Night shift work and breast cancer risk in healthcare workers

Whilst the debate about increased risk of breast cancer in shift workers has been going on for approximately 30 years, perhaps the first observation possibly linking breast cancer to work was made in the 18th century by Ramazzini [1], regarded as the father of occupational medicine, who noted that breast cancer was more common among nuns than married women, identifying for the first time the link between reproductive history and breast cancer. More recently, an editorial [2] published nearly 10 years ago in this journal commented on two earlier articles [3,4] published in 2001, which initially postulated a link between shift work and breast cancer in healthcare workers. The editorial [2] compared those earlier results with a more recent review of the literature at that time [5–7], which concluded that the relative risks found in more recent studies were generally lower than those found in the 2001 papers. Esposito et al. [8] is the latest paper to examine the link between night shift work and breast cancer and the possible risk in health care workers. This systematic review and meta-analysis included 12 studies, 60% of which they rated as having ‘definite’ or ‘probably high’ risk of bias in exposure characterization. The pooled RRs forever (versus never) worked nights, worked nights for ≥10 years and for worked nights for ≥30 years were not statistically significantly raised, but for worked ≥20 years, the pooled RR was 1.25 (95% CI 1.01-1.55), based on seven risk estimates. The authors highlighted that pooled RRs appeared higher in case-control/nested studies and studies assessing lifetime occupational history. The RR for ≥20 years of exposure lost statistical significance in an influence analysis (which identifies whether and how individual studies might sway the results of a meta-analysis) and approached unity after correction for possible publication bias, and so was not robust. An important question for occupational health professionals is whether the advice in the 2018 editorial [2] remains valid in light of current epidemiological evidence. Studying occupational carcinogens remains challenging because exposure to most occupational carcinogens also occurs outside work [9]. Furthermore, there are several barriers to studying the carcinogenic effect of shift work. The most prominent challenge is the definition of ‘shift work’ and how to quantify it. Following the publication of the IARC monograph [10] in 2007, which for the first time classified shift work as probably carcinogenic, it was clear that better epidemiological studies were required to reduce the uncertainty and refine the exposure assessment. Crucially, the IARC Working Group from the 2007 [11] IARC Monograph meeting suggested that a number of domains of a shift and shift schedules were important to capture in future epidemiological studies [11], including defining the shift system, cumulative exposure to the shift work, shift intensity and chronotype. These domains were reported to be based in part on the biological considerations. Thus, it is anticipated that researchers studying the impact of shift work on health in general and the carcinogenicity specifically will implement the IARC Working Group recommendations as far as possible. However, it seems that the latest epidemiological studies considered in Esposito’s [8] latest review still fall short of the suggested requirements from the IARC Working Group. As Takahashi and Koda observed [12], the lack of a consistent definition of shift work and shift schedule results in large inconsistencies, which adversely affect the ability to reach a conclusion on causality, which therefore restricts the decision makers and their advisors to plan protective measures if required. To date, the situation has not changed, and a wide variety of definitions of night shift work continue to be utilized by researchers. Therefore, it remains essential for researchers and those approving research to implement the recommendations of the IARC Working Group in future research. Esposito [8] has defined exposure as ever versus never night shift work according to the original studies’ specific definitions. This seemingly follows IARC’s move from the first monograph in 2007 [11], which categorized ‘shift work involving circadian disruption’ as probably carcinogenic to the 2019 update [13], when it was altered to ‘night shift work’. However, the papers that are included in Esposito’s [8] review, have not consistently defined the shift system or used the same definition as recommended by the IARC Working Group recommendations [12] which has created a relatively heterogenous collection; of the 12 studies included in this study, one has used workplace information without any definition, 6 have used an hour based definition comprising 1× working between 10 pm and 6 am, 1× working between 10 pm and 7 am, 3× working between 12 pm and 6 am, 1× working between 12 am with 8 hours between 7 pm and 9 am and the rest have not reported their definition. In line with these challenges, the authors [8] concluded that although long-term night shift work may increase the risk of breast cancer in health care workers, the association is far from established. There is extensive literature [14–16] in relation to risk factors for developing breast cancer. Strong evidence indicates that prolonged exposure to female hormones for reasons such as early menarche and late menopause [17], HRT [18] and contraception [19] are strong risk factors. Other risk factors that are strongly supported by evidence include age [20], race and ethnicity [21], reproductive history [22] (early pregnancy and breast-feeding being protective, nulliparity or no breast-feeding increasing the risk), family history of breast cancer [23], benign breast disease [24], alcohol consumption [25], obesity [26] and smoking [27]. More debatable risk factors may include physical inactivity [28], diet and nutrition and environmental toxicants [29]. Some of these risk factors are modifiable and therefore play an important role in preventative strategies. The studies that are included in Esposito’s [8] analysis have adjusted for one or more of these confounders; however, inevitably, many of them are not accounted for at all or only in one or two studies. This introduces a risk of bias, which compromises the ability to draw conclusions. Importantly, some of these risk factors overlap with the working environment (eg, environmental risk factors) or shift work (eg, poor diet and obesity), which makes the causation or even association harder to study and interpret. In conclusion, whilst there seems to be increasing evidence of a relationship between night shift work and breast cancer, the current level of information remains suboptimal to arrive at a conclusive decision. Therefore, the advice to workers and employers likewise remains consistent with previous recommendation in 2018 [2], which is aligned with the Health and Safety Executive advice [30], including optimizing shift work scheduling, promoting and enabling healthy lifestyle at the workplace and developing workplace policy for night work should develop a workplace policy for night work that informs workers about the potential cancer risks and possible strategies to minimize risks. The advice also remains the same for women with family/genetic predisposition and breast cancer survivors, that is, the evidence of the relationship between night shift work and breast cancer is not strong enough to treat such workers differently.