North American Association for the Study of Obesity

Articles

Content

Recommended Resources

Breast cancer is usually the furthest thing from your mind when planning for your 30th birthday. But for Jeannine Salamone of Alexandria, Virginia, a breast lump was an uninvited guest. She actually noticed the painful lump a few weeks earlier, but by the time she saw her gynecologist it had gotten bigger and more painful. A mammogram showed suspicious signs of calcifications in the breast and she was sent to a surgeon for a biopsy. “I got the results the next day,” she says, “the day I turned 30, and it was positive for cancer.”

Before her diagnosis Salamone says she had no clue that someone her age could get breast cancer. But she quickly learned that young women do get this disease.

In fact, although breast cancer is more common in older women, about 13,700 women younger than 40 years of age will get breast cancer this year in the United States.

A few of these women, like Salamone, will learn they carry mutations in one of the two known breast cancer genes, called BRCA1 and BRCA2, that greatly increase the risk of ovarian or breast cancer. Most of these young women with breast cancer, however, will not test positive for BRCA1 or BRCA2, although they may carry unknown breast cancer susceptibility genes that have not yet been discovered. In fact, cancer experts believe there are probably many genetic mutations that influence the risk of breast cancer.

The majority of women who carry a BRCA1 or BRCA2 mutation don’t know they have it unless they, or a family member, get tested for it. Sometimes, a family history of breast cancer or ovarian cancer can be a telltale sign of genetic risk, and young women who have two or more first-degree relatives with breast or ovarian cancer might consider genetic testing. Other risk factors include aging, getting your first period at an early age (before age 12), having your first child after age 30, and late age at menopause (after 55)—risk factors that can’t be affected by altering lifestyle. But for the most part no one knows why a woman, young or old, gets breast cancer.

Women under 40 who get breast cancer face unique challenges as they fight the disease. Most find less information and often less support than older women with breast cancer. “Your average 30-something doesn’t know another 30-something with breast cancer,” says Ann Partridge, MD, an oncologist at Dana-Farber Cancer Institute in Boston. “It’s true that most of the research studies in breast cancer are done on older women, but since the discovery of the BRCA genes, we are learning more about breast cancer in young women.”

A cancer diagnosis can feel particularly disruptive at an age when a woman may be just starting out in a marriage or relationship, building a career or starting a family. “Younger women are more likely to be at a stage in their life when things like sexual functioning, beauty and attractiveness, fertility and family planning may be of the utmost importance,” says Partridge.

Meredith Cobb of Colorado Springs, Colorado, had just had a baby at age 26 when her doctor evaluated a bloody nipple discharge. A mammogram and biopsy six weeks later diagnosed stage 1 breast cancer and extensive ductal carcinoma in situ (DCIS) in November 2003.

“I was hysterical,” she says. “I just looked at this little baby and wondered, ‘Am I ever going to see this baby grow up?’” But after a few weeks of roller-coaster emotions and being the youngest woman in the chemotherapy room by at least 30 years, Cobb knew she had to carry on with her day-to-day life as a mom. “I just took the kids to school and went to their games and did all that stuff,” she says.

Usually, the first decision a newly diagnosed breast cancer patient must confront is surgical. In many instances, women can choose removal of the tumor and surrounding tissue (lumpectomy) or removal of the entire breast (mastectomy). Both surgical procedures are considered standard treatment for young women with breast cancer, says Mark Robson, MD, an oncologist at Memorial Sloan-Kettering Cancer Center in New York.

He says that although the complexities for each individual need to be discussed carefully with the breast surgeon, breast cancer patients with a BRCA mutation may also consider prophylactic mastectomy of the healthy breast to reduce the chance of cancer in that breast.

Salamone, who had stage 2B cancer in one breast and a high risk of developing breast cancer in the other breast, opted for a bilateral mastectomy. Cobb, who does not carry a BRCA mutation, also chose bilateral mastectomy because she wanted to treat her disease aggressively and ensure her breasts would match after reconstruction.

Women who choose lumpectomy typically undergo six weeks of daily radiation after surgery to treat the remaining breast tissue. A new method for giving radiation therapy to the breast, however, may influence women’s surgical choices in the future. Researchers are investigating whether radiation directed at only part of the breast, the area directly surrounding where the cancer was found, can work as well as treating the whole breast. This technique, called accelerated partial breast irradiation, uses catheters or radioactive seeds placed inside the breast to deliver radiation directly to the vulnerable tissue. It also only takes days compared with weeks.

“There certainly are some very promising preliminary data using partial breast irradiation,” says Robson. A large randomized controlled trial is currently under way to test the effectiveness of partial breast irradiation, but most oncologists still consider it experimental and recommend conventional radiation in most cases.

Young breast cancer patients often have more aggressive disease than older women. Because young patients can usually tolerate more intense chemotherapeutic drugs, they tend to receive particularly toxic regimens.

Other treatment options are based on hormone receptor status. Women who carry BRCA1 mutations frequently have tumors that are negative for estrogen receptors, progesterone receptors and expression of HER2/neu. Women with these so-called “triple-negative” tumors are in a unique situation, says Partridge.

“These triple-negative cancers are fairly sensitive to chemotherapy but are more likely to come back,” she says. Furthermore, these tumors can’t be treated with targeted hormonal therapies or Herceptin. But Partridge notes that researchers are looking at new chemotherapy combinations to treat these breast cancers. Current trials are investigating whether preoperative Platinol (cisplatin) is effective in women with triple-negative cancer, although this drug is not usually effective in the more common types of breast cancer.

The goal of hormonal therapy for women with estrogen-positive tumors is to rob the cancer cells’ source of estrogen. In young women, the greatest source of estrogen comes from the ovaries. A century ago, one of the first therapies for breast cancer was to remove the ovaries, says Julie Gralow, MD, an oncologist at the University of Washington School of Medicine in Seattle.

The question is, if aromatase inhibitors work better than tamoxifen in postmenopausal women, should we try to shut down young women’s ovaries and give them aromatase inhibitors? 

Tamoxifen, the current standard treatment for premenopausal women with breast cancer, blocks the binding of estrogen to the breast receptors in premenopausal women with hormone-sensitive tumors. In postmenopausal women, the ovaries are no longer active and aromatase inhibitors, such as Arimidex (anastrozole), Femara (letrozole), or Aromasin (exemestane), can reduce circulating estrogen in the body to nearly undetectable levels. Although doctors know aromatase inhibitors are ineffective in premenopausal women with functioning ovaries, ongoing studies will determine how best to use aromatase inhibitors and tamoxifen.

Gralow and others, however, wonder if there is a way to still use these powerful medications in young women. “The question is,” says Gralow, “if aromatase inhibitors work better than tamoxifen in postmenopausal women, should we try to shut down young women’s ovaries and give them aromatase inhibitors?”

At age 27, Cobb underwent surgery to have her ovaries removed and began taking Arimidex. “That was the choice I made to essentially starve any cancer cells that could be in there,” she says. Already having three children and two stepchildren before her diagnosis, Cobb says she was less concerned about preserving her ability to have more kids. Still, her choice to instantly enter menopause was not without risk.

