Genetic markers as prognostic indicators in breast cancer

Identifying markers that have the potential to predict tumor behavior is important in breast cancer because of the variability in clinical disease progression. Genetic alterations in tumors may appear as changes in total DNA content, individual chromosomes, single genes, or gene expression. Alteration in DNA content is an imprecise but accessible measurement of the genome. Diploid tumors have been associated with a better clinical outcome, and increased ploidy correlates with other indicators of poor prognosis. Concurrent analysis of DNA content with markers of genetic expression is feasible (e.g., myc oncogene) and may increase its prognostic power. Chromosomal studies could provide a more precise tool for localizing genetic damage, but there is little cytogenetic information about primary breast cancers, no convincing evidence has emerged to target locations in the karyotype that appear specifically altered, and many primary and cultured breast cancers contain cells that appear chromosomally normal. Attempts to define molecular markers have used probes of different chromosomal sites, some chosen because of logical associations with hormonal activity, known oncogenes, or tumor-suppressor genes, and some by chance. Currently, to the authors' knowledge, none has shown uniform changes by mutation, loss, or overexpression in all breast cancers, although a remarkable number of loci are altered to some extent. These lesions must be associated with particular disease subsets or, retrospectively, with differential survival if they are to have prognostic value.

The authors examined several loci (ERBB2, INT2, MUC1) for gene amplification or loss of heterozygosity by Southern blotting and for gene expression by immunohistochemistry in breast tumors from patient groups selected by survival.

A retrospective series showed gene amplification at the erbB2 locus in 22% of rapidly recurrent (RR) tumors and 13% of tumors from long-term tumor-free survivors (LTS), but the difference was not statistically significant (P = 0.18). The erbB2 product was displayed histochemically with equal frequency between those with RR tumors and LTS patients. Moreover, the correlation was poor between different analytic measures on the same tumors. This result was tested using a prospective study of erbB2 to correlate DNA analysis with western blot findings and frozen and fixed histochemical results. Another oncogene, int2, showed significant correlation between amplification and recurrence; 16% of RR tumors showing genetic amplification (P = 0.02). Loci on other chromosomes, 1 (muc1) and 17 (cmm86), also are being investigated in groups selected for differences in survival.