Cancer development is stimulated by genetic components, environmental exposures, and lifestyle exposures; all impact the cellular microenvironment and initiate carcinogenesis.

Links between obesity and cancer have been documented for hormonally influenced cancers such as endometrial and breast cancer, and links to broader cancers are emerging.

Changes to systemic and microenvironment from obesity and hypernutrition not only cause significant risk for carcinogenesis but also impact the success and outcome of treatment.

BMI >40 kg/m ² has a 1.6-fold higher risk of cancer death.

The growing epidemic of cancers in obese young people (24–29) that have previously predominantly been seen in only the elderly indicate that the need for control of obesity is of key importance to all nations

The following cancers have been linked to obesity with variable, but consistent relationships:

• a.
  

  oesophageal (with greater increases for higher BMI)

  
  
• b.
  

  gastric

  
  
• c.
  

  liver

  
  
• d.
  

  kidney (renal cell)

  
  
• e.
  

  pancreatic

  
  
• f.
  

  colorectal

  
  
• g.
  

  gallbladder

  
  
• h.
  

  multiple myeloma

  
  
• i.
  

  meningioma

  
  
• j.
  

  potentially some thyroid and ovarian cancers.

Study of colorectal cancer risk shows a link to increased risk for colon, but not rectal cancer, based on waist circumference.

Clear differences for risk of different cancer types exist in different genders.

Obesity as a unique risk factor for the development of cancer differs by site.

The International Agency for Research on Cancer working group on Body Fatness in 2016 noted sufficient evidence for links between obesity and postmenopausal breast, colon, endometrial, oesophageal, gallbladder, kidney, liver, meningioma, multiple myeloma, ovary, pancreas, stomach, and thyroid cancer.

Others have proposed links between advanced prostate cancer, mouth, pharynx, and larynx, although the relationship is less clear.

50% of endometrial cancer is associated with obesity, with also a striking dose/response curve from 1.5-fold increase for overweight women to 7.1-fold increase for class 3 obesity.

Primary mechanism likely linked to increase in aromatase, conversion of androgens to oestrogens, and then the hormonal influence on proliferation of endometrial cells.

Other mechanisms proposed for nongynecological cancers may also play a role, such as chronic inflammation and production of inflammatory cytokines, increases in insulin-like growth factors, and their associated cellular and genetic impacts.

Weight reduction decreases the risk as show by the use of bariatric surgery.

Breast cancer also shows a strong association with obesity.

Women’s Health Initiative Clinical Study population shows increased risk for invasive breast cancer for overweight and above women compared to normal-weight women with the highest risks in those with grade 2 and 3 obesity.

Dose–response relationship was found again like endometrial cancer.

Also, primarily in hormone receptor positive disease cell types.

However, obese women who lost weight did not have a drop in risk unlike the impact seen with endometrial cancer and bariatric surgery.

When obesity most impacts the risk of breast cancer is unclear.

Obesity during trial may have been lifelong, and thus results reflect critical windows at reproductive age or earlier childhood as well.

Premenopausal obese women may actually have a protective effect from the body fat and decreased risk in that life stage.

Obesity in adolescence during breast development or premenopausal as an impact to risk factor compared to postmenopausal is difficult to study but important to understand for prevention.

High body fat proportions even in normal BMI may increase breast cancer risk.

Type and distribution of body fat is an area of intensive research and may hold keys to future prevention strategies.

Many potential pathways are engaged and could result in carcinogenesis with obesity.

Markers of disturbance of the microenvironment such as insulin resistance and inflammation may be more accurate risk predictors than BMI alone.

So too may waist-hip ratios as well as BMI.

Associated conditions, like metabolic syndrome and diabetes have significant impact on outcomes in breast cancer. However, mechanisms underpinning this relationship are still obscure.

Cross talk between adipocytes and macrophages is of particular interest as molecular mechanisms have been associated with adipocyte–macrophage breast cancer cell clusters.

Another component of the altered inflammatory environment may come from inhibition of natural killer cell activity. Further research on pathways in this area may provide additional avenues for cancer treatment specific to obesity-linked cancers.

Type and location of adipose deposits also play a role in hormones and cytokines secreted.

Association of increasing fat mass and increasing fasting insulin levels and hyperinsulinaemia implicates insulin as well as oestradiol as an important biologic link associating trunk adiposity with breast cancer risk.

Body composition rather than simply BMI has been highlighted as of great importance.