Menopause can hasten osteoporosis, says Gralow. It may also speed up a young woman’s risk of heart disease because estrogen from the ovaries may protect against heart disease. Aromatase inhibitors can also cause bone loss, but current research indicates agents called bisphosphonates, such as Zometa (zoledronic acid), can prevent bone loss. Boniva (ibandronate), a newer bisphosphonate taken by mouth once a month, received FDA approval in early 2005 for postmenopausal osteoporosis.

Non-surgical methods that temporarily stop ovarian function have been shown to reduce estrogen in premenopausal women. Medications called LHRH (luteinizing hormone-releasing hormone) analogues, which include Lupron (leuprolide) and Zoladex (goserelin), block signals from the brain that tell the ovaries to cycle. Shots of these medications can suppress the ovaries’ function and reduce estrogen in the body to postmenopausal levels.

Even so, Gralow says there is no conclusive data yet that ovarian suppression or aromatase inhibitors are effective in young, premenopausal women with local breast cancer. A study known as SOFT (Suppression of Ovarian Function Trial) is comparing tamoxifen alone to tamoxifen plus an LHRH analogue to an aromatase inhibitor (Aromasin) plus an LHRH analogue. Results of this study should help determine the optimal hormone therapy for young women with breast cancer.

Young women who plan to have children in the future confront difficult challenges regarding treatment. Both chemotherapy and hormone therapy for breast cancer can affect the ability to have children. Chemotherapy causes some women to enter premature menopause at any time after treatment.

Nevertheless, most patients under 40 will get their periods again after finishing chemotherapy, says Partridge. Hormonal therapy, on the other hand, affects fertility because doctors advise postponing pregnancy until the five-year treatment is over. Salamone, who did not have children when she was diagnosed, is in that position. “I’m in year four of tamoxifen, and there’s still a chance that my husband and I will have a baby,” she says.

In fact, many young women do have healthy children after breast cancer. Some women even elect to temporarily stop hormonal therapy to have a child before finishing the prescribed five years. Few data exist on how this affects recurrence, but for some women it’s an important personal decision.

Young women with breast cancer are truly in a unique position. Most young patients will live long, healthy lives, and they must weigh treatment decisions with that knowledge. “Younger women have a longer time to have long-term complications,” says Partridge, “and we worry about potential risks over time, such as osteoporosis or changes in cardiovascular health and cognitive health.”

Most young women with breast cancer successfully navigate their way through the choices and come out feeling stronger. As Salamone says, now in her fifth year of survivorship, her diagnosis feels like a long time ago. “I’ve moved on and try to do a lot of positive things.”

Features

The challenges of breast cancer in women under 40.

Unexpected & Unique

It has been just over 10 years since the discoveries of BRCA1 and BRCA2. Looking back on this decade of research, we have made clear advances in elucidating the genetics of breast cancer. However, instead of simplifying our understanding of breast cancer, this additional knowledge has added new levels of complexity.

A genetic (familial) component may account for approximately 5 percent of all breast cancers, and of that 5 percent, BRCA1 and BRCA2 probably account for no more than 70 to 80 percent, and possibly much lower. Recent data show that other genes are important in the development of cancer, but these genes are not as easily traceable to breast cancer.

BRCA1 and BRCA2 are “susceptibility genes” that confer a greater lifetime risk of developing cancer. It’s important to understand that BRCA1 and BRCA2 confer a susceptibility to cancer and do not directly cause cancer, so not every person who carries the gene will definitively develop cancer. Specifically, a mutation in these genes impairs the ability of a normal cell to fix damage to its DNA that under normal circumstances will accumulate over time. Some of these DNA mutations may lead to cancer. Women with BRCA1 or BRCA2 mutations have a 50 to 85 percent lifetime risk of developing breast cancer as well as an increased lifetime risk of ovarian cancer. Male BRCA2 carriers have a 6 to 7 percent risk of developing breast cancer over their lifetime.

The difficulty faced by patients stems from trying to put all of these figures together. Since researchers have only identified two of the many genes that may potentially cause breast cancer, a negative BRCA1/BRCA2 test doesn’t mean a person has no genetic risk of developing the disease. Similarly, a positive test doesn’t mean a woman will develop breast or ovarian cancer.

Beyond interpreting results of a test, the implications may have a profound effect on future decisions for the patient and family. Before having the test, a woman should talk to a genetic counselor and decide if knowing her genetic susceptibility will provide her or her family with information that can aid in making a decision about preventive measures. A woman should consider genetic testing if she was under 45 when diagnosed, has multiple family members with breast cancer on the same side of the family, has ovarian or male breast cancer in the family or is of Eastern European Jewish descent (Ashkenazi Jews).

The cost of these tests combined with genetic counseling can exceed $3,000, and the degree of coverage varies among insurers. BRCA1/BRCA2 testing has an important role in understanding and treating breast cancer, but the test and its resultant implications warrant careful guidance from a trained genetics team. The 

 provides an online directory of cancer genetics professionals.

The progress made in genetic testing for breast cancer.

The Complexities of Genetic Testing

A patient-friendly advance in radiation therapy means early-stage breast cancer patients have another treatment option after lumpectomy. For years, the standard treatment after lumpectomy has been whole breast radiation, which has involved external radiation to the entire breast for a period of five to seven weeks. But studies have shown that partial breast irradiation (PBI) can successfully treat the portion of the breast in and around the area where the tumor was removed—all in about a week.

Interest in this targeted method, which can be done in a number of ways, grew out of patient inconvenience and potential side effects (chronic chest wall or breast pain and cardiac toxicity, for example) and was not developed to specifically improve outcome. And though recent study results show that PBI has local control rates similar to whole breast radiation, radiation oncologists point out that it has been well established that lumpectomy with whole breast radiation achieves survival rates equal to mastectomy. Researchers still must determine which patients are most likely to benefit from PBI before its mainstream adoption.

National Surgical Adjuvant Breast and Bowel Project

 and the Radiation Therapy Oncology Group are currently recruiting patients for what is expected to be the key study in determining if PBI provides equivalent local tumor control compared with whole breast radiation and who may benefit from PBI. The phase III trial will enroll approximately 3,000 patients, with mature data expected in eight years. The PBI techniques that will be used in the study are described below.

 A doctor inserts a tube with a balloon attached to the end into the area where the tumor was removed. The balloon is filled with saline and a radioactive “seed” travels through the tube and into the balloon to deliver the radiation dose. Although the seed is removed after each treatment, the tube and balloon stay in the breast until the 10 treatments over five days are complete. The FDA approved MammoSite in 2002. To locate a treatment center, visit 

 Radioactive seeds are delivered through a series of catheters to the lumpectomy area. The number of catheters (tubes) used depends on the size of the breast and the size of the lumpectomy area. As with MammoSite, the seeds are removed after each treatment but the catheters stay in the breast until the 10 treatments over five days are complete.

3-D conformal partial breast irradiation.

 A pinpointed external beam of radiation delivers the dose to the area of the breast where the tumor was removed.

A more local approach to radiation therapy in less time.

Partial Breast Irradiation: A Convenient Alternative

High-risk women can develop breast cancer at a relatively young age when the breasts are dense, making it more difficult to detect a tumor using traditional mammography. But doctors are finding success with newer tests.

