New Guidelines on Cervical Cancer Screening Released
Experts convened the 2006 conference to incorporate new evidence on the natural history of cervical precancer and of HPV infection, the major cause of cervical cancer worldwide, into the previous guidelines issued in 2001. For example, explains Dr. Diane Solomon, medical officer in NCI's Division of Cancer Prevention and one of the authors of the new guidelines, "there is [now] recognition that young adolescent women are at high risk of being infected with HPV, but it's also very likely that HPV and any associated cellular changes will clear over time. In addition, these young women are at exceedingly low risk of cervical cancer. Therefore, one major change in these guidelines is to manage adolescent women who have an abnormality very conservatively, and follow them, unless they have evidence of severe precancer."
An accompanying clinical opinion article puts the new guidelines in the context of risk management, in which the results of any given test are not used alone to decide the next step for a woman diagnosed with a cervical abnormality, but integrated with additional information to gain a more accurate estimate of the likelihood that a cervical precancer or cancer is present. "I think these guidelines represent a significant step towards the concept of management according to risk strata," says Dr. Mark Schiffman, epidemiologist with NCI's Division of Cancer Epidemiology and Genetics (DCEG) and co-author of the clinical opinion article led by Dr. Philip Castle, also of DCEG.
Stem Cells, miRNA Influence Breast Cancer Metastasis in Mice
Two studies led by investigators from the Massachusetts Institute of Technology have identified mechanisms by which breast cancer cells in mice gain the ability to metastasize.
One study, published in the October 4 issue of Nature, found that mesenchymal stem cells (MSCs), which normally reside mainly in the bone marrow, can migrate to breast tumors in mice, likely in response to signaling from the cancer cells that is similar to that from injured normal tissue. Once in the tumor microenvironment, the MSCs release a protein called CCL5, which appears to influence the later steps of metastasis, including the movement of cancer cells from the bloodstream to adjacent tissue.
The influence of the CCL5 protein required the MSCs to be in close proximity to the cancer cells before they metastasized. When the investigators injected mice with a mixture of MSCs and human breast cancer cells, the mice developed tumors that spread to the lungs and other tissue sites. However, the MSCs did not metastasize along with the cancer cells, and cancer cells taken from the lung nodules failed to form tumors with elevated metastatic potential compared with cells taken from the original primary tumors.
The second study, published online September 26 by Nature, suggests a role for microRNAs (miRNAs) in breast cancer metastasis. The investigators focused on a specific miRNA, called miR-10b, which was found by microarray analysis to be expressed only in metastatic cancer cells.
When the investigators forced the expression of this miRNA in otherwise nonmetastatic human breast cancer cells injected into mice, the cancer cells formed tumors that were both highly locally invasive and metastatic. In contrast, control cancer cells not forced to express miR-10b did not invade local tissue or enter the bloodstream.
"I started looking at how the stromal microenvironment of a tumor regulates cancer cell metastasis, and Dr. Ma [author of the miRNA paper] started looking at the genetic material within the cancer cell itself that drives metastasis," explains Dr. Antoine Karnoub, lead author of the stem cell study. "Metastasis doesn't have to be [driven by only] one or the other - it could very well be a combination of both."
New Targeted Agent Shows Efficacy in Advanced Kidney Cancer
An experimental multitargeted antiangiogenesis agent has demonstrated promising activity in patients with advanced kidney cancer for whom a similar targeted drug failed to work. Speaking late last month at a large European cancer research conference, ECCO 14, Dr. Brian Rini from the Cleveland Clinic Taussig Cancer Center reported that, in a phase II clinical trial, the experimental tyrosine kinase inhibitor axitinib shrunk tumors in more than half of the 62 trial participants.
"Preliminary analysis shows that progression-free survival was on average more than 7.7 months," Dr. Rini said in a news release. "We think these results are impressive because these patients were heavily pretreated with drugs thought to be similar to axitinib."
All of the patients in the trial had metastatic renal cell carcinoma (RCC) and had not responded to sorafenib (Nexavar), which received FDA approval in December 2005 for the treatment of metastatic RCC. Of the 14 patients in the trial who had also been treated with another tyrosine kinase inhibitor approved by the FDA for the treatment of advanced RCC, sunitinib (Sutent), only 1 had a partial response, Dr. Rini reported.
Axitinib - which inhibits vascular endothelial growth factors 1, 2, and 3 in an intracellular signaling pathway regulated by a gene known as VHL - has also shown encouraging activity in patients with advanced pancreatic, lung, and thyroid cancer. (Clinical Trials for axitinib now enrolling patients.)
"These results of a novel agent targeting the VHL pathway in clear cell renal carcinoma are certainly interesting," says Dr. Marston Linehan, chief of the Urologic Oncology Branch in NCI's CCR, who, along with Dr. Berton Zbar, discovered the VHL gene. "Since there is currently no clear choice for second-line therapy in advanced clear cell renal carcinoma, this agent has the potential to fill that role."
Experimental Agent Improves HRPC Survival in Early-Phase Trial
In a secondary analysis of a recently completed phase II trial, an experimental agent for the treatment of men with a difficult-to-treat type of prostate cancer improved overall survival compared with placebo, even though there was no improvement in progression-free survival, the trial's primary endpoint.
"It is usual to use [progression-free survival] as an endpoint in phase II studies; however it can be difficult to measure accurately in patients with metastatic hormone-resistant prostate cancer (HRPC)," said the trial's principal investigator, Dr. Nick James from the U.K.-based Institute for Cancer Studies. "Overall survival is an unambiguous endpoint and clearly an important outcome for patients."
Patients in the randomized, double-blind trial - the results of which were presented late last month at the ECCO 14 conference in Barcelona - had metastatic HRPC, a disease for which only one chemotherapy agent, docetaxel, is currently approved. The drug used in this trial, ZD4054, is an endothelin A receptor antagonist. Studies have suggested that the endothelin A receptor molecule plays important roles in the inhibition of apoptosis, promotion of angiogenesis, and cancer cell invasion and metastasis.
Patients in the trial who received the 10 mg dose of ZD4054 fared best, with a median overall survival of 24.5 months, while patients who received the 15 mg dose of ZD4054 or placebo had a median overall survival of 23.5 and 17.3 months, respectively.
"The results look promising," said Dr. Boris Freidlin, division of NCI's Division Cancer Treatment and Diagnosis, noting the consistent overall survival improvements.
Based on the results, AstraZeneca, the drug's manufacturer, is launching three phase III trials using ZD4054 in men with HRPC. NCI is sponsoring a phase III trial, being led by the Southwest Oncology Group, of a different endothelin A receptor antagonist in a similar patient population.