The impact of body size changes on recurrence risk depends on age and estrogen receptor status in primary breast cancer

The survival of breast cancer patients has improved during the last decades due to advances in diagnostics and treatments [1, 2]. Concurrently, an obesity epidemic has emerged worldwide, which negatively impacts both breast cancer risk and recurrence [3, 4]. Preoperative body sizes increased significantly 2002–2016 with a negative prognostic impact [5]. Weight change has been investigated in multiple studies, but the impact on breast cancer prognosis remains unclear [6‐19]. Yet, overweight breast cancer patients in Sweden are often recommended to lose weight.

Weight change following breast cancer diagnosis and treatment is common but might differ according to patients’ age and treatments [6, 20‐22]. A possible U-shaped relationship with increased risk for both weight gain and loss has been suggested [7, 9, 12, 15, 16, 18]. Adipose tissue is biologically active, and multiple pro-carcinogenic processes associated with weight gain have been identified [3]. Less is known about the mechanisms behind the poor breast cancer prognosis associated with weight loss in observational studies [6, 7, 9, 11, 12, 15, 16, 18].

Central obesity is associated with metabolic syndrome [23], altered estrogen/testosterone ratio [24], overall mortality [25], and cancer survival [26]. Central obesity in breast cancer patients has been linked to all-cause and breast cancer-specific mortality [27], but associations might differ between ethnic groups [28].

Waist–hip ratio (WHR) can be used as surrogate measure of central obesity [29]. Recently, the anthropometric index ‘a body shape index’ (ABSI) was introduced, which is based on waist circumference (WC) adjusted for body mass index (BMI) and height [30]. Higher ABSI was associated with mortality risk in the general population [30‐33], but breast cancer recurrence and death due to other causes involve different pathways. The prognostic impact of ABSI in breast cancer is unknown.

We hypothesized that a stable body constitution during the first postoperative year after diagnosis would be associated with a favorable prognosis, but that associations might differ between subgroups of patients. The study aimed to investigate the prognostic impact of anthropometric changes from the preoperative visit to the 1-year postoperative visit in breast cancer patients.

Primary breast cancer patients assessed preoperatively since October 2002 at the Skåne University Hospital in Lund were asked to join a prospective cohort study regarding lifestyle factors, as previously described [5]. The preoperative visit typically took place a few weeks after diagnosis. The study was approved by the Lund University Ethics Committee (LU75-02, LU37-08, LU658-09, LU58-12, LU379-12, LU227-13, LU227-15, and LU458-15), and written informed consents were collected from all participants. By 31 December 2014, 1,578 patients were included in the cohort of whom 1,317 were included in the present study, after exclusion of patients without recorded weight or height, with carcinoma in situ, any preoperative treatment, or early metastases < 0.3 years. The associations between changes in anthropometric measures and prognosis were analyzed in 1,178 patients who were recurrence-free and had a 1-year visit with measured weight 0.9–1.5 years from inclusion (Fig. 1).

Patient characteristics, including weight, height, and waist and hip circumference, were measured by trained research nurses at the preoperative visit. These variables, with the exception for height, were measured once more at the 1-year visit. WC was measured at the umbilicus, and hip circumference was measured at the widest part between the hip and the major trochanter. The patients were also asked to complete a questionnaire, as previously described [34].

Tumor characteristics were obtained from each patient’s pathology report, regarding invasive tumor size, axillary nodal involvement, histological grade, estrogen receptor (ER), and progesterone receptor (PR) status. All tumors were analyzed at the Department of Pathology at Skåne University Hospital in Lund as previously described [34, 35]. Tumors with > 10% positive nuclear staining were considered receptor positive.

Adjuvant treatments, including chemotherapy, radiotherapy, tamoxifen, and aromatase inhibitors (AIs), were prescribed according to standard of care. Treatment and additional clinical data, recurrences, and new breast cancers were collected from patient charts and follow-up questionnaires. Only breast cancer treatment before any breast cancer event was considered in the analyses. Date of death was obtained from the Swedish population registry. Data on events and new cancers were also collected from the regional tumor registry, which is close to 100% complete.

In this study, 1-year postoperative changes in weight and WHR in breast cancer patients impacted differently on prognosis depending on age and tumor ER status. However, the association between changes in anthropometric measures and clinical outcome was not dependent on overweight. In younger patients, weight gain was associated with higher recurrence risk. Changes between WHR categories were associated with higher recurrence risk in patients with ER+ tumors and lower recurrence risk in patients with ER− tumors. High preoperative ABSI was strongly associated with shorter overall survival but not with recurrence risk.

In the present study, patients < 50 years were most likely to gain weight, which was associated with a higher recurrence risk. This is consistent with a recent scoping review, which concluded that younger chemotherapy-treated premenopausal patients were particularly at risk for weight gain [22]. One previous study showed a higher recurrence risk in premenopausal patients [10]. Another study compared the impact of BMI changes in clinical trials and found increases in BMI by 1 year to negatively impact outcomes only in pre-/peri-/early post-menopausal trial patients [19]. However, we found no benefit of weight loss in this age group and retaining preoperative weight might be most beneficial.

