New Biomarker May Predict Which Breast Precancers Will Progress

NATIONAL HARBOR, Md. — Measuring the presence and amount of the protein Vav2 may help identify breast precancers that will progress to invasive cancers, according to results presented here at the 12th Annual AACR International Conference on Frontiers in Cancer Prevention Research, held Oct. 27-30.

Marina Guvakova, Ph.D.

Because the biology of ductal carcinoma in situ (DCIS), a precancer of the breast, is not fully understood, there is a considerable dilemma in clinical practice about its management. While some DCIS progress to invasive breast cancers, some do not, and there is a need for new markers and tools to differentiate the progressive from nonprogressive DCIS.

“We have been searching for molecular markers to discriminate the so-called ‘pure DCIS’ from DCIS associated with microinvasion, a difficult-to-visualize microscopic extension of cancer cells into adjacent tissue,” said Marina Guvakova, Ph.D., senior research investigator and adjunct assistant professor in the Department of Surgery at the University of Pennsylvania in Philadelphia.

“Our candidate markers, IGF-IR, Rap1, and Vav2, are proteins whose upregulation has been implicated in promoting the aggressive behavior of cancer cells in preclinical models. It seemed reasonable to evaluate the clinical-translational utility of these proteins as markers of invasive potential of DCIS,” Guvakova explained.

Guvakova and colleagues developed an imaging-based technique with precision higher than standard visual evaluation, to measure the amount of their three candidate biomarker proteins in 211 breast tissue samples. Of these samples, 42 were normal breast tissue, 71 were DCIS, and 98 were invasive breast cancers. Of the 71 DCIS samples, 35 were pure DCIS, 11 had areas of microinvasive cancer (less than 1 mm), and 25 had areas of extensive invasion.

They found that two proteins, IGF-1R and Rap 1, were higher in DCIS and invasive cancer tissues compared with normal tissues. The amount of Vav2, however, was much lower in normal tissues and DCIS compared with invasive cancers. When the researchers further investigated Vav2 in the three types of DCIS, they found that the amount of Vav2 in pure DCIS was comparable to the amount in normal breast tissue, but it gradually increased in DCIS with microinvasive cancer and DCIS with invasive cancer, with the highest amounts present in invasive cancers.

The researchers also found that DCIS with higher amounts of Vav2 protein were more than twice as likely to progress to invasive cancers as DCIS with low amounts of this protein.

The researchers then determined that the predictive ability of Vav2 to distinguish progressive from nonprogressive DCIS was 0.71. A value of 1 means the marker has a perfect discriminating power, and a value of 0.5 means that the marker’s discriminating power is no better than chance, Guvakova explained.

“Our finding is a tip of an iceberg. We aim to expand our research by obtaining and analyzing more samples of preinvasive breast lesions in order to further characterize these amazingly diverse tumors,” said Guvakova. “Translation of scientific knowledge into clinical practice takes time and painstaking efforts, but when we succeed, it is highly rewarding to mankind.”

This study was funded by the intramural programs of the University of Pennsylvania. Guvakova has declared no conflicts of interest.

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