PHILADELPHIA — The American Association for Cancer Research (AACR) applauds the U.S. Food and Drug Administration’s (FDA) proposal to extend its regulatory authority to additional tobacco products as part of the implementation of the Family Smoking Prevention and Tobacco Control Act. The FDA’s proposed rule signals the agency’s intent to regulate products that meet the statutory definition of “tobacco products” and that are not currently regulated by the agency. These products may include e-cigarettes, cigars, pipe tobacco, nicotine gels, hookah tobacco, and dissolvables.
“The use of electronic cigarettes is on the rise,” said Roy S. Herbst, M.D., Ph.D., chief of medical oncology at Yale Cancer Center and chair of the AACR Tobacco and Cancer Subcommittee. “We do not know the nature of the long-term health consequences of these devices or what effect they will have on smoking continuation or uptake by adults and youth. Therefore, FDA regulation of these products is appropriate and welcomed by the AACR.”
Tobacco is the leading preventable cause of death in the United States and contributes to 18 types of cancer and one-third of all cancer deaths. Although cigarette smoking in the United States has declined significantly, the AACR is concerned about the increasing use of other dangerous combustible tobacco products and the rise in the use of e-cigarettes, especially among our nation’s youth.
“It is imperative that the FDA regulates all tobacco products, including e-cigarettes and cigars, and prohibit the sale and marketing of these products to children,” said Margaret Foti, Ph.D., M.D. (h.c.), chief executive officer of the AACR. “In the absence of such regulation, consumers are at risk, most significantly our nation’s children. Therefore, the proposed rule is an important step forward in expanding the FDA’s regulation of tobacco and protecting the health of the American people.”
The AACR will be providing input on the FDA’s proposed actions during the open public comment period and urges the FDA to move quickly to issue final regulations once the comment period closes.
PHILADELPHIA — The presence of chronic inflammation in benign prostate tissue was associated with high-grade, or aggressive, prostate cancer, and this association was found even in those with low prostate-specific antigen (PSA) levels, according to a study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.
An analysis of prostate tissue biopsies collected from some participants of the placebo arm of the Prostate Cancer Prevention Trial (PCPT) found that those whose benign prostate tissue had chronic inflammation had 1.78 times higher odds of having prostate cancer, and 2.24 times higher odds of having an aggressive disease (characterized by Gleason sum of seven to 10), compared with those whose benign prostate tissue had no inflammation.
“We had the unique opportunity to investigate biopsy tissue from patients who had no indication to prompt a biopsy,” said Elizabeth A. Platz, Sc.D., MPH, professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health and member of the Sidney Kimmel Comprehensive Cancer Center in Baltimore, Md. “Participants in the PCPT who were not diagnosed with prostate cancer during the trial were recommended to undergo prostate biopsy at the end of that trial, which meant that prostate tissue was available not just for men who had the diagnosis of prostate cancer, but also for those who did not have the diagnosis.
“We found that men who had at least one biopsy core with inflammation had a higher likelihood of having high-grade prostate cancer compared with those who did not have any inflammation in their biopsy tissue,” said Platz. “While we know that inflammation is common in prostate tissue from men who have some indication to prompt a biopsy, such as high PSA or an abnormal digital rectal examination [DRE], we were surprised to find that the prevalence of chronic inflammation in the men who didn’t have any such indication was really high, about 78 percent.”
Between 1993 and 1997, 18,882 men who were at least 55 years old and had a normal DRE with a serum PSA of 3 ng/ml or less, were recruited to the PCPT. All participants completed questionnaires that included demographics, lifestyle, and medical factors, and were followed for seven years after they were randomly assigned to receive either finasteride or placebo.
The investigators screened all participants for prostate cancer by PSA and DRE during annual visits. Those who had an indication underwent a “for-cause” biopsy if they had cancer, and those who did not have prostate cancer diagnosed during the trial were recommended to undergo an “end-of-study” biopsy at the end of the trial even if they did not have an indication.
From the placebo arm of this study, Platz and colleagues sampled 191 prostate cancer cases and 209 frequency-matched controls for whom biopsy tissue was available. They performed histopathological evaluation of the biopsy samples to identify the prevalence and extent of inflammation, and types of inflammation, i.e., acute or chronic inflammation.
