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Detecting cancer outcomes in the U.S. population following major changes in health behaviors often takes decades, as opposed to years. This is because many cancers are slow growing and don’t manifest themselves in a detectable way until years after the event or events that may initiate them. This delay in changing rates is particularly true for mortality outcomes in women for two cancers—lung and breast—affected by significant changes in health behaviors in the past 10 to 20 years.

Shifts in smoking patterns, both initiation and cessation, are fairly easy to track, and have been linked to a number of seminal events. Men started smoking at increasing rates during World War II and didn’t begin noticeable cessation efforts until after the U.S. Surgeon General’s announcement linking smoking to lung cancer in the 1960s. Even then, it took almost four decades to see a drop in death due to lung cancer for men, and indeed, it was not until the end of the 20th century that such drops were noticeable by statisticians. By contrast, women didn’t take up smoking as much as men until the 1960s, when cigarette manufacturers started designing and heavily promoting products for women. In part because they began smoking in large numbers later in the 20^th century, cessation of smoking by women occurred years after men began to quit.

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With the release of 2009 data from NCI’s SEER program on April 16, 2012, experts can now point to a statistically significant decline in lung cancer mortality for women. This turning point is particularly important, as lung cancer is the No. 1 cancer killer for both men and women. Lung cancer cases make up nearly a quarter of all cancers deaths in the U.S.  A continuation of the trends showing a drop in lung cancer mortality for both sexes would indeed be good news for the health of the nation.

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The other cancer in women that has been noticeably affected by a change in health behaviors this century is breast cancer. When NIH released the first results from the Women’s Health Initiative in 2002, the study pointed to an increased risk for breast cancer among women who used hormone replacement therapy. That news caused many women to stop taking hormone replacement drugs, and in 2003 the SEER program reported a marked decrease in breast cancer incidence.  Now, almost 10 years later, the SEER data for 2009 show no appreciable change in incidence of breast cancer since 2003.  Whether the decline in HRT use has affected breast cancer mortality rates is still unclear, in part, due to high survival rates experienced by many breast cancer patients.

In the accompanying video interview, Kathy Cronin, Ph.D., acting chief of NCI’s Surveillance Research Program, discusses lung and breast cancer results from the SEER 2009 release, as well as other outcomes reported in this year’s release.

For more information on using the data released as part of SEER’s annual Cancer Statistics Review, see our article from last year’s release:  Need stats? How to find the most up-to-date cancer statistics

Click here to view the embedded video.

This past weekend, more than 18,000 academic, industry, and government scientists; cancer survivors; philanthropic representatives; and industry professionals gathered in Chicago for the annual meeting of the American Association for Cancer Research. Founded in 1907, AACR is the world’s largest—and was the first—professional organization dedicated to advancing cancer research.

Over its four days the meeting features hundreds of speakers and sessions, thousands of papers presented in poster sessions, and dozens more minisymposia. As you might expect, NCI-designated Cancer Centers and their dedication to important research were on full display. Below are some highlights. Please check back often; this list will be expanding as embargoes expire.

• Cancer Institute of New Jersey

Functional Link Identified Between Two Causes of Breast Cancer Treatment Failure. Research from The Cancer Institute of New Jersey (CINJ) shows a functional link between two major causes of treatment failure in breast cancer, showing the protein behind one of these causes plays a role in increasing the drug resistance properties of the other.  The work, investigators say, could help to identify targeted therapies.

Coordinated Blocking of Cancer Cell Survival Pathways Could Play Role in Developing New Melanoma Therapies. A coordinated effort to block signaling pathways that promote cancer cell growth and survival enhances programmed cell death in melanoma.

Vaccine Regimen that Strengthens Body’s Immune Defenses Associated with Stable Disease in Treatment of Pancreatic Cancer. A series of vaccine injections given directly into a pancreatic cancer tumor is shown to be associated with stable disease in patients who are not candidates for surgery. Early results of a clinical trial being conducted at CINJ are being presented during a poster session.

• Case Comprehensive Cancer Center

Network signatures of survival in glioblastoma multiforme. A “systems” approach to finding networks of genes that may characterize short-term GBM survivors from long-term GBM survivors, rather than looking for individual proteins. (Added 4/4/12)

Proteomics signature of long-term versus short-term survival in glioblastoma. This study sought to identify protein biomarkers that can help physicians determine which patients may benefit from standard treatment for GBM.  Using research tumor samples from patients with short-term survival (defined as fewer than nine months after diagnosis) and patients with long-term survival (who lived greater than 18 months after diagnosis), the investigators found 183 proteins to be significant between survival groups.  Biomarkers have been identified in other cancers such as breast and colon but progress in treatment for GBM patients has been slowed by the absence of biomarkers to define treatment response.

• Fox Chase Cancer Center

Researchers Uncover a Viable Way for Colorectal Cancer Patients to Overcome Drug Resistance. The results, which highlight the use of a novel drug called ARI-4175, may eventually point to new approaches that can be used in treating other cancers. (Added 4/4/12)

Researchers Develop a New Cell and Animal Model of Inflammatory Breast Cancer. The new model may provide scientists with a better understanding of the disease and help with developing effective interventions. (Added 4/4/12)

New Compound Targets Key Mechanism Behind Lymphoma. The product, once available in the clinic, could be the first to hit a pathway that drives multiple types of lymphoma. (Added 4/3/12)

Scientists at Fox Chase Discover Link between Estrogen and Tobacco Smoke. The findings suggest that new therapies targeting estrogen’s metabolism may help prevent or treat lung cancer. (Added 4/3/12)

Protein Aurora-A is Found to be Associated with Survival in Head and Neck Cancer. Fox Chase scientists suggest that the findings could also serve as a new target for treatment.

The Protein Survivin Could be a Useful Biomarker for Pancreatic Cancer.

New Boost for Pancreatic Cancer Therapy. Additional compounds may help first-line drug kill cancer cells.

Researchers Identify a Gene that Predicts Recurrence in Squamous Cell Carcinoma of the Head and Neck. Results could lead to personalized treatment strategies for patients with this type of cancer

Researchers Uncover New Clues to the Development of Blood and Other Cancers. Latest findings from Fox Chase Cancer Center reveal that targeting inflammatory pathways may lead to new therapies.