High body fat levels associated with elevated levels of insulin, CRP, IL-6, leptin, and triglycerides, as well as lowered high-density lipoprotein cholesterol and sex hormone-binding globulin.

Functional causal mechanisms supported by obesity may differ between locations with chronic secretion and inflammation being posited for the elevation of gallbladder cancer risks, reflux oesophagitis and inflammation for oesophageal cancer risk, associated hypertension with renal cancer risk, and endogenous oestrogen with breast and endometrial cancer risks.

Ultimately actions affecting oncogenesis are carried out at a cellular level with inflammatory mechanisms a common component.

One pathway comes through the downstream influence of increased aromatase activity and stimulation from circulating oestrogens, as noted previously with visceral fat.

Varying pathways interact and other downstream linkages between obesity and cancer are being explored to tease out critical interactions including those leading to insulin resistance.

One characteristic of the obesity–cancer relationship appears to be the significant ongoing cross talk between adipose tissue components, their products, and the cancer cells themselves, leading to a microenvironment that not only promotes carcinogenesis but also promotes metastasis.

Possibly the more disturbed the environment is with insulin resistance and the more exposure to growth-promoting secretome of adipocytes, the more aggressive and potentially metastatic the resulting tumour.

Genes are emerging as potential bridges between obesity and cancer; research is needed to fully explore the gene regulation of the various components involved.

Weight reduction seems a clear path for prevention, lifelong, given the risk windows where obesity interacts with oncogenesis may differ for various cancers from adolescence through postmenopausal life stages.

Prevention of disruption of the microenvironment and prevention of proinflammatory state locally and systemically will reduce certain cancers, such as endometrial, and is likely to reduce others as well, in addition to reduction in high blood pressure, metabolic syndrome, and diabetes.

A low-fat dietary program has shown promise for increase in overall survival with breast cancer, including potentially fewer deaths from cancers.

Medications addressing the role of insulin pathway, for example, metformin have been shown to have a positive role in lowering cancer incidences in diabetics.

Oncologists need to be mindful of changing recommendations for the treatment of obese patients, particularly accuracy, and the need for modifications of dosing of chemotherapeutic agents to treat the cancers.

There is a paucity of effective tools or interventions to address this health issue consistently and effectively at present other than bariatric surgery.

Finding a means to engage the population with effective and sufficient support will likely require engaging a broader health team with nutritionists and counsellors as well as the educational and motivational support from all levels of the healthcare team.

Individual health providers can advocate for policies within their practice, locally and nationally, to support more active lifestyles, availability of healthy food options, and healthy diets.

Evidence is emerging that encouragement of healthy physical activity lifelong and promotion of a balanced diet may be the most important actions organisations can take.

Focusing food production on healthy food and an environment that promotes physical activity may do more than any other mechanism for reduction in the burden of obesity-related cancers.

The overall reduction in costs to economies from the reduction of multiple diseases and disabilities linked to obesity makes it worth governmental interventions.

There is a critical need to understand the cellular cross talk that results in the oncogenic environment stimulating cancers in obese individuals.

This not only offers a mechanistic understanding but also opens doors to potential targets for prevention, treatment of the cancer, and reduction of recurrence and metastatic disease.

Increasing understanding of basic genetic and neuronal information about homeostasis, particularly weight regulation and energy balance, may provide additional means to prevent obesity epidemic and oncogenic outcomes.

The role of weight loss on the control of cancer is a difficult area to research but one that is very important to understand moving forward.

Public health advocacy and leadership globally must address the obesity epidemic.

Continued research into evidence-based pathways to reduce individual obesity and control appetite will additionally assist in the prevention of these cancers.

Expanding global knowledge of the benefits of addressing obesity and risks for individuals and populations in failing to do so, including cancer risks, is an important advocacy role for every health provider.

Obesity accounts for about 40% of cases of endometrial cancer in the developed world.

There is a linear increase in risk of endometrial cancer with increasing weight and BMI.

Extensive evidence from studies suggests that overweight and obesity are strongly associated with type 1 endometrial cancer.

Overweight and obese have two to four times greater risk of developing endometrial cancer than healthy weight, regardless of menopausal status. Extremely obese are seven times more likely to develop type 1 endometrial cancer.

Obesity in menopause produces excess oestrogen production. Due to conversion of androgens into oestrone by aromatase.

