Early Detection of Digestive Cancers in Multiple Organs with DNA Stool Test

Mayo Clinic researchers have demonstrated that a noninvasive screening test can detect not only colorectal cancer but also the common cancers above the colon — including pancreas, stomach, biliary and esophageal cancers.

Gastrointestinal (GI) cancers account for approximately one in four cancer deaths. While high cure rates can be achieved with early-stage detection for each type, only colorectal cancer is currently screened at the population level. Most people associate colorectal cancer screening with invasive colonoscopy, but previous Mayo Clinic research has shown that stool DNA testing can identify both early-stage colorectal cancer and precancerous polyps. Researchers are now studying the use of noninvasive stool DNA testing to detect lesions and cancer throughout the GI tract.

“Patients are often worried about invasive tests like colonoscopies, and yet these tests have been the key to early cancer detection and prevention,” says David Ahlquist, M.D., Mayo Clinic gastroenterologist and lead researcher on the study. “Our research team continues to look for more patient-friendly tests with expanded value, and this new study reveals an opportunity for multi-organ digestive cancer screening with a single noninvasive test.”

The researchers studied 70 patients with cancers throughout the digestive tract. Besides colon cancer, the study looked at throat, esophagus, stomach, pancreatic, bile duct, gallbladder and small bowel cancers to determine if gene mutations could be detected in stool samples. Using a stool test approach developed at Mayo Clinic, researchers targeted DNA from cells that are shed continuously from the surface of these cancers. Also studied were 70 healthy patients. Stool tests were performed on cancer patients and healthy controls by technicians unaware of sample source. The stool DNA test was positive in nearly 70 percent of digestive cancers but remained negative for all healthy controls, thus demonstrating the approach’s feasibility.

Stool DNA testing detected cancers at each organ site, including 65 percent of esophageal cancers, 62 percent of pancreatic cancers, and 75 percent of bile duct and gallbladder cancers. In this series, 100 percent of both stomach and colorectal cancers were detected. Importantly, stool test results did not differ by cancer stage; early-stage cancers were just as likely to be detected as late-stage cancers.

“It’s very exciting to see this level of sensitivity for digestive cancer detection in our first look at this test application,” says Dr. Ahlquist, “Historically, we’ve approached cancer screening one organ at a time. Stool DNA testing could shift the strategy of cancer screening to multi-organ, whole-patient testing and could also open the door to early detection of cancers above the colon which are currently not screened. The potential impact of this evolution could be enormous.”

In October 2008, this Mayo Clinic research team published results of a multicenter study using first-generation stool DNA testing. In the seven-year, multicenter study (Ann Intern Med 2008;149:441-50), researchers found that the first-generation stool DNA tests were better than fecal blood tests for detecting cancer and precancerous polyps of the colon.

In January 2009 (Gastroenterology 2009;136:459-70), Mayo researchers published some technical improvements that nearly doubled the sensitivity of stool DNA testing for detecting premalignant polyps and increased cancer detection to about 90 percent, which is the approximate rate of detection observed for CT colonography.

Researchers hope that the next generation tests will have significant improvements in accuracy, processing speed, ease of patient use and affordability. “We anticipate that next generation tests will also be able to predict the tumor site, which will help physicians direct diagnostic studies and minimize unnecessary procedures,” says Dr. Ahlquist.

Source: Mayo Clinic, June 2, 2009

FDA Warns of Cancer Risk for Regranex in Treatment of Diabetics’ Foot and Leg Ulcers

The U.S. Food and Drug Administration (FDA) has announced the addition of a boxed warning to the label of Regranex Gel 0.01% (becaplermin) to address the increased risk of cancer mortality in patients who use 3 or more tubes of the product. Regranex is a topical cream indicated for the treatment of leg and foot ulcers that are not healing in diabetic patients.

The WARNINGS section of the product has been updated to include a BOXED WARNING and a description of the epidemiologic data that is the basis for the revised label. These data come from a retrospective study that compared cancer incidence and cancer mortality among 1,622 patients exposed to Regranex to 2,809 otherwise similar patients who were not exposed. The results were consistent with no overall increase in cancer incidence among the patients exposed to Regranex. However, there was a five-fold increased risk of cancer mortality in the group exposed to three or more tubes of Regranex.

"In announcing this label change, FDA still cautions health care professionals to carefully weigh the risks and benefits of treating patients with Regranex," said Susan Walker, M.D., director of the Division of Dermatological and Dental Products. "Regranex is not recommended for patients with known malignancies."

