TOX3 May Serve As Novel Biomaker in Luminal B Breast Cancer

High expression of the known tumor promotor TOX3 gene leads to poorer prognosis in breast cancer patients with luminal B disease, according to a new study.

A number of lines of evidence suggest that TOX3 renders tumors more aggressive and metastatic. A breast cancer-associated single nucleotide polymorphism (SNP) found in an enhancer region of the TOX3 gene encodes a nuclear protein expressed in estrogen receptor-positive (ER+) mammary epithelial cells.

“A decrease in TOX3 might favor a progenitor cell state that is more susceptible to tumorigenesis. However, in the context of breast cancer, our data has implicated TOX3 as a tumor promoter,” said lead author Jenny Jimmy Hong, MD, of Cedars-Sinai Medical Center in Los Angeles.

Dr. Hong presented the results of the study at the 2015 American Society of Clinical Oncology (ASCO) Breast Cancer Symposium in San Francisco (Abstract 130).

The Oncotype DX assay predicts the likelihood of distant recurrence in ER+ early-stage breast cancer, identifying patients who may benefit from the addition of adjuvant chemotherapy. “However, luminal B subtypes often have an intermediate recurrence score, where the absolute benefit of chemotherapy is unclear,” she said.

In a retrospective study, Hong and colleagues investigated whether TOX3 expression might help add to clinical and therapeutic decision making. The researchers examined tissue microarrays of 177 histologically defined luminal B breast tumors; 89 patients who had associated Oncotype DX data were stained with an anti-TOX3 monoclonal antibody to correlate with recurrence score and clinicopathologic outcomes.

TOX3 protein was expressed in a significant subset of luminal B tumors. “Patients with high TOX3 expression appear to have a poorer prognosis without correlation to Oncotype scores,” Hong said.

During 13 years of follow-up, in the 89 patients with TOX3 and recurrence score, 11% developed recurrence. Their 3-year recurrence-free survival (RFS) rate was 91%.

In 36 patients with intermediate recurrence score, higher T stage, grade III, presence of lymphovascular invasion, higher Ki-67, and adjuvant chemotherapy were associated with higher RFS. During follow-up, 17% developed recurrence and the 3-year RFS rate was 89%.

TOX3 expression and recurrence score were not associated with RFS, she said.

In conclusion, Hong said “SNPs in TOX3 have been associated with the development of breast cancer. TOX3 is most frequently expressed in luminal B breast cancers. Previous studies suggest that TOX3 may render tumors more aggressive.”

She noted that “in our cohort of luminal B breast cancers, no correlation was observed between expression of TOX3 and Oncotype DX recurrence score and TOX3. The lack of correlation may suggest a facet of the biology of ER+ aggressive cancers that may not be addressed by the Oncotype DX assay.”

Prospective studies examining the risks of recurrence and the benefits of chemotherapy should investigate TOX3 expression “as an adjunct novel biomarker to guide optimal personalized therapy for breast cancer patients,” she said.