Scientists Identify Key Protein Players in Hard-to-Treat Breast Cancers.

• Georgetown Lombardi Comprehensive Cancer Center

Stopping the Spread of a Deadly Childhood Bone Cancer. Many children with the bone cancer osteosarcoma die after the tumor spreads to their lungs. In a critical step toward finding a way to stop metastasis, researchers at Georgetown Lombardi Comprehensive Cancer Center say they have discovered an agent that prevents this cancer from spreading to the lungs in mice with the disease. (Added 4/3/12)

Two Specific Agents Worse Than One in Treating Endocrine Resistant Breast Cancer Cells. A new class of agents known as c-Src inhibitors is being tested in a number of different ways to treat breast cancer, but researchers at Georgetown Lombardi Comprehensive Cancer Center caution that they should not be used in combination with estrogen to treat endocrine resistant breast cancer. Their new study shows that using estrogen and a c-Src inhibitor, PP2, cancel each other out.

• Johns Hopkins Kimmel Cancer Center

Chemo may get boost from cholesterol-related drug. Johns Hopkins investigators are testing a way to use drugs that target a cholesterol pathway to enhance the cancer-killing potential of standard chemotherapy drugs.  Their tests, in mouse models of pancreatic cancer, may yield new and more effective combinations of current and possibly new anti-cancer drugs. (Added 4/3/12)

Scientists Reprogram Cancer Cells With Low Doses of Epigenetic Drugs. Experimenting with cells in culture, researchers at the Johns Hopkins Kimmel Cancer Center have breathed possible new life into two drugs once considered too toxic for human cancer treatment.  The drugs, azacitidine (AZA) and decitabine (DAC), are epigenetic-targeted drugs and work to correct cancer-causing alterations that modify DNA. The researchers said the drugs also were found to take aim at a small but dangerous subpopulation of self-renewing cells, sometimes referred to as cancer stem cells, which evade most cancer drugs and cause recurrence and spread.

Sequencing Cancer Mutations: There’s an App for That. Using precise information about an individual’s genetic makeup is becoming increasingly routine for developing tailored treatments for breast, lung, colon and other cancers. But techniques used to identify meaningful gene mutations depend on analyzing sequences of both normal and mutant DNA in tumor samples, a process that can yield ambiguous results. Now, a team of researchers says it has developed an easy-to-use online computer software application that can clear up any confusion faster and cheaper than other methods currently used to do the job.

Whole Genome Sequencing Not Informative For All. With sharp declines in the cost of whole genome sequencing, the day of accurately deciphering disease risk based on an individual’s genome may seem at hand.  But a study involving data of thousands of identical twins by Johns Hopkins investigators finds that genomic fortune-telling fails to provide informative guidance to most people about their risk for most common diseases, and warns against complacency born of negative genome test results.

• Kimmel Cancer Center, Thomas Jefferson University

New Biomarker to Identify Hepatitis B-Infected Patients at Risk for Liver Cancer. Hepatitis B-infected patients with significantly longer telomeres—the caps on the end of chromosomes that protect our genetic data— were found to have an increased risk of getting liver cancer compared to those with shorter ones, according to an abstract presented by researchers at Jefferson’s Kimmel Cancer Center. (Added 4/3/12)

• Siteman Cancer Center

New imaging technique could speed cancer detection. A new imaging technique relies on light and sound to create detailed, color pictures of tumors deep inside the body. The technology, called photoacoustic tomography, may eventually help doctors diagnose cancer earlier than is now possible and tomore precisely monitor the effects of cancer treatment – all without the radiation involved in X-rays and CT scans or the expense of MRIs. (Added 4/3/12)

Siteman Cancer Center expert honored nationally for prevention efforts. Graham A. Colditz, MD, DrPH, a disease prevention expert at the Siteman Cancer Center, will receive the Award for Research Excellence in Cancer Epidemiology and Prevention. (Added 4/3/12)

DNA sequencing lays foundation for personalized cancer treatment. Scientists at Washington University School of Medicine in St. Louis are using powerful DNA sequencing technology not only to identify mutations at the root of a patient’s tumor – considered key to personalizing cancer treatment – but to map the genetic evolution of disease and response to treatment.

• University of Pittsburgh Cancer Institute

Researchers Gain Better Understanding of Radiation-Mitigator Drug. Researchers from the University of Pittsburgh Cancer Institute (UPCI) and the University of Pittsburgh School of Medicine have a better way of understanding how a drug used to protect against and mitigate irradiation damage interacts inside human cells. The study was sponsored by the NIH and will presented as a poster presentation.

Researchers Build Mouse Model to Evaluate Compounds to Protect Against Radiation Exposure. Researchers have developed a mouse model that will allow scientists to study radiation-induced genetic changes and cellular defense mechanisms against radiation exposure at the same time. The study was sponsored by NIAD and will be presented as a poster presentation.

First-of-its-kind Study of Peptide Vaccine Shows Evidence of Immunological Response in Children with Gliomas. In a first-of-its-kind study, researchers from Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh Cancer Institute (UPCI) Brain Tumor Program have demonstrated that peptide vaccines in children with gliomas, the most common type of brain tumor, not only were well-tolerated but also showed evidence of immunological responses. This was sponsored by the NIH and will be presented as a poster presentation.

