National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
January 24, 2012 • Volume 9 / Number 2

Cancer Research Highlights

Ovarian Cancer Patients with BRCA Mutations May Fare Better than Non-Carriers

A large, multicenter study shows that women with ovarian cancer who have mutations in the BRCA1 or BRCA2 genes have better survival rates than women who do not have such mutations. The study is also the first to provide strong evidence that ovarian cancer prognosis is better for women with BRCA2 mutations than women with BRCA1 mutations. The results were published online today in JAMA.

Inherited mutations in BRCA1 and BRCA2 are the strongest known genetic risk factors for breast cancer and epithelial ovarian cancer, the most common form of ovarian cancer. These mutations are found in 6 to 15 percent of women with epithelial ovarian cancer; the relative prognosis for women who carry BRCA gene mutations compared with non-carriers has remained unclear due to differing study results.

“Because BRCA mutations are rare to begin with, and because ovarian cancer is also relatively uncommon, it’s hard to design studies that are big enough to provide definitive evidence on this question,” explained lead author Dr. Kelly Bolton, a UCLA medical student who is affiliated with the Laboratory of Translational Genomics in NCI’s Division of Cancer Epidemiology and Genetics.

Dr. Bolton and her colleagues combined data from 26 clinical research studies worldwide on the survival of women with ovarian cancer. This included data on 1,213 women with inherited BRCA1 or BRCA2 mutations and 2,666 women without these mutations. The women were followed for variable times between 1987 and 2010.

The research team’s analysis showed that the 5-year overall survival rate for ovarian cancer was 36 percent for non-carriers, 44 percent for BRCA1 mutation carriers, and 52 percent for BRCA2 mutation carriers. After adjusting for the stage and grade of a patient’s tumor at the time of diagnosis, as well as other factors that could affect prognosis, the researchers found that BRCA2 mutation carriers are twice as likely to survive than non-carriers in the 5 years following diagnosis, whereas BRCA1 mutation carriers have a 37 percent greater chance of survival in the 5 years following diagnosis than non-carriers.

“Our findings provide further support that BRCA1 and BRCA2 mutation carriers’ tumors are different biologically, and they should be treated separately,” said Dr. Bolton. “That’s really important for clinical trial design, especially if you’re studying drugs such as PARP inhibitors, which are being tested in BRCA1 and BRCA2 mutation carriers.”

The findings could eventually be used by clinicians when advising patients with ovarian cancer about their possible prognosis but further studies are needed, Dr. Bolton added.

Experimental Drug Improves Survival in Previously Treated Metastatic Colorectal Cancer

Treatment with the investigational agent regorafenib modestly improved survival for patients with metastatic colorectal cancer whose disease had progressed after multiple prior treatments, according to clinical trial results presented last week at the 2012 Gastrointestinal Cancers Symposium.

The trial’s Data and Safety Monitoring Committee stopped the trial after a preplanned interim analysis showed a 1.4-month improvement in median overall survival, said the trial’s lead investigator, Dr. Axel Grothey of the Mayo Clinic Cancer Center in Minneapolis.

In the trial, called CORRECT, 760 patients were randomly assigned to receive regorafenib in combination with best supportive care—that is, care designed to treat symptoms but not to cure the underlying disease—or a placebo and best supportive care. Regorafenib, which comes in pill form, targets several specific enzymes known as kinases that regulate key tumor cell processes, including cell growth and proliferation.

The median overall survival was 6.4 months for patients who received regorafenib and 5 months for patients who received the placebo. After the randomized phase of the trial was stopped, patients in the placebo arm could choose to cross over and receive regorafenib.

Approximately two-thirds of the patients in the trial had received at least four prior treatments. Common side effects of regorafenib included skin rash, fatigue, diarrhea, and hypertension, which could be managed with medications and dose reductions, Dr. Grothey explained.

Fewer than 2 percent of the patients who received regorafenib experienced significant tumor shrinkage. But 44 percent of patients who received regorafenib had no measurable tumor growth or worsening of symptoms compared with 15 percent of patients treated with placebo.

Unlike many chemotherapy drugs and targeted agents, which are cytotoxic—that is, they kill cancer cells—regorafenib appears to be primarily cytostatic, meaning it arrests tumor growth, Dr. Grothey noted.

Other primarily cytostatic agents are in development. Traditional measures of treatment efficacy, such as tumor shrinkage, will have to be reconsidered, Dr. Grothey noted, or “we might miss agents that are cytostatic” and can help control tumor growth and progression.

Last year the Food and Drug Administration granted regorafenib, which is manufactured by Bayer, “fast track” designation for the treatment of patients with metastatic colorectal cancer whose disease has progressed despite multiple treatments with FDA-approved drugs. The fast-track process is designed to expedite the agency’s review of treatments for diseases with unmet needs.

Differences in Estrogen Metabolism May Influence Breast Cancer Risk

The way a woman’s body processes, or metabolizes, the hormone estrogen may influence her risk of postmenopausal breast cancer, according to new data from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) published online January 9 in the Journal of the National Cancer Institute.

