression Symptomatology (QIDS-SR) (Table 1).

Overall, 12,962/2,554,762 cases of trauma, 1,667/2,554,762 cases of grief, and 694,537/2,554,762 cases of depression were reported at baseline (Table 2).

Regarding breast cancer, five articles studied the association with trauma, two with grief, and 20 with depression. Considering lung cancer, one article investigated the association with psychological trauma, and eight investigated the association with depression. No study included in this systematic review investigated the association between grief and lung cancer. The positive statistically significant results found are presented in relation to the six research questions defined.

The main goal of this systematic review was to identify, select, and evaluate studies that investigated the association between psychological factors and the risk of breast and lung cancer in people without a diagnosis of cancer. In this review 26 studies were analyzed, 25 cohort and one case-control. The epidemiological evidence identified was diversified by country of study, cancer subtype, time of follow-up, psychological factors at baseline, measures used, and control for confounding factors. The studies included individuals with different age groups, sex, and sociodemographic characteristics. The psychological data collection was carried out in most studies through self-reporting measures scientifically validated for the populations studied, while in other studies data was collected through clinical interviews using the diagnostic criteria of ICD and DSM. All studies adjusted their statistical models to the main variables known as risk factors, for both cancer subtypes (World Health Organization [WHO], 2020). Six research questions were defined.

The first research question sought to understand whether there is a consensual association between psychological trauma and breast cancer risk. This review shows evidence that some adverse life events/trauma are statistically associated to an increased risk of breast cancer in females and shows that death loss during the different phases of development has a well-established long-term impact on physical health (Schoemaker et al., 2016). In particular, the self-reported events perceived at baseline with psychological distress stand out, such as the death of a friend, close family member, or spouse (Jacobs and Bovasso, 2000; Lillberg et al., 2003; Schoemaker et al., 2016). These results corroborate the associations already found in previous systematic reviews (Duijts et al., 2003; Lin et al., 2013). Death as an adverse life event/trauma seems to contribute the most to breast tumor development (Bahri et al., 2019). Therefore, psychological treatment of adverse life events/trauma can reduce the occurrence of breast cancer in females. Bahri et al. (2019) already warned of the need to intervene psychologically after the occurrence of an adverse life event/trauma. Experiencing the death of a significant person seems to be enough to pose risks for health problems. Considering the neurobiology, alterations that occur with adverse life events/trauma cause dysregulation of the HPA axis, resulting in increased levels of cortisol and inflammatory cytokines, which are key factors in cancer-related inflammation (Mantovani et al., 2008; Scrivo et al., 2011). Even though a solid causal association to inflammation has not yet been specified, inflammatory mediators seen in chronic inflammatory responses are present in breast cancer (Mantovani et al., 2008). In fact, it is established that non-steroidal anti-inflammatory drugs reduce the risk of developing breast cancer and reduce the mortality caused by these cancers (Mantovani et al., 2008). Psychological trauma causes neurodevelopmental changes and consequently alterations in neuropsychological functioning, which influences and is also influenced by the nervous system and the interlinked endocrine and immune systems that are also involved in cancer risk (Carr et al., 2013; McKay et al., 2021).

The aim of the second question was to explore the association between grief and breast cancer risk. This association has apparently been poorly studied empirically. In the present review, we found only two studies which met inclusion criteria. Only one described a positive significant statistical association, in relation to unsolved recent grief among females, which makes it impossible to generalize results (Jasmin et al., 1990). Death loss appears to play a role in the risk of breast cancer, when analyzed as an adverse life event (Schoemaker et al., 2016), as reflected in the first research question. Therefore, it would be expected to find statistically significant positive associations in both studies analyzed, which did not occur. The reasons for these disparities are unclear, but methodological differences in defining grief may be the contributing factor. Thus, it would be interesting that further empirical studies explore the association between grief and the subsequent development of breast cancer to differentiate between grief and death loss as an adverse event.

The third question reviewed the existence of an association between depression and breast cancer risk. Our results show that depression was the most studied psychological factor, being associated with a small to moderate breast cancer risk in females (Jacobs and Bovasso, 2000; Montazeri et al., 2004; Ollonen et al., 2005; Hung et al., 2014; Chang et al., 2015). Thus, these results support the evidence already described in the literature, that depression is a factor to be considered in the subsequent development of overall cancer (McGee et al., 1994; Oerlemans et al., 2007). However, 15 of the 20 studies included in this systematic review do not support this relationship and meet the results found in previous reviews that point to non-consensual results, especially in breast cancer (Oerlemans et al., 2007; Sun et al., 2015; Jia et al., 2017). Several hypotheses can be put forward to explain these results, namely in relation to the measures used by each study to access depression. Time of follow-up may be a significant factor. Oerlemans et al. (2007) found that in studies with a follow-up of 10 or more years, the risk between depression and subsequent breast cancer increased to a significant statistical association. Likewise, other variables that were not evaluated in all of the studies may be influencing these results, such as duration of depression, use of psychiatric medication, among others. The duration of depression and the use of psychiatric medication influence the neurobiology and physiology, involving the nervous (HPA axis), endocrine, and immune systems, and may alter the pro-inflammatory state, all of which play an important role in cancer development (Mantovani et al., 2008; Scrivo et al., 2011).

The fourth question sought to understand whether there is an association between adverse life events or psychological trauma, and risk of lung cancer. No statistically significant association between adverse life events/trauma and lung cancer risk was reported (Gradus et al., 2015). However, these results cannot be generalized due to lack of studies.

The fifth questioned the possible association between grief and lung cancer risk. However, no studies that met the inclusion criteria were found with reference to this association.

Lastly, the sixth research question sought to understand whether there is an association between depression and the risk of lung cancer. Five of the eight studies report a significant statistical association regarding depression, among both sexes (Knekt et al., 1996; Pennix et al., 1998; Goldacre et al., 2007; Chang et al., 2015; Trudel-Fitzgerald et al., 2020). These results are in line with what was previously described in preceding systematic reviews (Jia et al., 2017; Wang et al., 2020). Large sample studies are required to further research and clarify these associations. However, the negative associations found also need to be reflected on. The association of depression to the use of tobacco has been studied. The use of tobacco is also a known risk factor in lung cancer etiology [Drope et al., 2018; World Health Organization [WHO] (2021)]. It is important to clarify whether the association depression-lung cancer is being mediated by the use of tobacco. This question has already been raised by Trudel-Fitzgerald et al. (2020).

Although non-consensual, the findings from the present systematic review suggest that, in addition to the known risk factors (World Health Organization [WHO], 2020), psychological factors may play an important role in the etiology of both breast and lung cancer. The psychological factors and mind-body connection in cancer should be considered and deserves further investigation.

To consider psychological factors as a variable that affects cancer development may be fundamental to opening new avenues for prevention and intervention.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

MP conceived and designed the study. MP and CC collected the data and all authors participated in analyzing the data. All authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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