Cover Story

Obesity and cancer: Effects on risk, screening and mortality

The obesity epidemic now has well-established links to a number of malignancies.

As the obesity epidemic in the United States and around the world continues to get worse, the links between excess weight and cancer incidence and mortality have come under increased investigation. With close to one-third of all U.S. adults classified as obese, according to the CDC, determining just what the risk between obesity and cancer is and what can be done about it is more important than ever.

At the beginning of this decade, evidence of the most solid links between specific types of cancer and obesity began emerging. Malignancies of the colon, endometrium, kidney and esophagus, as well as postmenopausal breast cancer, were found to be linked to excess weight. Now, the list has expanded, and experts are starting to learn more about how many cancer cases can be attributed to obesity. Furthermore, issues have arisen as to obesity’s effect on screening and diagnosis, as well as treatment, and there is strong evidence that it can increase mortality among cancer patients as well.

Although most research in recent years has looked for links between specific cancer types and obesity, some large cohort studies have shown an overall correlation between excess weight and cancer incidence. The Million Women Study in the United Kingdom enrolled more than 1.2 million women and followed them for 5.4 years for cancer incidence and for seven years to measure cancer mortality. For all cancers combined, there was a RR increase per 10 units of BMI of 1.12 (95% CI, 1.09-1.14). The study found that about 5% of all cancers among women in the United Kingdom, or about 6,000 total cases, are attributable to overweight or obesity.

James Abbruzzese, MD
James Abbruzzese, MD, of M.D. Anderson Cancer Center, researches links between obesity and pancreatic cancer.

Photo by: John Everett

In the United States, numbers appear to be similarly high. A study published in Cancer Detection and Prevention showed that, in 2002, about 41,000 new cases of all types of cancer were due to obesity; this was about 3.2% of all new cancers. Some speculate that these numbers may increase in the coming years, as the lag time for malignancies to develop will follow the recent upward spikes in obesity prevalence.

“I think this is a big worry in overall trends of cancer [incidence],” said James Abbruzzese, MD, of The University of Texas M.D. Anderson Cancer Center, who has worked on links between pancreatic cancer and obesity. “Between the overall aging of the population and the obesity epidemic, we may be poised to lose some of the gains that we’ve made [toward decreasing cancer mortality]. I think it is a huge problem.”

Which associations are strongest?

Although there is an association between obesity and overall cancer statistics, drilling down into specific malignancies may be a more important first step to understanding the mechanisms of the relationship between obesity and cancer, and combating the problem, according to the experts who spoke with HemOnc Today.

Some research being conducted today is beginning to explore these relationships. The Million Women Study found that with the excess 10 kg/m2 of BMI, the RR for endometrial cancer was 2.89; other significant associations were seen with adenocarcinoma of the esophagus (RR=2.38), kidney cancer (RR=1.53), pancreatic cancer (RR=1.24) and others.

A 2008 meta-analysis — published in The Lancet — of 221 distinct data sets also found highly significant associations between obesity and a number of specific malignancies. In this case, a 5 kg/m2 increase in BMI in men was associated with a RR of 1.52 for esophageal carcinoma and of 1.33 for thyroid cancer. Other associations were seen between cancers of the colon, rectum and kidney, malignant melanoma, multiple myeloma, as well as leukemia and non-Hodgkin’s lymphoma. Similarly, in women, strong correlations between obesity and malignancies of the gallbladder, pancreas and postmenopausal breast also reached statistical significance.

Multiple pathways

With so many cancers being linked to excess weight, determining the mechanisms underlying such connections is exceptionally difficult. As Roberts and colleagues wrote in a recent review in Annual Review of Medicine, “it is unlikely that there is a ‘one system fits all’ mechanism.”

One of the most often cited mechanisms is the insulin and insulin-like growth factor I axis. Although the details are not yet fully understood, it seems likely that insulin can strongly promote tumor growth in a number of locations, and the abnormal insulin production and tolerance that characterizes obesity could lead to malignancies, according to Roberts’ review.

