ORLANDO, June 1 — How small is too small to treat? That’s always a tough question, but findings reviewed in this MedPage Today InFocus discussion suggest that regardless of size, micrometastases in sentinel node biopsy should not be ignored.

Julie Gralow, M.D., an associate professor in the oncology division of the University of Washington School of Medicine in Seattle, said that she and other oncologists have struggled with the issue of when to treat axillary nodes in women with early stage breast cancer who have micrometastases of 2 mm or less discovered by analysis of the sentinel node.

Now, however, evidence from a Dutch study reported at the American Society of Clinical Oncology meeting indicates that the “no treatment” approach may increase the five-year risk of recurrence.

Also, in this installment of InFocus, Dr. Gralow and Peggy Peck, MedPage Today executive editor discuss conflicting data on the efficacy of tamoxifen when used concurrently with some antidepressants.

LITTLE FALLS, N.J., June 16 — CT colonography may be just as accurate as colonoscopy in high-risk colorectal cancer patients, a new study shows.

• Explain that in patients at high risk of colorectal cancer, CT colonography had a negative predictive value of 96.3% overall — a figure comparable to regular colonoscopy.
• Note, however, that the negative predictive value fell to 84.9% for those who had a positive fecal occult blood test.

The so-called “virtual colonoscopy” had a negative predictive value of 96.3% overall, a figure comparable to regular colonoscopy, according to Cristiana Laudi, M.D., of the Institute for Cancer Research and Treatment in Torino, Italy, and colleagues.

“Our values . . . suggest a potentially effective use of CT colonography as an alternative to colonoscopy for screening individuals with family history of advanced colorectal neoplasia,” the researchers reported in the June 17 Journal of the American Medical Association.

Virtual colonoscopy has been recognized as an alternative to traditional colonoscopy for colorectal cancer screening in average-risk patients.

Since it is less invasive and more tolerable, advocates say it may increase adherence to screening, the researchers said.

However, less information comparing the two procedures is available when it comes to patients at an increased risk of colorectal cancer.

So to assess the accuracy of CT colonography in detecting advanced colorectal neoplasia in patients at increased risk, the researchers conducted a multicenter cross-sectional study of 937 patients. All had a family history of advanced neoplasia in first-degree relatives, personal history of colorectal adenomas, or positive results from fecal occult blood tests.

Patients were recruited in 11 Italian centers and one Belgian center between December 2004 and May 2007.

Each underwent CT colonography and colonoscopy on the same day.

The researchers used unblinded colonoscopy as the reference standard.

Overall, they found that CT colonography identified 151 of 177 patients with advanced neoplasia 6 mm or larger for a sensitivity of 85.3% (95% CI 79% to 90%).

It correctly classified results as negative for 667 of 760 participants without such lesions for a specificity of 87.8% (95% CI 85.2% to 90%).

Positive and negative predictive values were 61.9% and 96.3%, respectively.

For disease-positive patients with neoplasia that were 10 mm or larger, the test identified them with a sensitivity of 90.8% and a specificity of 84.5%. Positive and negative predictive values were 48.8% and 98.3%, respectively.

The researchers said the sensitivity measurements for 6 mm and 10 mm are “comparable with figures reported in two large trials on average-risk individuals but higher than those of two previous multicenter studies that included patients with clinical indication for colonoscopy or those with family history of CRC.”

They noted that CT colonography can only classify a lesion by its size, so large hyperplastic polyps or rare, low-risk adenomas can generate false-positives.

However, when the results were stratified, the negative predictive value in the positive fecal occult blood test group dropped to 84.9% (95% CI 76.2% to 91.3%, P<0.001).

“Our results do not support using CT colonography as a first-line strategy in fecal occult blood test-positive subjects,” the researchers said.

“Because of the high prevalence of advanced neoplasia in this group of participants, colonoscopy would have been performed in 55% of the cases if CT colonography had been used as a screening test, making such a strategy not as cost-effective as using colonoscopy as a first-line screening test.”

The researchers said their study was limited in that protocols and radiologist experience were not uniform across the centers where the study was conducted.

Also, colonoscopy was used as a reference standard, and the test may miss some lesions. The researchers said longer-term follow-up is needed to determine whether clinically significant lesions were missed.