Adding MRI to X-ray mammography would detect most tumors in women at high risk for breast cancer, says a recent 

 study. The ability to detect a breast tumor increased from 40 percent with mammography alone to 94 percent when combined with MRI. The detection rate with MRI alone was also impressive, particularly among women in the study who tested positive for a BRCA1 mutation. Twenty-three percent of cancers in this subgroup were detected with mammography compared with 92 percent found with MRI.

MRI hasn’t become a mainstream breast-screening method like mammography because the test, which typically takes 30 to 60 minutes, leads to a high rate of false-positives. Mammography is also much better at detecting DCIS than MRI.

Most experts agree MRI scanning of the breast should be reserved for women at highest risk because of a strong family history, those with dense breasts and women with breast implants. In addition, MRI can cost at least 10 times as much as mammography—$1,000 or more, depending on geographic region, compared with $100-$150 for a mammogram.

Instead of acquiring an image on film, as with conventional mammography, the image is collected electronically and can be stored directly on a computer very similar to a digital photo. The image can be manipulated electronically, allowing a technician to zoom in and out or increase contrast. Images can be e-mailed and new software is making reading the images easier. Digital mammography only shows structural changes and as of yet has not been shown to be more effective than standard mammography in finding breast cancer.

Preliminary results from a large clinical trial of digital versus film mammography (DMIST) show no difference in detecting breast cancer for the general population of women in the trial. However, those women with dense breasts, who are pre- or perimenopausal (women who had a last menstrual period within 12 months of their mammograms), or who are younger than age 50 may benefit from having a digital rather than a film mammogram.

Breast cancer screening for women at high risk.

Screening: Finding the Tumor

I was diagnosed with breast cancer the week before my first child was born. When I was halfway through chemotherapy, I learned about a movie theater that showed matinees for parents with babies. I eagerly packed up my son and headed to the theater early to join in the pre-movie chats about nap cycles and pacifiers. But when I walked into the theater and saw 200 mothers—half of them breastfeeding&mdash;all I could think was, “I am not like them. I have cancer. I don’t belong here.”

Cancer is isolating. While my friends were soaring along with their careers and families, my life had been hijacked. I was now consumed with finding good veins for chemo and living until my son entered first grade. Standing in that theater, I feared I would be out of step with my peers forever.

For starters, I was bald. At the age of 33, I had been temporarily thrown into menopause, something my friends wouldn’t cope with for 20 years. Instead of breastfeeding my son, I was often too sick to give him his bottle. I lay awake at night fearing the cancer had spread, that the pain in my leg was really a tumor. I routinely looked at my son and wondered if he would remember me if I died in a few years.

How could my friends understand all of this? Some did and some didn’t. A few simply said, “You are going to be fine. I have a good feeling about this.” While I appreciated the sentiment, it minimized all the uncertainty I faced. They would have known how to comfort me through divorce or infertility, but cancer just wasn’t on their radar screens yet. That left me in the role of the educator, explaining each test and treatment option. Most friends were eager learners, but I longed to talk to people who already spoke the language.

And yet, I didn’t fully relate to the patients I met at the cancer center. The average age of breast cancer patients is 64, and most of the women at the center carried pictures of their grandchildren and talked about early retirement.

Then, in the middle of treatment, I found a support group for young women with breast cancer. When I walked into the first meeting and saw eight youthful faces, I was flooded with relief. These were women my age who were fluent in the ways of mammograms and CT scans, and who viewed cancer fears as routine aspects of life.

Marie, a 34-year-old mother of a toddler, told me she too felt guilty for not having enough energy to play with her child. Lara, a 36-year-old art therapist, shared her fear that chemo would take away her chance of having a baby. When I was considering a prophylactic mastectomy, Deborah, an attractive, irreverent engineer, lifted up her shirt to show me her scars. Maureen was the gentle group leader, diagnosed in her early 20s, who assured me that the fear of recurrence never goes away, but it comes less often. Hearing their stories, and watching them nod knowingly while I told mine, I discovered a new definition of what was normal. I had found a new community.

The friendships I made in the group sustained me through treatment and beyond. And slowly, as my body began to recover, so did my sense of being connected to those around me. Having hair helped. So did gaining the strength to carry my son and other small victories that most mothers take for granted. Gradually, I stopped feeling like a cancer patient and started regaining my old life back. I still had moments of feeling alone—contemplating mortality is a fundamentally lonely process&mdash;but my old friends were becoming more adept at listening.

About a year after I was diagnosed, my son learned to walk. One day at the park, I realized that none of the other parents would have guessed that I had just battled a life-threatening illness. To them, I was just another mother. In some ways I was, and some ways I wasn’t. But I knew I wasn’t alone.

Colm Scott is now 3 years old. Emily and her husband Dan Scott are expecting their second child in December.

Emily Cousins' personal story about dealing with breast cancer as a young mother.

Passing Isolation

When I was diagnosed with breast cancer at age 37 in 1985, one thing was made clear: There would be no hormone replacement therapy (HRT), drugs my mother relied on to quell the multiple symptoms of menopause and protect against osteoporosis.

But 10 years later when the hot flashes and mood swings hit, I still brought up the therapy that uses estrogen and progestin with my obstetrician when news of a study indicated that for those of us a certain number of years out, HRT would be OK. No way, she said. Not enough evidence.

Indeed, shortly after that discussion came a flurry of studies indicating not only that women with a history of breast cancer are at greater risk for metastasis on HRT, but also that some women who had not had breast cancer are at higher risk to develop the disease. The Women’s Health Initiative, which, among other things, researched the effect of combined estrogen-progestin in more than 16,000 healthy postmenopausal women, showed that HRT actually increases the risk of heart attack, stroke and blood clots. There are still many areas of HRT, menopause and breast cancer under investigation, but for the most part, women with a history of breast cancer should not take HRT.

So relief from menopausal symptoms, which can be brought on by chemotherapy and other hormonal treatments for breast cancer, needs to be addressed through other routes, such as the antidepressant Effexor (venlafaxine), which has been shown to reduce hot flashes; exercise and calcium supplementation to reduce bone loss; vaginal lubricants for sexual issues; and time, since menopausal symptoms eventually lessen. 

Women with a history of breast cancer  should not take HRT.

HRT: Not Our Mothers' Experience

On the face of it, the June 17, 2005 announcement seemed an innocuous shred of red tape. The Food and Drug Administration was changing the way AstraZeneca could label its anti-cancer drug Iressa (gefitinib). Just a wording change.

But that wording change spoke volumes. The FDA was essentially pulling its approval from Iressa by making distribution so restrictive that it had returned to being an experimental drug, and the only people who could get it were those currently showing benefit or subjects in clinical trials.

Although AstraZeneca continues to test the drug for potential niche markets (initial studies show a higher response rate among Asian lung cancer patients for reasons not fully understood), it will take the company years to do enough testing to convince the agency to give full approval. Luckily, patients can look to an alternative therapy called Tarceva (erlotinib), a new drug that acts on the same molecular pathway as Iressa. Nevertheless, for the first time, a drug that received accelerated approval has been pulled. And a series of other accelerated approval applicants has met with hardships or downright rejection from the FDA’s advisory committees. Is this just a one-time confluence of coincidences or the beginning of a new, stricter policy at the FDA?