Prolonged unopposed oestrogen exposure leads to a continuous spectrum of change from proliferative endometrium through endometrial hyperplasia/polyps to endometrial carcinoma.

Progesterone containing intrauterine contraceptive devices are good contraceptive choices for obese women.

Obesity increases the risk of breast cancer only in postmenopausal women not using HRT.

Obese women at greater risk of death from breast cancer postmenopause.

Adult weight gain is the most consistent and strongest predictor of postmenopausal breast cancer risk and a large portion of deaths may be avoided if women could maintain a healthy BMI.

Central obesity presents a greater risk than distribution over the lower extremities.

Adult weight gain is associated with a higher risk of postmenopausal breast cancer than actual BMI.

No significant difference in risk in postmenopausal HRT users.

Premenopausal, obese women are at lower risk than healthy weight.

Oestrogen levels are 50%–100% higher in obese postmenopausal women compared to lean; tumour growth is therefore faster but detected later as breast tumour is more difficult in overweight women.

Positive dose–response relationship between BMI and risk of epithelial ovarian cancer shown in research.

Higher BMI associated with a slight increase in risk of ovarian cancer, particularly in women who have never used HRT.

No association among users of HRT.

Obesity positively associated with clear cell tumours but less correlated with invasive endometrioid or mucinous tumours.

Association between obesity and ovarian cancer survival is not conclusive yet.

Weight adjustment for the dosing of carboplatin-based chemotherapy is challenging.

Incorporating a weight adjustment may cause greater grade 3 and 4 systemic side effects.

Not incorporating a weight adjustment may lead to an increased risk of disease progression if dose not high enough.

Women with obesity shown to have lower relative decrease in platelet counts and haemoglobin levels.

Trend toward increased risk for disease progression in women with BMI >30.

Associations between BMI and cervical cancer are limited and inconclusive.

Some studies reported cervical cancer to be associated with elevated BMI, others found a lower relative risk.

Increased risk among overweight and obese women was mainly for cervical adenocarcinoma with a smaller increased risk for squamous cell carcinoma.

Observed increased risk could be due to the decreased attendance for screening in the obese women population.

Retrospective study found BMI >35 with cervical cancer had a higher risk of both all-cause death and disease-specific death than normal weight counterparts. Treatment-related and biological factors may contribute to decreased disease-specific survival in morbidly obese patients with cervical cancer.

Obesity affects the production of peptides, sex hormone-binding globulin, and steroid hormones.

It is likely that the prolonged exposure to high levels of oestrogen and insulin associated with obesity may contribute to the development of female malignancies.

Oestrone and oestradiol levels are directly related to amount of adipose tissue in postmenopausal women. Androgens secreted from adrenal glands and ovaries are converted into oestrone by aromatase in the fat cells.

Lowered sex hormone-binding globulin results in higher circulating level of free active oestrogens.

Excess weight, increased plasma triglyceride levels and low levels of physical activity all raise circulating insulin levels causing chronic hyperinsulinaemia associated with breast and endometrium cancers.

Carcinogenic effects of hyperinsulinaemia could be directly mediated by insulin receptors in target cells or might be due to related changes in endogenous female sex hormone synthesis and bioavailability.

Insulin boosts IGF1 and both promotes cell proliferation and inhibits apoptosis.

Increased insulin and IGF1 blood levels result in reduced hepatic synthesis and blood concentrations of sex hormone-binding globulin, increasing bioavailability of oestradiol.

Proteins secreted by adipose tissue influence immune response and its regulation; vasculature and stromal interactions; angiogenesis; and extracellular matrix components.

Evidence of intention weight loss affecting cancer risk is limited, the risk reduction of breast cancer from daily physical activity was observed in an already healthy population, not the overweight or obese.

Obese patients have a poorer outcome compared to lean patients.

Obesity associated with both reduced likelihood of survival and increased likelihood of recurrence among patients with breast cancer regardless of menopausal status and after adjustment for stage and treatment.

Poorer outcomes reflect the biological effect of adiposity, delayed diagnosis, and higher treatment complication level.

Nonlocalised disease more common in high BMI self-detections.

Manual handling for examination of obese patients is more challenging and requires specific resources.

Dosage calculations and adjustments in treatment plans must be made in heavier patients.

A high BMI increases the risk of perioperative complications and mortality particularly in the presence of comorbidities.

Counselling should be given about these increased risks.

