Could a tampon help predict endometrial

cancer? Mayo Clinic researchers say yes

Researchers at Mayo Clinic (Rochester, Minnesota) have shown that it is possible to detect endometrial cancer using tumor DNA picked up by ordinary tampons. The new approach specifically examines DNA samples from vaginal secretions for the presence of chemical "off" switches – known as methylation – that can disable genes that normally keep cancer in check. The finding is a critical step toward a convenient and effective screening test for endometrial cancer, which is the most common gynecologic malignancy in the U.S. The results are published in the journal Gynecologic Oncology.

"Unfortunately, there is no equivalent to a Pap smear or a mammogram for endometrial cancer," says Jamie Bakkum-Gamez, a gynecologic oncologist at Mayo Clinic and lead author of the study. "We know that the earlier a woman is diagnosed, the better the likelihood is that she is going to have a positive outcome from cancer treatment. Our goal is to use our findings to develop a tool for the early detection of endometrial cancer that women could use in the comfort of their own homes."

The American Cancer Society (Atlanta) estimates that over 50,000 new cases of endometrial cancer will be diagnosed in 2015. Though the malignancy is more common in white women, blacks are usually diagnosed at a later stage and are more likely to die from the disease. In most cases, women discover they have endometrial cancer only after abnormal vaginal bleeding prompts a visit to the doctor. However, more insidious molecular changes take place long before such symptoms appear.

Before a cell can turn cancerous, it has to subvert the genetic checks and balances that normally keep it from growing out of control. Thousands of different genes likely play a role in suppressing the development of tumors. In cancer, these tumor suppressor genes are often mutated outright or simply masked with chemical tags or methyl groups known as methylation. Previous research has shown that a wide variety of genes are turned "off" by such methylation in different types of cancer, leading many investigators to explore how these molecular markers could be used to diagnose or even treat the disease.

A small study published in 2004 showed that DNA samples collected from tampons was excessively methylated or hyper-methylated in women with endometrial cancer compared to women without the disease. However, in the years since then little progress has been made in turning the approach into a practical screening test.

"No one really took that idea and ran with it," said Bakkum-Gamez. "We wanted to take this initial study one step further, and use advances in technology to see if we could develop a better method of differentiating between cancerous and benign cells."

First, Bakkum-Gamez and her colleagues obtained samples from 66 women who were about to undergo a hysterectomy, 38 because of endometrial cancer and 28 due to other indications. Each woman used an intravaginal tampon to collect vaginal secretions and also underwent endometrial brushing, a procedure that uses a wire brush to scrape cells from the inner lining of the uterus.

The researchers isolated DNA from the samples and then analyzed 97 methylation sites along 12 different genes, half initially discovered by members of the research team and half previously reported by other researchers. They found that methylation was higher in specimens from women with endometrial cancer for 9 of the 12 genes analyzed. The results were similar regardless of whether DNA was acquired through a tampon or endometrial brushing.

Despite the encouraging results, the researchers say they need to further refine their method before it can be used clinically. Now, Bakkum-Gamez and her colleagues are looking for additional genes that are mutated or methylated in the earliest stages of endometrial cancer. Once they have the final lineup of genes to use in the test, they plan to validate the test using samples obtained through a clinical trial that is currently accruing 1,000 women at higher risk of endometrial cancer.

The final product may look very similar to Cologuard, an at-home screening kit recently approved by the FDA. Cologuard was co-developed by Mayo Clinic and Exact Sciences (Madison, Wisconsin), and analyzes DNA from stool samples for alterations associated with colon cancer.

Detecting cancer cells in blood can give an

early warning of treatment failure

A blood test that measures the number of cells shed from prostate tumors into the bloodstream can act as an early warning sign that treatment is not working, a major new study shows.

Researchers showed that measuring the numbers of circulating tumor cells in the blood predicted which men were benefiting least from a prostate cancer drug after as little as 12 weeks of treatment.

They hope their work will allow doctors to switch patients to alternative treatments earlier than is currently possible, if these results are confirmed by further studies. The research could also hasten the development of cancer treatments by speeding up clinical trials, since doctors could tell much earlier whether a treatment is working.

The study was led in the UK by researchers at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and also involved several leading international institutions.

