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New Blood-based Biomarker May Predict Recurrence of Breast Cancer and Treatment Response

April 15, 2014
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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.

Saraswati Sukumar, Ph.D.

Saraswati Sukumar, Ph.D.
Photo credit: Johns Hopkins Kimmel Cancer Center

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.

Elana Simon Recognized With Inaugural AACR Young Champion in Cancer Research Award

April 14, 2014
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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.

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Irregular Menstruation May Predict Increased Risk of Death From Ovarian Cancer

April 9, 2014
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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

April 9, 2014
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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.

Higher Coffee Intake May Reduce Liver Cancer Risk

April 9, 2014
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SAN DIEGO — The more cups of coffee a person drank, the lower the risk for developing hepatocellular carcinoma (HCC), the most common type of liver cancer, according to results presented here at the AACR Annual Meeting 2014, April 5-9.

This study found that compared with those who consumed fewer than six cups of coffee per week, those who consumed one to three cups per day had a 29 percent reduction in their risk for developing HCC, and those who consumed four or more cups per day had a 42 percent reduction in their risk for developing HCC.

“Coffee intake has been suggested to lower the risk for HCC in epidemiologic studies, but these studies were conducted outside of the United States,” said

V. Wendy Setiawan, Ph.D., assistant professor in the Department of Preventive Medicine at the USC Norris Comprehensive Cancer Center in Los Angeles. “We wanted to examine whether coffee consumption is associated with risk for developing HCC in multiethnic U.S. populations.

“Data from a diverse group of men and women from various ethnicities followed up for 18 years showed a statistically significant dose-response relationship between increasing coffee consumption and lowered HCC risk,” added Setiawan. “Now we can add HCC to the list of medical ailments, such as Parkinson’s disease, type 2 diabetes, and stroke, that may be prevented by coffee intake. Daily coffee consumption should be encouraged in individuals who are at high risk for HCC.”

Setiawan and colleagues conducted a prospective analysis of 179,890 men and women, which included 45,641 Caucasians, 29,486 African Americans, 13,118 Native Hawaiians, 52,548 Japanese Americans, and 39,097 Latinos. The researchers collected data on coffee consumption and other dietary and lifestyle factors upon study entry and followed them for up to 18 years.

Of the study participants, 498 developed HCC: 67 Caucasians, 73 African Americans, 34 Native Hawaiians, 171 Japanese Americans, and 153 Latinos.

The researchers found that the relationship between coffee consumption and lowered risk for HCC was independent of the study participants’ ethnicity, gender, body mass index, smoking status, alcohol intake, and diabetes status.

They had information on hepatitis B and C infections for 152 participants who developed HCC and 460 participants who did not develop HCC, and found that the effect of coffee consumption on HCC risk was also independent of hepatitis infections. Data, however, fell short of statistical significance.

“The roles of specific coffee components that are actually protective against HCC remain open to discussion,” said Setiawan. Her team will next examine whether coffee consumption is associated with incidence and mortality associated with various chronic liver diseases across ethnic groups.

This study was funded by the National Cancer Institute. Setiawan declares no conflicts of interest.

Nearly $5 Million in Research Grants Awarded for Innovative Pancreatic Cancer Research

April 9, 2014
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SAN DIEGO — The Pancreatic Cancer Action Network and the American Association for Cancer Research (AACR) awarded 14 grants through the 2014 Research Grants Program here today to outstanding scientists throughout the country, supporting their innovative research in the field of pancreatic cancer.

The grants support research into high-priority areas in an effort to reach the Pancreatic Cancer Action Network’s goal to double pancreatic cancer survival by 2020. Pancreatic cancer has historically been understudied and underfunded, yet it is the fourth leading cause of cancer death in the United States, and has the lowest survival rate of major cancers, at just 6 percent.

The diverse research topics funded this year include determining whether sudden-onset diabetes could be an early indicator of pancreatic cancer, strategies to starve pancreatic cancer cells of necessary nutrients, and a treatment method that involves harnessing the patient’s immune system to fight the tumor.

“Pancreatic cancer is among the most deadly of cancers,” said Margaret Foti, Ph.D., M.D. (h.c.), chief executive officer of the AACR. “With death rates steadily climbing over the past decade, more research into pancreatic cancer is urgently needed. The AACR is, therefore, proud to be partnering with the Pancreatic Cancer Action Network to support cutting-edge scientific research projects that have the potential to lead to major breakthroughs in the prevention, detection, and treatment of this devastating disease.”

“The most promising science has been selected for funding through a rigorous peer-review process. This year’s grant recipients hail from leading institutions throughout the country and range from early career investigators continuing to build the field of pancreatic cancer leaders to more senior scientists,” said Julie Fleshman, president and CEO of the Pancreatic Cancer Action Network. “Their collective efforts have the potential to answer important questions that could lead to significant scientific advances for pancreatic cancer, and ultimately improve patient outcomes. We look forward to working with our new grantees and welcoming them to our team.”   

The Pancreatic Cancer Action Network, in collaboration with the AACR, introduced the grants program in 2003, and has since awarded 108 research grants totaling more than $22 million to bright and motivated scientists across the country with the goals of developing a pipeline of researchers dedicated to studying the disease, supporting innovative ideas and approaches, and enabling the organization to reach its 2020 goal.