Most experts, and the FDA itself, say the accelerated approval process is alive and well. Richard Pazdur, MD, director of the FDA’s newly formed Office of Oncology Drug Products, says commercial sponsors and the agency have gained increasing experience with the process to expedite drugs to the American public. He says the Iressa issue only demonstrates that the accelerated approval process works.

“At the time Iressa was approved, there were no other therapies for refractory lung cancer,” says Pazdur. “Subsequently, Tarceva was approved, and several randomized confirmatory trials failed to demonstrate the benefit of Iressa.”    “Iressa is a one-off event,” says Charles Bennett, MD, PhD, an oncologist at Northwestern Comprehensive Cancer Center in Evanston, Illinois, who has studied the process. “It’s not a policy shift or paradigm.” What is happening, Bennett and others say, is that the FDA is dealing with a flood of new experimental cancer drugs, and with the hits come misses. Among the Gleevec (imatinib) and Erbitux (cetuximab) success stories of accelerated approval, there are bound to be failures like Iressa. In addition, Zarnestra (tipifarnib), a drug for acute myeloid leukemia patients, was denied accelerated approval in May of this year but is still in phase III testing and may be resubmitted for approval in two to three years.

At the heart of the accelerated approval system is the simple desire to make drugs that appear to offer hope to otherwise untreatable maladies available to patients as early as possible. A typical drug approval can take five to 10 years after the initial application. In the early 1990s, AIDS activists demanded a shortcut for promising drugs, even if the data were incomplete. In 1992, the FDA responded by revamping an earlier, little-used compassionate care program (see sidebar, page 40) into an official accelerated approval system, complete with official benchmarks and phone-book-size regulatory manuals. 

To qualify for the system, a drug must show significant potential to treat a disease that otherwise has no treatment. An accelerated approval drug doesn’t need to show a clinical endpoint (proof that the disease is being cured or deaths are being reduced), but there must be compelling evidence to believe that progress is being made in fighting the disease or symptoms are being relieved. That evidence can be physical (tumor shrinkage) or it can be relational (a decrease in a protein that tends to appear when cancer is present). It also doesn’t have to be overwhelmingly convincing. Data from clinical studies that test only a few dozen or a few hundred patients can be submitted, whereas thousands of subjects in double-blinded studies must be tested for full approval. 

“Drugs approved under accelerated approval are based on a surrogate that is reasonably likely to predict clinical benefit,” says Pazdur. “Therefore, there is an element of risk acknowledged by the FDA in approving drugs under accelerated approval.” Pazdur notes that accelerated approval is meant to be only a temporary measure. Drug companies are required to do full studies to prove the drug is safe and effective. But he says accelerated approval can negatively impact patient accrual for these studies. “The approval has implications for completion of confirmatory trials since oncologists and patients have commercial access to the drug after accelerated approval.” 

Vicki Vandamme found herself on the Iressa roller coaster. An avid windsurfer from Marin County, California, the 51-year-old nonsmoker saw minor shrinkage of her lung tumor while on chemotherapy. She was then put on Iressa, but her June 16 checkup proved that Iressa wasn’t working. The tumor had grown and spread to her lymph nodes. The FDA announced its stricter labeling provision for Iressa just one day later.

At the heart of the accelerated approval system is the simple desire to make drugs that appear to offer hope to otherwise untreatable maladies available to patients as early as possible.

Vandamme, who is adamant she can beat the disease, is back on chemotherapy and hopes to start Tarceva soon.

Although the Iressa case is the first example of effective withdrawal of an accelerated approval drug, the case of Zarnestra sheds more light on the accelerated approval process.

When Zarnestra was denied accelerated approval in May, some patient advocates and pundits publicly voiced concern that the accelerated approval process, meant to be an expressway, was now slowing to a crawl. A closer look at the Zarnestra story, however, shows that this wasn’t a bureaucratic slowdown. For one thing, the 11-member panel wasn’t unanimous in its recommendation. The final vote was seven to four.“It was a very heated debate and it wasn’t an easy decision to make,” says Art Flatau, a leukemia survivor who represented patients on the committee. Flatau voted against approval. “I just didn’t see the compelling evidence.”

Flatau and the other committee members who voted against accelerated approval had reason to be skeptical. Only 136 elderly, newly diagnosed AML patients were evaluated in the phase II trial used to support Zarnestra’s approval. Johnson & Johnson, maker of the drug, claimed that 15 percent of patients had a complete remission. Flatau compared that success rate with chemotherapy results, which, according to a database search by fellow panel member and M. D. Anderson Cancer Center leukemia specialist Susan O’Brien, MD, can be as high as 40 percent remission. Topping Flatau’s concerns was the fear that many elderly patients would choose the drug, if approved, over chemo-therapy out of a fear of side effects. “It’s clear that this drug is safer than chemotherapy,” he says, but adds that there’s no evidence it’s more effective.

Ronald Bukowski, MD, director of experimental therapeutics at the Cleveland Clinic and another member of the FDA committee, disagreed with Flatau and voted for the accelerated approval of Zarnestra. That doesn’t mean he was satisfied with the data, though. “The trial should have been designed for patients that aren’t eligible for chemotherapy,” he says. Johnson & Johnson is enrolling patients in a phase III trial for newly diagnosed AML patients 70 and older.

Zarnestra isn’t the only issue that has upset FDA critics. Rep. Edward Markey of Massachusetts published a staff report in June that quantified another argument against the early approval process. His office did a public records search of drugs that received accelerated approval and then failed to do the required follow-up studies. According to the report, half failed to do the required studies. “The system is broken,” he said in a June press conference. 

The FDA disagrees. Robert Temple, MD, associate director of the agency’s office of medical policy, points out that of the 24 oncology-related drugs that have received accelerated approval, nine have been upgraded to full approval after follow-up studies. Of the other 15, seven were just approved in the past two years—not nearly long enough to complete a full phase III trial. “And the rest are working on studies,” says Temple. “It’s not a useful observation to say that the drug companies haven’t finished their trials in such a short time frame.” 

Temple insists the system isn’t broken but that it could stand a tune-up. He points out that the structure of trials is crucial. “We’re much more interested in seeing the early results from a large randomized trial than the early results from a small trial,” he says. In other words, if the early results of a phase III trial are promising enough, the ears at the FDA will be more sympathetic toward accelerated approval. “That way, the follow-up data are already in the process of being collected.” 

Indeed, most experts agree the accelerated approval process isn’t in need of an overhaul but could use some minor tinkering to correct fixable flaws. Bennett lauds the program for its success rate, but he is still anxious about the tendency to approve drugs that have been tested in few subjects because “it raises some safety questions,” he says.

Nevertheless, Bennett says the positives outweigh the negatives of the program. According to his data, accelerated approval knocks hundreds of days from the typical time it takes a drug to get full approval. And on each of those days, patients with terminal diseases have access to drugs they otherwise wouldn’t have a chance to get.

Indeed, most experts agree the accelerated approval process isn’t in need of an overhaul but could use some minor tinkering to correct fixable flaws.

Accelerated process speeds drugs to the patient, but some rally for changes to the system.

Accelerated Drug Approval: Taming the Shortcut?

