Title : The effect of bariatric surgery and weight loss on the future incidence of oestrogen-sensitive gynaecological cancers
Abstract:
Obesity is a risk factor for 13 obesity-associated cancers. This is especially so for oestrogen-sensitive gynaecological cancers including endometrial, breast, and ovarian malignancies. Women with obesity also have a poorer prognosis after treatment for oestrogen-sensitive cancers. Our meta-analysis of outcomes after bariatric surgery (BMS) found weight loss was associated with a reduced overall incidence of cancer (RR=0.62, 95%CI 0.46–0.84, p <0.002), obesity-related cancer (RR=0.59,95%CI 0.39–0.90, p =0.01) and cancer-associated mortality (RR=0.51,95%CI 0.42–0.62, p <0.00001). In specific cancers, bariatric surgery was associated with reduction in the future incidence of HCC (RR=0.35,95%CI 0.22–0.55, p <0.00001), CRC (RR=0.63,95%CI 0.50–0.81, p =0.0002), PDAC (RR=0.52, 95%CI 0.29–0.93, p =0.03) and gallbladder cancer (RR=0.41,95%CI 0.18–0.96, p =0.04), as well as female specific cancers, including breast cancer (RR=0.56,95%CI 0.44–0.71, p <0.00001), endometrial cancer (RR=0.38,95%CI 0.26–0.55, p <0.00001) and ovarian cancer (RR=0.45,95%CI 0.31–0.64, p <0.0001).
Obesity-associated carcinogenesis is closely related to metabolic syndrome; visceral adipose dysfunction; WAT aromatase activity and detrimental cytokine, adipokine and exosomal miRNA release. Metaflammation in obesity is associated with increased interleukin 6 (IL-6) and TNF-α release, which activates the NF-κB signalling pathway and increases expression of the aromatase gene CYP19A1. Transcription of CYP19A1 is suppressed by p53-this is reversed by the action of both PGE2 and leptin. Under the influence of CYP19A1, adipose tissue in obese patients has increased expression of aromatase, which upregulates the synthesis of oestrone (E1) from androstenedione and 17-β-oestradiol (E2) from testosterone. These androgen precursors are derived from the adrenal cortex or the postmenopausal ovary. Oestrone is then converted to 17-β-oestradiol by 17B-HSD. 17-β-oestradiol activates ER-α receptors which promotes proliferation in hormone-sensitive (ER+) breast cancer cells via nuclear translocation of ER-α and the oestrogen response element. 17-β-oestradiol can also activate membrane-bound G-protein-coupled oestrogen receptors (GPER) which promotes triple-negative breast cancer (TNBC) and endometrial proliferation and cancer by activating cytoplasmic Src/EGFR/ERK signalling. Local tissue levels of E2 in post-menopausal breast cancers can be 50–100 times higher than in serum due to breast WAT aromatase activity. Responses to aromatase inhibitors such as anastrozole are inferior in obese patients with breast cancer vs normal weight patients, and contribute to a poorer prognosis.
Most (70%) of the increased risk of endometrial cancer in women with obesity vs women with normal weight is mediated by free E2, inflammation and hyperinsulinemia. Postmenopausal patients with T2DM have a 20% higher risk of breast cancer compared to non-diabetic women, which is independent of BMI. This association is lost in premenopausal women. Elevated levels of insulin and IGF-1 also affect cancer prognosis, with worse outcomes in patients with diabetes and hyperinsulinemia.
Meta-analyses of pooled studies have suggested bariatric surgery results in a substantial improvement in the future risk of oestrogen-sensitive cancers in women (breast, endometrial, ovarian); overall cancer incidence; non-hormonal obesity-associated cancers; and cancer-related mortality. This is related to the reversal of adipocyte dysfunction, OSA, NASH, hyperlipidaemia, aromatase activity, systemic inflammation, hyperleptinaemia/hyperinsulinaemia, and metabolic syndrome with the loss of VAT volume and decreased CLS/WAT inflammation after BMS.
