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Obesity and breast cancer


17.1

Epidemiology

  • 1.

    Breast cancer (BC) is the most prevalent female cancer, responsible for 15% of all cancer deaths in women worldwide.

  • 2.

    33% of BCs in post menopause are due to obesity.

  • 3.

    Linear association between obesity and overall risk of BC in menopause has been reported with a hazard ratio of 1.05 (99% Confidence interval, CI 103–1.07), for each body mass index 5 kg/m 2 increase.

  • 4.

    Inverse correlation between obesity and BC in premenopause, however level of effect varies depending on many other anthropometric parameters (Hazard ratio, HR 0.89, 99% CI 0.86–0.92).

  • 5.

    In premenopause women, for each 5 kg/m 2 increase in BMI, there was a 7% and 5% reduction in BC risk in Caucasian and African women, respectively, while there was a 5% increase in Asian women. These risks were very sensitive to waist hip ratio and height of the women.

  • 6.

    Obesity increases risk of developing hormone receptor positive BC (both oestrogen and progesterone) in women greater than or equal to 65 years old (HR 1.25, 99% CI 1.16–1.34).

  • 7.

    But obesity does not increase hormone receptor positive BC in women less than or equal to 49 years old (HR 0.79, 99% CI 0.68–0.91).

  • 8.

    Relationship between obesity and hormone receptor negative BC is more complex:

    • a.

      Obesity increases risk in premenopausal women (Relative risk, RR 1.06, 95% CI 0.71–1.60)

    • b.

      Decreases risk of hormone receptor positive BC (RR0.78, 95% CI 0.67–0.92)

    • c.

      Hormone receptor negative BC risk increased in postmenopausal women who have never used HRT (multivariate HR 1.59, CI 1.08–2.34).

  • 9.

    Overall risk of obesity-dependent BC is lower for women on HRT, suggesting HRT is confounding factor in obesity-cancer relationship.

  • 10.

    No association between obesity and risk of specific BC subtypes demonstrated to date.

  • 11.

    Intentional weight loss is associated with lower BC risk.

  • 12.

    In bariatric surgery observational trials, a weight loss of approximately 30% was associated with a reduction in BC risk of up to 80%.

17.2

Pathogenic mechanisms

  • 1.

    Development of BC in obese women may be influenced by various factors including:

    • a.

      endogenous sex hormones

    • b.

      hyperinsulinaemia

    • c.

      insulin-like growth factor 1

    • d.

      hyperglycaemia

    • e.

      adipokines

    • f.

      chronic inflammation

    • g.

      microbiome

17.2.1

Sex hormones

  • 1.

    Oestrogen levels are higher in obese women due to peripheral conversion of circulating androgens to oestradiol by aromatase enzyme.

  • 2.

    Obese women have reduced sex hormone binding globulin, causing greater bioavailability of oestradiol and testosterone.

  • 3.

    Oestrogens have mitogenic and mutagenic effects to promote proliferation, genetic instability, and DNA damage in both normal and neoplastic mammary epithelial cells.

  • 4.

    The risk of developing BC is not only due to an increase in oestrogen levels, but higher levels of androgens in both premenopausal and postmenopausal obese women also play a role in the pathogenesis.

17.2.2

Hyperinsulinaemia

  • 1.

    Obesity is closely related to metabolic syndrome, insulin resistance and hyperinsulinaemia.

  • 2.

    80% diabetic women are obese.

  • 3.

    Raised waist circumference or waist–hip ratio also predicts T2DM risk, irrespective of BMI.

  • 4.

    Hyperinsulinaemia promotes carcinogenesis by (a) direct promotion of cell growth or (b) indirect use of IGF-1 axis.

  • 5.

    Overexpression of insulin and IGF-1 receptors in cancer cells may also create expression of hybrid receptors capable of binding to both molecules.

  • 6.

    Hyperinsulinaemia causes increased IGF-1 concentration due to suppression of the binding proteins 1 and 2. Also due to activation of GH receptor increasing secretion of GH stimulating IGF-1.

  • 7.

    Insulin and IGF-1 binding triggers various mechanisms which promote carcinogenesis and neoplastic spread.

  • 8.

    There is a direct relationship between higher levels of circulating IGF-1 and the risk of developing BC, specifically ER + tumours and the risk of developing chemotherapy resistance.

  • 9.

    Excess insulin acts synergistically with IGF-1 and increases aromatase enzyme activity via sex hormone route.

  • 10.

    Hyperglycaemia is also linked to visceral fat and influences tumour development.

  • 11.

    Elevated glucose levels promote metastasis and increased invasiveness due to the epithelial to mesenchymal transition process.

  • 12.

    Hyperglycaemia also acts indirectly on BC cells by increasing insulin and IGF levels, inflammatory cytokines such as IL-6 and TNFα, oxidative stress, and platelet activation.

  • 13.

    Hyperglycaemia also alters the epigenetic regulation of neoplastic cells,“hyperglycaemic memory” to activate oncogenic pathways even if blood glucose levels return within normal range.

17.2.3

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