In late March, 2008 the FDA issued an Ongoing Safety Review Communication on Regranex notifying the public that it was conducting a safety review. This follow-up communication is in keeping with FDA’s commitment to notify the public of any regulatory changes with this FDA approved product.

Regranex is a medicine that is a recombinant form of human platelet-derived growth factor which is applied directly to diabetic foot and leg ulcers that are not healing. The recombinant form of platelet growth factor has a biologic activity that is much like that produced naturally by the body. Growth factors cause cells to divide more rapidly. It is for this reason that the manufacturer continued to monitor studies begun before Regranex was approved in December 1997 for any evidence of adverse effects such as increased numbers of cancers. In a long term safety study completed in 2001, there were more deaths from cancer in people who used Regranex than in those who did not use it.

Following the report of the study completed in 2001, an additional study was performed using a health insurance database that covered the period from January, 1998 through June, 2003. This study used the database to identify two groups of patients with similar diagnoses, drug use, and use of health services, one of which used Regranex and one group that did not. The results of this study showed that deaths from cancer were higher for patients who were given three or more prescriptions for treatment with Regranex than those who were not treated with Regranex. No single type of cancer was identified, but rather deaths from all types of cancer, combined were observed.

Source: FDA, June 6, 2008

Sports and Exercise Reduces Breast Cancer Rates

Women who actively participate in sports are 25% less likely to get breast cancer, though the benefits are not seen in obese women, and lean women see the lowest breast cancer rates.

The type of activity undertaken, at what time in life and the woman’s body mass index (BMI) will determine how protective the activity is against the disease.

The researchers reviewed the literature and analysed 62 studies looking at the impact of physical activity on breast cancer risk. They then examined the findings to find out how breast cancer risk appeared to be affected by type of activity, intensity of activity, when in life the activity was performed and other factors.

They found the most physically active women were least likely to get breast cancer. All types of activity reduced breast cancer risk but recreational activity reduced the risk more than physical activity undertaken as part of a job or looking after the house. Moderate and vigorous activity had equal benefits.

Women who had undertaken a lot of physical activity throughout their life had the lowest risk of breast cancer, and activity performed after the menopause had a greater effect than that performed earlier in life.

Physical activity reduced breast cancer risk in all women except the obese and had the greatest impact in lean women (BMI < 22kg/m2)

Women who were mothers, had no family history of breast cancer, were not white and had oestrogen receptor negative tumours also had a reduced risk of breast cancer.

The authors said the way in which physical activity protected against breast cancer was likely to be complex and may involve effects on sex hormones, insulin-related factors, the immune system and other hormone and cellular pathways.

Source: British Journal of Sports Medicine 2008; doi:10.1136/bjsm.2006.029132

New Study Begins for Kids with High Risk Cancer, Neuroblastoma

Molecular Insight Pharmaceuticals has announced the initiation of a clinical trial of Azedra in pediatric neuroblastoma patients. Neuroblastoma is a type of neuroendocrine cancer that primarily affects children and is the most common solid tumor in children outside of the brain.

The drug Azedra is a small, targeted radiotherapeutic molecule that binds to the norepinephrine transporter, a protein highly expressed on neuroendocrine tumors such as neuroblastoma. Because of this preferential binding, Azedra can deliver a greater amount of radiation to the tumor cell, thus increase tumor killing while reducing side effects.

“Neuroblastoma is an aggressive and difficult to treat form of neuroendocrine cancer that usually affects children under five years of age,” said Katherine Matthay, M.D., Chief of Pediatric Hematology and Oncology at the University of California San Francisco Children’s Medical Center. “Unfortunately, the prognosis for many of these children is quite poor. There currently are no FDA-approved treatments available for patients who have progressive, recurrent or refractory disease, and our current treatment options are extremely limited.”

Usage of Testicular Cancer Markers Too Limited, Say Researchers

A standard part of testicular cancer care isn’t used in more than half of all patients who have the condition, researchers have found.

Doctors generally rely on a series of three serum-based tumor markers for testicular cancer, since these are helpful with diagnosis, prognostication and surveillance for disease recurrence following treatment.

Reviewing 4,700 testicular cancer cases however, the researchers found that a combination of two of these tumor markers were used less than half of the time, while all three tumor markers were measured in just 16 percent of the cases.

The study authors also discovered that only 45% of cases used the tumor markers AFP (alpha fetoprotein) and HCG (human chiorionic gonadotrophin), with a third tumor marker, LDH or lactate dehydrogenates, used in combination with the other two, just 16% of the time. These results are reported in Urologic Oncology, Seminars and Original Investigations.

"Tumor markers play a central role in showing physicians how a patient is responding to treatment and whether the disease has recurred," says lead author Scott M. Gilbert, M.D., clinical lecturer in the University of Michigan Department of Urology. "We were extremely surprised by the low rates of usage."