In postmenopausal women, higher levels of estrogen are known to be associated with an increased risk of breast cancer. Laboratory work, however, has suggested that how estrogen is metabolized may also be important for risk. Two major hypotheses for the role of estrogen metabolites have dominated the field: one, that specific metabolites stimulate tumor growth and progression; and two, that specific metabolites function as mutagens and initiate DNA damage that can turn a normal cell into a cancerous one. This study confirms that estrogen metabolism is important and lends credence to both hypotheses.

“Those are the results we’re most excited about and also the most cautious about, because it’s the first time that we’ve been able to measure the relevant metabolites in blood in an epidemiologic setting,” said Dr. Barbara Fuhrman, a postdoctoral fellow with DCEG and lead author of the study. She and her colleagues used a novel liquid chromatography/mass spectrometry assay that allowed them to measure 15 different parent estrogens and estrogen metabolites accurately at the very low concentrations present in postmenopausal women.

They performed their analyses on blood samples taken from women enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Researchers compared the blood samples of 277 postmenopausal women who later developed breast cancer and 423 matched women without the disease. None of the women were taking menopausal hormone therapy at the time of blood collection.

Apart from the expected strong relationship with estradiol, the researchers found no clear relationships between individual hormone and metabolite concentrations and cancer risk. When they considered relationships among the three major estrogen metabolic pathways and their components, the clearest patterns emerged when they compared the pathways to one another and to the total pool of parent estrogens available for metabolism. Two metabolic patterns seemed to influence breast cancer risk in a statistically significant manner independent of circulating estradiol. One pattern was associated with an increased risk of breast cancer, whereas the other was associated with a decreased risk. When the researchers included a measure of each of these patterns in an established risk prediction model for breast cancer, the calculated risk for a considerable number of the women changed substantially.

“Although these findings are of great research interest, they need to be replicated and there are no immediate clinical implications,” said Dr. Regina Ziegler, also of DCEG and the senior author on the study. “We are still at the beginning of our understanding of the complex role of estrogen in the etiology of breast cancer. By improving our knowledge of the role of estrogen metabolism, we may uncover novel strategies for chemoprevention and treatment and be better able to predict an individual’s risk of breast cancer.”

Epigenetic Study Suggests Possible Treatment for Retinoblastoma

Based on a new model of the genetic and epigenetic changes underlying the childhood cancer retinoblastoma, researchers have identified a potential strategy for treating this rare disease. The model, published online in Nature January 11, suggests that inhibiting a protein called spleen tyrosine kinase (SYK) could benefit patients with this cancer of the eye.

Drugs that inhibit SYK are being developed to treat blood cancers and certain other diseases. In cell cultures and animal models, two of these drugs killed retinoblastoma cells, researchers with the Pediatric Cancer Genome Project found.

Both copies of a gene called RB1 are inactivated in nearly all retinoblastomas, but other molecular changes are required for the disease to progress rapidly. To identify additional DNA alterations, the researchers sequenced the tumor and normal genomes of four affected patients.

The analysis did not reveal any suspicious mutations or structural changes in the genome, however. “This was really surprising,” said Dr. Michael Dyer of St. Jude Children’s Research Hospital and the study’s senior author. “We wondered how these tumors could progress as rapidly as they do.”

In a further analysis based in part on a previous study, the authors focused on epigenetic changes, including DNA methylation and histone modification, which can alter the activity of genes without causing changes in the DNA sequence. When they compared the epigenetic profiles of normal cells and cancer cells, new clues about the disease emerged.

Several cancer-related genes in retinoblastoma cells appeared to be regulated by epigenetic mechanisms, including the SYK gene.

Although SYK has no known function in the eye, the protein may increase the production of a protein called MCL1 that is important for the survival of retinoblastoma cells. Blocking SYK may reduce the amount of MCL1 and trigger the death of retinoblastoma cells, the study authors said.

As a next step, the researchers have begun to develop a formulation of the most relevant SYK inhibitor, called R406, for the eye. The new formulation might provide a way to get more of the drug into the eye, Dr. Dyer said. But the researchers need to assess the potential toxicities of this version of the drug before planning a clinical trial, he added.

Also in the Journals: Before Breast Cancer Surgery, Two Anti-HER2 Drugs May Be Better than One

Women with HER2-positive breast cancer who received both lapatinib (Tykerb) and trastuzumab (Herceptin) fared better than women who received either drug alone in the NeoALLTO  trial. The results were reported online January 16 in The Lancet.

In the phase III trial, 455 women were randomly assigned to receive trastuzumab, lapatinib, or both drugs combined for a total of 18 weeks prior to surgery. After the first 6 weeks, paclitaxel chemotherapy was added to the anti-HER2 treatments. The researchers found that dual HER2 blockade had significantly greater antitumor effects than those obtained with lapatinib or trastuzumab alone.

About 50 percent of the women who received both anti-HER2 drugs were free of residual cancer in the breast or regional lymph nodes at the time of surgery, compared with fewer than 30 percent of the women who received lapatinib or trastuzumab alone.

These results are consistent with a recent phase II study testing dual HER2 blockade with two anti-HER2 antibodies, trastuzumab and pertuzumab, in the neoadjuvant setting. Both studies provide support for investigating new targeted agents for breast cancer earlier in treatment, “when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest,” the study authors noted.