National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 9, 2010 • Volume 7 / Number 3

Cancer Research Highlights

Symptoms of Ovarian Cancer May Not Help Early Detection

Some women with ovarian cancer report symptoms before diagnosis, including abdominal pain, bloating, and feeling full. But a new study concludes that monitoring women for these relatively nonspecific symptoms would be of limited value in detecting the disease. Doctors would have to evaluate 100 women with these symptoms to find one ovarian cancer, the researchers reported online in the Journal of the National Cancer Institute on January 28.

These findings come nearly 3 years after a consensus statement issued by three U.S. medical organizations advised women who experience certain symptoms over a period of time to consider talking with their physicians. Recognizing symptoms reported by women who develop ovarian cancer could assist with diagnosis, the statement said.

In the new study, Dr. Mary Anne Rossing of the Fred Hutchinson Cancer Research Center and her colleagues interviewed 812 patients with ovarian cancer and 1,300 women without the disease about their symptoms. In most cases, symptoms appeared less than 6 months before a diagnosis.

“We would all like to find a perfect way to detect ovarian cancer in its early stages,” said Dr. Rossing. “Knowing, however, that the symptoms are fairly nonspecific and that ovarian cancer is relatively rare in the general population, it’s not surprising that these symptoms would have a low ability to predict the disease in the general population.”

The findings “highlight the urgent need to develop better molecular markers and improved imaging modalities for ovarian cancer screening,” noted Drs. Ilana Cass and Beth Karlan of Cedars-Sinai Medical Center in an accompanying editorial.

Trastuzumab Benefits Women with Locally Advanced, Inflammatory Breast Cancer

Findings from an international clinical trial suggest a new treatment option for some women with aggressive types of breast cancer. In the trial, women treated with trastuzumab (Herceptin) and chemotherapy before surgery (neoadjuvant) and trastuzumab again after surgery (adjuvant) had a reduced risk of the disease recurring or progressing after 3 years compared with women who received pre-surgical chemotherapy but no trastuzumab. The findings were published in the January 30 Lancet.

The 230 women enrolled in the trial had either locally advanced or inflammatory breast cancer that was HER2-positive. Although trastuzumab has been shown to improve overall survival in women with HER2-positive early stage and metastatic breast cancer, the drug has not been closely studied in women with these intermediate stages of breast cancer, the research team wrote.

Patients who were randomly assigned to receive trastuzumab took the drug for a total of 1 year. Three-year event-free survival—with an event defined as disease recurrence, progression, or death from any cause—was 71 percent in patients treated with trastuzumab and 56 percent in those who did not receive it. The pathologic complete response rate, or no detectable presence of cancer, was nearly doubled among the women who received trastuzumab.

To date, there is no statistically significant improvement in overall survival among the women who received trastuzumab. This could be due to the fact that 17 percent of the women in the chemotherapy-alone arm also received adjuvant trastuzumab, while some other patients received the drug following a recurrence, explained the trial’s principal investigator, Dr. Luca Gianni of the Italian National Cancer Institute, in a Lancet podcast.

There were no significant issues with cardiac side effects, which have been a recurring problem in other breast cancer trials involving trastuzumab and doxorubicin, a drug that was part of the chemotherapy regimen used in the trial.

According to Dr. Massimo Cristofanilli, chair of the Department of Medical Oncology at Fox Chase Cancer Center, pathologic complete response “is the most important prognostic factor” in women with these breast cancer types. The low rates of cardiac side effects, he noted, were likely due to the fact that patients in the trial had not been pretreated, had optimal heart function, and the cumulative doses of doxorubicin were below those typically associated with cardiotoxicity.

Tumor-targeting Antibodies Against Glycoproteins May Be Markers of Early Cancer

In a proof-of-concept study, researchers from the NCI-funded Alliance of Glycobiologists for Detection of Cancer and Cancer Risk showed that autoantibodies targeting abnormal glycoproteins (proteins with sugar molecules attached) produced by tumors may serve as biomarkers for cancer detection. Autoantibodies are antibodies directed against the body’s own tissues, including tumor cells. The findings were published February 2 in Cancer Research. The work was coordinated by Dr. Karl Krueger of the Cancer Biomarkers Research Group (CBRG) in NCI’s Division of Cancer Prevention.