Dr. Gilbert conduct regular checks on all three markers in their patients, because if the markers stay elevated after therapy, it shows the cancer remains; or if the markers begin to rise during the observation period following successful treatment, this too shows the cancer has returned.

One explanation for the low rates of marker usage could be poor documentation in medical records, since incidents of tumor marker use were not always recorded, says senior author Brent K. Hollenbeck, M.D., M.S., assistant professor in the U-M Department of Urology. "Even if it isn’t a problem related to the care of the patients, it is a quality problem at the medical centers that are not recording the data properly. Either way, major improvements need to occur," he says.

But other data in the study suggest that the reporting of tumor marker use may not be the problem. Using the data from the Surveillance, Epidemiology, and End Results (SEER) program, the researchers found substantially more documentation of PSA use in prostate cancer patients compared to the testicular cancer tumor markers. That information supports the notion that recording may not be the problem, but that the use of testicular cancer markers is in fact very low.

Source: University of Michigan

Researchers Find that a Small Molecule Can Block Cancer Cell Division

By activating a cancer suppressor gene, a small molecule called nutlin-3a can block cancer cell division, according to researchers at the National Cancer Institute (NCI), part of the National Institutes of Health.

This activation of the p53 gene leads to cellular senescence, a process by which cells lose their ability to grow and divide. An opportunity for new genetic mutations occurs each time a cell divides, so limiting the number of cell divisions in a cancer cell inhibits tumor progression.

Activation of p53 can suppress tumor growth through more than one mechanism. It can interfere with the cell cycle, prompting a cell with unrepaired DNA damage to commit suicide through a complex signaling pathway called apoptosis. Alternatively, p53 may trigger cellular senescence in response to DNA damage or cellular stress.

The expression of p53 is regulated by Mdm2, a protein that is overexpressed in several human cancers. ,are small-molecule inhibitors that prevent the p53 protein from forming a complex with Mdm2, resulting in activation of p53. Previous studies have shown that nutlin can induce apoptosis in human cancer cells.

"Although p53 is mutated or deleted in about half of all cancers, it is still potentially functional in the other 50 percent," said Curtis C. Harris, M.D., chief of the Laboratory of Human Carcinogenesis at NCI’s Center for Cancer Research and an author of the study. "A better understanding of molecules, such as nutlin-3a, that can activate p53 may lead to the development of new treatment options for certain cancers."

To examine the effects of nutlin-3a on cellular senescence, the Harris team exposed human skin cells and cancer cells to two different forms of nutlin-3: forms a and b. (Nutlin-3a has a 150-fold greater affinity for Mdm2 than nutlin-3b.) After a seven-day exposure period, the scientists found that almost 100 percent of the cells treated with nutlin-3a had stopped proliferating. These cells did not regain the ability to proliferate even after being removed from nutlin-3a, indicating that they had undergone permanent senescence. By contrast, nutlin-3b had little effect on the cells.

Next, the researchers investigated whether the senescence induced by nutlin-3a is dependent on the presence of p53 protein. After exposure to nutlin-3a for seven or 14 days, more than 80 percent of the human cells containing a functional p53 gene exhibited signs of senescence. The researchers also found that nutlin-3 treatment increased the expression of p53. However, the researchers did not observe any changes in p53-deficient cells.

Previous research by this team showed that the genes affected by p53 activation differed depending on the type of activator. To gain a better understanding of nutlin-3a-induced senescence, the researchers used microarray analysis to determine the effect of p53 activation on gene expression after cancer cells were treated with nutlin-3a. Microarray analysis is a technique that allows researchers to examine the expression of thousand of genes simultaneously. Almost 3,000 genes were differentially expressed when cells with normal p53, cells with mutant p53, and p53-deficient cells were compared. Among the genes with increased expression after nutlin-3a-activation of p53 were several genes that play a role in cellular senescence and cell death.

The researchers also found that the inhibitor of growth 2 gene (ING2) was among those with decreased expression in response to nutlin-3a treatment. ING2 regulates gene activation or expression, and it may play a role in tumor development, cell proliferation, and senescence. The researchers found that p53 seemed to suppress ING2 expression by binding directly to two sites on the ING2 promoter.

"This study further characterizes the actions of nutlin-3a on genes that can play a role in the development of cancer," said Harris. "Our study reinforces the idea that using Mdm2 inhibitors, such as nutlin-3a, to promote the growth suppressive and cell-killing activity of p53 is a potentially valuable strategy to pursue in cancer treatment."

