Understanding the carcinogenicity of circadian disruption: a systematic review and meta-analysis of night shift work and breast cancer risk in female health care workers

Introduction The International Agency for Cancer Research has classified night shiftwork (NSW) as probably carcinogenic to humans. This classification was based on “limited evidence of cancer in humans (specifically breast, prostate, colon, and rectum cancers), sufficient evidence of cancer in experimental animals, and strong mechanistic evidence in experimental animals” [1]. In recent years, several research groups investigated this relationship [2-5], but the issue remains largely unquantified. The association between circadian disruption and the development of malignant neoplasms is hypothesized to involve the promotion of uncontrolled cell growth due to repeated phase shifting and subsequent defects in circadian cell-cycle regulation. Additional mechanisms include the up-regulation of estrogen effects on breast epithelial cells due to melatonin suppression, and the facilitation of malignant clones and growth caused through the suppression of immune surveillance as a consequence of sleep deprivation [6]. Furthermore, epigenetic modifications, such as altered DNA methylation patterns, and markers of biological aging, such as telomere length, have been investigated as potential mechanisms for cancer development [7-9]. Healthcare workers (HCWs) are exposed to several occupational health and safety hazards, including biological, chemical, physical, biomechanical, and psychosocial factors, some of which are potentially carcinogenic. The International Labour Organization reported that millions of HCWs worldwide suffer from work-related illnesses, and many die from occupational hazards [10]. Selected studies reported an excess incidence of selected cancer among HCWs [11-14]. HCWs are frequently exposed to NSW, which may contribute to this increased cancer risk. Objectives To investigate and clarify the role of NSW and breast cancer risk we conducted an updated systematic review and meta-analysis of all observational studies published through November 23, 2023, on the association between NSW and the risk of breast cancer in the female population of HCWs. Methods We systematically searched PubMed and Embase, evaluated the risk of bias (RoB) of the included studies, using the OHAT Risk of Bias Rating Tool for Human and Animal Studies, and estimated pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) of breast cancer among women exposed to NSW versus those not exposed, using random-effects models. Whenever data were available, we also investigated the duration-risk relationships. Results After removing duplicates, we retrieved and screened 1050 records from Pubmed and Embase. Of the 70 full-text articles assessed for eligibility, 12 distinct populations/studies were included, accounting for 12,132 breast cancer cases. Of these, 60% were rated as “definitely” or “probably” high RoB in the exposure characterization domain. Compared to never-exposed individuals, the pooled RR was 1.05 (95% CI: 0.96-1.14, I2=39%) for ever-exposed individuals (Figure 1). The corresponding RRs were 1.11 (95% CI: 0.96-1.28, based on 9 studies, I2=62%) for ≥10 years of night work, 1.25 (95% CI: 1.01-1.55, based on 7 studies, I2=59%) for ≥20 years, and 1.68 (95% CI: 0.77-3.65, based on 3 studies, I2=79%) for ≥30 years. Pooled RRs appeared higher in case-control/nested studies and studies assessing lifetime versus partial occupational history. The RR for ≥20 years of exposure lost statistical significance in an influence analysis, excluding each study in turn from the meta-analysis, and approached unity after correction for possible publication bias using the trim and fill approach. Conclusions Epidemiological evidence suggests a possible role of long-term night shift work in breast cancer risk. However, due to limitations in the quantification of night work exposure in epidemiological studies and the lack of robustness in meta-analytic results, the association is far from established. Given the high prevalence of night shift work among HCWs, any excess risk, if real, could contribute to a substantial number of breast cancer diagnoses. Future steps: Thanks to a grant from the University of Milan Piano Sostegno alla Ricerca 2022-2023, we aim to complement and expand the research on this topic by investigating the association between NSW and DNA methylation, DNA changes, as well as telomere length among healthy HCWs at Clinica Mangiagalli.