Dr. Sharma's Obesity Notes

Regular readers will be quite familiar with the limited utility of BMI in predicting health status. The same appears to be true regarding the use of BMI in patients with cancer cachexia.

In a paper just published in the Journal of Clinical Oncology, Lisa Martin and colleagues from the University of Alberta studied around 1,500 patients with various stages of lung or gastrointestinal cancer presenting with a wide range of BMI (17% obese, 35% overweight, 36% normal weight, and 12% underweight).

Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation (measured by CT).

Irrespective of BMI, high weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival.

Compared to a survival model containing conventional covariates (cancer diagnosis, stage, age, performance status), a model ignoring these variables but including only BMI, weight loss, muscle index, and muscle attenuation proved a far better predictor of patient survival.

Patients who had higher weight loss and lower muscle indicators survived 8.4 months, regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months.

From these finding the authors conclude that, regardless of BMI, cancer patients presenting with involuntary weight loss, muscle depletion and muscle attenuation share the poorest prognosis.

Thus, the authors note that,

“Our findings provide evidence in support of the proposed international consensus definition of cancer cachexia as a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass with or without loss of fat mass.”

Once again, simply stepping on a scale appears to be a rather limited measure of health.

AMS
Edmonton, Alberta

Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, Murphy R, Ghosh S, Sawyer MB, & Baracos VE (2013). Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PMID: 23530101

One of the consistent findings in the medical literature is the fact that although excess weight is associated with an increased risk for a wide range of medical problems (including the earlier onset of such complications), once people have these problems, excess weight appears to be either ‘protective’ (the so-called obesity ‘paradox’) or have little influence on long-term outcomes.

Thus, a study by Kai Bickenback and colleagues from the Memorial Sloan-Kettering Cancer Center, New York, NY, published in the Annals of Surgical Oncology, failed to find an impact of obesity on long-term survival of patients with gastric (stomach) cancer.

In their study, the researchers examined dat from about 1,800 patients who underwent curative intent resection for gastric carcinoma from 1985 to 2007.

Overall, there was no difference in survival between overweight or obese and normal weight patients.

However, overweight patients did have more proximal tumors and a lower tumor (T) stage at surgery.

Overweight and obese patients also had about twice the rate of wound infections and anastomic leaks than normal weight patients.

In multivariate logistic regression analyses, higher BMI, total gastrectomy, and use of neoadjuvant chemotherapy were all associated with increased wound infection and anastomotic leaks.

Thus, the authors note that although peri-operative complications may be more common in overweight and obese patients undergoing surgery for gastric cancer, their survival rates are no worse than those of normal weight individuals.

Obviously, given the higher peri-operative complication rates, costs for hospital stay and doctor visits may be higher in the overweight and obese patients (not analysed in this paper) – however, this should certainly not prove a barrier to providing the same care to overweight and obese patients with gastric cancer as one would to normal-weight individuals with this unfortunate condition.

AMS
Edmonton, Alberta

photo credit: Defence Images via photo pin cc

Bickenbach KA, Denton B, Gonen M, Brennan MF, Coit DG, & Strong VE (2012). Impact of Obesity on Perioperative Complications and Long-term Survival of Patients with Gastric Cancer. Annals of surgical oncology PMID: 22976377

Although, much of the discussion around the health risks of obesity tends to focus around diabetes and heart disease, it is important not to forget that in women, excess weight is closely linked to the risk for post-menopausal breast cancer (by far the most common form of breast cancer).

Now, a team of researchers led by Kristin Campbell from the University of British Columbia, Vancouver, in a paper published in the Journal of Clinical Oncology, shows that weight loss achieved by calorie restriction and exercise can significantly reduce circulating levels of the sex-hormones implicated in the development of post-menopausal breast cancer.

The single-blind, 12-month, randomized controlled trial was conducted in 50 to 75 year-old women with a BMI greater than 25, who were assigned to one of three intervention groups: (1) reduced-calorie weight loss diet (“diet”; n = 118), (2) moderate- to vigorous-intensity aerobic exercise (“exercise”; n = 117), (3) combined reduced-calorie weight loss diet and moderate- to vigorous-intensity aerobic exercise (“diet + exercise”; n = 117), or (4) control (n = 87).