Another mechanism that is particularly associated with postmenopausal breast and endometrial cancer — two of the stronger associations between obesity and cancer — is estrogen level. As Cleary and colleagues wrote recently in Endocrinology, among postmenopausal women, estrogen production is primarily performed at peripheral sites (rather than the ovaries), and among obese women, the primary source is adipose tissue.

Some studies have shown that women with postmenopausal breast cancer have higher levels of estrogen than control patients, and the higher rates of estrogen production in obese women can at least partially explain the increased risk of breast tumors. Aromatase, an enzyme that mediates estrogen synthesis, is found in breast adipose tissue as well as tumor tissue, leading to substantially higher estrogen levels in breast tumors compared with circulating levels. This results in an increased risk for breast tumors as weight and estrogen levels rise, Cleary wrote.

Other potential mechanisms that mediate the obesity-cancer link are under investigation as well. One involves adipocytokines, including leptin and adiponectin. Adiponectin is produced in adipose tissue, and its concentration is inversely proportional to weight: As a person becomes more obese, adiponectin concentrations diminish.

The protein acts as a strong angiogenesis inhibitor and tumor cell inhibitor, so as concentrations decrease, the ability to ward off tumor growth may decrease. Research into adiponectin and prostate cancer — the incidence of which obesity has a very small effect on, but appears to be associated with more aggressive tumors — has indicated that the lower levels of the protein could contribute to obesity’s negative effects.

Stephen J. Freedland, MD
Stephen J. Freedland

“If I’m given $10,000 and I can bet on which pathway is the most important, [the one] I’m putting most of it on is either estrogen or insulin,” said Stephen J. Freedland, MD, an associate professor of urology and pathology in the Duke Prostate Center at Duke University, who has done work on the adipocytokine connections to prostate cancer. “The adiponectin story is interesting, but it’s a side bet. It may turn out to be really important, but it may turn out to be not so important.”

Finally, a paper in the International Journal of Cancer in 2002 postulated that the abdominal pressure brought on by increasing obesity could cause increased gastroesophageal reflux, which in turn can contribute to malignancies of the esophagus as well as the gastric cardia. This mechanical explanation most likely does not extend to most other forms of cancer, but could explain the increasing rates around the world for those two types of cancer.

Although Abbruzzese said that we still lack a good understanding of mechanisms underlying any specific links, “there is an increasing understanding that fat tissue is not inert, it is a metabolically active organ. It changes hormonal balance in women, and I think there is only going to be more information in the next few years toward really understanding what is behind all this.”

Screening, treatment and mortality

Obesity also plays a role in screening for cancer. There are only a few recommended screening tests for women in the United States, and a 2008 review in Cancer found that screening rates for cancers of the cervix and breast tend to drop as BMI rises (no association was seen for colorectal screening tests).

Freedland said there is some indication that with prostate cancer screening in men, obesity might actually be linked to higher rates of screening.

“It’s the only cancer we screen by just checking a box on the blood collection form, and thus obese men with their greater comorbidities are seeing their doctors more often and getting blood drawn more often. Also for prostate cancer, we have the specific problem that the excess blood volume among obese men dilutes out the PSA making PSA levels lower in obese men and more cancers can go undetected leading to a potential delay in diagnosis,” he said.

“With other types of screening, due to comorbidities, you may be less worried about particular cancers. Also, certainly a very large breast can make mammography more challenging, and doing a good rectal exam can be more difficult as well.”

Nisa Maruthur, MD, an assistant professor of medicine at Johns Hopkins University in Baltimore, and colleagues published two papers in early 2009 that further showed the low rates of screening among obese women; the association was strongest with Pap testing for cervical cancer, with the most obese women (those 40 kg/m2 or more) showing an OR for screening of 0.62 compared with normal weight women. “It is probably a multifactorial issue, with both patient- and physician-related barriers,” Maruthur said. “There is literature that shows that obese women delay medical care, and then certainly there is a perceived lack of respect from health care providers.”