• USC Norris Comprehensive Cancer Center

A fusion toxin for the treatment of acute lymphoblastic leukemia. The research identifies a toxin that could be an effective alternative approach to chemotherapy for the treatment of primary and relapsed acute lymphoblastic leukemia, the most common childhood cancer. (Added 4/4/12)

A novel ovarian cancer-imaging agent based on integrin ligation. Swenson and colleagues have developed a non-invasive radiologic method for the diagnosis of early stage ovarian cancer and the detection of residual disease after surgery or other treatment, which appears to be more effective than traditional methods such as MRI or CT scans. (Added 4/4/12)

Mechanisms underlying racial/ethnic differences in obesity-related cancer risk. While obesity is clearly linked to cancer—obese people are 50 percent more likely to die from cancer than lean people—not much research has been done on how race or ethnicity may affect that association. Minorities, blacks and Hispanics in particular, are more likely to be obese and minorities who are obese tend to experience more complications than obese Caucasians. (Added 4/3/12)

Exploring the colorectal cancer methylome. Data from The Cancer Genome Atlas Project shows that epigenetics plays a causal role in a variety of human cancers, in colorectal cancer in particular. Researchers compared the tumor’s methylome to normal colon tissue and identified several important clues about the genetic instructions that a cancer cell interprets. (Added 4/3/12)

Macrophage migration inhibitory factor (MIF) plays roles in proliferation, survival and migration of Ewing tumor cells by activation of a CD74-CD44 receptor complex. The identification and understanding of proteins called cytokines, which have been associated with the abnormal proliferation and survival of certain tumor cells, may help develop better-targeted therapies for those types of cancer. Researchers found high expression of the MIF cytokine in Ewing sarcoma tumors, indicating that the protein and its signaling pathways may be promising targets for Ewing tumor therapy. (Added 4/3/12)

Protooncogenic TLR4 generates NANOG-dependent tumor-initiating stem-like cells through LIN28-Let7 pathway in experimental and clinical carcinogenesis. Examining the interaction between environmental and genetic risk factors for hepatocellular carcinoma (e.g., heavy alcohol intake, high fat diet, hepatitis C), researchers have identified a signaling pathway that may help sensitize chemo-resistant cancer cells to drug treatment. Their research shows that other cancers such as lung and breast may have a similar pathway.

Integrative analysis identifies functional prostate cancer risk SNPs in genomic regulatory regions defined as enhancers. Researchers have developed a bioinformatics tool that consolidates large data sets to identify regions in the genome that may confer a higher risk for prostate cancer and other cancers. They have confirmed that eight of nine identified regions are associated in the development of prostate cancer.

Real-time sequencing of cancer and germline genomes for clinical trial optimization. Recent advances in next-generation sequencing have allowed the real-time identification of cancer mutations in the clinic. The presentation explores how best to incorporate these genomic measurements in clinical trials.

• Vanderbilt-Ingram Cancer Center

Cruciferous vegetable intake after diagnosis of breast cancer and survival: a report from the Shanghai Breast Cancer Survival Study. (Added 4/3/12)

Children in resource poor countries are at high risk of dying from cancer

Major advances have been made in the treatment of childhood cancer but this progress predominately benefits patients who live in resource affluent, developed countries. In resource poor, developing nations, where 80 percent of all childhood cancers occur, the majority of youngsters with potentially treatable disease will die from lack of therapy.

Of all of the world’s developing countries, those in sub-Saharan Africa are among the poorest and its children at greatest risk. 

At the most basic level, the easiest way to increase survival rates in these children would be to train more doctors and nurses in their care and to add facilities where they can be adequately treated. To do this, cultural and financial disparities endemic to this population need to be addressed. Scientists at NCI are working with colleagues, including those at International Network for Cancer Treatment and Research (INCTR), toward this end.

Impact of poverty, social and cultural issues in developing countries

In developing countries, parents and caregivers of children with cancer may not have access to health clinics or money to pay for treatments. They may also have a limited understanding of their child’s disease and of risks and potential outcomes.

Social and psychological support may also be limited, or nonexistent, for a child with cancer. In countries where cancer is stigmatized and the patient rejected, a father’s perception weighs heavily on the medical treatment his child will receive. Since body image is also critical in many of these countries, a girl without an eye or other facial deformity (as a result of surgery) is not considered marriageable, and thus will be a burden to her family. So, acknowledgement of the child’s cancer, and the subsequent treatment of it, may be withheld.

Additionally, herbal remedies are often used or preferred in developing countries over drugs used in developing, or western countries, particularly in sub-Saharan Africa. This may be detrimental to treatment since many of these herbal remedies are often not well researched or are poorly regulated. Herbal remedies may also be combined with western drugs, creating the potential for harmful drug interactions for young patients.

Based on these factors, a child with cancer may receive a late diagnosis and their parents or caregiver may refuse treatment, stop treatment, or treat the child indiscriminately with herbal remedies.

Deficiencies in resources—professional and public health

Another concern in developing countries is that family doctors, pediatricians, and non-cancer specialists may not have the expertise to recognize and treat childhood cancers. Incorrect diagnoses of cancer are not uncommon since symptoms associated with cancer such as anemia, bruising, fever and swollen glands are also often found in more common conditions such as tuberculosis and malaria. The wrong diagnoses may cause children to receive inappropriate or inadequate care and therapy that may further weaken them.

Even if cancer is properly diagnosed in these children, they most likely will not have access to pediatric oncologists, surgeons (e.g., those that treat the eyes or bones), and radiotherapists who can effectively manage their care.

Many developing countries also lack a strong national policy for control of childhood cancer. Inaccurate cancer incidence and death statistics, few or incomplete cancer registries in rural areas, and a shortage of national clinical and laboratory research, further add to the disease burden of children in these nations.

NCI and the importance of regional research

Clinical trials in developed countries primarily address cancers common to their population, and do not fully address advanced cases of cancers, such as Burkitt lymphoma, which are found in children in developing countries, particularly those in sub-Saharan Africa. Also, since differences in disease biology, drug handling and co-morbidities occur in diverse ethnic groups and environments, treatment for this population of children may also vary.

To develop treatment protocols and support in resource poor countries, researchers at the NCI’s Office of HIV and AIDS Malignancies (OHAM) and INCTR are conducting various projects in specific areas of cancer control, with cancers in women and children having highest priority. In developing countries, women die unnecessarily from cancers and infectious diseases, such as HIV/AIDS, as well as from problems associated with pregnancy and childbirth. Safeguarding women’s health, while educating them on medical issues relative to them and their families, directly benefits the health and welfare of their children.