Source: Cancer Research, May 1, 2008 and National Institutes of Health (NIH)

Protecting Yourself from the Sun to Avoid Skin Cancer

Before leaving home for a day of outdoor activity, take appropriate precautions to ensure that your and your family’s skin is well-protected, as the majority of all skin cancers are caused by the sun.

According to Susan Chon, M.D., assistant professor of dermatology at The University of Texas M. D. Anderson Cancer Center, a sunscreen with an SPF of at least 30 is a good choice for most people. One ounce of sunscreen (enough to fill a shot glass) is considered sufficient to properly cover sun-exposed areas. To get the most protection from sunscreen, generously reapply throughout the day. This is especially important because factors such as humidity, perspiration and uneven product application can cause sunscreen to lose its effectiveness.

Sun Protection Checklist
Chon recommends gathering the following items before heading outdoors.

  • Sunscreen with SPF 30 or greater
  • Lip balm with SPF 30
  • Hat with a brim or cap
  • Long-sleeved shirt (preferably sun protective clothing)
  • Sunglasses with UV protection

"These are great items to keep handy in your bag to prepare for the sun as it intensifies throughout the day," Chon said.

Application Time Line
Chon suggests the following time line for when to best use these items.

Morning: 8 – 10 a.m. Apply sunscreen with SPF 30, at least 30 minutes before sun exposure.
Reapply sunscreen every two hours.
Wear a hat, sunglasses and lip balm.

Midday: 11 a.m. – 2 p.m. (hottest time of the day)
Seek shade for extra protection.
Wear a long-sleeved shirt with a hat and sunglasses.
Reapply sunscreen and lip balm every two hours.

Afternoon: 3 – 5 p.m.
Keep wearing a hat and sunglasses.
Reapply sunscreen and lip balm every two hours.

"Remember, if you are sweating or swimming, you may need to reapply more often," Chon said. Avoid reflective surfaces such as water, sand, snow and concrete. "You can burn from indirect exposure to the sun, too," Chon said.

According to the American Cancer Society, more than one million cases of basal cell or squamous cell cancers, the most common types of skin cancer, occur annually. The most serious form of skin cancer is melanoma, of which more than 60,000 people are expected to be diagnosed in 2008.

Source: University of Texas M. D. Anderson Cancer Center

Obese Women Experience More Aggresive Breast Cancer

Obese women with breast cancer have lower rates of survival, and suffer a more intense form of the disease, according to recently-published research.

"The more obese a patient is, the more aggressive the disease," said Massimo Cristofanilli, MD, associate professor of medicine in the Department of Breast Medical Oncology at The University of Texas M.D. Anderson Cancer Center. "We are learning that the fat tissue may increase inflammation that leads to more aggressive disease."

606 women with breast cancer were observed by Cristofanilli and colleagues, and classified by body mass index into three groups—normal/underweight (24.9 or below), overweight (at least 25 but less than 30), or obese (more than 30). At five years, overall survival was 56.8 percent among obese women, 56.3 percent among overweight women and 67.4 percent among normal weight women. The 10-year survival rate was 42.7 percent among obese women, 41.8 percent among overweight women and 56.5 percent among normal weight women. Researchers found that the rate of inflammatory breast cancer was 45% among obese women, compared with 30% in overweight women, and 15% in women with normal weight.

Obese or overweight women also displayed a higher risk of breast cancer recurrence. Obese women (50.8%) reported a recurrence after 5 years, compared with normal weight women (38.5%). After 10 years, the rate of recurrence was 58% in obese women and 45.4% in women with normal weight.

"Obesity goes far beyond just how a person looks or any physical strain from carrying around extra weight. Particular attention should be paid to our overweight patients," Cristofanilli said.

Drugs commonly used to treat cancer patients, such as tamoxifen, said Dr. Cristofanilli tend to increase weight gain during treatment – an effect physicians should note carefully. "We have actually become quite good at managing acute side effects such as nausea in our chemotherapy patients and it goes away within a couple of days," Cristofanilli said. "Following the nausea, our patients tend to overeat, which further increases their risk of weight gain. We need to implement lifestyle modifications interventions and develop better methods to follow these patients closely."

Clinical Cancer Research, March 15, 2008

Genistein in Soybeans May Halt Prostate Cancer Spread

Genistein, an antioxidant found in soybeans, almost completely prevented the spread of human prostate cancer in mice, according to a study published in the journal Cancer Research. In the study, genistein was used in an amount equivalent to what a human being would consume in a soybean-rich diet.