Because the sugars that are attached to certain glycoproteins, called O-glycoproteins, on the surface of cancer cells have been found to be abnormal, researchers led by Dr. Hans H. Wandall of the University of Copenhagen synthesized a large number of abnormally glycosylated peptides (protein fragments) and used them to make a microarray for detecting autoantibodies against abnormal O-glycoproteins. Glycosylation is the process of adding sugar molecules to proteins, lipids (fats), or other biological molecules.

The researchers tested the microarray using blood samples from 20 breast cancer patients who were enrolled in a clinical trial of an anticancer vaccine targeting O-glycoproteins. The researchers knew from previous analyses that many of the patients had developed immunoglobulin G antibodies against several O-glycoproteins, and these autoantibodies were indeed detected by the new microarray.

The researchers then used the microarray to scan blood samples from 58 patients with newly diagnosed breast, ovarian, or prostate cancer and from 39 age- and sex-matched healthy control subjects.

Autoantibodies to several of the O-glycoproteins on the microarray were found in 5 out of 26 breast cancer patients, 5 out of 20 ovarian cancer patients, and 4 out of 10 prostate cancer patients. No autoantibodies to any of the O-glycoproteins were found in the healthy control subjects.

“Thanks to emerging technologies such as the one used in this study, scientists have identified biomarkers based on the carbohydrate (sugar) portion of a glycoprotein that may be novel targets for the early detection and diagnosis of certain cancers,” said Dr. Sudhir Srivastava, chief of the CBRG. Nevertheless, he added, additional work is needed and larger sets of specimens must be analyzed to fully define the clinical value of this approach.

Gene Mutation Linked to Poor Survival in Children with Medulloblastoma

Results from a small, retrospective study suggest that a single genetic mutation may be linked to poor survival in children with medulloblastoma, the most common type of pediatric brain tumor. In the study, released online February 8 in the Journal of Clinical Oncology, no patient with medulloblastoma whose tumor had a mutation in the TP53 gene was alive after 5 years, even though the large majority of patients were considered to be at average risk for disease progression after treatment, reported Dr. Cynthia Hawkins and colleagues from the Hospital for Sick Children in Toronto.

With modern treatment protocols, approximately 80 percent of average-risk patients with medulloblastoma—classified as such based on whether their tumor could be completely removed, their age, and whether they had metastases—survive for 5 years or more. “So we’ve identified a group of patients based on clinical factors who do well, on average, but still 20 percent of those patients are dying and we don’t know why,” Dr. Hawkins said.

The study involved 108 children treated for medulloblastoma between 1995 and 2007. Tumor samples were available for DNA sequencing from 49 of these children, and 8 had a TP53 mutation. TP53 mutations were strongly associated with early tumor recurrences. Of the 27 patients considered to be at average risk from this group of 49 children, 8 died within 5 years, 6 of whom had TP53 mutations.

Overall, 5-year survival rates for patients with TP53 mutations was 0 percent, compared with 74 percent for patients whose tumors had a normal, or wild-type, TP53 gene. Among the average-risk patients, the discrepancy for progression-free survival was greater still, 0 percent compared with 87 percent.

“All patients with TP53-mutated medulloblastomas presented with local disease and experienced recurrence locally,” the researchers wrote. “This implies that, as opposed to other molecular alterations found in medulloblastoma that are associated with dissemination, TP53 mutation causes an aggressive phenotype through other mechanisms.”

The finding of an association between TP53 status and medulloblastoma outcome is “important information,” said Dr. Javed Khan of NCI’s Pediatric Oncology Branch in the Center for Cancer Research. Dr. Khan concurred with the authors that the findings need to be validated in a larger, prospective study.