Additional issues with treatment and outcomes in obese patients also occur after a malignancy is found. There is now very strong evidence that mortality increases in many cancers among obese individuals, and as Freedland said, treatments are often made more difficult among people with substantial excess weight.

“There are a lot of technical difficulties in screening, detection and, ultimately, treatment. It is hard to operate on an obese man. It is physically and technically more challenging,” he said. “With prostate cancer, we have the luxury of saying, ‘Look, go lose 20 lb and come back in three months and we’ll do your surgery.’” Other more aggressive cancers do not provide such an advantage and can lead to difficult treatment decisions with obese patients.

Fast Facts

With regard to mortality, many malignancies have higher rates among obese individuals. In a large 2003 analysis published in The New England Journal of Medicine, the RR of death for men with a BMI of at least 40 was 1.52; for women the RR was even higher at 1.62. Those risks were for all cancers combined, and increased risks of mortality for the heaviest members of the cohort were also found for cancers of the prostate, esophagus, colon, rectum, liver, gallbladder, pancreas and kidney, as well as for NHL and multiple myeloma. Even those cancers that did not have a significant correlation with increased mortality showed a trend in that direction; these included cancers of the stomach in men and of the breast, uterus, cervix and ovary in women.

Meir J. Stampfer, MD, DrPH, a professor of medicine at Harvard Medical School, said that prostate cancer stands out in this realm for the way obesity contributes to the disease. “[Obesity] also contributes substantially — perhaps a quarter or more — to prostate cancer mortality, though not to incidence.”

The Million Woman Study cohort in the United Kingdom found increased mortality risk as BMI increased for a number of cancers. The strongest correlations in that study were found in malignancies of the esophagus and the endometrium.

Obese individuals often have far more comorbidities than normal weight patients, but the effects of excess weight on mortality are hard to ignore, Freedland said. And although persuading people to lose weight as a method of potentially avoiding some cancers is difficult, his group’s efforts to convince already-diagnosed prostate cancer patients that taking off some of their excess weight will help with treatment has been extremely successful, at least at getting the men to lose weight. Whether that slows tumor growth remains to be seen.

What next?

With the amount of data on the connections between obesity and cancer mounting, the question of how to translate those data into practice may be lost. There are a limited number of studies that have actually looked at weight loss as a means of cancer prevention; in other words, are the mechanisms that may be responsible for increasing an obese individual’s risk reversible? This is one of the many questions that researchers have as the field moves forward, Abbruzzese said.

For now, though, adding the apparent cancer risks to the already robust list of reasons to maintain a healthy weight could play a role in public health messaging.

“I think most people associate overweight/obesity with risk of diabetes and heart disease and not so much with cancer,” Stampfer said. “Cancer is understandably highly feared, in part because there are fewer obvious avenues for prevention — compared with heart disease, for example. If people understood better the strong link of overweight with some aspects of cancer, it could provide additional motivation to maintain good body weight.” – by Dave Levitan

POINT/COUNTER
Could cancer be prevented through weight loss or the reversal of the mechanisms identified as increasing an obese individual’s cancer risk?

For more information:

  • Calle EE. NEJM. 2003;348:1625-1638.
  • Cleary MP. Endocrinology. 2009;150:2537-2542.
  • Cohen SS. Cancer. 2008;112:1892-1904.
  • La Vecchia C. Int J Cancer. 2002;102:269-270.
  • Maruthur NM. Obesity. 2009;17:375-381.
  • Maruthur NM. J Gen Intern Med. 2009;24:665.-677.
  • Polednak AP. Cancer Detection and Prevention. 2003;27:415-421.
  • Reeves GK. BMJ. 2007;335:1134.
  • Renehan AG. Lancet. 2008;371:569-578.
  • Roberts DL. Annu Rev Med. 10.1146/annurev.med.080708.082713.