Looking at Larry Menkhoff, it’s hard not to be a little skeptical as he  launches into his history with oral cavity cancer. In 1999 the discovery of a  tumor against his upper teeth and palate resulted in removal of the teeth on the  upper left side, half of his palate and jawbone and a sinus cavity. The  discovery of another tumor in a salivary gland a few years later meant more  surgery and radiation. 

But to any but the highly observant, Menkhoff looks normal, a comment that  prompts him to remove the prosthesis that fills out his cheek and sinus cavity  for closer inspection. “It’s the gift that keeps on giving,” Menkhoff says of  his cancer. 

Oral cavity cancer is included in the larger category of head and neck  cancers, which account for 3 to 5 percent of all cancers diagnosed  in the United States and result in nearly 13,000 deaths a year. There are more  than 500,000 head and neck cancer survivors living in the United States today.  In addition to oral cavity cancer, cancers of the larynx, pharynx, salivary  glands and lymph nodes are also included in the designation.

Within each location are subsites, says Nancy Leupold, oral cavity cancer  survivor and founder of Support for People with Oral and Head and Neck Cancer  (SPOHNC). “There are so many locations for head and neck cancer and then each of  those have subsites and then they are divided even further by cell types,” she  explains, “meaning no two people’s cancers are quite the same.”

The majority of head and neck cancer diagnoses—about 39,000 Americans each  year&mdash;are oral cavity cancer, which includes the lips and their lining, cheeks,  the small area behind the wisdom teeth, the floor of the mouth, the front  two-thirds of the tongue, the top of the mouth (hard palate) and the gums. Most  head and neck cancers, like that of Menkhoff and Leupold, are squamous cell  carcinomas that develop in the tissue lining the hollow organs of the body.

Leupold felt a painless bump on the floor of her mouth that was diagnosed as  malignant in 1990 when she was 51. She lost 11 of her 13 bottom teeth during  surgery to remove the tumor. But she is hopeful because, while the side effects  of treatment are still a major concern, new treatment options as well as  surgical and radiation techniques mean fewer deaths and decreased side effects.  

Tobacco and alcohol use appear to cause most squamous cell head and neck  cancers, says Merrill Kies, MD, professor of thoracic/head and neck medical  oncology at M. D. Anderson Cancer Center in Houston.

In fact, 85 percent of head and neck cancers are linked to tobacco use, and  studies show that people who use both tobacco and alcohol are at greater risk  for developing these cancers than people who use either tobacco or alcohol alone. In adults who neither smoke nor drink, cancer of the mouth and  throat are rare.

Both Menkhoff and Leupold smoked, but not heavily. Leupold described herself  as a social smoker. “I never smoked a lot,” says the Locust Valley, New York,  resident. “But when I was told I had cancer, I quit for good. ”

In addition to tobacco and alcohol use, leukoplakia (white spots or patches in the mouth) may lead to cancer in approximately one third of patients.  People who have had radiation to the head and neck or those exposed to  Epstein-Barr virus are also at increased risk.

Oral cavity cancer is usually found as a result of changes in the mouth, such  as painful patches, a sore that won’t heal, bleeding, loose teeth or pain when  swallowing. Menkhoff, a procurement program manager in Arlington, Texas, says it  was a move and a new dentist that saved his life.

“My old dentist kept saying it was a piece of bone or something,” Menkhoff  says of the spot on his hard palate that flared up occasionally. “My wife and I  moved from South Texas to North Texas and I found a new dentist. He took one  look in my mouth and told me to clear my calendar, because I needed to see an  oral surgeon.”

Diagnostic tests, which may include X-rays, endoscopic exams and advanced  imaging scans, help physicians determine a cancer’s stage. Stage 1 and 2 cancers  are small, localized and often curable. Stage 3 and 4A cancers typically are  locally advanced or have spread to nearby lymph nodes. Stage 4B cancers are  usually metastatic and many times are inoperable.

“The treatment plan for each patient depends on a number of factors,  including the exact location of the tumor, the stage of the cancer, the person’s  age and general health,” Kies says. “Treatment options should be carefully  considered because they might affect the way a patient looks, talks, eats or  breathes.”

By the time Menkhoff was diagnosed, his cancer had grown from his palate  across the teeth line and up into the jawbone. “We didn’t know if it had invaded  the sinus, so to be sure, we removed it,” he says. Menkhoff talked with two  surgeons before proceeding because his research indicated surgery could be done  through the mouth without cutting through the cheek, the method he preferred and  received.

Menkhoff was offered chemotherapy but declined, since the oncologist could  not guarantee there would be any additional benefit. His second diagnosis two  years later in a salivary gland, identified as a metastasis by one physician and  a second primary by another, required a neck dissection to look at his lymph  nodes followed by radiation.

Joseph Kuhn, MD, assistant director of surgical education at Baylor  University Medical Center in Dallas, says diagnosis of any head and neck cancer  includes thorough clinical exam, tissue biopsy, X-rays and radiographic staging.  From there, Kuhn says, the initial diagnosis of oral cavity cancer may  involve not only a head and neck surgeon but also a maxillofacial surgeon, who  specializes in restorative surgery.

“Every case gets simultaneous consultation with a radiation oncologist. If  there is any radiation that is going to be given, they will see an oral surgeon  or someone who knows about radiation effects on the teeth,” he says.

In addition to staging, the choices of surgery, radiation and chemotherapy  are determined by where the cancer is found since an inch can mean the  difference between the use of one or all three treatment modalities, Kuhn  says, trying in all instances to maintain function and cosmetic appearance and  reduce side effects.

Leupold’s cancer was diagnosed at stage 1; she had surgery shortly after  diagnosis. “I was lucky because I didn’t need radiation,” she says. “But I was  not prepared for the bruising, swelling, burning sensation, numbness and dry  mouth I had after surgery. And during surgery, a nerve to my tongue was  sacrificed, so I have no feeling in half of my tongue.”

Although an increasing number of patients with squamous cell head and neck  cancer can be treated with radiation alone or with radiation and chemotherapy,  many still require surgery as either the definitive initial treatment or for  salvage of primary treatment failure.

Surgery may change a patient’s ability to chew, swallow or talk. The face and  neck may be swollen for several weeks. If lymph nodes are affected, the flow of  lymph fluid may become sluggish and collect in the tissues; in this case,  swelling may last much longer.

Analyzing the lymph nodes becomes important for staging, Kuhn says, and  in head and neck cancer there are guidelines regarding which locations may  result in node involvement.

“For cancer on the floor of the mouth, the chance of having a positive lymph  node is about 40 percent. For a small tongue cancer, the chance is 25 percent,” Kuhn says, adding that studies are under way to determine if sentinel node  biopsy, in which only the first lymph node is taken, will be effective and  require fewer neck dissections to look at multiple nodes.

“Although an increasing number of patients with  squamous cell head and neck cancer can be treated with radiation alone or with  radiation and chemotherapy, many still require surgery as either the definitive  initial treatment or for salvage of primary treatment failure,” says Dong M.  Shin, MD, professor of hematology and oncology, director of the Clinical and  Translational Cancer Prevention Program and co-director of the Translational  Aerodigestive Tract Malignancies Program at the Winship Cancer Institute of  Emory University School of Medicine in Atlanta.