The study was supported by grants from the Italian Association for Cancer Research, Progetti di Ricerca Finalizzata from Region Piemonte, the Fondazione Cassa di Risparmio di Torino, and the Compagnia di San Paolo. The researchers reported no conflicts of interest.

Primary source: Journal of the American Medical Association

Source reference:

Regge D, et al “Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in individuals at increased risk of colorectal cancer” JAMA 2009; 301(23) 2453-61.

A low cellular level of a tiny fragment of RNA appears to increase the spread of breast cancer in mouse models of the disease, according to researchers at Whitehead Institute for Biomedical Research.

Measuring levels of this so-called microRNA, which is also associated with metastatic breast cancer in humans, may more accurately predict the likelihood of metastasis (which accounts for 90% of cancer-related deaths) and ultimately help determine patient prognoses.

In the study, whose results are reported in the June 12 issue of Cell, Scott Valastyan, a graduate student in Whitehead Member Robert Weinberg’s laboratory, screened patient breast cancer samples for microRNAs with potential roles in metastasis. MicroRNAs are single strands of RNA about 21-23 nucleotides long. Within a cell, a single microRNA can fine-tune the expression of dozens of genes simultaneously. This capability could be particularly important in metastasis, a multi-step process that could be influenced by a single microRNA at several points.

The screened samples were classified as either metastatic cancer or non-metastatic cancer. After analysis, the microRNA miR-31 stood out because of its inverse correlation with metastasis. In samples where a patient’s original tumor had not metastasized, the cancer cells retained high levels of the microRNA. But where the tumor had metastasized, the cancer cells came to possess lower levels of miR-31.

The functional role of miR-31 in metastasis regulation was then confirmed in mice. When Valastyan removed miR-31 from normally non-aggressive breast cancer cells and implanted those cells into mice, the cells formed highly aggressive tumors. Mice injected with the cancer cells lacking miR-31 had 6 to 10 times more cancer cells that metastasized to their lungs than did their counterparts implanted with unmodified cancer cells.

To see how increasing miR-31 levels could affect metastasis, Valastyan introduced miR-31 into breast cancer cells that readily metastasize. After injecting these altered cells into mice, the mice had four to 40 times fewer metastases than mice injected with the unaltered cells.

Valastyan says that quantifying miR-31 levels in a patient’s cancer cells could one day support a more accurate prognosis. Currently, breast cancers are divided into three major categories, two of which are typically associated with poor prognoses.

“This microRNA seems to be quite unique, in that it seems to provide some prognostic utility across these existing subclassifications [of cancers],” says Valastyan. A better-defined prognosis could help patients determine whether they might benefit from poorly tolerated cancer therapies.

In addition, miR-31 could be a useful target for cancer therapy. Weinberg, who is also a professor of biology at MIT, is cautiously optimistic. “At present, it’s quite difficult to inhibit the action or promote the actions of a microRNA in a whole organism,” he says, “but in the future, microRNAs like this one might prove to be very important in altering the clinical progression of a tumor or causing it to revert to a more benign state.”

This research was supported by the National Institutes of Health (NIH), MIT Ludwig Center for Molecular Oncology, U.S. Department of Defense (DoD), Breast Cancer Research Foundation, Harvard Breast Cancer Specialized Program of Research Excellence (SPORE), and a DoD Breast Cancer Research Program (BCRP) Idea Award.

Robert Weinberg’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Full Citation:

“A Pleiotropically Acting microRNA, miR-31, Inhibits Breast Cancer Metastasis”
Cell, June 12, 2009
Scott Valastyan (1,2), Ferenc Reinhardt (1), Nathan Benaich (1,3), Diana Calogrias (4), Attila M. Szász (4), Zhigang C. Wang (5,6), Jane E. Brock (4), Andrea L. Richardson (4), and Robert A. Weinberg (1,2,7).

References

1.Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3. Department of Biology, Williams College, Williamstown, MA 01267, USA
4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
5. Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
7. MIT Ludwig Center for Molecular Oncology, Cambridge, MA 02139, USA

Source
Whitehead Institute for Biomedical Research