The weight loss diet intervention was a modification of the dietary component of the Diabetes Prevention Program36 and the Look AHEAD (Action for Health in Diabetes) lifestyle intervention programs, with a goal of daily energy intake of 1200 to 2000 kcal/d based on baseline weight, less than 30% daily energy intake from fat, and a 10% reduction in body weight by 6 months with maintenance to 12 months.

The exercise intervention goal was  45 minutes of moderate- to vigorous-intensity aerobic exercise, 5 days per week (225 minutes/wk). Each week, participants attended three monitored exercise sessions at the study facility and two at home. The program progressed to the maintenance target of 70% to 85% maximal heart rate for 45 minutes by week. Activities with four or more metabolic equivalents,38 such as brisk walking, were counted toward the prescribed exercise target.

These interventions resulted in significant weight loss at 12 months: diet alone and diet + exercise resulted in about 11-12 Kg weight loss, exercise alone resulted in about 3.5 Kg weight loss, the control group lost no weight.

Compared with controls, estrone decreased 9.6% with diet, 5.5% with exercise, and 11.1% with diet + exercise.

Estradiol decreased 16.2% with diet, 4.9% with exercise, and 20.3% with diet + exercise.

Sex hormone-binding globulin (SHBG) increased 22.4% with diet and 25.8% with diet + exercise.

Free estradiol decreased 21.4% with diet and 26.0% with diet + exercise.

Free testosterone decreased 10.0% with diet and 15.6% with diet + exercise.

Thus, weight loss significantly lowered serum estrogens and free testosterone, findings that support the notion that weight loss can likely reduce risk for breast caner by lowering the exposure to breast cancer biomarkers.

It may be worth recalling, that surgical weight loss studies have shown a remarkable 60% decrease in cancer mortality, including a reduction in breast cancers.

Thus, the potential of obesity treatment as a means to reducing breast cancer risk should not be underestimated.

AMS
Philadelphia, PA

Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR, Mason C, Imayama I, Kong A, Xiao L, Bain CE, Blackburn GL, Stanczyk FZ, & McTiernan A (2012). Reduced-Calorie Dietary Weight Loss, Exercise, and Sex Hormones in Postmenopausal Women: Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PMID: 22614972

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Regular readers of these pages are probably well aware of the increasing data on the importance of obesity as a risk factor for cancers.

This is particularly true for hormone-sensitive cancers like post-menopausal breast and ovarian cancer, which are significantly more common in women with excess weight. In addition, excess weight appears to negatively affect the prognosis and recurrence of these cancers irrespective of menopausal status.

One of the key genetic factors associated with breast and ovarian cancers is the tumor suppressor gene BRCA1, which plays an important role in DNA repair. Women who carry mutations in this gene have a 80% lifetime risk of breast cancer – but reduced activity of BRCA1 has also been found in cancers of women who do not carry BRCA1 mutations.

So can excess weight modify expression of BRCA1?

A new study by Li-Jun Di and colleagues from the US National Cancer Institute, Bethesda, ML, published in the latest issue of Nature Structural & Molecular Biology, now shows that the expression of the BRCA1 is regulated by a co-repressor and metabolic sensor called C terminal-binding protein (CtBP), which is in turn regulated by energy levels in a cell.

Simply put, when cells see too many calories, CtBP can switch off BRCA1 thereby negatively influencing DNA repair.

This situation is particularly harmful for tissues like the breast or ovaries which, in obesity, are at the same time stimulated by excess activation of estrogen in fat tissue.

Thus, excess weight not only causes breast and ovarian tissue to grow but at the same time it indirectly inhibits one of the key DNA repair molecules, thereby making it far more likely that mutations will cause malignant growth of these cells.

As recently discussed in another post, this is another example that the strong link between excess weight and cancers may not lie in the excess weight causing genetic defects, but rather in the weight affecting important repair mechanisms that would normally protect against cancers.

