National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
July 14, 2009 • Volume 6 / Number 14

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Cancer Research Highlights

Risk of Ovarian Cancer from Hormone Therapy Confirmed

Women who have taken hormone therapy are at a higher risk of developing ovarian cancer than women who have not, according to a nationwide study involving nearly 910,000 women in Denmark. The findings, which confirm and extend the results of previous studies, suggest that the risk of ovarian cancer should be a factor when women consider using hormone therapy to treat postmenopausal symptoms.

Lina Steinrud Mørch of Copenhagen University and her colleagues used detailed information from national registries to detect an increased risk of ovarian cancer among former and current hormone users, compared with non-users. A woman’s risk did not seem to depend on the type of hormones, the duration of use, or the mode of administration. The findings translate into about 1 extra ovarian cancer per approximately 8,300 women taking hormone therapy each year, the researchers reported in the July 15 Journal of the American Medical Association.

Since the Women’s Health Initiative reported in 2002 that combination hormone therapy (estrogen plus progestin) was associated with an increased risk of breast cancer, several studies have linked estrogen-alone therapy to the risk of ovarian cancer. There have also been hints of an increased risk from combination therapy, and these are now confirmed.

“Here we see that combination therapy had essentially the same amount of increased risk as estrogen-alone therapy,” said Dr. Garnet Anderson, an ovarian cancer researcher at the Fred Hutchinson Cancer Research Center. The results, she added, are not likely to alter the current guidelines on hormone therapy, which urge women to use the smallest possible dose for the shortest time period.

Hormone therapy may have caused approximately 140 extra cases of ovarian cancer in Denmark during the study period, or 5 percent of the ovarian cancers. “Even though this share seems low, ovarian cancer remains highly fatal, so accordingly this risk warrants consideration when deciding whether to use hormone therapy,” the authors concluded.

Second Cervical Cancer Vaccine Protects Against Additional HPV Types

A large international trial funded by GlaxoSmithKline Biologicals shows that the Cervarix vaccine is highly effective against infections with human papillomavirus (HPV) types 16 and 18. Final results of the Papilloma Trial Against Cancer In Young Adults (PATRICIA) were published July 8 in The Lancet.

Dr. Jorma Paavonen, of the University of Helsinki in Finland, and his colleagues in the PATRICIA study group followed 18,644 women aged 15 to 25 for a median of 34.9 months after vaccination (17,106 women received the full sequence of three injections). About half of the women were in a blinded control group that received a hepatitis A vaccine conferring no protection against HPV infection.

The Cervarix vaccine reduced the risk of precancerous lesions known as grade II cervical intraepithelial neoplasias (CIN2+) by nearly 93 percent in participants who completed the full sequence. The vaccine also provided a lesser but significant degree of cross-protection against HPV types 31, 33, and 45. This added protection could raise the potential effectiveness of HPV vaccination from about 70 percent to between 81 and 86 percent.

About 62 percent of women in the trial had never been exposed to any of the 14 HPV types associated with cervical cancer. This group “is closest to the population targeted by universal mass HPV vaccination,” said the authors, referring to young girls who are not sexually active. Only one event of CIN2+ was observed in 5,449 of these unexposed study participants.

Although it is important to continue testing for HPV in vaccinated and unvaccinated women, “HPV vaccination has the potential to substantially reduce the incidence of cervical cancer and precancer,” the authors concluded.

Cervarix is licensed in 90 countries and was approved last week by the World Health Organization, which allows United Nations agencies and partners to use the vaccine in developing countries. The vaccine is still under review and awaiting approval by the FDA.

Genome Scans Provide Clues to Brain Cancer Risk

Common genetic variations may increase a person’s risk of developing brain cancer, and it is now possible to identify these potential risk factors. In two genome-wide association studies, researchers have discovered and validated a small number of inherited genetic variants linked to the disease. The causes of brain cancer are not well understood, and the findings, published online in Nature Genetics July 5, could provide clues for investigating the inherited component of disease risk.

In one study, researchers at the University of Texas M.D. Anderson Cancer Center and the Institute of Cancer Research in the United Kingdom scanned the DNA of 1,900 patients with gliomas, the most common brain tumor, and several thousand unaffected individuals. The top “hits” among the patients pointed to five genes, including CDKN2A, which plays a role in activating the tumor-suppressor gene p53. Another gene, TERT, is known to be active in tumors.

Four of the five genes turned up in the second study, led by Dr. Margaret Wrensch of the University of California, San Francisco. In addition, two genes, CDKN2A and CDKN2B, were implicated in the risk of melanoma and basal cell carcinoma, a type of non-melanoma skin cancer. This evidence appeared in separate studies also published by Nature Genetics.

“Some of the genes suspected in brain cancer are crossing over to other types of cancer, and it appears that there may be some common risk genes in cancer,” said coauthor Dr. Melissa Bondy of M.D. Anderson. She noted that the results represent a new beginning. “This is a hard tumor to understand. But we now have the technology to untangle the puzzle that we’ve been trying to work on for so many years.”

Study Aims to Improve Common Protein Discovery Method

A new study has identified several common problems that hinder the accuracy and reproducibility of using mass spectrometry to discover potential protein biomarkers of cancer. With feedback and training for laboratories conducting these analyses, the study authors believe, these issues can be overcome. The study was published in the June 2009 Nature Methods.

