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

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

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

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.

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

80% diabetic women are obese.

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

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

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

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.

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

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.

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

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

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

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.

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

Family of polypeptides synthesised by adipocytes including over 100 different molecules—common studied molecules are leptin and adiponectin, which have opposite biological effects

Leptin is a potent proinflammatory agent and its concentrations are proportional to total body fat levels.

Leptin has several activities: mitogenic, antiapoptotic, immunosuppressive, proangiogenic alone, and acts in synergy with vascular endothelial growth factor expression, all relating to carcinogenesis.

Binding of leptin to long form receptor activates several signalling pathways involved in the control of cell survival, proliferation, differentiation, migration, and invasion.

Meta-analysis demonstrated a positive association between leptin levels and BC risk.

Leptin and receptor are associated with more severe BC cases and potentially act as BC risk biomarkers.

Adiponectin is secreted by the visceral adipose tissue, has potent antiinflammatory activity, and levels are inversely correlated with body fat.

Adiponectin has various influences on carcinogenesis as it reduces fatty acid and protein synthesis cellular growth, proliferation, DNA mutagenesis, and increases apoptosis.

All these effects are indirectly achieved by sensitising cells to insulin and inhibiting inflammation.

They are directly achieved by sequestering growth factors at pre-receptor level or activating and inhibiting pathways.

Low adiponectin concentrations are associated with increased BC risk and an inverse association between adiponectin concentrations and BC recurrence in ER/PR patients has been reported.

Obesity is a state of chronic low-grade inflammation which plays an important role in tumour development and progression.

Visceral fat, leptin, and oestrogen levels are associated with an increase in proinflammatory molecules in obese women, promoting carcinogenesis.

IL-1β, IL-6, and TNFα are all increased in obese women and promote T-regulatory lymphocytes chemotaxis and inhibit the cytotoxic activity of CD8 ⁺ T cells. This mechanism is associated with poor BC prognosis.

Human microbiome is proven to play a fundamental role in some diseases including cancer.

Greater microbial alterations are observed in BC patients than healthy women.

Increased caloric intake leads to dysbiosis, creating alterations in the carbohydrate and lipid metabolism, insulin resistance, and perturbations in endocrine systems.

The gut microbiota may induce the transformation of chemical compounds derived from the host diet into obesogenic and diabetogenic molecules that play a role in carcinogenesis.

Alterations in the gut microbiota may also influence the production of oestrogen metabolites and the circulating levels of oestradiol.

Dysbiosis, obesity, and increased oestrogen levels may act synergistically to increase the risk of BC.

More difficult to ventilate and intubate obese patients making anaesthesia more risky.

There is a higher risk of deep venous thrombosis, pulmonary embolism, urinary tract infections, myocardial infarction, pneumonia, and reoperation.

Obesity is linked to an increase in major and minor surgical complications in primary breast surgery even without reconstruction.

Cosmetic outcome of breast reconstructive surgery in both implant-based and autologous-based is poorer in obese than healthy women.

Complications include wound dehiscence, haematoma, seroma, and flap failure or necrosis.

A BMI >40 kg/m ² has been identified as the threshold at which complication rates become prohibitively high.

The cosmetic outcome with breast conservation (lumpectomy and radiation) is poorer in obese than in nonobese women, as women with BMI >30 kg/m ² had more postoperative breast asymmetry and deformity.

Obese patients have higher incidence of surgical site infections, return to emergency department after discharge, and hospital readmission within 30 days of surgery.

Sentinel node mapping is more difficult in obese women as node identification rates are lower.

Obese patients may receive increased doses to critical organs such as heart and/or lungs especially in supine position. Prone whole-breast radiation and hypofractionated radiotherapy minimise toxicity.

High BMI and large breast size are associated with increased risk of dermatitis after whole-breast radiotherapy.

Challenges present due to the presence of comorbidities and balance between efficacy and toxicity.

Obese patients are more likely to receive insufficient chemotherapy doses compared to normal weight which can have a negative impact on disease-free and overall survival.

American Society of Clinical Oncology recommends full weight-based chemotherapy doses are used in the treatment of obese cancer patients and toxicity managed as in nonobese women.

Obesity has been associated with a higher risk of cardiotoxicity after treatment with Trastuzumab in women with HER-2 positive BC requiring close monitoring and risk factors management.

Obesity is considered a factor of resistance to anticancer therapy.

Obesity modifies the pharmacokinetics of chemotherapy drugs and is hypothesised to induce biological modifications of adipose tissue promoting resistance to the drugs used.

Endocrine therapy may be less effective as obesity is associated with elevated aromatase activity and serum oestrogen levels in postmenopause.

Current literature reports that Anastrozole is associated with worse outcomes than Tamoxifen.

For obese postmenopausal women, Letrozole, as a more potent inhibitor of aromatase, should be used.

Currently for obese premenopausal women, it is recommended to use Exemestane plus ovarian suppression when indicated.