NCI-supported clinical trials in Africa— a Burkitt lymphoma case study

Dr. Trish Scanlan (red dress), volunteer, and young patients at pediatric cancer ward in Muhimbili National Hospital in Tanzania. Credit: Used with the permission of INCTR

NCI has supported research by INCTR investigators who are conducting clinical trials of Burkitt lymphoma, including HIV positive Burkitt lymphoma in sub-Saharan Africa. Their goal is to improve both pathology services (diagnosis) in participating countries, and the survival rate, with a regimen suitable for children in resource poor settings with respect to toxicity and cost.

The team has conducted a large study of the treatment of Burkitt lymphoma in Tanzania, Uganda, Kenya, Democratic Republic of Congo and Nigeria, using a simple chemotherapy regime that is suitable for these resource poor regions.

Over 500 children have been treated initially with a simple and inexpensive three-drug regimen originally developed in Africa in the early 1970s, and still widely used. Patients who achieve only partial response, or who have recurrence shortly after therapy is complete, i.e., are resistant to this regime, are given a second regimen which has proved to be effective even in patients who do not achieve remission or relapse with the first-line therapy, resulting in an approximately 38 percent complete response rate in these resistant patients and improving long-term survival.

Mother and her child with Burkitt lymphoma are at the Ocean Road Cancer Institute in Tanzania. Credit: Used with the permission of INCTR

Overall survival, in excess of 60 percent at two years and beyond, is much lower than that in Europe and the United States, for example, where much more intensive regimens can be used, but represents a marked improvement in outcome for Africa. So far, HIV-positive patients constitute only some four percent of children with Burkitt lymphoma, but their survival rate, when treated with anti-retroviral therapy in addition to the same therapy received by the HIV-negative children, is essentially identical, although numbers to date of HIV-positive patients are small.

Researchers plan to use these cancer centers as training sites to improve regional and national treatment of children with other cancers. A computerized data base, specially designed for the African setting will be used to collect and analyze data, and local health providers will learn to track, monitor, and measure outcomes of patient care (toxicity and response) so that these, and future children with cancer will receive better treatments for their disease.

The next step in the Burkitt lymphoma study will be to combine the two regimens from the beginning in high-risk patients, which is likely to result in much better survival rates.

Surgeons and a nurse performing surgery

Ovarian cancer has proven to be a very difficult cancer to diagnose at a curable stage and thus treat successfully.  Even though it has one of the highest mortality rates of all gynecological cancers in the United States, there are no validated or proven screening tests, making it a challenge to diagnose at an early stage. To date, there is no evidence that any of the various screening tests that are performed, including pelvic examinations, transvaginal ultrasounds and a CA-125 assay (a test that measures the level of CA-125 in the blood to see if it is elevated), leads to a decrease in ovarian cancer deaths.  These tests have not been shown to diagnose ovarian cancer early, and the risk of falsely calling a benign mass a cancer when it is not present is unacceptably high.  This can lead to unnecessary surgery, treatments, and stress for patients.

Ovarian cancer symptoms are  fairly non-specific, therefore only about 19 percent of all cases are detected at an early, localized stage. In the U.S. alone, an estimated 22,000 women will be diagnosed with, and 15,000 women will die from this disease in 2011.  Even with all these challenges, researchers have made important clinical advances over the years in chemotherapy regimens, surgery techniques and biologic therapies to find better treatment options for ovarian cancer patients.

Three-panel drawing of stage IA, IB, and IC ovarian cancer. Credit: Terese Winslow

The image above depicts stage IA, IB, and IC ovarian cancer. The first panel shows a stage IA tumor inside one ovary. The second panel shows two stage IB tumors, one inside each ovary. The third panel shows two stage IC tumors, one inside each ovary, and one tumor has a ruptured capsule. An inset shows cancer cells floating in the peritoneal fluid surrounding abdominal organs.

The primary surgical objective in ovarian cancer treatment is removal of the tumor. It has been shown consistently that the more complete the resection, or removal of the tumor, the better the clinical outcome since the current surgical aim is removal of disease to the point that there is no visible disease present.  However, not every woman can undergo such surgery.  This fact led to a trial, recently reported by the European Organization for Research and Treatment of Cancer–Gynecologic Cancer Group (EORTC–GCG) and the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) examining the question of whether surgery should precede chemotherapy or if chemotherapy should come first, a method called neoadjuvant chemotherapy.  Results demonstrated that there was no difference between the approaches and that neoadjuvant chemotherapy could be considered, given the similar survival outcomes and the increased side-effects of primary surgery.  Newer GOG trials will allow physicians and their patients to elect neoadjuvant therapy or traditional chemotherapy after primary surgical debulking, or removal of the malignancies.

Cisplatin crystals, a platinum compound used as a chemotherapy drug.

In 1978, the U.S. FDA approved cisplatin, a chemotherapy drug containing platinum, for treatment of metastatic ovarian cancer.  Shortly after that approval, the delivery of anticancer drugs intraperitoneally (IP) was established—a technique where chemotherapy drugs are administered through a surgically implanted catheter, allowing passage of fluids into the abdominal cavity. This method allows direct administration of drugs to the intra-abdominal cancer, creating higher local drug exposure.  Some of the drugs used intraperitoneally, such as cisplatin and its close relative carboplatin, are also absorbed into the general circulation and assist with attacking ovarian cancer that has spread to other parts of the body.

The next significant pharmaceutical advancement was the approval of paclitaxel in the mid-90’s; the first of a class of drugs known as taxanes. Paclitaxel interferes with cell growth and division in rapidly dividing cells, such as cancer cells.  Unlike the platinums, the taxanes do not get absorbed when administered into the abdominal cavity and thus provide high local drug exposure.

Researchers studied both cisplatin and paclitaxel extensively and found that chemotherapy regimens that contain both types of drugs are most effective in preventing recurrence of ovarian cancer and improving a woman’s survival period. The combination of cisplatin and paclitaxel has become the standard recommended therapy for treatment for women with ovarian cancer who may benefit from chemotherapy.  Further improving this method in 2006, a study by the Gynecologic Oncology Group (GOG) showed that women with advanced ovarian cancer who receive a combination of intravenous (IV) and IP chemotherapy post-surgery extended their overall survival by about a year.  The combined method of delivering drugs into the vein and directly into the abdomen simultaneously allows for improved progression-free survival.  It is possible that this was due to the intra-abdominal administration of the drugs; however, more total chemotherapy was administered on the combination IV and IP therapy arm, suggesting that quantity of drug, known as dose density, may be the factor.