They found that 86.2 percent of cases and 78.2 percent of controls had at least one biopsy core with inflammation, most of which was chronic, and this difference was statistically significant. They also found that the association between chronic inflammation and aggressive prostate cancer did not change after adjusting for known risk factors including body-mass index, pack-years of cigarettes smoked, and history of diabetes.
In addition, this association held true even among men whose PSA levels were less than 2 ng/ml. “We detected chronic inflammation in prostate tissue of men who had prostate cancer but had PSA levels lower than 2 ng/ml, and thus our work supports an association between inflammation and prostate cancer that is not explained by PSA-associated detection bias,” said Platz.
Among men whose PSA levels were less than 2 ng/ml at the time of biopsy, those whose prostate tissue had inflammation had 4.11 times higher odds of having aggressive prostate cancer, compared with those whose prostate tissue did not have any inflammation.
“Our team is next studying the type of inflammatory cells that may be influencing the risk of aggressive prostate cancer,” said Platz. “This study is a stellar example of multidisciplinary research involving epidemiologists, pathologists, immunologists, urologists, and biostatisticians,” Platz added.
Angelo De Marzo, M.D., Ph.D., professor in the Department of Pathology at the Johns Hopkins Hospital, is a co-leader of this study.
This study and the PCPT, which was conducted by Southwest Oncology Group, were funded by the National Cancer Institute. Platz and De Marzo declare no conflicts of interest.
PHILADELPHIA — A newly developed, noninvasive blood-based assay, cMethDNA, is highly sensitive and specific in detecting breast cancer recurrence early, and shows promise as a viable tool in predicting treatment outcome, according to data published in Cancer Research, a journal of the American Association for Cancer Research.
The cMethDNA assay is a blood-based test built on a panel of 10 breast cancer-specific genes. Blood collected from breast cancer patients is processed to isolate circulating tumor DNA, and the assay detects if any of the 10 genes are hypermethylated, a process by which the activity of some genes that keep the cancers in check are “silenced.” Detection of hypermethylation in any of these genes in blood indicates that the patient may have a disease recurrence.
“Currently, the parameters used to find out whether a patient has had a recurrence after being treated successfully is mostly self-reported complaints, followed by imaging studies,” said Saraswati Sukumar, Ph.D., professor of oncology and pathology at the Johns Hopkins University School of Medicine in Baltimore, Md. “Our goal was to develop a noninvasive assay that can potentially detect recurrence in breast cancer patients before traditional methods, and administer this test during their scheduled visits.
“Using cMethDNA, we were able to detect a drop in methylation levels as early as two weeks, and weeks before traditional imaging methods can detect a recurrence,” added Sukumar. “Detecting early on whether or not the treatment is working for a patient can greatly help prevent unnecessary exposure to highly toxic agents, save time, and help initiate other treatments more likely to be beneficial.”
Development of this assay required two critical strategies: sensitivity, to ensure that the methylated genes floating in the serum are highly indicative of the tumor, and specificity, to ensure that these genes are not hypermethylated in white blood cells or in any other normal tissue.
To this end, Sukumar and colleagues did a large-scale, genomewide search for genes specifically found to be methylated in the blood and tumor tissues of cancer patients. Then, they selected a panel of genes that best differentiated between cancer and normal samples.
Next, this carefully selected panel was tested in independent samples from patients who participated in prospective clinical trials. Using this approach, they confirmed that the blood test detected the presence of cancer DNA in the serum with a sensitivity and specificity that were higher than 90 percent.
The researchers then analyzed blood samples from patients with metastatic breast cancer, collected before and at different times during treatment. Using the cMethDNA assay, they found a significant decrease in serum DNA methylation levels in patients who responded to the treatment, while no such decrease was observed in patients who showed no response or in those whose disease progressed.
The 10 genes in the panel include seven novel markers, AKR1B1, COL6A2, GPX7, HIST1H3C, HOXB4, RASGRF2, and TM6SF1, and three previously described markers, ARHGEF7, TMEFF2, and RASSF1.
Using data from The Cancer Genome Atlas, the researchers also determined that this assay may be efficient in detecting recurrent lung, colon, and rectal tumors. cMethDNA, however, requires further validation, according to Sukumar.