As the obesity epidemic in the United States and around the world continues to get worse, the links between excess weight and cancer incidence and mortality have come under increased investigation. With close to one-third of all U.S. adults classified as obese, according to the CDC, determining just what the risk between obesity and cancer is and what can be done about it is more important than ever.

At the beginning of this decade, evidence of the most solid links between specific types of cancer and obesity began emerging. Malignancies of the colon, endometrium, kidney and esophagus, as well as postmenopausal breast cancer, were found to be linked to excess weight. Now, the list has expanded, and experts are starting to learn more about how many cancer cases can be attributed to obesity. Furthermore, issues have arisen as to obesity’s effect on screening and diagnosis, as well as treatment, and there is strong evidence that it can increase mortality among cancer patients as well.

Although most research in recent years has looked for links between specific cancer types and obesity, some large cohort studies have shown an overall correlation between excess weight and cancer incidence. The Million Women Study in the United Kingdom enrolled more than 1.2 million women and followed them for 5.4 years for cancer incidence and for seven years to measure cancer mortality. For all cancers combined, there was a RR increase per 10 units of BMI of 1.12 (95% CI, 1.09-1.14). The study found that about 5% of all cancers among women in the United Kingdom, or about 6,000 total cases, are attributable to overweight or obesity.

James Abbruzzese, MD
James Abbruzzese, MD, of M.D. Anderson Cancer Center, researches links between obesity and pancreatic cancer.

Photo by: John Everett

In the United States, numbers appear to be similarly high. A study published in Cancer Detection and Prevention showed that, in 2002, about 41,000 new cases of all types of cancer were due to obesity; this was about 3.2% of all new cancers. Some speculate that these numbers may increase in the coming years, as the lag time for malignancies to develop will follow the recent upward spikes in obesity prevalence.

“I think this is a big worry in overall trends of cancer [incidence],” said James Abbruzzese, MD, of The University of Texas M.D. Anderson Cancer Center, who has worked on links between pancreatic cancer and obesity. “Between the overall aging of the population and the obesity epidemic, we may be poised to lose some of the gains that we’ve made [toward decreasing cancer mortality]. I think it is a huge problem.”

Which associations are strongest?

Although there is an association between obesity and overall cancer statistics, drilling down into specific malignancies may be a more important first step to understanding the mechanisms of the relationship between obesity and cancer, and combating the problem, according to the experts who spoke with HemOnc Today.

Some research being conducted today is beginning to explore these relationships. The Million Women Study found that with the excess 10 kg/m2 of BMI, the RR for endometrial cancer was 2.89; other significant associations were seen with adenocarcinoma of the esophagus (RR=2.38), kidney cancer (RR=1.53), pancreatic cancer (RR=1.24) and others.

A 2008 meta-analysis — published in The Lancet — of 221 distinct data sets also found highly significant associations between obesity and a number of specific malignancies. In this case, a 5 kg/m2 increase in BMI in men was associated with a RR of 1.52 for esophageal carcinoma and of 1.33 for thyroid cancer. Other associations were seen between cancers of the colon, rectum and kidney, malignant melanoma, multiple myeloma, as well as leukemia and non-Hodgkin’s lymphoma. Similarly, in women, strong correlations between obesity and malignancies of the gallbladder, pancreas and postmenopausal breast also reached statistical significance.

Multiple pathways

With so many cancers being linked to excess weight, determining the mechanisms underlying such connections is exceptionally difficult. As Roberts and colleagues wrote in a recent review in Annual Review of Medicine, “it is unlikely that there is a ‘one system fits all’ mechanism.”

One of the most often cited mechanisms is the insulin and insulin-like growth factor I axis. Although the details are not yet fully understood, it seems likely that insulin can strongly promote tumor growth in a number of locations, and the abnormal insulin production and tolerance that characterizes obesity could lead to malignancies, according to Roberts’ review.