This year’s recipients will be honored today at the AACR Annual Meeting 2014, held April 5-9.

Meet the grant recipients and learn more about their funded projects.  

The 2014 Pancreatic Cancer Action Network-AACR Research Acceleration Network Grants are three-year grants totaling $1 million each. These grants offer strategic funding and project management services to high-priority projects already underway within the pancreatic cancer research community. This year’s recipients are:

  • Giulio F. Draetta, M.D., Ph.D., The University of Texas MD Anderson Cancer Center, Houston, Texas; and, Co-PI, Lewis C. Cantley, Ph.D., Joan and Sanford I. Weill Medical College of Cornell University, New York, N.Y.
    “Developing a novel oxidative phosphorylation inhibitor in pancreatic cancer”
  • Dung T. Le, M.D., Johns Hopkins Kimmel Cancer Center, Baltimore, Md.; and, Co-PI, Todd S. Crocenzi, M.D., Providence Portland Medical Center, Portland, Ore.
  • “GVAX + CRS-207 heterologous prime boost vaccination with PD-1 blockade”
    Supported by the Fredman Family Foundation

The 2014 Pancreatic Cancer Action Network-AACR Pathway to Leadership Grant is a five-year grant totaling $600,000. This grant is designed to support the future leadership of pancreatic cancer research by funding an outstanding early-career investigator beginning a postdoctoral, mentored research position and continuing through a successful transition to independence. This year’s recipient is:

  • Gina M. DeNicola, Ph.D., Joan and Sanford I. Weill Medical College of Cornell University, New York, N.Y.
    “Therapeutic targeting of NRF2-regulated metabolism in pancreatic cancer”

The 2014 Pancreatic Cancer Action Network-AACR Innovative Grants are intended to promote the development and study of novel ideas and approaches in basic, translational, clinical, or epidemiological research that have direct application and relevance to pancreatic cancer. These two-year grants provide $200,000 over the grant term. This year’s recipients are:

  • Michael Thomas Barrett, Ph.D., Translational Genomics Research Institute, Scottsdale, Ariz.
    “Genomic drivers of therapeutic responses in metastatic disease”
  • Dafna Bar-Sagi, Ph.D., New York University School of Medicine New York, N.Y.
    “PDA development: Heads or tails?”
  • Anirban Maitra, MBBS, The University of Texas MD Anderson Cancer Center, Houston, Texas
    “Macrophage function in pancreatic cancer-associated diabetes”
  • George Miller, M.D., New York University School of Medicine, New York, N.Y. “Regulation of pancreatic tumorigenesis by necroptosis”
    Supported by Celgene Corporation
  • Diane M. Simeone, M.D., University of Michigan Medical Center, Ann Arbor, Mich.
    “Mesenchymal stem cells in pancreatic cancer biology and therapeutic development”

The 2014 Pancreatic Cancer Action Network-AACR Career Development Awards are two-year grants of $200,000 that are designed to attract and support early-career scientists as they conduct pancreatic cancer research and establish successful career paths in the field. This year’s recipients are:

  • David G. DeNardo, Ph.D., Washington University in St. Louis, St. Louis, Mo.
    “Origins and impact of macrophages in pancreatic cancer”
  • Eugene J. Koay, M.D., Ph.D., The University of Texas MD Anderson Cancer Center, Houston, Texas
    “Changes in mass transport as a biomarker of response in pancreatic cancer”
  • Florencia McAllister, M.D., The University of Texas MD Anderson Cancer Center, Houston, Texas
    “Targeting IL-17 signaling axis in pancreatic ductal adenocarcinoma”
  • Kenneth L. Scott, Ph.D., Baylor College of Medicine, Houston, Texas
    “Functionalizing metabolic pathway driver aberrations in pancreatic cancer”
  • Kathryn E. Wellen, Ph.D., University of Pennsylvania, Philadelphia, Pa.
    “Understanding metabolic control of the pancreatic cancer epigenome”

The 2014 Pancreatic Cancer Action Network-AACR Fellowship is a one-year grant of $45,000 designed to support a postdoctoral investigator’s work in pancreatic cancer research. This year’s recipient is:

  • Barbara M. Grüner, Ph.D., Stanford University, Stanford, Calif.
    “Multiplexed in vivo drug screening: Inhibitors of metastatic seeding”
    Supported in memory of Samuel Stroum

American Association for Cancer Research Concludes Annual Meeting, Sets Attendance Record

April 8, 2014
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SAN DIEGO — The American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego (April 5-9) set an attendance record with more than 18,500 attendees.

This was two percent over last year’s Annual Meeting held in Washington, D.C. The AACR held its first Annual Meeting in 1907 as a one-day event at the Willard Hotel in Washington, D.C., with 11 scientists. For the past decade, the meeting has typically drawn between 15,000 and 17,000 people.

The AACR Annual Meeting is the premier destination for cancer research and draws scientists, clinicians, industry representatives, cancer survivors, high school students, and news media.

The AACR will hold its Annual Meeting 2015 in Philadelphia, where its headquarters are located, April 18-22. The AACR also has offices in Boston and Washington, D.C., and plans to open an office in China later this year.

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