This study was funded by the Avon Foundation, the Rubenstein family, the John A. Sellon Charitable Trust, the Department of Defense Center of Excellence on Targeting Metastatic Breast Cancer Grant, Susan G. Komen, and the Breast Cancer Research Foundation. Sukumar is a co-inventor of and U.S. patent holder on the cMethDNA assay.
SAN DIEGO — The American Association for Cancer Research (AACR) honored Elana Simon, a survivor of fibrolamellar hepatocellular carcinoma who also conducted groundbreaking research investigating the molecular characteristics of the disease, with the first AACR Young Champion in Cancer Research Award at the AACR Annual Meeting 2014, held in San Diego, Calif., April 5-9.
Simon was presented with the award during the opening ceremony, Sunday, April 6, in recognition of her pioneering efforts to further the understanding of fibrolamellar hepatocellular carcinoma, and for serving as an inspiration to both junior and senior cancer researchers who are working hard to conquer cancer.
The AACR established the Young Champion in Cancer Research Award this year to recognize an individual who has made an early contribution to cancer research and enhanced public understanding about the disease.
“I would like to thank the American Association for Cancer Research and President Charles Sawyers for this award,” Simon said. “I would also like to thank my surgeon, Dr. Michael La Quaglia, for his support; everyone in my father’s lab who took time off from whatever they were doing to help me out, to work with me; and all of the fibrolamellar patients who raised the funds, donated their tissues, and even volunteered to work in the lab. Through working together with the public we can forge an alliance in which we will all win.”
Simon was diagnosed with fibrolamellar hepatocellular carcinoma, a rare variant of hepatocellular carcinoma that predominantly affects adolescents and young adults, six years ago, when she was just 12. She is now cancer-free and a co-author on a recently published Science paper that reports the identification of a chimeric transcript that characterizes the disease.
Simon was a central figure in bringing together fellow patients, their doctors, surgeons, and basic researchers from numerous disciplines, including cellular biophysics and genomics, to make a breakthrough that has the potential to transform the diagnosis and treatment of fibrolamellar hepatocellular carcinoma. Her ability to unite people from diverse fields and perspectives to rapidly achieve a scientific breakthrough highlights the importance of team science in the fight against cancer.
SAN DIEGO — Women with irregular menstrual cycles had a twofold increased risk of death from ovarian cancer, according to a large, prospective study presented here at the AACR Annual Meeting 2014, April 5-9.
“Among reproductive cancers, ovarian cancer is the most common cause of death, because it is usually diagnosed late in the disease process after it has spread,” said Barbara A. Cohn, Ph.D., M.P.H., director of the Child Health and Development Studies at the Public Health Institute in Berkeley, Calif. “Unfortunately, there is no reliable method for early diagnosis or screening, and symptoms like abdominal pain and bloating often do not come to a woman’s attention until the cancer has spread.
“In this large, prospective study, we found that those who had irregular menstrual cycles had a 2.4-fold increased risk of death due to ovarian cancer,” Cohn added. “This information may help earlier diagnosis and perhaps lead to a strategy to prevent ovarian cancer by pointing toward how the cancer develops and spreads.
“It is notable that the 2.4-fold increase in risk of ovarian cancer death we observed for women with irregular/infrequent cycles in this study is close to the threefold increase in risk observed for women with a family history of ovarian cancer in a first-degree relative,” explained Cohn. “Our study finding could lead to better understanding of the 90 percent of ovarian cancers that occur in women with no family history of ovarian cancer and with no known high-risk inherited mutations.”
Between 1959 and 1967, the Child Health and Development Studies enrolled more than 15,000 pregnant women and followed them for more than 50 years to study factors impacting health during pregnancy. This report is based on 14,403 women who had a single live birth. Cohn and colleagues used medical reports and self-reported data from these women on their menstrual irregularity, including those whose cycles were longer than 35 days, and those who had anovulation. The researchers used this information as a proxy for polycystic ovarian syndrome (PCOS).
Of these women, 13 percent reported menstrual irregularities when they were about 26 years of age and 64 of them died from ovarian cancer, around 69 years of age.
