Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study

BMJ 2007; 335 doi: http://dx.doi.org/10.1136/bmj.39367.495995.AE (Published 29 November 2007)
Cite this as: BMJ 2007;335:1134

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A mini review: Indicator of higher cancer risk--Increased BMI or Excess hidden visceral fat depot??

Prof (Dr) Jogenananda Pramanik.MD Professor & Head of Biochemistry & Genetics,
and Director of International Relations, Allianze College of Medical Sciences, Penang-13200,Malaysia. www.acms.edu.my E-mail: jpramanik@acms.edu.my.

Reeves GK and his colleagues, once again made it clear to all of us that higher body mass index (BMI) is significantly associated with an increased risk of fatal cancers (1) which has been described earlier by several other researchers (2).

In recent years, the body mass index (BMI) is popularly used to gauge the obesity. However, there is a growing body of literature emerging with a different picture which cannot be ignored.

In the recent past, a number of researchers described that one can have normal BMI and yet carry unseen excess fat causing masked obesity which is not at all free from fatal cancer risk. Earlier Jennifer J. Griggs et al, argued that the definition of obesity itself is controversial. It is unclear whether BMI is the most appropriate measure of obesity.BMI makes no distinction between body weight from muscle and body weight from fat (3). Muscular individuals i.e Sumo wrestlers in Japan, can be categorized as overweight or obese when obviously they are not. In 1953, the average weight of a sumo wrestler was 317 pounds, while the average height was 5-foot 11, according to the sumo association. Today, the average wrestler is just 3.2 inches taller, but 95 pounds heavier. ( http://www.flickr.com/photos/acatinjapan/2557786791/in/photostream)

In a current study, T.Ohki et al (2009), revealed that in contrast to BMI, visceral fat accumulation is considered to be directly causative of non-B and non-C hepatocarcinogenesis, through disturbing the adipocytokine balance of insulin resistance, which is a major cause of hepatic fat accumulation. Excessive fat in the liver will lead to hepatocellular injury and possibly result in hepatocarcinogenesis through the direct cellular toxicity of excessive free fatty acids, oxidant stress and lipid peroxidation, or some other mechanism. Visceral fat accumulation may be involved in both tumor initiation and promotion or progression steps through these mechanisms (4).

Therefore, it is not at all surprising that preoccupation with body weight, fitness, and diet is spreading exponentially all over the world. Interest in physical activity, at least as evidenced by scores of joggers, in-line skaters, bicyclists, and walkers, seems to be increasing in Asian countries as well. Health clubs and fitness centers have proliferated, and home exercise equipments are readily available everywhere at a reasonable price. Moreover, Wandy Y Chen (2008) mentioned in his commentary that there is a weakness in the current study of Reeves GK et al. because this study was conducted within short follow-up time, especially for cancer mortality. He also mentioned about a general methodological concern in this study protocol regarding studies linking BMI and mortality. That is, people may lose weight for a period of time before the actual diagnosis of cancer (or death from cancer in mortality analysis) and, therefore, lower BMI may be associated with worse cancer incidence and mortality when actually it is the cancer that is causing the BMI change and not vice versa.(5) Despite existing challenges and limitations in our knowledge base regarding altered responses of our own body system and resultant impact on cancer genes, we need to continue to examine the relationship between obesity and cancer. We concluded that the current study provided renewed impetus to health care providers to counsel patients regarding the importance of maintaining a healthy body weight.

References:

1 Reeves GK, Pirie J, Beral V, Green J, Spencer E, Bull E. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study BMJ, Nov 2007; doi:10.1136/bmj.39367.495995.AE.

2. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003.

3. Jennifer J. Griggs, Michael S. Sabel: Editorial: Obesity and cancer treatment: Weighing the evidence: Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4060-4062 DOI: 10.1200/JCO.2008.17.4250.

4.T.ohki, R Tateisi, S Shina et al,: Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH: Gut 2009;58:839-844 doi:10.1136/gut.2008.164053.

5. Wendy Y. Chen: Million Women Study: Higher BMI Increases Cancer Incidence and Mortality (2008) http://www.medscape.com/viewarticle/573620.

Competing interests: The author is a member of the editorial boards of Lab Medicine (ASCP)Journal,Chicago,USA;Hektoen International Journal,Chicago,USA and Social Science & Medicine Journal,UK.

Jogenananda Pramanik, Professor & Director of International Relations

Allianze college of Medical Sciences, Penang-13200,Malaysia.

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Gillian Reeves and colleagues found a significant increased relative risk (RR) of endometrial cancer with increasing BMI in the Million Women Study (MWS) for both postmenopausal (RR 3.98 for 1149 cases) and premenopausal (RR 1.77 for 164 cases) women.1

I have been studying the role of Insulin and Nitric Oxide in malignancy for the past decade. In July, 2010 in Anaheim I spoke on this topic and ignited the discussion. The first International Congress on Insulin Resistance in Malignancy was held in LA in 2003. Since then few congresses were held in USA and Canada. It has now become well known fact that obesity, metabolic syndrome, pre- diabetics and diabetics are prone to suffer from malignancy many more folds than their their age and sex related counterparts without these clinical conditions. In these subjects there is a development of insulin resistance and simulataneously disturbed nitric oxide synthesis in the system. Insulin takes a pivotal role in cellular proliferation and over all growth of the tissues in the living system and so is nitric ixide which takes a key role in apoptosis(i.e. programmed cell death). Thus it is not surprising that Gillian Reeves and colleagues noted an increase in relative risk of cancer incidence among the obese individuals. As many rssearchers including us around the world have studied the roles of insulin and nitric oxide in cancer and found the development of insulin resistance and diminution of nitric oxide synthesis in cancer(2). The increase in incidence of cancer was observed more in cancers affecting breast, colon, lung,prostate and panceas. In all these scenario there was the deveolpment of insulin resistance and disturbance in nitric oxide synthesis. Not only that the anti-diabetic drug metformin which is also revives the insulin sensitivity in the system is being used by many oncologists with notable positive responses. Now the time has come to understand the body's own altered mechanism in cancer and thence devise the more realistic and less toxic therapeutic modalities to tacle the cancer to sustain a good quality of life among the cancer sufferers.