Another mechanism that is particularly associated with postmenopausal breast and endometrial cancer — two of the stronger associations between obesity and cancer — is estrogen level. As Cleary and colleagues wrote recently in Endocrinology, among postmenopausal women, estrogen production is primarily performed at peripheral sites (rather than the ovaries), and among obese women, the primary source is adipose tissue.

Some studies have shown that women with postmenopausal breast cancer have higher levels of estrogen than control patients, and the higher rates of estrogen production in obese women can at least partially explain the increased risk of breast tumors. Aromatase, an enzyme that mediates estrogen synthesis, is found in breast adipose tissue as well as tumor tissue, leading to substantially higher estrogen levels in breast tumors compared with circulating levels. This results in an increased risk for breast tumors as weight and estrogen levels rise, Cleary wrote.

Other potential mechanisms that mediate the obesity-cancer link are under investigation as well. One involves adipocytokines, including leptin and adiponectin. Adiponectin is produced in adipose tissue, and its concentration is inversely proportional to weight: As a person becomes more obese, adiponectin concentrations diminish.

The protein acts as a strong angiogenesis inhibitor and tumor cell inhibitor, so as concentrations decrease, the ability to ward off tumor growth may decrease. Research into adiponectin and prostate cancer — the incidence of which obesity has a very small effect on, but appears to be associated with more aggressive tumors — has indicated that the lower levels of the protein could contribute to obesity’s negative effects.

Stephen J. Freedland, MD
Stephen J. Freedland

“If I’m given $10,000 and I can bet on which pathway is the most important, [the one] I’m putting most of it on is either estrogen or insulin,” said Stephen J. Freedland, MD, an associate professor of urology and pathology in the Duke Prostate Center at Duke University, who has done work on the adipocytokine connections to prostate cancer. “The adiponectin story is interesting, but it’s a side bet. It may turn out to be really important, but it may turn out to be not so important.”

Finally, a paper in the International Journal of Cancer in 2002 postulated that the abdominal pressure brought on by increasing obesity could cause increased gastroesophageal reflux, which in turn can contribute to malignancies of the esophagus as well as the gastric cardia. This mechanical explanation most likely does not extend to most other forms of cancer, but could explain the increasing rates around the world for those two types of cancer.

Although Abbruzzese said that we still lack a good understanding of mechanisms underlying any specific links, “there is an increasing understanding that fat tissue is not inert, it is a metabolically active organ. It changes hormonal balance in women, and I think there is only going to be more information in the next few years toward really understanding what is behind all this.”

Screening, treatment and mortality

Obesity also plays a role in screening for cancer. There are only a few recommended screening tests for women in the United States, and a 2008 review in Cancer found that screening rates for cancers of the cervix and breast tend to drop as BMI rises (no association was seen for colorectal screening tests).

Freedland said there is some indication that with prostate cancer screening in men, obesity might actually be linked to higher rates of screening.

“It’s the only cancer we screen by just checking a box on the blood collection form, and thus obese men with their greater comorbidities are seeing their doctors more often and getting blood drawn more often. Also for prostate cancer, we have the specific problem that the excess blood volume among obese men dilutes out the PSA making PSA levels lower in obese men and more cancers can go undetected leading to a potential delay in diagnosis,” he said.

“With other types of screening, due to comorbidities, you may be less worried about particular cancers. Also, certainly a very large breast can make mammography more challenging, and doing a good rectal exam can be more difficult as well.”

Nisa Maruthur, MD, an assistant professor of medicine at Johns Hopkins University in Baltimore, and colleagues published two papers in early 2009 that further showed the low rates of screening among obese women; the association was strongest with Pap testing for cervical cancer, with the most obese women (those 40 kg/m2 or more) showing an OR for screening of 0.62 compared with normal weight women. “It is probably a multifactorial issue, with both patient- and physician-related barriers,” Maruthur said. “There is literature that shows that obese women delay medical care, and then certainly there is a perceived lack of respect from health care providers.”