The association between menstrual irregularities and ovarian cancer death was independent of age, race, parity, and weight, and this association was stronger after the women reached their mid-60s, about 40 years after they entered the study, according to Cohn. The researchers ruled out use of fertility drugs or contraceptives prior to pregnancy as an explanation for their findings. An advantage of the study was that infertility was ruled out as an explanation for findings since all women in the study had achieved a live birth, she added.
They also found that when the data were analyzed by ovarian cancer type, menstrual irregularities increased risk for serous-type cancers and for endometrioid-type cancers by nearly threefold and fourfold, respectively. The sample size for endometrioid-type ovarian cancer was small and needs further evaluation in a larger group of women, said Cohn.
The researchers also found that the incidence of late-stage ovarian cancer was twofold higher for women with irregular or infrequent menstrual cycles, and this finding was consistent with their higher risk for death from ovarian cancer.
Findings from this study are contrary to the existing expectation that PCOS, which is characterized by less frequent ovulation and irregular or long menstrual cycles, would protect the ovary. But infrequent ovulation is not the only hallmark of PCOS, and there are a number of anatomical, hormonal, and metabolic abnormalities associated with PCOS that might explain the study findings, said Cohn.
This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, an institute of the National Institutes of Health. Cohn declares no conflicts of interest.
Prediagnosis Obesity Predicts Poor Outcome for Colorectal Cancer Patients, Even Those With a Tumor Marker Linked to Better Outcomes
SAN DIEGO — High body mass index (BMI), an indicator of obesity, before a colorectal cancer diagnosis was associated with increased risk of death after diagnosis, and this was seen even when tumors harbored the microsatellite instability (MSI) marker normally associated with better prognosis, according to results of a large prospective study presented here at the AACR Annual Meeting 2014, April 5-9.
“Our study, to our knowledge, is the first study with sufficient numbers to investigate how these independent risk factors work together to influence survival after a colorectal cancer diagnosis,” said Peter T. Campbell, Ph.D., director of the Tumor Repository in the Epidemiology Research Program at the American Cancer Society in Atlanta. “Colorectal cancer patients with tumors with the MSI-high characteristic have a better prognosis than patients with tumors lacking this feature. How obesity, as defined by a high BMI, influences survival of colorectal cancer patients has not been clearly determined.
“We found that a high prediagnosis BMI is associated with increased all-cause and colorectal-cancer specific mortality after diagnosis,” Campbell said. “We also found that high BMI overrides the survival advantage conferred on patients by an MSI-high tumor.
“Our data provide further evidence that maintaining a healthy body weight throughout life is very important,” Campbell continued. “They also suggest that prediagnosis BMI may be something that clinicians should consider when managing patient care.”
BMI is calculated as weight in kilograms (kg) divided by height in meters squared (m2). It is used to define healthy weight, overweight, and obesity. In adults, a BMI of 30 or more kg per m2 is considered obese.
Campbell and colleagues identified 6,763 patients with invasive colorectal cancer among participants who enrolled in the Colon Cancer Family Registry from 1997 to 2008. BMI two years before diagnosis was calculated from self-reports of height and weight. Tumor MSI status was available for 4,987 patients. Median follow-up was 5.3 years.
The researchers found that higher BMI two years before diagnosis increased risk of all-cause mortality after diagnosis: Every 5 kg per m2 increase in BMI increased risk of all-cause mortality by 10 percent. Similar associations were seen for patients with MSI-high and MSI-stable/MSI-low tumors: Every 5 kg per m2 increase in BMI increased risk of all-cause mortality by 19 percent and 8 percent, respectively.
According to Campbell, similar patterns of association were seen for colorectal cancer-specific mortality: Every 5 kg per m2 increase in BMI increased risk of colorectal-cancer specific mortality by 7 percent.
“Now that we have seen that obesity attenuates the survival advantage observed for patients with MSI-high tumors, we are looking at how it affects other tumor markers that have relevance for colorectal cancer survival,” said Campbell. “Ultimately, we would like to investigate associations between obesity and somatic tumor mutations to see if we can figure out how obesity drives cancer.”
This study was funded by the National Institutes of Health and National Cancer Institute. Campbell declares no conflicts of interest.