Biologic therapy is another area of interest that is being explored for ovarian cancer treatments. Researchers continue to study the benefits of targeted agents in the form of monoclonal antibodies and small molecules to treat a number of other cancers, including ovarian cancer. Anti-angiogenic agents, a form of targeted therapy that uses small molecule drugs or antibodies to stop tumors from making new blood vessels, have also shown promise in clinical settings. Trials are currently underway to investigate whether the addition of bevacizumab, a type of anti-angiogenic drug, to first-line treatment will improve clinical outcomes. In 2010, a study by the Gynecologic Oncology Group (GOG) found that women who received bevacizumab (Avastin) during their initial chemotherapy for ovarian cancer and continued up to 16 months after completion of initial chemotherapy had a reduced risk of progression of 28 percent compared to those who received chemotherapy alone.  The benefit was short-lived leaving the community in a quandary regarding application of this therapy as a new standard of care.  A newer study, reported this spring, the OCEANS trial, added bevacizumab to carboplatin and gemcitabine for women with first recurrence of ovarian cancer.  There was a greater reduction in risk of progression in this study and an improvement in overall survival.  How these studies will change practice patterns for the future is not yet known.

One of the most exciting recent advances in ovarian cancer has been the discovery and use of a new class of targeted agents, the PARP inhibitors.  Olaparib, one type of PARP inhibitor, blocks the activity of PARP1 and PARP2 proteins that are necessary for cells to repair damaged DNA.  This agent was found to be clinically active in breast and ovarian cancer patients who carry germ line mutations in the BRCA1 or 2 genes, and olaparib has also been active in high grade serous ovarian cancer, a type of epithelial ovarian cancer.  Researchers hope that combining a PARP inhibitor, like olaparib, with traditional chemotherapy drugs, such as the platinums, will produce greater anticancer effects than either chemotherapy or a PARP inhibitor alone.  This approach is based on the observation that cells are unable to survive if they accumulate high levels of DNA damage. Additional PARP-inhibitors are now under development and their roles are being investigated in women who are both BRCA1 and 2 mutation carriers and other women with ovarian cancer.

Acknowledging the poor prognosis of ovarian cancer, The Cancer Genome Atlas (TCGA) sponsored by the NCI, selected serous ovarian cancer, the most prevalent form of the disease, as one of the first to have its genomic changes charted in depth.  The goal of the TCGA profiling was to look for gene expression patterns that are linked to differences in patient survival and to establish whether certain gene changes can be linked to response to therapy.  To date, TCGA has achieved comprehensive sequencing, characterization, and analysis of the genomic changes in ovarian cancer.  Their initial findings, just reported in the journal Nature, were of interest to many investigators.  It showed that there are no frequent driving genetic mutations in ovarian cancer as has been shown in many other solid tumors.  Serous ovarian cancer distinguished itself by its genetic complexity and variability.  Investigators are now combing this remarkable data collection to identify leads for typing ovarian cancer in ways that will focus therapy for greater clinical benefit, survival advantages, and to reduce toxicity and patient injury.

Scientists prepare clinical lots of measles virus to use in clinical trials against cancer. Credit: Mayo Clinic.

The Cancer Genome Atlas (TCGA) is undertaking a large-scale review of cancer genes. The most recent study results were published June 30, 2011, in Nature. As part of this work, TCGA investigators searched for existing drugs that might inhibit genes that were suggested to play a role in ovarian cancer. The search identified 68 genes that could be targeted by existing Food and Drug Administration-approved or experimental therapeutic compounds. As a result, investigators found that 50 percent of ovarian cancer tumors might be responsive to drugs that exploit the genetic instability of cancer cells.

But the TCGA results also point out the need to study other approaches to treatment. An example of such is a modified virus that is made by inserting specific genes into the attenuated, or weakened, Edmonston measles vaccine strain. This type of engineered measles virus has emerged as a novel therapeutic agent against ovarian cancer because of its antitumor efficacy and safety record in humans

Scientists at the Mayo Clinic, Minn., have developed this therapy to treat women with recurrent ovarian cancer. They engineered the measles virus to attack tumor cells and leave healthy cells unharmed, and then tested the new strain in cancer patients in a phase I clinical trial, which showed the treatment to be safe and well-tolerated.

“Within a three year period, we pioneered the use of a modified measles virus against ovarian cancer, moving our discovery from bench research to the first clinical trial of its kind,” said principal investigator Evanthia Galanis, M.D., an oncologist and chair of the Mayo Clinic Department of Molecular Medicine. “This rapid translation offers patients with a difficult to treat cancer a promising new therapy.”

The research in these studies was conducted at the Mayo Clinic Cancer Center and was supported by a NCI Specialized Program of Research Excellence (SPORE) grant that focuses on ovarian cancer. A summary of their studies follows.

Measles virus strains use surface receptor protein to gain entry into cancer cells

The Edmonston measles virus strains enter cells via the surface receptor CD46, a type of protein that works with the immune system to protect cells against destruction. CD46 is over-expressed in many cancer types, including ovarian cancer, as compared with normal cells.

Upon entry into CD46-expressing cells similar to ovarian cancer cells, the virus strain begins to replicate and causes a virus-induced cell-to-cell fusion that results in the development of syncytia (giant cells with multiple nuclei) that eventually cause cell death.  Because of the low level of CD46 expression in normal cells, syncytia formation does not occur, so normal cells are spared. The difference in this expression explains the efficacy of the Edmonston strain in killing tumor cells, according to the scientists. This type of virus is called an oncolytic virus, since it lyses, or destroys, tumor cells.

After performing their experiments in the lab, the scientists wanted to test the safety of oncolytic viruses in mice. But since rodents do not express the measles receptor gene CD46, they were not appropriate models for study without first genetically engineering a mouse strain to express the CD46 gene. This was done in the laboratory of Roberto Cattaneo, Ph.D, also of the Molecular Medicine Department, using a yeast artificial chromosome cloning technique.

