Expression of the microtubule-binding protein Tau is not a reliable means of selecting breast cancer patients for adjuvant paclitaxel chemotherapy, according to research led by The University of Texas M. D. Anderson Cancer Center.

Presented Dec. 13, 2008 at the CRTC-AACR San Antonio Breast Cancer Symposium, the researchers found that Tau expression does predict survival, yet in an unexpected way.

In earlier neoadjuvant studies, investigators from M. D. Anderson found that low levels of Tau predicted a good response to pre-operative chemotherapy. In vitro studies had shown that down-regulation of Tau expression increased the sensitivity of breast cancer cell lines to paclitaxel. Other studies suggested that high levels of Tau partially protect microtubules from paclitaxel binding and that low levels of the protein leave microtubules more accessible and vulnerable to the drug.

"If you treat patients who have a low level of Tau protein expression with pre-operative chemotherapy in neo-adjuvant studies, they are very likely to have a good response to the chemotherapy," said Lajos Pusztai, M.D., D. Phil, associate professor of medicine in the Department of Breast Medical Oncology at M. D. Anderson and the study's first author. "We wanted to see if this correlation would hold up in predicting survival in adjuvant studies."

Working with researchers from the National Surgical Adjuvant Breast and Bowel Project (NSABP), the investigators assessed Tau protein expression in primary breast cancer specimens from 1,942 patients in the NSABP-B28 clinical trial. The goal was to evaluate the prognostic value of Tau in these patients, who were treated with four courses of doxorubicin/cyclophosphamide (AC) or AC followed by four courses of paclitaxel. All hormone receptor-positive patients in the trial also received adjuvant endocrine therapy.

The hypothesis was that patients whose tumors expressed low levels of Tau would preferentially benefit from the addition of paclitaxel to their adjuvant regimen, Pusztai explained. Univariate and multivariate analyses found that both Tau-positive status (high Tau expression) and estrogen receptor (ER) -positive status were associated with better disease-free and overall survival. However, the researchers found no significant correlation between Tau expression and benefit from paclitaxel in the total population or among estrogen receptor (ER) -positive or ER-negative patients.

"We eventually found that Tau is very predictive of survival but in the opposite manner than we initially thought," Pusztai said. "Low Tau expression was actually associated with a relatively poor survival despite a higher sensitivity to chemotherapy."

"On the other hand," he continued, "patients with high levels of Tau-and we knew these patients were not particularly sensitive to chemotherapy-actually did very well. They had a significantly better survival in this large randomized study."

Pusztai noted that survival is determined by baseline prognosis, endocrine sensitivity and sensitivity to chemotherapy-and that Tao is a marker of receptivity for two of these important variables.

"It's receptive to chemotherapy sensitivity but also to endocrine therapy sensitivity," he added, "and the receptivity is in an opposite manner: Low Tau means higher chemotherapy sensitivity, but it also means lesser sensitivity to endocrine therapy and vice versa. Patients with high Tau expression do very well because they all tend to be ER-positive and very sensitive to endocrine treatment."

This complex interaction between Tau and outcome is not unique, according to Pusztai. It is the same association as with many other biomarkers, including the Oncotype DX breast cancer assay and the proliferation marker Ki-67-an inverse relationship between chemotherapy sensitivity and endocrine sensitivity.

The issues would be far less complicated, Pusztai added, if ER-negative and ER-positive breast cancer were treated as distinct entities. "The most important thing we've learned is that we need to develop prognostic markers, response markers, or any type of biomarker separately for the ER-negative and ER-positive tumors."

This research was supported by a grant to Pusztai from the Breast Cancer Research Foundation and by the Nellie B. Connally Breast Cancer Research Fund.

In addition to Pusztai, other M. D. Anderson co-authors include: Gabriel N. Hortobagyi, M.D., professor and chair, Department of Breast Medical Oncology; W. Fraser Symmans, M.D., and Yun Gong, M.D., Department of Pathology; Other authors include: Jong-Hyeon Jeong of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Biostatistical Center; Jeffrey S. Ross of the Department of Pathology, Albany Medical College, Albany, NY and Chungyeul Kim and Soonmyung Paik of the Departments of Biostatistics and Pathology at the University of Pittsburgh.

About Breast Cancer

• Ductal carcinoma in situ (DCIS): This is the most common type of non-invasive breast cancer (85 - 90% of all cases). DCIS means that the cancer is only in the ducts. It has not spread through the walls of the ducts into the tissue of the breast. Nearly all women with cancer at this stage can be cured. Often the best way to find DCIS early is with a mammogram.
• Lobular carcinoma in situ (LCIS): This condition which occurs in approximately 8% of all cases, begins in the milk-making glands but does not go through the wall of the lobules. Although not a true cancer, having LCIS increases a woman's risk of getting cancer later. For this reason, it's important that women with LCIS to follow the screening guidelines for breast cancer.

• Inflammatory breast cancer (IBC): This uncommon type of invasive breast cancer accounts for about 1% to 3% of all breast cancers. Usually there is no single lump or tumor. Instead, inflammatory breast cancer (IBC) makes the skin of the breast look red and feel warm. It also gives the skin a thick, pitted appearance that looks a lot like an orange peel. Doctors now know that these changes are not caused by inflammation or infection, but by cancer cells blocking lymph vessels in the skin. The breast may become larger, firmer, tender, or itchy. IBC is often mistaken for an infection in its early stages. Because there is no defined lump, it may not appear on a mammogram, which may make it even harder to catch it early. It usually has a higher chance of spreading and a worse outlook than invasive ductal or lobular cancer.
• Paget's disease of the nipple. Paget's disease of the nipple or breast is a rare type of breast cancer, which can occur in women and men. It shows up in and around the nipple, and usually signals the presence of breast cancer beneath the skin. Most cases are found in menopausal women, but can also appear in women that are as young as 20.  Early stages symptoms include redness, scaly and flaky, and  mild irritation of  nipple skin. Advanced stages may include: tingling in nipple skin, very sensitive skin on the nipple, burning or painful nipple skin, ooze or bloody discharge from the nipple (not milk), itchiness that doesn't respond to creams, nipple retraction (pulls into the breast), scaly rash on areola skin, and/or breast lump beneath the affected skin.

• a lump or a thickening in the breast or in the armpit. Note Most breast lumps are benign (be-nine); that is, they are not cancer. Benign breast tumors are abnormal growths, but they do not spread outside of the breast and they are not life threatening. But some benign breast lumps can increase a woman's risk of getting breast cancer. Most lumps turn out to be caused by fibrocystic (fi-bro-sis-tik) changes. Cysts are fluid-filled sacs. Fibrosis is the formation of scar-like tissue. Such changes can cause breast swelling and pain. The breasts may feel lumpy, and sometimes there is a clear or slightly cloudy nipple discharge.
• a change of size or shape of the mature breast
• fluid (not milk) leaking from the nipple
• a change of size or shape of the nipple
• a change of color or texture of the nipple or the areola, or of the skin of the breast itself (dimples, puckers, rash)
• a discharge from the breast

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For four of the past six years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.