Trials Demonstrate Potential Role of HPV Screening Test

Results from two large, randomized clinical trials confirm findings from earlier studies that DNA tests for human papillomavirus (HPV) are more sensitive than Pap tests and can play an important role in screening for cervical cancer. However, cautioned several researchers, the trials' results still leave unanswered many important questions about optimal cervical cancer screening practices.

Both published in the October 18 New England Journal of Medicine (NEJM), the trials had different designs. The first trial, conducted in Canada, included more than 10,000 women 30 or older who received both the HPV DNA test and a Pap test in a randomly assigned sequence. Each test was evaluated as a stand-alone screening test. As has been seen in previous studies, the HPV DNA test had a far greater sensitivity for grade 2 or 3 cervical lesions compared with the Pap test, 94.6 percent vs. 55.4 percent. Also consistent with earlier research, the HPV DNA test had a slightly lower specificity than the Pap test, 94.1 percent vs. 96.8 percent.

The second trial, conducted in Sweden, included more than 12,500 women aged 32 to 38 who were randomly assigned to an HPV DNA test in combination with a Pap test or a Pap test alone. Participants were followed for approximately 4 years. For the initial screening, detection of cervical cancer or grade 2 or 3 cervical lesions was 51 percent higher in the combination screening group compared with those screened with a Pap test alone. At the follow-up screening, however, participants in the combined testing group were approximately 40 percent less likely to have grade 2 or 3 lesions or cancer compared with those in the Pap test alone group, which the study authors argued "could allow extended screening intervals, requiring fewer Pap smears and possibly lowering the costs of initial screening."

A third major trial with similar conclusions was announced earlier this month in The Lancet based on 5-year follow-up of more than 17,000 women. Results from the three trials are expected to accelerate the shift toward new procedures for cervical cancer screening. The question is not whether molecular assays will be incorporated, but rather how, says Dr. Diane Solomon from NCI's Division of Cancer Prevention. "We need to develop screening algorithms that capitalize on the sensitivity of molecular assays and also avoid overreferral, by use of a second 'triage' test that might include repeated HPV testing, and/or increasing the screening interval."

More Genetic Markers Found for Prostate Cancer Risk

Evidence that prostate cancer risk can be inherited has increased dramatically in 2007, with several major studies locating markers in the q24 band of chromosome 8. New results from researchers at Wake Forest University School of Medicine identified 2 regions in this area of the chromosome where genetic variants occurred more frequently in a case-control study of 1,563 European American men with prostate cancer. The study was published in the October 17 Journal of the National Cancer Institute.

Led by Drs. S. Lilly Zheng and Jielin Sung and funded in part by NCI, the researchers genotyped 18 single nucleotide polymorphisms (SNPs) in the 8q24 region, and looked for the presence of these SNPs in gene panels of prostate tumor tissue taken from the patients, as well as samples from 576 control subjects without cancer. One SNP, called rs6983267, had recently been identified in NCI's Cancer Genetic Markers of Susceptibility (CGEMS) study. A second set of SNPs found close to rs1447295, was previously identified as a risk marker for more aggressive disease.

What is important and novel, say the authors, is that the risk associated with each of these SNPs is additive. Because their occurrence was not linked, "the risk alleles at each are common, [and] these loci together may account for substantially more prostate cancer than previously appreciated," they note. More than a third of patients had SNPs at one or both locations. If the SNPs were found at one location, risk was increased 70 percent; if found at both locations, 168 percent.

In an editorial, Drs. Sharon A. Savage and Mark H. Greene of NCI's Division of Cancer Epidemiology and Genetics note that this study was bolstered by access to publicly available prepublication data from CGEMS, exemplifying the value of innovative data sharing policies. "We hope that a policy of more liberal early access to datasets of this kind will soon become the accepted standard worldwide," they wrote.

Paclitaxel Benefit May Depend on HER2 Status

Data from the Cancer and Leukemia Group B (CALGB) clinical trial CALGB 9344, first reported in 1998, showed a significant increase in disease-free and overall survival with the addition of paclitaxel to chemotherapy with doxorubicin and cyclophosphamide for women with lymph node-positive breast cancer. However, a new retrospective analysis of the data, published in the October 11 NEJM, indicates that only the subset of women with HER2-positive disease actually benefited from the addition of paclitaxel.

The CALGB investigators randomly selected 1,500 of the 3,121 women who originally participated in the trial, and examined tissue samples from 1,322 of them. They tested the samples for HER2 and estrogen-receptor (ER) status, and compared disease-free survival between women whose cancer was HER2-positive/ER-negative, HER2-positive/ER-positive, and HER2-negative/ER-positive.

While the addition of paclitaxel improved disease-free survival or women with HER2-positive tumors regardless of ER status, "paclitaxel did not benefit patients with estrogen-receptor-positive, HER2-negative cancers," state the authors. The group of women with HER2-negative/ER-positive cancers accounted for more than half the participants in CALGB 9344.

"Our studies suggest that [patients with HER2-negative/ER-positive cancer] could avoid the toxic effects associated with adjuvant paclitaxel when given after doxorubicin plus cyclophosphamide," conclude the authors. However, they explain, because these results are based on a retrospective analysis not planned for in the original design of the trial, "our results require validation before adoption into clinical practice."

"This is not a call to abandon taxanes for this group of patients," says Dr. Anne Moore from Weill Cornell Medical College in an accompanying editorial. Other taxane drugs or treatment schedules may still benefit patients with HER2-negative/ER-positive cancer, she explains, and analysis of other trial results based on HER2 and ER status will be important.

Batracylin Blocks DNA Replication in Cancer Cells

Batracylin, an experimental anticancer drug developed by NCI's Developmental Therapeutics Program, has been found to block two enzymes that assist in the DNA replication process - topoisomerase I and topoisomerase II. Investigators in NCI's Center for Cancer Research (CCR) report that this drug targets DNA replication and can help limit cancer's uncontrolled growth. The findings appear in the October 15 Cancer Research.

Other chemotherapy drugs, such as etoposide and camptothecin, can block either topoisomerase I or topoisomerase II, but not both enzymes. Since cancer cells can use either enzyme to replicate, transcribe, or repair DNA, resistance develops to drugs that only target one topoisomerase.

Earlier experiments showed batracylin's activity against topoisomerase II, indicated by an increase in double-strand DNA breaks in treated cells. The new in vitro experiments using colorectal cancer cells also showed the drug's activity against topoisomerase I, indicated by an increase in single-strand DNA breaks. Batracylin's interference with DNA replication lasted significantly longer in cell culture than interference caused by either etoposide or camptothecin. Subsequent in vivo studies will be conducted to determine whether a shorter treatment schedule might be possible with batracylin.

"Only a few dual topoisomerase inhibitors have been identified and are being developed as anticancer treatments," state the authors, led by Dr. Yves Pommier, chief of CCR's Laboratory of Molecular Pharmacology.

Dr. William Bonner, an investigator in the same laboratory, patented a biomarker that allowed the Pommier team to measure the DNA damage caused by batracylin treatment. The biomarker is a protein, called γ-H2AX, which forms a complex with stretches of bases that flank the region of DNA strand breaks. When cells were treated with very small doses of batracylin, γ-H2AX/DNA aggregates could be detected after the first hour, and increased up to 15 hours after treatment.

Batracylin and the molecular test are now being evaluated in an NCI clinical trial at the NIH Clinical Center in patients with solid tumors or lymphoma.