In addition to the mouse studies, toxicology studies of the oncolytic viruses were also conducted in a measles-susceptible primate species. No evidence of toxicity was observed after administration of the virus in these animal models, which provided additional reassurance that the cancer-fighting measles virus platform would be safe to use in people.

Phase I clinical trial results show that a modified measles virus can safely treat ovarian cancer patients

The investigative team of Galanis, Kah Whye Peng, Ph.D., and Lynn Hartmann, M.D., successfully tested the safety of their measles virus strain in patients with recurrent ovarian cancer in a phase I clinical trial. The virus used in this trial carried an additional tag—a marker protein called carcinoembryonic antigen, or CEA.

CEA is used to monitor the spread of infection in patients’ tumors after they received the measles virus-CEA construct. CEA is found in many different cells of the body and it is often associated with tumors. However, ovarian cancer cells rarely expresses CEA, so detection of CEA after treatment is indicative of virus infection.

Results from the trial showed safety and tolerability of the measles-CEA construct with some evident biological activity; 14 of 21 (67 percent) heavily pretreated patients, i.e., those who had received chemotherapy prior to the trial, had stable disease for up to eight months. In addition, median survival doubled as compared to the expected survival for this patient group. These results now allow administration of higher and potentially even more effective viral doses, according to the scientists.

FDA approves extension of phase I clinical trial to test new gene in measles virus combination

Members of the of the Galanis, Peng, Toxicology, and Vector Production laboratories at Mayo Clinic.

The investigative team has received FDA approval to extend their phase I clinical trial to include 16 additional patients, who will receive a new virus, measles virus-NIS. This construct includes the sodium iodine symporter (NIS) gene, which traps radioactive iodine and will therefore allow imaging of the sites of viral gene expression in vivo (within the living body).

This study will determine whether measles virus-NIS construct has a safety profile similar to measles virus-CEA construct and will establish the feasibility of using measles virus-NIS expression to facilitate tumor imaging. The use of radioactive iodine may also increase the efficacy of oncolytic viral therapy. The first eleven patients have been treated without significant toxicity.

Stem cells tested to augment measles virus delivery

Because anti-measles virus antibodies may neutralize the virus and therefore limit the effectiveness of the virotherapy, Galanis and Peng are testing the use of mesenchymal stem cells (MSC) as carriers for the measles virus in order to augment the anti-tumor effects.  MSCs are multi-potent stem cells that can differentiate into a variety of cell types. A new clinical trial using fat tissue-derived MSC as measles virus carriers in ovarian cancer patients is being planned.

Other strategies to modify the anti-viral immune response, such as use of the immunosuppressive agent cyclophosphamide, are also being tested.

Next steps

In addition to the ovarian cancer trial, the modified measles virus is being tested in glioblastoma multiforme (brain cancer) and multiple myeloma clinical trials at Mayo Clinic. Clinical trials for mesothelioma (tumor of the lining of lungs, heart and abdomen) and head and neck cancer will soon be started.

“There are few safe and effective treatments for recurrent ovarian cancer,” said Toby T. Hecht, Ph.D., acting associate director of NCI’s Translational Research Program, Division of Cancer Treatment and Diagnosis. “We are looking forward to seeing the results of further studies with this innovative oncolytic approach to cancer therapy, not only for ovarian cancer, but other cancers as well.”

Watch Dr. Richard Fagerstrom, NCI mathematical statistician, discuss the NLST concept design and primary results:

Click here to view the embedded video.

For more information on these results, view today’s press release.

Click here to view the embedded video.

For more information on these results, view today’s press release.

More details about The Cancer Genome Atlas, including Quick Facts, Q&A, graphics, glossary, a brief guide to genomics, and a media library of available images can be found at http://cancergenome.nih.gov.

Ovarian cancer arises in the fallopian tube. Credit: Drapkin

Ovarian cancer kills an estimated 14,000 American women each year. The high mortality rate for women with ovarian cancer stems from a lack of early symptoms or screening methods for the disease. As a result, most ovarian cancer patients are diagnosed with advanced-stage disease as highlighted by the findings from the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, or PLCO trial, presented at the annual American Society of Clinical Oncology meeting June 4, 2011.

In addition to the PLCO trial, the National Cancer Institute has funded numerous aspects of ovarian cancer research, including studies as part of the Specialized Programs of Research Excellence, or SPORE. The ovarian cancer SPORE grants address the full range of prevention, early detection, and treatment of ovarian cancer.

Like other SPORE grants, the ovarian cancer SPOREs are designed to enable the rapid and efficient movement of basic scientific findings into clinical settings, as well as to determine the biological basis for observations made in individuals with cancer or in populations at risk for cancer.

In 2009, ovarian cancer SPORE grants were awarded to:

• Brigham and Women’s Hospital, Boston, Mass.
• Fox Chase Cancer Center, Philadelphia, Penn.
• Fred Hutchinson Cancer Center, Seattle, Wash.
• Mayo Clinic, Rochester, Minn.
• University of Texas, MD Anderson, Houston

The following is a highlight of work being conducted by scientists at the ovarian cancer SPORE program at Brigham and Women’s Hospital, which is a teaching affiliate of Harvard Medical School in Boston. Over the next several months, studies by investigators at other ovarian cancer SPORE groups will be featured.

Early precursor lesions to ovarian cancer arise in the fallopian tubes

Scientists at the ovarian cancer SPORE at Brigham and Women’s Hospital have found evidence that a majority of serous cancers, a lethal type of ovarian cancer, arise in fallopian tube fimbria, which are the fringed far ends of the fallopian tube, rather than on the surface of the ovaries.

Christopher P. Crum, M.D., of the Brigham and Women’s Hospital, and Ronny I. Drapkin, M.D., Ph.D., who is also affiliated with Dana-Farber Cancer Institute, have conducted additional studies that show serous cancers begin as precursor lesions in the fallopian tube fimbria that spread to the surface of the ovary, or shed into the peritoneal cavity. Serous cancer is often found in the ovaries, peritoneal cavity, and fallopian tubes. Until the emergence of these finding on the genesis of serous cancer, it was thought that all three sites represented independent sites of origin and risk.