Conducted by the international Human Proteome Organization (HUPO), the study involved 27 laboratories that were asked to independently identify test samples spiked with 20 human proteins, each one with at least one specific peptide (a sequence of amino acids that join together to form proteins) of approximately the same mass. Each lab performed a mass spectrometry-based analysis of the samples, using their typical methodology, and reported the results and their raw data to HUPO for a centralized analysis.

Only 7 of the labs correctly identified all 20 proteins, and only 1 identified all of the peptides. However, when the raw data submitted by each lab was reanalyzed by the study leaders, they found that “members of each of the labs, with a few exceptions, had in fact generated mass spectrometry data of very high quality, more than sufficient to identify” all of the proteins and most of the peptides, the study authors wrote. Across the participating labs, several common problems led to the protein misidentifications, the researchers reported, such as discrepancies in searching the protein databases to match peptides to their respective proteins and test sample contamination.

Aside from the database issues, many of the problems encountered by individual labs “could be rapidly found and diagnosed,” explained the study's lead investigator, Dr. John Bergeron. In fact, after providing feedback to the participating labs on the problems discovered by the centralized analysis, all of the labs were then able to correctly identify the 20 proteins.

The study by HUPO “shows that with sufficient experimental care and technical training, currently available mass spectrometry-based methods” could produce accurate results, wrote Dr. Ruedi Aebersold, director of the Institute of Molecular Systems Biology at the University of Zurich in Switzerland, in an accompanying editorial. “It also makes a strong case for making data from proteomic studies accessible for comparison and meta-analyses and for the optimization and testing of software tools.”

Death Rates for Certain Cancers Remain Higher for African Americans

Although breast cancer death rates in the United States have declined substantially during the last 15 years, the trend has been less favorable for African American women, according to a study published online July 7 in the Journal of the National Cancer Institute (JNCI).

Using SEER data, Dr. Idan Menashe and his colleagues from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) calculated ratios of mortality, incidence, hazard of death, and incidence-based mortality for nearly 250,000 women diagnosed with breast cancer from January 1990 through December 2003. They found a statistically significant higher hazard of death in African American women diagnosed with breast cancer compared with Caucasian women, especially during the first few years after breast cancer diagnosis. These results suggest that the widening black-to-white disparity in breast cancer mortality rates in the United States is largely driven by the consistently higher hazard of death among African American women, irrespective of tumor estrogen-receptor (ER) expression at diagnosis. 

The authors noted that various biological and non-biological factors could have caused the differential hazard rate patterns among African Americans and Caucasians within each ER category, including response to innovations in breast cancer treatment and access to these treatments. “Hence, greater emphasis should be placed on identifying the reasons for these increased hazards among black women, especially during the initial years following diagnosis, and on developing new therapeutic approaches to address the disparity,” they wrote.

In a second study in JNCI, Dr. Kathy Albain of Loyola University Medical Center and her colleagues analyzed records from more than 19,000 patients who participated in phase III cancer clinical trials conducted by the Southwest Oncology Group. Their analysis showed that even when African American patients received the same cancer treatment as all other patients, their overall survival rates were lower following treatment for breast, prostate, and ovarian cancers, but were equivalent after treatment for all other major cancers.

These two articles “help bring some focus to [racial disparities in cancer incidence and mortality] and help better define the questions that should be asked,” wrote American Cancer Society Chief Medical Officer Dr. Otis Brawley in an accompanying editorial. “It is only through clearly defining the problem that we can most appropriately address it and develop the interventions that may overcome these disparities.”

Mayo Clinic Streamlines Development Process for Cancer Trial Protocols

By streamlining the development process for clinical trial protocols, the Mayo Clinic Cancer Center reduced by approximately 40 percent the time from the initiation of protocol to submission of the document to an institutional review board (IRB) for approval. Results of the initiative were reported June 29 in the Journal of Clinical Oncology.

Cancer clinical trials with prolonged activation times have been shown to have less success in meeting patient accrual goals. Such failed trials may delay getting potentially beneficial new cancer treatments to patients.

Mayo investigators and protocol development staff used Six Sigma, an improvement process developed and widely used in industry, to analyze where time was spent during protocol development and how process changes could reduce delays. They found that of a total of 199 days required to finalize a trial protocol, 174 days were “non-value-added”—that is, days spent waiting for something to happen (e.g., a revision, a response to a question, a document signature).

By introducing a standard template for all clinical trial processes and making other process changes, such as identifying steps that could be completed concurrently rather than sequentially, the cancer center reduced the “turnaround time” (that is, the time from initiation to IRB submission) from 25 weeks to 10 weeks for internally authored protocols and from 20.6 weeks to 7.8 weeks for externally authored protocols.

The experiment showed that significant progress can be made “in decreasing protocol development [turnaround times] through focused process engineering,” the authors, led by Terre A. McJoynt of the Mayo Clinic Cancer Center Research Office, wrote. “Such improvements can be realized within an extremely short timeframe and with little or no incremental investment in administrative resources.”

The group is now undertaking a second phase of the improvement effort, which will focus on the entire protocol development time from study concept through patient enrollment.