Genistein decreased metastasis of prostate cancer to the lungs by 96% compared with mice that did not eat the compound, the first demonstration that genistein can stop prostate cancer metastasis in a living organism. "These impressive results give us hope that genistein might show some effect in preventing the spread of prostate cancer in patients," said the study’s senior investigator, Raymond C. Bergan, MD, director of experimental therapeutics for the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"Diet can affect cancer and it doesn’t do it by magic," Bergan said. "Certain chemicals have beneficial effects and now we have all the preclinical studies we need to suggest genistein might be a very promising chemopreventive drug."

Bergan has already shown in prostate cell cultures that genistein slows detachment of cancer cells from a primary prostate tumor, and checks cell invasion. It does this by blocking activation of p38 MAP kinases, molecules which regulate pathways that activate proteins that loosen cancer cells from their tight hold within a tumor, pushing them to migrate. "In culture, you can actually see that when genistein is introduced, cells flatten themselves in order to spread out and stick strongly to nearby cells," he said.

Researchers implanted groups of mice with an aggressive form of prostate cancer, having first fed them genistein. The amount of the chemical in the mouses’ blood was equivalent to human blood concentrations after eating soy foods, said Bergan. Genistein stopped lung mestasis almost completely, although it did not reduce the size of the tumors that developed within the prostate. Repeating the experiment produced he same result.

The size of tumor cells’ nuclei in the animals’ tissue was checked, to see whether he cells had flattened t in rder to spread. "Within a tumor, it is hard to tell where the borders of cells stop, so one way to measure adherence is to look at the size of the nuclei in cells and see if they are wider due to cell spread," Bergan said. "And that is what we found, demonstrating that the drug is having a primary effect on metastasis."

"What we think is happening here is that the cells we put in the mice normally like to move. When genistein restricted their ability to do so, they tried to compensate by producing more protein involved in migration. But genistein prevented those proteins from being activated," he said. "This is really a lesson for researchers who depend on biomarker studies to test whether a treatment is working. They need to be aware that those biomarkers might be telling only half of the story."

Source: Cancer Research, a journal of the American Association for Cancer Research. March 15, 2008.

Genetic Markers Identify Probability of Lung Cancers Recurrence

Genetic alterations in tumors and tissue taken from early-stage lung cancer patients are clear pointers to which cancers might recur. Researchers say the findings could change the approach to treating even the smallest lung cancers—the size of a pea—which are known to recur within five years in 30 to 40 percent of patients.

"This is DNA forensics for cancer," says Malcolm Brock, M.D., associate professor of surgery at Johns Hopkins. "While there may be no trace of cancer that we can spot after surgery with a microscope, the DNA evidence from these tumors may have been left at the scene, especially in lymph nodes."

The research team from Johns Hopkins Kimmel Cancer Center identified methyl groups that connect with the DNA structure of a gene. The development of cancers signals cells to switch certain genes on or off, and methylation is a common phenomenon in this process. Disruption to these signals may create abnormal proteins that lead to cancer or its recurrence.

In the study, Brock and his team checked more than 700 surgical samples from 167 early stage non-small lung cancer patients, looking for specific methylation patterns linked o cancer. For 51 patients, whose cancers recurred within 40 months, tumor and lymph node tissue was compared with samples from the remaining 116 patients whose cancer did no recur. The scientists tested all the samples for methylation on seven genes linked to the development of lung cancer. Four of them—p16, H-cadherin, APC and RASSF1A—showed the highest amounts of methylation in patients who had a recurrence of the cancer.

For many of the genes, the study revealed a twofold difference in methyl marks between recurrent cancers and those that did not return.

"The DNA evidence we see for many of the recurring cases suggests it may be wise if our work is confirmed to reclassify such cancers as advanced disease instead of early stage," says Brock.

Higher than normal methylation, combining two genes known as p16 and H-cadherin located in both tumor tissue and a lymph node remote from the tumor area, meant that cancers returned faster than average in 11 patients. For 8 of them this methylation pattern had cancers returning within a year; for the remaining 3 it took 30 months for the cancers to recur.

When analyzing the results to quantify the odds on a patient’s cancer returning, they noted a 5 to 25-fold in risk depending on the particular methylation pattern. While the small sample size meant that some of the gene markers lacked statistical significance, they believed that odds predictions were valid for p16 and H-cadherin.

Kimmel Cancer Center medical oncologist James Herman, M.D. says if these results are confirmed, it may lead doctors to consider treating high-risk patients more aggressively with chemotherapy after surgery. He also believes that therapies which target these gene patterns by stripping off methyl groups hold promise as well. "These marks of aggressive disease also are themselves targets for therapy."

The study appeared in the March 13 issue of the New England Journal of Medicine.