Kuhn says it’s possible to cure a 1-centimeter tongue cancer equally with  either surgical removal or radiation. “But once you have given the radiation you  can’t give it again, and it does lead to dry mouth and dental problems,” he  says. “We rarely operate on the base of the tongue, but instead use radiation  and chemotherapy.”

Radiation treatments may cause mouth sores (oral mucositis), dry mouth (see  sidebar), thickened saliva or difficulty swallowing. Changes in taste sensations  may decrease appetite and affect nutrition. But Kuhn points out that in many  cases today’s targeted radiation can pinpoint areas and avoid damage to the  salivary glands.

When Menkhoff received radiation for his second diagnosis in the salivary  gland, he started injections of Ethyol® (amifostine), a drug that protects  salivary function. “It worked somewhat for me. I have limited function.”

Menkhoff also developed oral mucositis but resisted having a feeding tube  inserted, which is frequently required for patients whose treatment makes eating  extremely difficult. “I bought some weight gain products and mixed it with sweet  milk and bananas and had those three times a day. It was high in calories and  protein.”

Chemotherapy, especially for later stage head and neck cancers, has shown  increasing efficacy as a treatment modality. Initially, single agents were used,  but more recently combination chemotherapy has brought together numerous drugs  that, when used together, offer greater response rates than when used alone.

“Chemotherapy drugs, such as 5-FU, cisplatin, carboplatin, Taxol and  Taxotere, are widely used to treat more advanced head and neck cancers,  particularly those in the nasopharynx, hypopharynx and larynx. Their  effectiveness against other head and neck cancers has been tested in clinical  trials,” Shin remarks.

At the 2004 meeting of the American Society of Clinical Oncology,  investigators reported superior overall survival rates in patients who received  Taxotere® (docetaxel) plus a standard therapy (Platinol® [cisplatin]/5-FU) for  non-resectable locally advanced squamous cell carcinoma of the head and neck.  Patients in this phase III trial had statistically significant improved  progression-free survival and cancer response rates, as well as fewer severe  side effects compared with standard therapy alone.

“In this trial, investigators reported that the Taxotere/Platinol/5-FU  regimen was well tolerated and had a generally predictable and manageable safety  profile, ” says Kies.

Chemotherapy, like radiation, brings with it a wide array of possible side  effects that may include destruction of not only cancer cells but also other  rapidly growing cells, including healthy blood cells that fight infection, cells  in the lining of the mouth and digestive tract and those in hair follicles. As a  result, patients may have lower resistance to infection, sores in the mouth and  on the lips, loss of appetite, nausea, vomiting, diarrhea and hair loss. They  may also feel unusually tired and experience skin rash, itching, joint pain or  other discomforts.

Other treatments are being tested to prevent recurrence and/or second primary  cancer. In a recent issue of the Archives of Otolaryngology-Head and Neck  Surgery, Shin and Barbara A. Murphy, MD, associate professor of medicine and  director of the Head & Neck Oncology Program and the Pain & Symptom  Management Program at Vanderbilt-Ingram Cancer Center in Nashville, and  colleagues published results of a phase II study combining isotretinoin,  interferon-alpha and vitamin E as bioadjuvant therapy after definitive local  therapy.

“In this study, we report the long-term (49.4 month median) follow-up from  our previous chemoprevention trial using these substances,” says Shin.  “Among the 45 patients with stage 3 and 4 squamous cell carcinoma of the head  and neck treated under the protocol, 80 percent experienced progression-free  survival for at least five years. These results are significantly better than  the historical five-year overall survival of about 40 percent.

“We conclude that the bioadjuvant combination is highly effective in  preventing recurrence or second primary cancer,” he adds, “and its role as  standard therapy in advanced head and neck cancer is currently being  investigated in a randomized phase III trial.”

Shin says that one of the biggest treatment challenges is to find  effective ways to destroy the cancer while preserving normal organ function,  particularly in the voice box, and suppressing debilitating side effects. “There  are several therapeutic agents now in clinical trials that show promise,” he  says.

Among the new drugs being tested are Erbitux (cetuximab), Tarceva (erlotinib) and Iressa (gefitinib). Although each targeted therapy may work  differently, most focus their activity on proteins that stimulate cancer cell  growth, such as the epidermal growth factor (EGF). These growth-stimulating  factors act by either binding to specific receptors on the cell’s surface or by  using the receptor as an entry point, disrupting molecular signals that  stimulate cell growth. Many cancers, including lung, breast, ovarian, bladder,  prostate, colorectal, kidney and head and neck, produce too many EGF proteins  and depend on these proteins for growth.

ImClone Systems, the maker of Erbitux, submitted a supplemental new drug  application on August 30 for approval in treating squamous cell carcinoma of the  head and neck. Erbitux, a monoclonal antibody, is currently approved in  combination with Camptosar (irinotecan) for treating colorectal cancer that has  stopped responding to Camptosar-based chemotherapy.

Serving as support for the new indication is a phase III trial presented at  the 2004 ASCO meeting that tested Erbitux with and without radiation in 424  patients with advanced head and neck cancer. Those who received radiation plus  Erbitux showed significant improved survival (54 months) compared with those  receiving radiation alone (28 months). Furthermore, adding Erbitux to radiation  prevented the spread of cancer beyond the head and neck region more effectively  than radiation alone. Other studies indicate Erbitux is also effective as  second-line therapy in patients who received platinum-based therapy.

Overall, it’s a very exciting time in the treatment of head and neck cancer. Using a multidisciplined approach, we’re starting to develop  efficacious treatments combining targeted therapies and conventional treatments.

In other studies, researchers are trying to find ways to make radiation  therapy more effective against cancer and less damaging to healthy tissue by  using drugs that make cancer cells more sensitive to treatment while protecting  normal cells from radiation damage. Researchers are also testing new methods of  aiming radiation therapy more accurately, and studying how differences in  fractionation (how often radiation is given) help or hinder effectiveness.

In gene therapy approaches, researchers have found that many head and neck  cancers have mutations (genetic changes) of the p53 tumor suppressor gene.  Scientists are studying several gene therapies that target this gene by  replacing it with a normal gene, or using a modified adenovirus (cold virus) to  inactivate the p53 gene.

Past attempts to inject therapeutic genes directly into solid tumors have  shown promise, but treating metastatic cancer has been less successful because  either a patient’s immune system reacts against the therapy or the genes can’t  find their way to cancer cells.

“Overall, it’s a very exciting time in the treatment of head and neck  cancer,” says Kies. “Using a multidisciplined approach, we’re starting to  develop efficacious treatments combining targeted therapies and conventional  treatments. I believe we will make great strides in preserving function with no  marked increase in toxicity.”

Murphy agrees, adding, “It took nearly two decades of study to find out  that combination chemotherapy and radiation treatment improves outcome compared  with radiation alone. The role of induction chemotherapy remains unclear. Our  next challenge will be to determine which chemotherapy agents combined with  radiation provide the best outcome and whether induction therapy can benefit  selected patients. It will be years before we are able to complete the cohort of  studies that will answer these questions.”

“Although we have a long way to go,” Shin says, “I am increasingly  optimistic about new gene therapy and advanced drug delivery by nanotechnology  approaches for earlier treatment and, ultimately, to a strategy that may help  prevent cancer development.”

