A rare medical archive -- which combines preserved breast cancer tissues with long-term follow-up information on each patient -- has enabled researchers from the University of Chicago Medical Center to determine how precisely two tumor characteristics can predict which breast cancers are likely to spread. They found that patients whose tumors had high levels of the product of a gene family called nm23 (for non-metastasis) and low density of newly formed blood vessels were far more likely to be alive 14 years after treatment. Further multi-variate analysis showed that nm23 and vessel density were "the most important tumor characteristics predicting outcome."
This report, in the July 1 issue of Cancer Research, is the largest study ever completed of node-negative breast cancer patients who received no adjuvant treatment -- radiation, hormone or chemotherapy after surgery -- and have been followed long enough to fully express the malignant potential of the disease.
While 91 percent of patients with high nm23 were alive an average of 14 years after treatment, only 70 percent of those with low nm23 survived that long. The lack of angiogenesis -- growth of new blood vessels to supply the budding tumor -- was an equally valid predictor; 92 percent of patients with a low micro-vessel count (MVC) survived at least 14 years versus only 70 percent of those with a high vessel density.
"Our study provides the best clues to date about how to treat patients with node-negative breast cancers, the kind we try to find with mammography," said first author Ruth Heimann, M.D., Ph.D., professor of radiation and cellular oncology at the University of Chicago. "We hope to use these data in our efforts to devise an individualized treatment plan for each patient, to separate those who will benefit from radiation and chemotherapy after surgery from those who don't need it."
"Our inability to make that distinction, to predict who is at risk for distant spread and who is cured by surgery, has resulted in treatment that is too much for most and too little for some," adds co-author Samuel Hellman, M.D., the A.N. Pritzker Distinguished Service Professor of radiation and cellular oncology.
The study used tumor tissue from 163 patients, median age 57, treated at the University of Chicago Hospitals between 1927 and 1987 with mastectomy alone. These patients received no additional radiation, hormone or chemotherapy. Most had fairly small tumors, three centimeters or less, and no lymph node involvement. They were followed for an average of 14 years, some as long as 36 years.
The researchers found that low MVC -- few new capillaries -- was associated with excellent prognosis. High MVC, they note, "appears necessary but not sufficient for metastasis to occur."
Unfortunately, the growth of new blood vessels tends to occur quite early for most cancers; even small tumors found via mammogram frequently have a high MVC. However, patients with high MVC combined with high protective levels of nm23 also do quite well, 90 percent surviving 14 years.
The study also provides insights into the progression of breast cancers, suggesting that angiogenesis and metastasis are two separate and usually sequential events.
Decreased levels -- or mutant, nonfunctional versions -- of nm23 seem to appear somewhat later than angiogenesis. Loss of nm23 appears to be a crucial second event that must occur before the cancer can spread to distant sites.
While these markers are useful, they do not tell the whole story, insist the authors, since even for those with both high angiogenesis and non-functioning nm23 about 70 percent survive. This indicates that there are other as yet unidentified critical changes needed for tumor spread.
"Those patients with high MVC and low nm23 would be advised to have both radiation and chemotherapy following surgery," said Hellman. But for patients without a lot of tumor vessels, or even those who have some angiogenesis but still protective high nm23 levels, it might be quite reasonable to skip adjuvant chemotherapy and avoid its costs, inconvenience and discomfort. Finding better and better markers of who needs more therapy is a big step toward more rational treatment decisions."
Since breast cancer deaths result not from the original tumor but from its dissemination to distant sites, preventing metastasis, even for patients with limited risk, is a fundamental aspect of treatment, agree the authors. But "a worthwhile secondary goal is avoiding either unnecessary or insufficient treatment," notes Heimann, "and these markers, even when measured in archival, paraffin-embedded tissue, appear to provide excellent clues about who does and who doesn't need more therapy."
Journal
Cancer Research