The impact of obesity and bariatric surgery on circulating and tissue biomarkers of endometrial cancer risk

Abstract

Obesity is the strongest risk factor for endometrial cancer (EC). To inform targeted screening and prevention strategies, we assessed the impact of obesity and subsequent bariatric surgery‐induced weight loss on endometrial morphology and molecular pathways implicated in endometrial carcinogenesis. Blood and endometrial tissue were obtained from women with class III–IV obesity (body mass index ≥40 and ≥50 kg/m 2 , respectively) immediately prior to gastric bypass or sleeve gastrectomy, and at two and 12 months’ follow up. The endometrium underwent pathological examination and immunohistochemistry was used to quantify proliferation (Ki‐67), oncogenic signaling (PTEN, pAKT, pERK) and hormone receptor (ER, PR) expression status. Circulating biomarkers of insulin resistance, reproductive function and inflammation were also measured at each time point. Seventy‐two women underwent bariatric surgery. At 12 months, the mean change in total and excess body weight was −32.7 and −62.8%, respectively. Baseline endometrial biopsies revealed neoplastic change in 10 women (14%): four had EC, six had atypical hyperplasia (AH). After bariatric surgery, most cases of AH resolved (5/6) without intervention (3/6) or with intrauterine progestin (2/6). Biomarkers of endometrial proliferation (Ki‐67), oncogenic signaling (pAKT) and hormone receptor status (ER, PR) were significantly reduced, with restoration of glandular PTEN expression, at 2 and 12 months. There were reductions in circulating biomarkers of insulin resistance (HbA1c, HOMA‐IR) and inflammation (hsCRP, IL‐6), and increases in reproductive biomarkers (LH, FSH, SHBG). We found an unexpectedly high prevalence of occult neoplastic changes in the endometrium of women undergoing bariatric surgery. Their spontaneous reversal and accompanying down‐regulation of PI3K‐AKT–mTOR signaling with weight loss may have implications for screening, prevention and treatment of this disease.

Interventions to improve insulin resistance for the prevention of endometrial cancer

“…Intentional weight loss, particularly in women who were obese at baseline, has been reported to lower the risk of endometrial cancer (Luo 2017). These findings are consistent with reports that sustained weight loss a er bariatric (weight-loss) surgery has been associated with lower endometrial cancer risk in severely obese women (MacKintosh 2019;McCawley 2009;Sjostrom 2009). Improvements in insulin resistance (as measured by the Homeostatic Model of Insulin Resistance (HOMA-IR), are seen shortly a er surgery and, indeed, before any significant weight loss has occurred.…”

Endometrial cancer and obesity

“…While the greatest benefit is seen in women who achieve a normal body mass following surgery, even those who remain obese have a lower risk of endometrial cancer. This suggests that the effect is predominantly mediated through rapid improvements in insulin sensitivity . The National Institute for Health and Care Excellence (NICE) does not currently list cancer prevention as an indication for bariatric surgery, but eligible women should be counselled about the additional positive effects of weight loss surgery on endometrial cancer risk.…”

“…Using the 6–12 month progestin treatment window to address endometrial cancer risk factors, including obesity and insulin resistance, may improve outcomes for obese endometrial cancer patients. Weight loss may increase pathological complete response rates to progestin treatment, reduce recurrence after treatment cessation, enable minimal access hysterectomy if progestin treatment fails, improve natural fecundity, enable assisted reproduction and/or improve the likelihood of its success, and improve general health and quality of life (Figure ). The continuing ANZGOG feMME trial aims to be the first RCT to determine the efficacy of treatment with LNG‐IUS ± metformin ± weight loss on pathological complete response rate in early‐stage endometrial cancer in obese women at 6 months …”

Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer

“…A recent small (n = 6) prospective cohort study demonstrated the ability of metabolic surgery to reverse complex atypical hyperplasia of the endometrium, a known endometrial cancer precursor. Hyperplasia resolved in the majority of cases (5/6; 83%) with 3/6 (50%) resolving with metabolic surgery alone [23]. Endometrial biopsies taken before and after surgery demonstrated reduced expression of oestrogen and progesterone receptors at 2 and 12 months after metabolic surgery and a 17% reduction in the Ki-67 proliferation index seen 12 months after metabolic surgery.…”

“…The small study by MacKintosh et al [23], demonstrates the importance of longitudinal studies to assess the impact of weight loss on established [25] and emerging [26] hallmarks of cancer development. This includes the pathways involved in inflammation, angiogenesis, invasion and metastasis, cellular energetics and genomic instability.…”