Obese patients should receive thorough cardiovascular and respiratory preoperative assessment as these patients are at a much higher risk of postoperative complications.

It is advisable to have planned admission to high dependency units for these patients.

Women with gynaecological malignancies can be managed in standard fashion in most instances, there is no need to compromise surgical treatment where indicated.

The route of surgery must be considered as abdominal procedures are more of an issue than vaginal.

Obesity may be a limiting factor in application of laparoscopic surgery, it may not allow a steep Trendelenburg and may prevent adequate mobilisation of small bowel out of the pelvis for proper visualisation.

However, laparoscopic, and robotic surgery has additional benefits for obese patients making it a desirable option.

Obesity presents a variety of problems in laparotomy incision placement and closure as well as the increased risk of wound infection and failure.

Possible aetiologies include decreased oxygen tension, immune impairment and tension, and secondary ischaemia along suture lines.

Pelvic access is challenging, and incidence levels of intraoperative complications are higher.

Experience, good assistance, retraction, and lighting are essential.

Regional anaesthesia (spinal or epidural) is encouraged as it can also help with postoperative pain control.

However, regional anaesthesia may be difficult or impossible with high BMI leading to difficulty locating the spine, an experienced anaesthetist is preferred.

Research shows bariatric surgery lowers risk of incident cancer, especially obesity-related cancers.

It was also found to result in significant beneficial changes in circulating biomarkers of insulin resistance, inflammation, and reproductive hormones in endometrial morphology and in molecular pathways that are implicated in endometrial carcinogenesis.

These results may have important implications for screening, prevention, and treatment of endometrial cancer.

At the tissue level, all cancers are the result of the cumulative effect of environmental insults and genetic changes leading to dysregulated, uncontrolled growth of abnormal clones of cells.

In a minority of cases, these tissue-specific genetic alterations leading to cancer are predisposed to by highly penetrant, inherited germline mutations.

Sporadic cancers are the result of detrimental genetic dysregulation of growth in the affected organ.

Whereas in the so-called inherited cancers, the underlying factors are genetic changes affecting all cells of the body.

In reality, there is a spectrum between true sporadic and inherited disease and many cancers may result from the cumulative effect of a number of lower penetrance familial genetic alterations.

The majority of gynaecological malignancies occur sporadically but both ovarian and endometrial are prominent features of key cancer predisposition syndromes.

The lifetime risk of women developing ovarian cancer is increased in BRCA hereditary breast and ovarian cancer syndrome and Lynch syndrome. Both syndromes are caused by mutations in tumour suppressor genes.

The BRCA hereditary breast and ovarian cancer syndrome is caused by mutations in the genes BRCA 1 and BRCA2, which are involved in postreplication DNA repair. The syndrome is associated with a significant increase in breast and ovarian cancer risks as well as the risk of other malignancies including prostate and pancreas.

Lynch syndrome is caused by mutations in a family of genes involved in DNA repair known as mismatch repair genes. The syndrome is associated with an increased risk of many cancers including colorectal, endometrial, gastric, and ovarian.

The women’s age, previous personal history of cancer, and relevant family history of malignant disease can be pointers to a possible genetic predisposition and the genogram is useful.

A woman being diagnosed with ovarian cancer in her early 40s with a strong family history of breast cancer will need to be counselled for the possibility of an underlying BRCA mutation.

In a woman diagnosed with endometrial cancer in her 50s who has a past history of colorectal cancer, the possibility of Lynch syndrome will need to be considered.

Women and their families being offered genetic testing should be counselled comprehensively about the nature of the tests and the implications of their results,

Counselling should address the complex medical, ethical, and psychosocial aspects that are inherent to this process, especially the possibility of identifying variants of unknown mutations. Such discussion should take place at the multidisciplinary genetics clinic.

Causal role of obesity in gynaecological malignancies must be researched and defined.

Dysregulation of adipokines is likely to contribute not only to tumorigenesis and tumour progression but also to metastatic potential.

Intervention strategies at individual and community levels are important for weight loss.

Future trials may study the effect of dietary changes on weight gain and cancer risk, the effect of patterns of physical activity in relation to weight gain and cancer risk. The combined effects of changes in diet and activity on obesity and female cancer risk.

Clinicians should be aware that preventing/treating obesity should be considered part of cancer prevention.

Further research must clarify the mechanism and role of bariatric surgery to lower the risk of incident cancer in severe obesity.