National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
July 12, 2011 • Volume 8 / Number 14

Cancer Research Highlights

EGFR-Targeted Drug Effective for Some Lung Cancer Patients

Patients with advanced non-small cell lung cancer (NSCLC) whose tumors have specific mutations in the EGFR gene lived longer without their disease progressing when treated with the drug erlotinib (Tarceva) than patients who received chemotherapy alone, according to results from a phase III trial presented last week at the 2011 World Conference on Lung Cancer in Amsterdam. 

Based on a recommendation from its independent data monitoring committee, the 174-patient EURTAC trial was halted in January after an interim analysis found that it had met its primary endpoint of improved progression-free survival.

Other trials have also shown that patients whose tumors have EGFR mutations have better outcomes when treated with an EGFR-targeted agent such as erlotinib or gefitinib (Iressa), which are both tyrosine kinase inhibitors. However, those trials included only Asian patients, and only one trial to date, called OPTIMAL, limited enrollment to participants whose tumors had EGFR mutations. The EURTAC trial was the first to enroll patients from Western countries (primarily Europe) with advanced NSCLC whose tumors had EGFR mutations, explained the lead investigator Dr. Radj Gervais of Centre François Baclesse in France.

Patients were randomly assigned to receive, as their initial treatment, either erlotinib or a chemotherapy regimen containing a platinum drug until their disease progressed. Patients treated with erlotinib lived a median of 9.7 months without their disease progressing compared with 5.2 months for patients treated with chemotherapy. There was also a very high response rate in the patients treated with erlotinib, Dr. Gervais reported, with 58 percent experiencing substantial tumor shrinkage compared with only 15 percent of patients who received chemotherapy.

Overall survival was slightly better in patients treated with erlotinib, but the improvement was not statistically significant. An overall survival improvement may never be seen, Dr. Gervais explained during a press briefing, because patients treated with chemotherapy as their first-line therapy were switched to erlotinib once their disease began to progress, which is in line with current clinical practice.

Because of this crossover to treatment with erlotinib, “showing a survival improvement will be a difficult task,” agreed Dr. Roy Herbst, a leading lung cancer researcher at the University of Texas M. D. Anderson Cancer Center, during the briefing.

As early as the end of the year, Astellas Pharma expects to submit an application to the FDA seeking approval for erlotinib as a first-line treatment in patients with NSCLC who have EGFR mutations. Roche funded the EURTAC trial.

Clinically Relevant Family Histories of Cancer Change Over Time

A person’s clinically relevant family history of certain cancers changes substantially between ages 30 and 50, particularly for colorectal and breast cancer, as more family members are diagnosed, a new study shows. The study highlights the importance of having an accurate, up-to-date family history.

The findings were reported July 12 in JAMA by investigators from the Cancer Genetics Network (CGN), a research resource that includes a national registry of people with a personal or family history of cancer. CGN is an NCI-funded project directed by Dr. Dianne Finkelstein of Massachusetts General Hospital and Harvard University.

“We wanted to find out how often changes in a person’s family history of cancer over time would affect the cancer screening schedule and tests recommended by standard guidelines,” said Dr. Sharon Plon of Baylor College of Medicine, the senior author on the paper.

The researchers examined family history data for colorectal, breast, and prostate cancer among 11,129 individuals enrolled in the CGN. Family history is an important predictor of risk for all three cancers. CGN investigators have followed registry participants for a decade with annual questionnaires on family history updates and other factors.

Using family history data that the participants provided when they entered the registry, investigators determined retrospectively the rate of change in each person’s family history from birth until the time of enrollment into CGN. They also examined the participants’ family history changes prospectively, from the time of their enrollment in the CGN to the time of their most recently completed questionnaire.

In particular, CGN investigators looked for changes in family history that would make someone a candidate for earlier or more intensive screening according to current American Cancer Society (ACS) guidelines. For individuals considered to be at high risk, ACS guidelines include earlier and more frequent screening for colorectal cancer and the addition of annual breast magnetic resonance imaging (MRI) for breast cancer.

The analyses showed that the participants’ clinically relevant family history changed substantially between the ages of 30 and 50, especially for colorectal and breast cancer. The proportion of individuals who should be recommended for high-risk screening for these two cancers increased 1.5 to 3-fold between ages 30 and 50.

“The results of this study could guide how often health care providers should ask their patients for an update in their family history,” said Dr. Finkelstein. “It is important to inform the physician of new diagnoses of cancer in family members at routine [annual] check-ups,” she added, noting that patients “should be aware of which of their close relatives have had cancer, the location or organ where the cancer started, and the age at which the relative was first diagnosed with cancer.”

Lung Tumor Study Reveals Variability of CT Scans

Doctors and researchers use imaging tools such as computed tomography (CT) to monitor the size of a patient’s tumor and to assess responses to new therapies during clinical trials. To evaluate the performance of CT for these purposes, researchers compared measurements of tumor size on scans of the same patient taken just minutes apart. On many repeat scans, the study found, radiologists identified changes in tumor size that, if real, would be considered clinically important.