As tumors grow and progress, they shed cancer cells into the bloodstream, some of which can seed new secondary tumors elsewhere in the body. So the researchers wanted to see whether a high number of circulating tumors cells was an indication of a growing tumor that wasn't responding to treatment, and could predict a lower chance of survival.

The study, published in the Journal of Clinical Oncology, involved the detailed analysis of blood samples from 711 men who took part in a major Phase III trial of the prostate cancer drug abiraterone.

Researchers measured numbers of circulating tumor cells at four-week periods after the start of treatment with the drug, along with a range of other biomarker molecules in the blood including lactate dehydrogenase (LDH), high levels of which are a sign of general tissue damage.

The trial itself had used the standard trial end points of average overall survival and survival free of cancer progression to show abiraterone's effectiveness in late-stage prostate cancer. But the researchers were able to cross-reference those results with data on circulating tumor cells and LDH levels in each man taking part.

They found a correlation between those men who had responded least well to treatment with abiraterone, and higher levels of cancer cells and LDH in the bloodstream, measured 12 weeks after starting treatment. They showed that levels of circulating tumor cells varied independently of a range of other biomarkers.

To prove the effectiveness of a new drug, clinical trials normally need to be run until the cancer is progressing clinically for each patient – and often until many of the patients on the trial have died. But with this new blood test, it might be possible to use circulating tumor cells as an early indicator that a drug is or is not working, and as a predictor of survival.

Study leader Professor Johann de Bono, Professor of Experimental Cancer Therapeutics at the ICR and Honorary Consultant at The Royal Marsden NHS Foundation Trust, said: "The past decade has seen unprecedented success in the development of new drugs for advanced, metastatic prostate cancer. One of the major challenges we face now is in optimizing the use of these new treatments by making sure that the right men receive them, and only for as long as they are benefiting.

New score predicts heart disease and stroke

risk for anyone in world aged over 40

For the first time, scientists have developed a new risk score that can predict the 10-year risk of developing heart disease or having a stroke in persons aged 40 years or older in any world country.

The research is published in The Lancet Diabetes & Endocrinology journal, and was led by Goodarz Danaei, Assistant Professor of Global Health at the Harvard T. H. Chan School of Public Health in Boston.

Danaei and colleagues developed, validated, and evaluated the new score, called Globorisk, using data from eight cohort studies, including more than 50,000 participants. Unlike previous risk scores, Globorisk can be updated to fit local conditions and risk factor levels in different countries using routinely available information.

Danaei explains, "Globorisk is an important advance in the field of global cardiovascular disease prevention. Until now, most prediction scores were developed using a single cohort study and were never validated for accuracy in national populations for low- and middle-income countries. Therefore, clinicians and public health policy makers in these countries were left without a reliable tool to predict cardiovascular risk in their patients, community, or country."

Globorisk measures cardiovascular risk in individuals aged 40 or older by factoring in the person's smoking status, blood pressure, diabetes status, and total cholesterol level, whilst adjusting for the effects of sex and age on cardiovascular disease between countries.

The researchers recalibrated and applied their risk score to 11 countries from different world regions, using data from recent national health surveys to replace the average age-and-sex risk factor levels in each country and incorporating cardiovascular disease death rates for each age-and-sex group. They developed country-specific risk charts for predicting individuals' risk of cardiovascular disease, and country-specific assessments of the 10-year cardiovascular disease burden.

They estimate that the proportion of people at high risk (10% or higher) of having a fatal heart attack or stroke within 10 years is higher in low- and middle-income countries (eg, China and Mexico) compared with high-income countries (eg, South Korea, Spain, and Denmark). For example, in China around a third of men and women (nearly 170 million aged between 40 and 84 years) have a high 10-year risk of dying from a cardiovascular event compared with only 5%-10% of men and women in Spain and Denmark.

According to Danaei, "Globorisk can be used to identify individuals at high risk of developing cardiovascular disease who are most likely to benefit from lifestyle changes or preventive drug treatment. Moreover, by estimating the number of people who have a high risk in any given country we have more chance of accurately measuring progress towards the WHO target of 50% coverage of multi-drug treatment and counseling for people aged 40 years and older at high risk of cardiovascular disease."