Gene Profile Rivals Standard Tests for Breast Cancer Tumor Status

HOUSTON, Feb. 16 -- For establishing the tumor status of women with breast cancer, a gene expression microarray appears to have accuracy approaching standard tests, researchers found here.

The microarray results correlated closely with results of immunohistochemical (IHC) or fluorescence in-situ hybridization (FISH) tests for estrogen receptor and Her-2/neu status in 495 breast cancer tumor samples, said Yun Gong, M.D., of the M.D. Anderson Cancer Center, and colleagues.

The Affymetrix U133AGene Chip had an overall accuracy ranging from 88% to 96% for identifying estrogen receptor status and 89% to 93% for confirming Her 2/neu positive status, they reported online today in The Lancet Oncology.

The report follows by a week the FDA's approval of a microarrary genetic test, the MammoPrint in-vitro multivariate index assay. That test, which measures 70 genetic markers, was designed to aid in predicting the risk of stage I or II breast cancer recurrence or metastasis.

The Affymetrix U133AGene Chip is commercially available, but it is not an FDA-approved test.

Two hundred and seventy four tumors were tested for estrogen receptor status. In 21 (8%) of those the Affymetrix finding differed from IHC findings.

One hundred and forty-two tumors were tested for Her-2/neu status and of those 16 (11%) had results that differed from FISH or IHC results.

Additional findings:

• In the first validation set, the overall prediction accuracy for estrogen receptor status was 88% (95% CI, 81-93%), sensitivity 86%, specificity 89%, positive predictive value 88% and negative predictive value 88%.
• In the second estrogen receptor validation set, the accuracy was 96%, sensitivity 98%, specificity 83%, positive predictive value 97% and negative predictive value 91% (P<0.0001).
• In the first validation set for Her-2/neu the accuracy was 89% (95% CI 81-94%), sensitivity was 79%, specificity 94%, positive predictive value 88%, negative predictive value 89%.
• Results from the Her-2/neu second validation set were: accuracy 90%, sensitivity 100%, specificity 88%, positive predictive value 60%, and negative predictive value 100% (P<0.0001).

Previous studies have shown correlation between mRNA concentrations and clinical receptor status but Dr. Gong said the strength of this study to extend those findings and to establish statistical thresholds for estrogen receptor and Her-2/neu status.

Data from 195 fine needle aspirate samples were used to define an mRNA cutoff value of 500 for estrogen receptor positive status and an mRNA threshold of 1,150 for Her-2/neu or ERBB2 -- v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian)-status.

Ten IHC-positive tumors had estrogen mRNA values of less than 500 and 11 of the IHC-negative tumors had an mRNA value of 500 or more.

Eight tumors that were Her-2/neu positive by standard tests had mRNA values of less than 1,150 and eight that were known to be Her-2/neu negative had values of 1,150 or more.

Because the authors used a single gene chip system for hybridization and scanning and then normalized the expression data to the same standard the "thresholds do not apply to data generated on other platforms" nor can they be extended to other probe sets.

They noted that clinical trials have demonstrated that the higher the estrogen expression, "the higher the probability of benefit from endocrine treatment." Gene expression, the authors suggested, would provide a better quantitative assessment of estrogen expression than IHC.

But they cautioned that "how well mRNA-based receptor determination predicts clinical outcome is yet to be established."