In the report of their findings, published online July 5 in the Journal of Clinical Oncology (JCO), the researchers noted that decreases in tumor size of less than 10 percent may not be distinguishable from changes caused by inherent variability in the scanning process. Dr. Gregory Riely of Memorial Sloan-Kettering Cancer Center (MSKCC) led the study.

Radiologists have known that many nonbiological factors can create apparent changes in tumor size on repeat CT scans. This study, for the first time, has quantified the effect.

The researchers scanned 30 patients with non-small cell lung cancer twice within 15 minutes using the same CT machine. Three radiologists then read the images without knowing the interval between the scans. They reported changes of more than 2 mm in tumor diameter on many of the repeat scans.

Clinical trials have increasingly reported small changes in tumor size as evidence of drug activity, the study authors noted. They point out, however, that changes of this magnitude could be solely the result of variability in imaging. As such, these kinds of changes should not by themselves be a marker of efficacy in clinical trials, the authors said.

This unprecedented study of the performance characteristics of CT may have “important implications for the future of drug development,” noted Dr. Michael Maitland of the University of Chicago and his colleagues in an accompanying editorial.

Blocking Cdk1 Protein May Sensitize More Tumors to PARP Inhibitors

Investigators have found a potential way to compromise DNA repair in cancer cells that lack BRCA mutations, making them sensitive to treatment with PARP inhibitors. The results of the research, which was led by Dr. Geoffrey Shapiro of Dana-Farber Cancer Institute and Harvard Medical School, were published online June 26 in Nature Medicine.

Cancer cells that have BRCA mutations respond to treatment with PARP inhibitors because they have a defect in the DNA-repair pathway that becomes critical for cells when the DNA-repair pathway that involves PARP is disabled. The researchers hypothesized that blocking the activity of a protein called Cdk1 might create an effect similar to a BRCA mutation in cancer cells that lack such a mutation. Cdk1 controls the function of the normal BRCA1 protein in DNA repair and helps regulate the cell cycle.

To test their hypothesis, the researchers blocked Cdk1 function in several cancer-cell lines lacking BRCA mutations using either RNA interference or drugs designed to inhibit Cdk1 activity.

After blocking Cdk1 function and exposing the cells to gamma radiation, which damages DNA, they observed a 70 to 80 percent reduction in the formation of the DNA-repair machinery that can compensate for inhibition of the DNA-repair pathway that involves PARP.

When the researchers used RNA interference to block Cdk1 activity in two different cell lines lacking BRCA mutations, the cells were 100 to 200 times more sensitive to treatment with a PARP inhibitor than the same cell lines with normal Cdk1 levels. They saw similar results after blocking Cdk1 function with a drug.

In lung tumors lacking BRCA mutations that were grown in genetically engineered mice, the combination of a drug to block Cdk1 activity and a PARP inhibitor caused sustained tumor regression in 9 out of 13 mice that were treated for 3 weeks. Two of the mice remained alive 15 weeks after treatment without additional tumor growth. No damage to normal tissues or organs was observed with the drug combination.

The authors proposed that the combination of drugs should be tested in early-phase clinical trials. “Our hope is that doses of the Cdk1 inhibitor and the PARP inhibitor that we would study in clinical trials would be effective without harming normal tissues,” explained Dr. Shapiro.

Gene Mutations Linked to Altered Telomeres in Cancer Cells

Researchers have identified an association between mutations in two genes and highly abnormal telomeres in multiple forms of cancer, including the most common and aggressive form of malignant brain tumor, glioblastoma multiforme (GBM). Among hundreds of tumors tested, those with mutations in either of the two genes also had abnormal telomeres, researchers at the Sol Goldman Pancreatic Cancer Research Center and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins reported online June 30  in Science.

The researchers can now investigate whether the mutations contribute directly to changes in telomeres and cancer, which could have clinical implications. The work builds on a recent genetic analysis of pancreatic neuroendocrine tumors (PNET), a type of pancreatic cancer, by Hopkins researchers. This prior study found frequent mutations in one of two genes involved in the packaging of DNA—DAXX and ATRX.

The proteins encoded by these genes modify chromosome structure and are active at the telomeres. In the new study, the researchers hypothesize that the inactivation of these genes may make it possible for cancer cells to lengthen their telomeres, ensuring their survival. Normally, telomere DNA is progressively lost as a cell divides until the cell is no longer viable.

“The mutations in DAXX or ATRX seem to allow cancer cells to overcome the natural loss of telomere DNA and to keep dividing indefinitely,” said Dr. Alan Meeker, a molecular pathologist at the Kimmel Cancer Center and a lead author of the study. “This hypothesis needs to be tested through rigorous functional studies in the lab.”

When he and his colleagues analyzed more than 400 tumors, every sample that had mutations in the ATRX gene had abnormal telomeres. (They did not find any DAXX mutations in the non-PNET samples.) The association was relatively common in certain cancers, including central nervous system tumors, particularly GBM in children and adults.

“There was a perfect correlation between mutations in DAXX or ATRX and abnormal telomeres,” said Dr. Meeker. “This was really exciting. You rarely ever see a perfect correlation in biological research.” Understanding the mechanisms involved in generating the abnormal telomeres could reveal new therapeutic targets for cancer, he added.