1 Reeves GK, Pirie J, Beral V, Green J, Spencer E, Bull E. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study BMJ, Nov 2007; doi:10.1136/bmj.39367.495995.AE 2.Sinha .A.K. and Ray U et al-Neutralization by antineoplastin of insulin- activated nitric oxide synthase antibody and its effects in cancers-- Juornal of Cancer Research and Clinical Oncology,2002

Competing interests: I have been working on the Roles of Insulin and Nitric oxide in Cancer and Chrnic Kidney diseases for the few years and presented my works in few national and international scientific meetings.

Udayan Ray, Assoc.Professor and Director of Chemical Pathology

Royal Hobart Hospital ,University of Tasmania,Australia

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The complete influence of physical activity on good health remains a mystery. Some of the benefits and risks (like injuries) are unquestionable. Moreover, the optimum ( moderate or extreme) amount of regular exercise/physical activity and the exact pathophysiology of the benefits and risks is unknown and needs further research.

One of the areas of debate remains the role of exercise in breast cancer. It is presumed that physical activity may have a link in the causation and influence outcome (prognosis)in breast cancer. Breast cancer has been linked to amount and duration of oestrogen exposure and there is a strong possibility that regular exercise affects the level of circulating natural oestrogen, though not to the same extent as the day of the menstrual cycle. Race(low in asians) and pregnancy are known to affect oestradiol and prolactin levels. Therefore, exercise may be one of the other factors which might affect the hormonal levels and hence influence breast cancer by altering the ovarian function.

It is believed that insulin metabolism and weight loss have some influence on breast cancer across different age groups. Similarly, other mechanisms such as growth factor, immune function and stress would modify with physical activity and hence have some influence on health. Physical activity and energy balance are complex processes and hopefully future research will answer many of the unanswered questions.

The incidence of breast cancer and survival time from it have been improving over the last decade in the western world. However, the recent spurt in the obese population, increasing BMI and lack of exercise risks offsetting the current trend. Therefore, the public has to be educated about the benefits of regular excercise.

Competing interests: None declared

Competing interests: None declared

Saurabh Upadhyay, Foundation Doctor

Oncology Department, Ninewells Hospital and Medical School, Dundee DD2 9SY

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Gillian Reeves and colleagues found a significant increased relative risk (RR) of endometrial cancer with increasing BMI in the Million Women Study (MWS) for both postmenopausal (RR 3.98 for 1149 cases) and premenopausal (RR 1.77 for 164 cases) women.1

The MWS authors referred to speculation published in 1988 that, “whereas the effect of obesity on postmenopausal endometrial cancer is thought to be due to increased concentrations of unopposed oestrogens, any effect in premenopausal women may be due to progesterone deficiency rather than an excess of oestrogen”. There is no physiological evidence to back this suggestion. Endometrial hyperplasia and endometrial cancer result from higher levels of oestrogen than is usual in the follicular phase of a normal ovulatory cycle, at time when progesterone levels are low.

Furthermore, menopausal status was difficult or impossible to define at baseline for some women and more would have become postmenopausal during the follow-up years whentheir cancers were registered. Between 1996 and 2001 the MWS recruited 1 084 110 women aged 50-64. At baseline 54% of the women had previously taken oral contraceptives and 50% were users or past users of HRT. 83% were postmenopausal, including women whose periods had ceased either naturally or as the result of a bilateral oophorectomy and women aged 53 and over who had either had a hysterectomy without oophorectomy or had begun use of HRT before their natural menopause. 7.1% were listed as perimenopausal. 10% women (all aged 50-52) were listed as of unknown menopausal status because of hysterectomy and/or HRT use before the menopause.

Although only 5.8% of women were premenopausal at baseline, 12.8% of endometrial cancers, 9.3% of ovarian cancers and 17% of breast cancers occurred in premenopausal women.

Menopausal status is being emphasized, rather than age, perhaps because more young women have had hysterectomies and oophorectomies in the decades since the contraceptive pill became to be used at some time by a majority of younger women. By 1981, in England and Wales, 34,500 women under age 45 had hysterectomies and had 6,500 oophorectomies. In the same year, 119 women developed endometrial cancer and 411 developed ovarian cancer. Such large-scale preventative surgery in young women must have contributed to the conflicting findings of epidemiological studies on the risks of endometrial and ovarian cancer with use of progestogens and oestrogens whether given for contraception (decreased) or for HRT (increased). Follow-up studies have underestimated the total carcinogenicity of exogenous progesterones and oestrogens by muddling up hormone use in different age groups. HRT users have been listed as never users in hormonal contraceptive studies and hormone contraceptive users as never users in HRT studies.

Also there are many metabolic and immunological reasons why exogenous progesterone and oestrogen use can cause obesity. This increases the storage of lipophilic environmental contaminants with hormonal activity in body fat. Rapid weight gain is a common reason for discontinuing hormone use.

1 Reeves GK, Pirie J, Beral V, Green J, Spencer E, Bull E. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study BMJ, Nov 2007; doi:10.1136/bmj.39367.495995.AE

Competing interests: None declared

Competing interests: None declared

Ellen C G Grant, physician and medical gynaecologist

Kingston-upon-Thames. KT2 7JU, UK

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