These observations certainly help explain the dramatic decrease in cancer risk seen with intentional weight loss in patients undergoing bariatric surgery.

AMS
Toronto, Ontario (in transit)

Di LJ, Fernandez AG, De Siervi A, Longo DL, & Gardner K (2010). Transcriptional regulation of BRCA1 expression by a metabolic switch. Nature structural & molecular biology PMID: 21102443

Metastasizing Cancer Cell

Later today, I will be presenting an overview of the etiological assessment and management of obesity in a plenary session also featuring Eric Westman (USA), speaking on low-carbohydrate interventions, and Jim Levine (USA), speaking on non-exercise activity thermogenesis (NEAT).

I also have the privilege of chairing a poster session on adipose tissue and inflammation.

But this morning, I attended a session devoted to obesity, diabetes and cancer.

As regular readers will be well aware, obesity accounts for almost 30% of all cancers – and one of the main reasons why bariatric surgery reduces mortality is because of its profound effect on cancer-related mortality.

Regarding the potential molecular link between excess weight and cancers, Jeff Holly (UK), spoke about the important role of metabolic pathways in determining cancer risk.

As Holly pointed out, we all carry countless gene mutations that are potentially cancerogenic in many of our cells (e.g. in the skin, colon, prostate, etc.) and that the number of these cancerous cells increases dramatically with age.

Fortunately, however, we also have very effective systems that keep these cancerous cells in check, which is why most of these cancer cells never develop into clinical disease.

Nevertheless, we know that these defense mechanisms can be substantially influenced by environmental factors. Thus, for e.g. migration and adoption studies show that moving into a western lifestyle, can quickly increase the risk of cancer, not by increasing the number of gene mutations, but rather by affecting the mechanisms that normally keep these early cancerous growths in check.

Even in studies on highly penetrant cancers like breast cancers caused by BRCA mutations, the actual development of clinical cancer varies with environmental exposure.

In his talk, Holly reviewed the role of the insulin-signaling pathway, which also appears to play a key role in tumorgenesis pathways. A key molecule here is Insulin-like Growth Factor (IGF) -1, higher levels of which appear to be associated with higher risk of cancer.

IGF-1 levels can be affected by many environmental factors, which affect genes involved in metabolic pathways relevant to cancer growth.

But substrate availability may also be important. Thus, in vitro studies show that high lipid and glucose levels can both promote the growth of cancerous cells and/or reduce their sensitivity to chemotherapeutic agents.

In summary, metabolic pathways can play a key role in promoting growth of the many pre-cancerous cells – thereby increasing the risk of these cells growing into clinical cancer. This of course provides a sound rationale for the observation that lifestyle factors can have such an important role in reducing the risk of cancers.

Following this presentation, I was particularly delighted to listen to Tobias Pischon from the German Institute of Nutrtition (DIFE), Potsdam-Rehbrucke, further discussing the association between obesity and cancer. Tobias, incidentally, is a former student of mine, whose MD thesis I had the privilege of supervising, before he went off to spend time at the Harvard School of Public Health.

Pischon pointed out that the link between obesity and cancer is not just related to excess weight, but rather to the presence of abdominal obesity, which readers will know, is the kind of fat distribution that is most relevant for the metabolic complications of excess weight.

Thus, as for cardiovascular and metabolic risk, BMI is not the best measure of cancer risk, but rather, increased cancer risk is far ore closely related to waist circumference (a surrogate for abdominal obesity). In fact, as Pischon demonstrated on the large EPIC data set, adding waist circumference to BMI resulted in a much better prediction of cancer risk than using BMI alone.

Thus, I guess if we continue to call obesity a “lifestyle” disease, I guess we can only say the same for most common cancers.

I herewith officially coin the term “lifestyle cancers” – a term that I am sure many people with cancer or cancer-survivors would probably not like to be labelled with (in the same manner that people with obesity don’t like the term “lifestyle” associated with their condition).

AMS
Stockholm, Sweden

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