The oldest patients (≥ 70 years) that lost weight had a poorer prognosis compared to other old patients. However, this was no longer evident after exclusion of patients that had died within one year after the 1-year postoperative visit, which suggests reverse causality and a symptom of an underlying disease where frailty and muscle wasting might be present. Multiple observational studies have reported poor breast cancer prognosis associated with weight loss [6, 7, 9, 11, 12, 15, 16, 18]. However, a systematic review indicated a considerable risk of bias in some studies because of lack of information on whether the weight loss was intentional or not [39]. No association was found between weight changes and recurrences or death in the age group 50 to < 70 years, which might reflect the mix of peri- and early post-menopausal patients. Further, changes in weight and BMI do not necessarily reflect body fat distribution, which can be better measured by other methods.

Individuals with a normal weight and BMI might still have an unhealthy metabolic body composition with excess body fat, especially central accumulation, referred to as sarcopenic obesity [40]. In the present study, measurements of WHR and the new index ABSI were used to capture central body fat accumulation. Patients with preoperative WHR > 0.85 had a poorer overall survival, which is in line with most [27, 41‐43], but not all [12, 44] studies. The change in WHR category conferred prognostic impact with strong effect modification with ER status independent of weight change in the present study. To the authors’ knowledge, this is the first study to investigate the prognostic impact of early changes in anthropometric measures in breast cancer patients, and it is unknown whether this difference reflects a change in hormonal profile in endocrine-treated patients or impacts therapy response to one or more treatment types. The median follow-up was only five years from inclusion. Most recurrences occur within five years in patients with ER− tumors, while ER+ tumors tend to recur over a longer period of time.

Different treatments could affect both body composition and prognosis [45]. Smoking also impacts body composition in young women [46], as well as the clinical outcome after endocrine therapy [47]. Smoking and alcohol consumption or treatments were included in separate adjustment models but did not explain the results. Menopause occurred in some patients either as result of age or treatment, which might have affected body constitution [48].

We hypothesize that the different prognostic impacts of weight and WHR changes according to age and tumor ER status in part reflect shifts in the inflammatory and hormonal profile caused by changes in the central adipose tissue. The release of free fatty acids, particularly associated with abdominal visceral adipocytes [29], activates the nuclear factor kappa B (NF-κB) pathway [3]. The upregulation of inflammatory cytokines and subsequent increases in aromatase activity and estrogen synthesis might stimulate ER+ breast cancer cells [3]. The generation of crown-like structures associated with inflammation and increased aromatase activity might also play a role [49]. Increased levels of insulin and insulin-like growth factors (IGFs), particularly associated with central obesity [50], also increase the bioavailability of estrogens by downregulation of sex hormone-binding globulin (SHBG) [51]. Surprisingly, weight loss has been associated with increase in IGF-1 levels in post-menopausal women in contrast to findings in animal studies [52], reflecting the complexity of the pathways involved in changes in body measures. However, factors that promote tumor growth may not affect prognosis in patients who died from other causes and it was also observed that changes in anthropometric measures impacted recurrence risk and death somewhat differently.

Our study confirmed previous findings that higher preoperative ABSI was strongly associated with overall survival but no association with breast cancer recurrences was found. The association with overall survival was evident in patients with and without a recurrence but was stronger in patients without a previous recurrence (data not shown). A previous study reported that higher ABSI increased cancer mortality in women [32]. Raising ABSI over a 7-year period was associated with greater mortality [31]. In the present study, however, 1-year changes in ABSI were not associated with recurrence risk or death.

A significant strength of the present study is that research nurses obtained body measurements at both visits to avoid the risk of recall bias or self-presentational bias. The cohort is population-based and representative for breast cancer patients treated at this clinic [47] with excellent follow-up rates [53]. The patients were included preoperatively before any procedures that could affect body composition had taken place. Patients of all ages were included, which allowed for the study of the prognostic impacts of anthropometric changes in different age groups. However, there are limitations. Importantly, no information was available as to whether weight change was intentional or how fast the weight changes occurred. Since unintentional weight loss can arise due to an underlying disease, this can lead to reverse causality. Rapid weight loss might have other biologic effects than more gradual loss [54]. No information on muscle or fat mass was available for evaluation of sarcopenic obesity. Additionally, information on exercise, comorbidities, and socioeconomic status were missing, all of which might impact prognosis [55‐57]. Only weight change by the 1-year visit was analyzed, although 76.8% remained in the same weight change category by the 2-year visit. Chemotherapy, which is administered during the first postoperative year, conferred both weight gain and loss, while late treatment effects were not captured. Few events occurred in some subgroups, resulting in lower power. Multivariable analyses were performed, including several potential confounders. Since this is an observational study, residual confounding remains possible.

In conclusion, changes in weight and anthropometric measures during the first postoperative year impacted differently on breast cancer prognosis depending on age and tumor ER status, but were independent of overweight. Whether the effect modifications of ER status results from endocrine therapy or impacts therapy response remains to be elucidated and confirmed in an independent cohort, preferably a randomized trial. Stratification of patients according to age and tumor ER status in future studies could further elucidate the impact of weight changes in subgroups of patients. Weight gain was associated with recurrences only in patients < 50 years. Weight loss did not improve prognosis in any age group. This challenges the prevailing opinion that weight loss must be beneficial in overweight patients and further research is imperative before recommending weight loss for all overweight breast cancer patients.