Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study
BMJ 2007; 335 doi: https://doi.org/10.1136/bmj.39367.495995.AE (Published 29 November 2007) Cite this as: BMJ 2007;335:1134
All rapid responses
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.
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: No competing interests
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: No competing interests
A mini review: Indicator of higher cancer risk--Increased BMI or Excess hidden visceral fat depot ??
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.