Genomic Changes Predict Breast Tumor Grade and Metastatic Potential

CLEVELAND, May 16 -- Breast tumor grade and the potential for regional nodal metastasis can be determined by genomic alterations in the tissue surrounding invasive sporadic malignancies, investigators here reported.

Analyzing DNA from the stroma and epithelia of 220 primary sporadic invasive adenocarcinomas of the breast, Charis Eng, M.D., Ph.D., of the Cleveland Clinic, and colleagues, found that loss of heterozygosity and allelic imbalance in specific chromosomal locations were associated with clinical and pathologic features of the tumors.

"These results support a model in which genetic changes in both stromal and epithelial compartments occur during tumorigenesis, and progression is codetermined by local interaction between these cell populations within the primary tumor," they wrote in the May 16 issue of Journal of the American Medical Association.

The findings could help to explain why there is a high degree of variability in both clinical outcomes and in tumor biology among women with sporadic breast cancers, and might, if validated in further studies, help improve prognosis and treatment planning, the authors suggested.

The task now is to determine whether the findings might be applicable to improving prognosis or tailoring clinical care to individual patients, they said.

"It has been recognized for decades that identical chemotherapeutic regimens for similar stage and grade in patients with, for example, breast cancer (or virtually any malignancy) respond differently," Dr. Eng and colleagues wrote. "The complexities of genetic alterations in breast cancer may provide a primary basis for these consequent (secondary) clinicopathological features, an idea supported by prior positive correlations between certain breast cancer genotype and phenotype."

They noted that some tumors, such as grade 1, or well-differentiated, breast cancers have a low number of genetic alterations, whereas grade 3, or poorly differentiated, tumors, exhibit complex changes that may involve both DNA amplifications and DNA losses.

To see whether genomic alterations were associated with clinicopathological features in sporadic breast cancers, they conducted a retrospective cross-sectional analysis of DNA from the epithelium and stroma of 220 primary sporadic invasive breast carcinomas.

The authors examined the samples for global genomic alterations by looking for loss of heterozygosity/allelic imbalance with 386 microsatellite markers.

Their main outcome measure was any association of the loss of heterozygosity/allelic imbalance, in both the stroma and epithelium, with pathologic features such as tumor grade, expression status of estrogen and progesterone receptors, the human epidermal growth factor receptor 2, clinical stage, and regional lymph node metastases.

"We found significant associations between loss of heterozygosity/allelic imbalance on chromosome 11 in the stroma and tumor grade (P=0.0013), on chromosomes 1, 2, 5, 18, 20, and 22 in the stroma and regional lymph node metastasis (P=0.0002-0.0016), and on chromosome 14 in the epithelium and progesterone-receptor expression status (P=0.002)," they wrote.

They also identified specific chromosomal markers contributing to the loss of heterozygosity/allelic imbalance on chromosome 11 in the stroma that were associated with tumor grade. The markers were D11S1999 (P=0.00055) and D11S1986 (P<0.0022), although the latter did not meet the prespecified test for statistical significance of P=0.0042.

The loss of heterozygosity/allelic imbalance at various markers in the stroma was significantly associated with regional lymph node metastasis in other markers, including ATA42G12 on chromosome 1 (P=0.00095), D5S1457 (P=0.00095), D5S1501 (P=0.0011), D5S816 (P=0.0008), D18S858 (P=0.0026), D20S103 (P=0.0027), D20S851 (P=0.0045), D22S683 (P=0.00033), and D22S1045 (P=0.0013).

"There were more correlations between clinicopathological features and the loss of heterozygosity/allelic imbalance in the stroma than in the epithelium, suggesting that stromal genomic alterations may help account for clinical diversity," the authors wrote.

"As with any patient- oriented study, our data should be validated, perhaps with emerging novel technologies, in larger series especially those with event-free survival data and therapeutic trials with longer follow-up," the investigators wrote.