Gene markers could guide breast cancer treatment

Molecular analysis of key markers for the tumor-suppressing gene TP53 provides important information about the gene’s activity, which could ultimately play a role in the choice of chemotherapy, according to a study of more than 600 breast cancer patients.

“TP53 transcriptional activity provides information about the biological characteristics of breast selection,” a study investigator said at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

Using tissue microarray to assay 615 successive, unselected breast carcinomas, the University of Nottingham, England and other colleagues identified six phenotypes based on the expressions of tumor protein p53, protein MDM2, and the cyclin-dependent kinase inhibitor p21, which play a role in the activity of the tumor-suppressing gene TP53. Due to similarities of clinicopathologic features and outcomes, we reduced (the six phenotypes) into two groups; low risk and high risk.

Loss of tumor suppressor gene TP53 function is a critical step in tumor formation  more than half of human cancers show somatic mutations of TP53. It is also an important prognostic factor, Intact TP53 is critical for modulating response to adjuvant therapy. A previous study showed that immunohistochemistry of p53, MDM2, and p21 can be used to discriminate functional and nonfunctional TP53.

Median follow-up for the women was 10 years. Adjuvant therapy was scheduled based on the Nottingham prognostic index, estrogen receptor status, and menopausal status.

It was found that the high-risk group mainly showed completely inactive p53 pathways, while the low-risk group mainly showed active or partially active p53 pathways.

Most of those in the high-risk group had high expression of p53. High p53 expression was strongly associated with several unfavorable parameters, including triple-negative phenotype, basal-like tumors, reduced overall and disease-free survival, and little adjuvant therapy benefit.

The subgroup of highly p53-expressing patients who were p21-positive had a greater frequency of estrogen receptor positivity, a lower frequency of triple-negative disease, a higher frequency of both local recurrence and distal metastases and shorter overall and disease-free survival. The worse prognosis for this group was related to the administration of chemotherapy.

The high-risk group also included patients who were p53-negative, MDM2-negative, and p21-negative. This group showed clinicopathologic features similar to the high p53 expression group. Also in the high-risk group were those patients who were p53-negative, MDM2-negative, Bc12-negative, and p21 negative. This group had similar clinicopathologic characteristics as the other two high-risk subgroups.

For patients who were p53-negative, MDM2-positive, and p21-positive (or Bcl-positive) there was a strong association with favorable clinical parameters: absence of basal-like tumors, absence of triple-negative disease, and prolonged overall and disease-free survival. Interestingly, this is the only group that benefited from hormonal therapy.

Among patients who were p53-negative, those who over expressed MDM2 and/or MDM4 (p21+/Bcl+) had the same clinicopathologic characteristics as the (p53-, MDM2+, p21+/Bcl+) group but did not benefit from hormone therapy.