Tau-positive patients unexpectedly show overall better survival

December 15, 2008

Expression of the microtubule-binding protein Tau is not a reliable means of selecting breast cancer patients for adjuvant paclitaxel chemotherapy, investigators from Houston’s M.D. Anderson Cancer Center stated, adding that while Tau expression does predict survival, it does so in an unexpected way.

SAN ANTONIO-Expression of the microtubule-binding protein Tau is not a reliable means of selecting breast cancer patients for adjuvant paclitaxel chemotherapy, investigators from Houston's M.D. Anderson Cancer Center stated, adding that while Tau expression does predict survival, it does so in an unexpected way.

In a study of samples from the NSABP-B28 adjuvant trial of 1,942 patients, Tau expression was not correlated with benefit gained from paclitaxel, reported lead researcher Lajos Pusztai, MD.

"We found that Tau is very predictive of survival but in the opposite manner than we initially thought," Dr. Pusztai said.

Low Tau expression was actually associated with a relatively poor survival despite a higher sensitivity to chemotherapy.

"Tau-positive patients had better overall survival, which was driven by the favorable prognosis among estrogen receptor-positive, Tau-positive cancers that are sensitive to endocrine therapy," he said.

Previous neoadjuvant studies found that low levels of Tau predicted a good response to preoperative chemotherapy. This fit with in vitro studies showing that down-regulation of Tau expression increases the sensitivity of breast cancer cell lines to paclitaxel, that high levels of Tau protect microtubules from paclitaxel binding, and that low levels of Tau leave microtubules more accessible and vulnerable to the drug.

"If you treat patients who have low levels of Tau protein expression with neoadjuvant chemotherapy, they are very likely to have a good response to chemotherapy," Dr. Pusztai said. "We wanted to see if this correlation would hold up in predicting survival in adjuvant studies."

Investigators assessed the prognostic value of Tau by evaluating its expression in primary breast cancer specimens from the 1,942 NSABP-B28 patients, who were treated with four courses of doxorubicin/cyclophosphamide (AC) or AC followed by four courses of paclitaxel (plus endocrine therapy if hormone receptor-positive). The hypothesis was that tumors with low levels of Tau would preferentially benefit from the addition of paclitaxel to the regimen, Dr. Pusztai said (SABCS abstract 54).

By univariate and multivariate analyses, both Tau positivity (high Tau expression) and ER positivity were associated with better disease-free and overall survival. Patients with high Tau expression had a 10-year overall survival rate of 80%, compared to 65% for Tau-negative patients. The same pattern was seen for disease-free survival, Dr. Pusztai reported.

However, there was no significant correlation between Tau expression and benefit from paclitaxel in the total population or among ER-positive or ER-negative patients.

Interestingly, patients with high Tau levels, who are not particularly sensitive to chemotherapy, generally had good outcomes, including significantly better survival. This could be because survival is determined by-in addition to baseline prognosis-endocrine sensitivity as well as sensitivity to chemotherapy, two factors that are correlated with Tau in opposite ways.

Low Tau correlates with greater chemotherapy sensitivity but lesser sensitivity to endocrine therapy.

"Patients with high Tau expression did better because they tended to be ER-positive and their endocrine treatment compensated for less chemotherapy sensitivity," Dr. Pusztai said.

Thus, ER-positive and ER-negative tumors behave very differently and should be treated as distinct entities, he argued.

"We need to develop prognostic markers, response markers, or any type of biomarker separately for these tumors," he said.