Women with BRCA mutations have precursor lesions in fallopian tubes

Studies in the Crum laboratory found a small abnormal population of cells within fallopian tube biopsy samples taken from women with BRCA 1 or BRCA 2 gene mutations. BRCA gene mutations are associated with hereditary serous cancer; these women had their ovaries and fallopian tubes surgically removed as a preventative measure against this disease.

The scientists microscopically examined the entire inside lining of the fallopian tube and its fimbriated ends. Results of these biopsy sample studies showed that up to 15 percent of women with the BRCA gene mutation had small, predominately non-invasive tumors within the fallopian tube fimbria, while about 33 percent had pre-malignant precursor lesions, called the p53 signature.

Serous cancer, or the p53 signature identified. Credit: Drapkin

The p53 signature is a benign-appearing population of secretory cells that are characterized by DNA damage, p53 gene mutations, and accumulation of the p53 protein, the latter of which can be detected by tissue staining, a method used to give contrast to the tissue or to highlight a particular feature.

One of the functions of the p53 gene is to block cell division when a cell has sustained DNA damage. However, if the p53 gene itself becomes disabled, damaged cells will proliferate and possibly lead to cancer. The scientists reasoned that the repeated cellular injury and repair of the fallopian tube fimbria, secondary to repeated ovulatory cycles, might cause the DNA damage that leads to the appearance of the p53 signature.

Women without cancer have precursor lesions in fallopian tubes

Next, the scientists tested to see if the p53 signature was present in fallopian tubes biopsy samples taken from women not genetically predisposed to cancer. Their studies demonstrated that fewer of these women (less than 5 percent) were diagnosed with cancer; however, nearly the same proportion, almost 33 percent, harbored a p53 signature. Some of these lesions were early molecular changes only; the damaged cells looked normal under the microscope.

“The significance of finding secretory cells that look normal, but are actually damaged at the DNA level, with wide-spread DNA damage and mutations, is that they likely represent precursor lesions to serous cancer,” said Crum. “Importantly, scientists have looked for a precursor to this cancer for a long time and never found it in the ovary.”

There are a number of implications that make these findings significant:

• From a clinical perspective, it warrants thorough analysis of all fallopian tubes, especially in women who have risk-reducing surgeries because they are at high-risk for serous cancer. This is already being implemented in many parts of the country and around the world.

• There is active discussion now about whether surgeons should consider simply removing the fallopian tubes or the just the fimbria in women at high-risk of developing serous cancer (BRCA gene mutation carriers).

• All basic and translational science on serous ovarian cancer has been based on using the ovarian surface epithelial cells as the starting point, i.e. the cell of origin. This new model warrants careful study of the fallopian tube epithelial cells and the development of models systems to do so.

Experimental models test precursor lesions to serous cancer

Drapkin with scientists in his lab.

Work in the Drapkin lab is focused on the development of two experimental model systems to clearly define the p53 signature and to develop methods to test the hypothesis that this lesion may be the precursor to serous cancers.

The first model is a novel ex vivo cell culture system where primary fallopian tube cells are harvested directly from women who had their fallopian tubes removed for reasons unrelated to cancer. These cells are grown on special filters that enable them to mimic the behavior of tubal cells in vivo (inside of the living body).

“Using this system, we found that the secretory fallopian cells display a delayed ability to respond to DNA damage. The damage, as we expected, is probably a result of monthly ovulation, a known risk factor for ovarian cancer. The inability of these cells to repair their DNA damage in a timely manner potentially leaves them susceptible to the accumulation of additional mutations to their genes over time.  Our work is now directed at deciphering the underlying mechanism of this behavior,” said Drapkin.

For the second model system, Drapkin’s group removed secretory cells from the fallopian tube ex vivo model and immortalized them, i.e. altered the cell’s genetic programming so they could divide indefinitely.  These cells are now being used to study the biology of fallopian tube secretory epithelial cells to determine how genetic alterations contribute to tumor development in vitro and in vivo.

“Research has indicted that ovarian cancer is not a mutation-driven disease, rather, it is a disease of copy instability, i.e. the tumors show broad irregularities in the number of copies of a certain gene–too many, too few, or none at all. Using our new fallopian tube transformation system, in which we can genetically alter a cell by the introduction of defined genetic elements, we are in the position to figure out which alterations contribute to transformation and which may be simple bystander aberrations due to genomic instability,” said Drapkin.

Cancer Statistics Review website

The most frequent request NCI receives from reporters is to provide the latest cancer statistics: incidence, mortality, and survival, often broken down by age, race, or gender.  To provide this information, press officers from NCI’s Office of Media Relations turn to the Cancer Statistics Review, a report published by NCI’s Surveillance, Epidemiology and End Results (SEER) program.

The CSR, updated just this morning with new incidence statistics, contains the most recent data available on incidence (the rate or number of new cases), mortality (deaths), survival, prevalence, and lifetime risk statistics for 27 cancers.  Unlike other statistical cancer reports (Annual Report to the Nation and Cancer Trends Progress Report), the CSR is purely about numbers, without interpretation.  The CSR is updated each year, as soon as new numbers are ready, ensuring that its figures are as up-to-date as possible.  Today’s update includes data on incidence rates through 2008 (previously 2007).  Mortality and lifetime risk updates for 2008 are expected in a few months. The three-year lag between the date of diagnosis or death and the posting of information is due to the time it takes for local registries to assemble and deliver individual case outcomes to NCI, along with the time it takes for those cases to be vetted for quality assurance.  For a number of years, NCI has also included delay-adjusted numbers in its report, in order to compensate for underestimates that may be caused by additional cancers diagnosed in 2008 or prior years that the statisticians anticipate will be reported after the CSR is released.

For reporters seeking cancer statistics, the 2008 data are as up-to-date as they come.