Patients undergoing both chemotherapy and radiation experience severe side  effects that dramatically affect their day-to-day lives, says Murphy, who  defines the side effects as acute, occurring during treatment, or late,  occurring after treatment. Kuhn adds that for his patients, quality of life  is difficult the first year after treatment.

After treatment, head and neck cancer patients may need rehabilitation that,  depending on location of the cancer and type of treatment, may include physical  therapy, dietary counseling and speech therapy. Reconstructive and plastic surgery may be needed as well.

Menkhoff has grown accustomed to his prosthesis, which he removes twice a day  to irrigate the cavity in his jaw and sinus. But he still has to work daily for  35 minutes to an hour to have the ability to open his mouth, a result of the  muscles tightening after surgery.

Murphy says medical professionals must help the  patient with their physical as well as emotional needs. Leupold agrees, adding,  “Sometimes, I was seeing a different health professional once or twice a day  because there were different specialists treating me.”

But Leupold found she needed more; she needed support from those going  through similar experiences. When she couldn’t find a support group, she started  her own in 1991. Today, her organization, SPOHNC (800-377-0928, 

),  has about 40 chapters throughout the nation and is expanding  internationally.

Menkhoff, now an active member of SPOHNC, says he wishes he had found the  organization with his first diagnosis instead of his second. Today he mentors  the newly diagnosed and continues to actively research the disease.

Leupold has remained cancer-free and devoted to  promoting awareness about head and neck cancer. “I learn more about the disease  in hopes of finding new information to pass along to those who are newly  diagnosed and to support those who are living with the disease,” she says. “A  patient support organization like SPOHNC is a vital component of the healing  process. It can have a positive impact on meeting the psychosocial needs of head  and neck cancer survivors as well as preserving, restoring and promoting their  physical and emotional health.”

New therapies may turn the tide for this disfiguring cancer.

Speaking Out On Oral Cavity Cancer

Yvette Cardozo has struggled with her weight all her life. She has tried weight  loss medications and fad diets. She exercises regularly and consumes fewer than  2,000 calories a day, but at 5 foot 8 inches and 190 pounds, she is classified  as overweight. “I can’t tell you how frustrating it is to have people tell us to  eat less and exercise more when it flat out doesn’t work for me and never has,”  says Cardozo, a 60-year-old writer and photographer from Seattle.

Cardozo knows researchers have linked obesity with certain cancers. It stays in  the back of her mind, especially with her family history of cancer and obesity.  Both of Cardozo’s parents died of cancer—her father of spinal cancer at age 49  and her mother of colorectal cancer. Her sister died of cardiac arrest, possibly  due to adult-onset diabetes, both obesity-related conditions. But even with  diet, exercise and annual cancer screenings, she wonders if she ’s doing  enough.

Obesity is the second leading cause of preventable death in the United States  after tobacco with nearly 200 million Americans categorized as overweight or  obese, according to the Centers for Disease Control and Prevention. As a  national health objective for the year 2010, the National Institutes of Health  is working to cut the obesity rate among adults by half—to less than 15 percent.  But unlike tobacco users, the rapidly increasing number of overweight or obese  Americans has doubled to more than 64 percent in the past 20  years.

Obesity is defined by body mass index (BMI), a combined  measurement of weight and height. A BMI of 25 to 29 is considered overweight,  and a BMI over 30 is considered obese. Though health experts hesitate to confirm  a link, recent research shows obesity may also contribute to several major  cancers, including colon, endometrial, kidney and esophageal cancers and breast  cancer in postmenopausal women. The obesity-cancer association may also lead to  an increased risk of dying from cancer.

Scientists haven’t discovered why obesity may predispose certain people to  cancer, but several obesity-fighting measures, including diet, exercise and  weight loss drugs, may lower cancer risk. Many cancer survivors have already  tapped into these potentially lifesaving measures, reporting in recent studies  that they are healthier in regards to diet, exercise and other lifestyle changes  after diagnosis.

With obesity and physical inactivity also linked to heart disease, diabetes,  hypertension and stroke, doctors are concerned about the number of  obesity-related deaths. “We are really at risk in this country for turning  around two centuries of progressively longer life expectancies,” says Richard  Boland, MD, chief of gastroenterology at Baylor University Medical Center in  Dallas. “It’s conceivable that in the next 20 to 30 years, we could see that  peak and actually turn around, and that would be terrible

Obesity occurs when the body takes in more calories than it can burn off, but  a lot more science lies underneath the fat.

“A person who has the genetic predisposition in the right environment—and we  have the right environment here in the United States&mdash;has a higher chance of  developing obesity,” says Caroline M. Apovian, MD, director of clinical research  at the Obesity Research Center at Boston Medical Center. While genetics does  play a role in excess weight gain, the obesity pandemic has only skyrocketed in  the past 20 years. Before drive-through restaurants, people stored fat as a  survival mechanism when food was scarce. The human body has not adapted to a  society with abundant high-fat foods and a sedentary lifestyle.

As new research looks at whether diet, genetics, physical activity, or weight plays the greatest role, scientists examine several potential biological causes, including myriad hormones, such as estrogen, leptin, ghrelin, and insulin.

Unfortunately, when people try to lose excess weight, the body works against  them. For overweight people, the body produces several hormones and other  chemicals to preserve its fat stores. These hormones alert the brain when weight  is lost, which decreases energy expenditure, lowers metabolism and increases  hunger. The body thinks it’s starving, so it tries to save as much fat as  possible.

Once a person achieves weight loss, it becomes harder to keep the weight off.  Levels of leptin, a hormone produced by fat cells, decrease as fat cells shrink.  When leptin levels go down, the brain recognizes that the body has less fat and  works to prevent further weight loss while trying to regain its stores.

“It seems that people who lose weight and keep it off have to work with fewer  calories to maintain their weight, probably because of leptin levels,” Apovian says. “Leptin levels are constantly down afterward, so the body’s trying  to gain that weight back and it drops the metabolic rate. They have to work  harder to keep the weight off.”

The hormone ghrelin also regulates the body’s weight. The gastrointestinal  (GI) tract produces this hormone after fasting and before meals, signaling the  brain to increase hunger. While over 10 other GI products signal the body to  stop eating, many of which are being researched as weight loss treatments,  ghrelin tells the body to eat more.

While numerous studies link obesity and certain cancers, scientists haven’t  discovered why the association exists or to what degree.

Twenty-four years ago, a paper published in the 

 estimated that a third of cancer-related deaths could be  attributed to diet, defined in the report as nutrition, not caloric intake.  Increased research actually produced more questions than answers, including what  each study meant by diet. Unlike the 

 article, recent studies cite  BMI or weight distribution. Also contradictory to the 

 report was a  major study in 2003 that found excessive weight and obesity may contribute to  only 17 percent of cancer deaths.

While BMI is the easiest and most widely used method to determine obesity,  factors such as body shape, muscle mass, diet and physical activity may be more  important than numbers on a scale. Citing studies that show ethnic groups  develop obesity-related diseases at different BMIs, organizations such as the  International Obesity Task Force have made recommendations to the World Health  Organization to revise the BMI standards for various ethnic groups.