Additional issues with treatment and outcomes in obese patients also occur after a malignancy is found. There is now very strong evidence that mortality increases in many cancers among obese individuals, and as Freedland said, treatments are often made more difficult among people with substantial excess weight.

“There are a lot of technical difficulties in screening, detection and, ultimately, treatment. It is hard to operate on an obese man. It is physically and technically more challenging,” he said. “With prostate cancer, we have the luxury of saying, ‘Look, go lose 20 lb and come back in three months and we’ll do your surgery.’” Other more aggressive cancers do not provide such an advantage and can lead to difficult treatment decisions with obese patients.

Fast Facts

With regard to mortality, many malignancies have higher rates among obese individuals. In a large 2003 analysis published in The New England Journal of Medicine, the RR of death for men with a BMI of at least 40 was 1.52; for women the RR was even higher at 1.62. Those risks were for all cancers combined, and increased risks of mortality for the heaviest members of the cohort were also found for cancers of the prostate, esophagus, colon, rectum, liver, gallbladder, pancreas and kidney, as well as for NHL and multiple myeloma. Even those cancers that did not have a significant correlation with increased mortality showed a trend in that direction; these included cancers of the stomach in men and of the breast, uterus, cervix and ovary in women.

Meir J. Stampfer, MD, DrPH, a professor of medicine at Harvard Medical School, said that prostate cancer stands out in this realm for the way obesity contributes to the disease. “[Obesity] also contributes substantially — perhaps a quarter or more — to prostate cancer mortality, though not to incidence.”

The Million Woman Study cohort in the United Kingdom found increased mortality risk as BMI increased for a number of cancers. The strongest correlations in that study were found in malignancies of the esophagus and the endometrium.

Obese individuals often have far more comorbidities than normal weight patients, but the effects of excess weight on mortality are hard to ignore, Freedland said. And although persuading people to lose weight as a method of potentially avoiding some cancers is difficult, his group’s efforts to convince already-diagnosed prostate cancer patients that taking off some of their excess weight will help with treatment has been extremely successful, at least at getting the men to lose weight. Whether that slows tumor growth remains to be seen.

What next?

With the amount of data on the connections between obesity and cancer mounting, the question of how to translate those data into practice may be lost. There are a limited number of studies that have actually looked at weight loss as a means of cancer prevention; in other words, are the mechanisms that may be responsible for increasing an obese individual’s risk reversible? This is one of the many questions that researchers have as the field moves forward, Abbruzzese said.

For now, though, adding the apparent cancer risks to the already robust list of reasons to maintain a healthy weight could play a role in public health messaging.

“I think most people associate overweight/obesity with risk of diabetes and heart disease and not so much with cancer,” Stampfer said. “Cancer is understandably highly feared, in part because there are fewer obvious avenues for prevention — compared with heart disease, for example. If people understood better the strong link of overweight with some aspects of cancer, it could provide additional motivation to maintain good body weight.” – by Dave Levitan

POINT/COUNTER
Could cancer be prevented through weight loss or the reversal of the mechanisms identified as increasing an obese individual’s cancer risk?

For more information:

  • Calle EE. NEJM. 2003;348:1625-1638.
  • Cleary MP. Endocrinology. 2009;150:2537-2542.
  • Cohen SS. Cancer. 2008;112:1892-1904.
  • La Vecchia C. Int J Cancer. 2002;102:269-270.
  • Maruthur NM. Obesity. 2009;17:375-381.
  • Maruthur NM. J Gen Intern Med. 2009;24:665.-677.
  • Polednak AP. Cancer Detection and Prevention. 2003;27:415-421.
  • Reeves GK. BMJ. 2007;335:1134.
  • Renehan AG. Lancet. 2008;371:569-578.
  • Roberts DL. Annu Rev Med. 10.1146/annurev.med.080708.082713.