Each year the SEER program teams up with the American Cancer Society and others to apply incidence and mortality rates (usually per 100,000 people in the U.S. population), from the CSR against current population data from the U.S. Census Bureau, in order to estimate the number of cancer cases expected in the current year. The calculations of estimates for the number of new cancer cases for 2011 will be completed in several months. These estimates, which will be reported in the CSR, as well as ACS’s Facts and Figures, may seem more current, but those projections will be extrapolated from the 2008 data.

The CSR provides three ways to access the data provided in the report.  You can:

• Browse through individual tables and charts
• Access the entire report in PDF form, or
• Generate custom reports

Browse the Tables and Figures

The first option allows you to pick individual tables and charts by first selecting the type of cancer you are interested in, followed by selecting the table. Once you make your selection, your table will appear just below the selection boxes, and you will have the option to download and/or print the data.

This option is best if you know exactly what you are looking for, and only need one type of statistic.

Access Contents in PDF

The second option, which is preferred by several of NCI’s press officers, is to view the report’s table of contents to select data in PDF form. While it can be a bit daunting at first, this option lets you see everything that is available in the report, to help you figure out what you are looking for.  The contents are broken down into three columns; summary tables, CSR sections (or chapters), and pages grouped by topic.

In the first column (see image), the summary tables provide data for some of the most commonly requested statistics, across several cancer sites. There are charts comparing lifetime risk of developing certain cancers, cancer mortality rates by race, and average age of diagnosis, to name just a few examples.

In the second column, the CSR sections are divided by cancer site. This option is best if you want to see every type of statistic available for a particular type of cancer.  In addition to organ-sites, there are chapters for childhood cancers, adolescent/young adult cancers, and soft tissue sarcomas, as well as info on benign (non-cancerous) brain tumors.

In the final column, as in the summary, the tables presented represent all 27 types of cancer and are grouped by topic.  These groupings provide more data in each section, however, as they represent all the data, and are not summaries.

Generate Custom Reports

The final option, generating custom reports, is best for people who need to distribute, in a single document, a collection of several of the tables and figures described above.  This particular option tends to be less useful to members of the media than the previous two browsing methods.  However, those who need this type of customized report can select multiple statistics, cancer sites, and race/ethnicities by using the Advanced Options.

Since 1973, the SEER program has been collecting data on cancer cases from various locations and sources throughout the United States. Over the years, their data has been helpful to many as they try to communicate cancer research news.  As always, if you are a member of the media and would like help navigating the CSR, or if would like to request an interview with one of our statisticians, NCI’s Office of Media Relations is  only a phone call, email or tweet away.

Credit: Teresa Winslow (artist), for NCI

People with a history of smoking have a high risk of lung cancer – a disease with a five-year relative survival rate (for smokers and non-smokers combined) of only 15.8 percent.  Previous attempts at developing a test to find lung cancer early, when it is easier to treat, have not been able to demonstrate a decrease in mortality rates. Now, a study sponsored by the National Cancer Institute (NCI) has determined that low-dose helical computed tomography (CT) scans can reduce lung cancer mortality for current and former heavy smokers.  In the nation-wide study, which included over 53,000 participants, researchers found 20 percent fewer lung cancer deaths among those who were screened with low-dose helical CT (also known as spiral CT) compared with those who were screened with chest X-rays. In addition, deaths from all-causes (including lung cancer) were seven percent lower in those who received the low-dose helical CT scans.

“This is the first time that we have seen clear evidence of a significant reduction in mortality with a lung screening test in a randomized controlled trial.  The fact that low-dose helical CT provides a decided benefit will be a result that will have implications for the screening and management of lung cancer for many years to come,” said Christine Berg, M.D., NLST project officer for the NCI, in a press release.

In September 2002, the NCI launched the largest lung cancer screening study ever conducted.  The National Lung Screening Trial, or NLST, compared the effects of two lung cancer screening procedures, low dose helical CT and chest X-ray, in reducing mortality in current and former heavy smokers aged 55 to 74. Unlike previous trials, the NLST was a randomized control trial, the gold standard in clinical trials. Participants were randomly assigned to one of two comparable groups – chest X-ray or helical CT – and received three annual screenings based on their assigned technology.  The groups were followed for at least five years beyond the final screening. (Read an article in this publication from the launch of the trial in 2002)

“The results of this trial provide objective evidence of the benefits of low-dose helical CT screening in an older, high-risk population and suggest that if low-dose helical CT screening is implemented responsibly, and individuals with abnormalities are judiciously followed, we have the potential to save thousands of lives,” said Denise Aberle, M.D., NLST national principal investigator for ACRIN, in an NCI press release.  “However, given the high association between lung cancer and cigarette smoking, the trial investigators reemphasize that the single best way to prevent lung cancer deaths is to never start smoking, and if already smoking, to quit permanently.”

Low dose helical CT, which was introduced in the 1990’s, uses computer-controlled X-rays to scan the entire chest in about 7-15 seconds during a single, breath-hold. The CT scanner rotates around the person, who is lying still on a table as the table passes through the center of the scanner.

(Figure A:) Conventional CT scan. (Figure B:) Spiral CT scan. Credit: NCI Cancer Imaging Program

A computer creates images from the X-ray information coming from the scanner and assembles these images into a series of two-dimensional slices of the lung at very small intervals so that increased details within the organs of the chest can be identified.  Virtually all hospitals and free-standing radiology facilities in the United States now have a helical CT machine, which are routinely used for diagnostics. While some facilities do perform helical CT scans for the purpose of screening for lung cancer, such practice has not been previously supported by evidence and is not currently covered by most insurance providers.

Screening with CT scans comes with its own risks.  Radiation exposure from repeated CT scans can lead to illness, including cancer, and people who get false-positive results may be subjected to unnecessary surgical procedures.   It’s important to note that most abnormalities detected with CT screening are not cancer, even in people who are at high risk.

There are over 94 million current and former smokers in the United States who are at high risk for lung cancer.  In 2010, it is estimated that 222,520 people will be diagnosed with, and 157,300 will die from lung cancer, the leading cause of cancer death in the United States.

More information about the new results of the NLST is available in National Lung Screening Trial – Initial results: Questions and Answers and Fast Facts on NLST.  For more information on lung cancer and screening, please visit our Lung Cancer Homepage.