Alfred Neugut, MD, PhD, head of cancer prevention at Herbert Irving  Comprehensive Cancer Center at New York’s Columbia University, says little  scientific research exists on obesity-associated cancers. “It’s not an easy  subject to study. Do people have a higher risk because of their weight or their  lifestyle?” Dr. Neugut queries.

As new research looks at whether diet, genetics, physical activity or weight  plays the greatest role, scientists examine several potential biological causes,  including myriad hormones, such as estrogen, leptin, ghrelin and  insulin.

 Insulin helps convert the sugar glucose to energy inside the cell.  When the body’s fat cells produce free fatty acids, resistin and several other  hormones, they impair the body’s ability to use insulin to convert glucose to  energy, causing a buildup of glucose. The pancreas perceives insufficient levels  of insulin as the cause of the excess glucose, so it begins producing additional  insulin. As insulin levels rise in the body, insulin-like growth factor 1 (IGF1)  also rises, promoting normal cell growth and possible tumor cell growth. An  obese person’s body then begins to utilize the glucose at higher insulin levels  than a normal-weight person.

Add to this the theory linking some cancers, namely breast and ovarian  cancers in postmenopausal women, to alterations in sex hormones, including  estrogen. “The hypothesis is that in postmenopausal women who are overweight or  obese, the fat is actually a source of estrogen,” says Shine Chang, PhD,  associate director of the National Cancer Institute’s Office of Preventive  Oncology. Before menopause, the ovaries produce most of the body’s estrogen.

Overweight postmenopausal women increase their risk of developing breast cancer by half over normal-weight women.

In heavy postmenopausal women, estrogen levels are higher than in  normal-weight postmenopausal women. Estrogen-sensitive tissues have continued  exposure to estrogen after menopause, leading to stimulation of  estrogen-responsive breast tumors. Overweight postmenopausal women increase  their risk of developing breast cancer by half over normal-weight women.

Researchers with the Women’s Intervention Nutrition Study (WINS) examined  whether a dietary fat reduction would lower the risk of recurrence and increase  survival in postmenopausal women with breast cancer. While the study showed a  decreased risk of recurrence and increased survival, women who had estrogen  receptor (ER)-negative breast cancer actually lowered their relative risk of  recurrence more than the women with ER-positive breast cancer, a finding that  surprised Rowan Chlebowski, MD, PhD, lead author of the study and an oncologist  at the Los Angeles Biomedical Research Institute.

“Our original hypothesis was that estrogen change would mediate any benefit,”  says Dr. Chlebowski. “If the effect is greater in ER-negative disease, it  suggests other factors mediate, such as insulin-related hormones.” Weight loss,  increased fruits and vegetables, less red meat and increased exercise may have  contributed to the benefit, but as with other studies in this area, the  difficulty becomes distinguishing what caused the positive results.

Studies consistently show an increased risk of colon cancer with obesity,  mostly in obese men. Weight distribution or increased abdominal fat may be more  important in colon cancer risk than overall BMI, and men tend to have more  abdominal fat than women. Colon cancer may also be diet or exercise driven. A  2002 review of several studies on exercise and colon cancer risk found that even  moderate physical activity reduced risk by half, and exercise often lowered risk  regardless of BMI.

Boland says most colon cancers are weakly tied to genetics, but the  predisposition to colon cancer can be brought out with other factors, such as a  diet high in fat and red meat and a lifestyle with little or no exercise.

“It’s hard to know what might be going on with being obese, because people  who eat too much might not exercise enough, but those that exercise are possibly  more conscious about what they eat and are less likely to eat red meat and fat.”  The issue of a low-fiber diet contributing to colon cancer is less apparent.  Several studies showed patients with adenomatous polyps who underwent a  several-year change to a low-fiber diet demonstrated no change in their risk for  recurrent colon polyps.

Though research identifies a complex association between obesity and cancer, a cause-and-effect link has not been made.

More elusive is the obesity and prostate cancer connection. “The one thing  surfacing now is the role between obesity and poor prognosis for prostate  cancer,” says Wendy Demark-Wahnefried, PhD, a nutritionist and former director  of the Program of Cancer Prevention, Detection and Control Research at Duke  University.

Two studies reported in 2004 found that obese prostate cancer patients are  more likely to have aggressive tumors and experience cancer recurrence after  surgery compared with patients with a BMI under 30. A study reported in August  2005 confirmed these results, showing men with a BMI over 35 are more than twice  as likely as normal-weight men to develop prostate cancer. Dr. Demark-Wahnefried  is working on a study in prostate cancer, testing whether a low-fat diet with or  without flaxseed lowers prostate cancer risk.

It may not be just how much you weigh, but where you store excess weight.  Higher levels of estrogen and prolactin, primarily female hormones, appear to  promote fat deposition on the lower body, which may be why women typically have  a pear-shaped body. Corticosteroids contribute to abdominal fat, resulting in an  android shape typically seen in obese men. An overweight or obese person who  carries weight around the midsection has a higher risk of developing diabetes,  heart disease or hypertension than a person who carries weight on their hips,  buttocks and thighs. Studies show this may also be true for obesity-associated  cancers. Many cancer risk studies use BMI to determine obesity, but BMI doesn’t  take body composition into consideration, which may be important in determining  cancer risk.

The different types of fat could also determine risk. Subcutaneous fat,  typically found underneath the skin of the hips, buttocks and thighs, is not  considered as unhealthy as visceral fat. The increased health risk comes from  visceral fat found inside the abdomen and around the organs. Visceral fat and  subcutaneous fat also feel different. A person with a soft, pudgy belly probably  has a lower risk of obesity-related diseases than a person with a hard belly,  which signifies visceral fat.

Many frustrated dieters have turned to interventional weight loss methods, a  multibillion-dollar-a-year industry in the United States. Many weight loss drugs  produce only a modest loss and only two are approved for long-term use.

But even modest weight loss could be beneficial. A 5 to 10 percent weight  loss can decrease lipid levels and blood pressure, increase good cholesterol  levels and lower the risk of diabetes and heart disease. A 2003 study looked at  the effect of intentional weight loss on cancer risk in over 21,000  postmenopausal women and reported a 14 percent decrease in relative risk. Women  who lost at least 20 pounds, resulting in a healthy BMI, had the same risk as  healthy-weight women who never lost weight. But the effect of weight loss on  cancer risk remains unclear.

Understanding fat and how it affects cells gives clues to a possible tie to cancer

Fall 2005 | CURE

Recommended Resources

Unexpected & Unique

The Complexities of Genetic Testing

Partial Breast Irradiation: A Convenient Alternative

Screening: Finding the Tumor

Passing Isolation

HRT: Not Our Mothers' Experience

Accelerated Drug Approval: Taming the Shortcut?

Speaking Out On Oral Cavity Cancer

The Science Behind Obesity

v4n3 - Breaking a Bad Habit

Types of Head & Neck Cancers

Calculating Risk

Radiation Side Effects: The Top 2

The Biology of Fat Cells

Exercise & Diet in the Cancer Patient

Fighting Fat

v4n3 - Care for the Cancer Survivor

v4n3 - Now What?

v4n3 - Resolving Conflict

v4n3 - The Drug Chase

Latest News