New Tests Could One Day Predict Response
to Chemotherapy and Presence of Metastatic Disease in Patients with Breast Cancer

by Katie Prout Matias

Intensive research over the past several years has made breast cancer one of the most well-understood cancers and led to the development of several new drugs that can prolong survival. Because of these life-prolonging treatment options, the mortality rate from breast cancer has dropped about 2% each year since the late 1980s in both the United States and Western Europe. However, oncologists still have no good way of determining which treatment is best for an individual patient or whether a patient will respond to a particular treatment. This is especially true for chemotherapy.

Several chemotherapy regimens are available for patients with newly diagnosed breast cancer, but no regimen is effective in more than 50% to 60% of patients. Therefore, each patient has only about a 50% chance of benefiting from any given treatment, and many patients receive costly and toxic treatments that do not work.

To solve the problem of determining which chemotherapy regimen will work best in a particular patient, a team of researchers led by Lajos Pusztai, M.D., Ph.D., an assistant professor in the Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center, has set out to develop a tumor gene–screening test to predict the efficacy of chemotherapy regimens. Fifteen percent to 30% of patients with newly diagnosed breast cancer have a complete pathologic response to chemotherapy; that is, all microscopic evidence of invasive tumor cells disappears. “These patients still require surgery, but their long-term outcome is very good, and most of these individuals will be cured, regardless of how aggressive their disease appeared before starting chemotherapy,” said Dr. Pusztai.

The researchers in Dr. Pusztai’s team took tumor tissue samples from more than 80 patients newly diagnosed with breast cancer and examined more than 20,000 genes in each specimen. The patients were then given paclitaxel, 5-fluorouracil, doxorubicin, and cyclophosphamide (T/FAC, a commonly prescribed regimen at M. D. Anderson). Six months later, the patients underwent cancer surgery and pathologic analysis for response to the chemotherapy, and the gene expression profiles of patients who had a complete response were compared with those of patients who did not.

Analyzing the results from the first 24 patients, the researchers found a profile of 74 genes that was associated with complete response to chemotherapy. They incorporated these 74 genes into a mathematical algorithm to create a test that was 75% accurate and 50% sensitive in predicting who among a second sample of 21 patients would have a complete response to the same chemotherapy regimen. Patients whose tumors tested positive had a 75% chance of having a complete response to T/FAC. These results were presented at the plenary session of the 2003 annual meeting of the American Society of Clinical Oncology.

The researchers are now developing a second-generation T/FAC response predictor test based on a larger patient sample, which they hope will be more sensitive. They are also working on a portfolio of similar gene profile–based predictors for other commonly used preoperative chemotherapy regimens.

“If these new predictive tests prove similarly accurate and treatment regimen specific, it will fundamentally change how we select treatment,” said Dr. Pusztai. “For example, if the predictor test indicated that several options would work equally well in a patient, her physician could choose the cheapest, shortest, and least toxic of those regimens. For patients in whom a complete response is unlikely with any of the current standard treatments, participation in a clinical trial with new drug combinations may be the most beneficial. This would also help speed up drug development because you could focus on developing new drugs for people who do not benefit from existing treatments.”

While Dr. Pusztai’s team is trying to improve survival rates by predicting who will respond favorably to chemotherapy regimens, other researchers at M. D. Anderson are trying to predict unfavorable outcomes.

Twenty percent to 30% of all women with apparently localized breast cancer will eventually die of metastatic disease. To identify these patients, researchers are using new blood tests to analyze what may be early metastatic events: cancer cells in the peripheral blood and bone marrow.

According to Kelly Hunt, M.D., an associate professor in the Department of Surgical Oncology at M. D. Anderson, circulating cancer cells are found in a large number of patients with breast cancer, even those with early-stage disease. “What that tells me is that these cancers are systemic from the very beginning,” said Dr. Hunt.

Researchers want to determine how the circulating cells differ from primary tumor cells, whether they can grow outside the primary tumor site, and their effect on prognosis and treatment. A 2000 German study found that bone marrow disease was a good indicator of prognosis: Breast cancer was more likely to recur in patients with cancer cells in their bone marrow.

To build on this study, researchers at M. D. Anderson are participating in a multicenter American College of Surgeons Oncology Group trial in which bone marrow aspirations are being performed on patients with breast cancer to test for circulating cancer cells. The prognostic value of the presence of cancer cells in the bone marrow is then compared with that of sentinel lymph node biopsy to determine whether bone marrow aspiration could also be used as a prognostic tool.

“We’ve done well with breast cancer treatment over the past few decades, but there are still patients who fall through the cracks and for whom the treatment fails, so I think that we still need to refine the way that we identify which patients need which treatment,” said Dr. Hunt. “I see bone marrow aspiration as one other way of getting a closer look at that patient and what’s going on with her disease.”

Bone marrow aspiration could also be used to determine the efficacy of common chemotherapy regimens. Massimo Cristofanilli, M.D., an associate professor in the Department of Breast Medical Oncology at M. D. Anderson, is giving preoperative chemotherapy to patients with bone marrow disease and testing their bone marrow to see whether the chemotherapy reduced the number of cancer cells.

Dr. Cristofanilli is also investigating the significance of cancer cells in the peripheral blood. In a study presented at the 2003 annual meeting of the American Association for Cancer Research, he and a team of researchers found that 24 of 41 patients with untreated metastatic breast cancer had cancer cells circulating in their peripheral blood. The researchers then correlated the number of circulating cells, or “tumor load,” with treatment response and survival.

“It was very clear that the presence of cells and even the number of cells could predict the outcome of the patient. The patients who did not have cells had a very good prognosis. If they had cells, they had very short survival,” said Dr. Cristofanilli. He pointed out that even patients with slow-growing estrogen receptor–positive tumors, which are not considered to be very aggressive, had poor survival rates if they had circulating tumor cells. “This is a very important point, I think, because this may help clinicians decide when to treat, when to treat aggressively, and when not to treat.”

The most important question to ask, said Dr. Cristofanilli, is how the circulating cells differ from the original or primary tumor cells. The researchers want to determine whether the circulating cells have a different gene expression or microenvironment. Dr. Cristofanilli also wants to determine if a correlation exists between circulating tumor cells and patient response to various treatment protocols.

“I think the big picture is that clinicians want to be more aggressive in trying to improve our understanding of what a treatment does in patients,” said Dr. Cristofanilli. “There have been significant advances in our knowledge of tumor biology, but the treatments themselves have essentially remained the same. We use the same type of treatment for every patient, whether their disease is newly diagnosed or metastatic, and we develop clinical trials using the same unselected
approach. I think it’s time to change. We need to be able to better select or stratify patients based on the biological makeup of their tumor and develop targeted treatment for every specific biological group or clinical scenario. Most of the currently proposed treatment modalities in breast cancer are modifications of standard chemotherapy regimens. In my opinion, just changing the schedule or the dose of administration will not have a significant impact on outcome for women with breast cancer. If we do not understand this fundamental concept and take the appropriate steps right now, in the next five years we’ll be in the same situation.”

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, March 2004 issue:

• Translational Research Speeds the Journey from Lab Results to Clinical Outcomes
• House Call: Mind-Body Approaches for Patients with Cancer

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