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AACR CONFERENCE: MOLECULAR DIAGNOSTICS IN CANCER THERAPEUTICS

Test Predicts Which Breast Cancer Patients Will Benefit from Chemotherapy

Laino, Charlene

doi: 10.1097/01.COT.0000295288.90018.be
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CHICAGO—A test that measures proteins involved in tumor growth and suppression shows promise for differentiating which breast cancer patients will benefit from chemotherapy, researchers reported here at the American Association for Cancer Research conference on Molecular Diagnostics in Cancer Therapeutic Development: Maximizing Opportunities for Individualized Treatment.

The results of the study of 2,380 women with breast cancer suggest that the test can also identify those women for whom chemotherapy is most likely to be helpful, said the chief investigator, A. Raymond Frackelton, Jr., PhD, a staff scientist at Roger Williams Medical Center in Providence, RI, and Vice President of Research at Catalyst Oncology in Worcester, MA, which is marketing the test.

“If chemotherapy is not likely to be helpful, clinicians can then consider alternative treatment strategies,” he said in an interview. “Better predictors of adjuvant chemotherapy benefit would clearly improve clinical management of breast cancer patients.”

The test, called OncoPlan, is already being used to predict disease aggressiveness, and studies have shown that it is also a strong predictor of disease outcome. The new findings suggest that the test “will also help to ensure that women receive the most beneficial therapies,” Dr. Frackelton said.

The participants in the study were diagnosed with invasive breast cancer—717 of the 2,380 had received chemotherapy as part of their initial treatment and 1,663 had no adjuvant therapy.

Measures Two Forms of Shc Protein

All were given the new test, which measures two forms of the so-called Shc protein in tumor cells that have a ying-yang relationship with each other: tyrosine-phosphorylated (PY)-Shc, which helps drive many of the pathways involved in the development of aggressive cancer; and p66 Shc, which after initial stimulation, works to inhibit the very growth pathways the other Shc proteins promote.

What this means, Dr. Frackelton said, is that tumor cells are better able to thrive and survive if p66 Shc levels are low.

“The mechanism by which chemotherapy kills tumor cells does not require p66 Shc, however, suggesting that patients with low levels of p66 Shc levels might respond well to chemotherapy,” he said. “That's because the other mechanisms by which cytotoxic drugs work, such as p53, are likely to be in place.”

All that is required for the test is a small slice of the tumor from a biopsy or surgical specimen. In the study, Shc staining was scored on a continuous five-point scale by two pathologists, blinded to patient data.

Study Results

Over a median of 13 years of follow-up, 854 women had disease relapse and 501 died of the disease. For the total population of patients, chemotherapy appeared to be protective, reducing the risk of relapse by 26% and the risk of dying by 19%.

But when looked at by p66 Shc status, the situation changed.

Specifically, the 60% of women classified as being at high risk of recurrence due to low levels of p66 Shc were strongly protected by chemotherapy, with the drugs cutting their risk of relapsing by 47% and their risk of dying by 49%.

By drug, high-risk patients were most protected by anthracycline, which reduced the risk of relapse by 69% and by CMF (cyclophosphamide, methotrexate, fluorouracil), which reduced risk by 52%.

In contrast, among the 40% of women classified as being at low risk of recurrence due to high levels of p66 Shc, chemotherapy appeared to be a hazard, raising their of dying by 90%. Their risk of relapse was also increased, by 20%, but the figure did not reach statistical significance.

The researchers used multivariate Cox models adjusted for nodal status, HER-2, and estrogen-receptor status, age, tumor size, and tumor grade to arrive at their results.

Continuing Study

Other investigators said there is clearly a need for tests such as OncoPlan, but that further research is needed.

William J. Gradishar, MD, Director of Breast Medical Oncology at Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine in Chicago, said, “The Shc protein has been implicated in many molecular pathways of aggressive cancers.” The OncoPlan is an immunohistochemical test that reports on the phosphorylated form, the inhibitory form, of Shc.

“This retrospective analysis of a large data set suggests that it may be useful to identify patients who will likely gain little benefit from chemotherapy and conversely a group of patients who will likely gain the most benefit.”

That said, prospective clinical studies will be required, he added. “In an era where molecular assays such as Oncotype Dx are coming into the marketplace, it will be important to distinguish how these tests are different from one another, what the added information provided adds to clinical management, and for what type of patient and/or tumor is the test valid.”

Eric P. Winer, MD, Director of the Breast Oncology Center in the Department of Adult Oncology at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, agreed.

“The OncoPlan test appeared to be predictive of the benefit of adjuvant chemotherapy, and there is no question that we need more robust predictors of the benefit of adjuvant chemotherapy,” he said.

“But it needs to be evaluated in additional datasets, ideally in datasets where there is uniform treatment before it can used in clinical decision-making.”

J. Leonard (Len) Lichtenfeld, MD, Deputy Chief Medical Officer of the American Cancer Society, also said the test shows promise. However, “the predictive ability is not yet sufficient that oncologists would make a decision on whether or not to give chemotherapy based on the results,” he said. “Further study is warranted.”

Dr. Frackelton agreed, and said the company plans further testing to validate the results before marketing it for this use.

The research was supported in part by a grant from the Susan G. Komen Breast Cancer Foundation.

Educational Booklets on Childhood Brain Tumors Now Available in Spanish

The Pediatric Brain Tumor Foundation has educational booklets on childhood brain tumors available for the first time in Spanish.

“The need for these translations is dire,” said Louise Noble, MSW, the Foundation's Family Support Program Manager. “Hispanics are the fastest-growing segment of the US population, not just in Texas, California, and Florida, but all over the country.”

The titles that are now available in Spanish are:

  • Basic Facts About Pediatric Brain and Spinal Cord Tumors.
  • Questions for Your Medical Care Team When Your Child Has a Brain Tumor.
  • Basic Facts About Medulloblastoma/PNET.
  • Basic Facts About Juvenile Pilocytic Astrocytoma.
  • Basic Facts About Astrocytoma.
  • Basic Facts About Ependymoma.
  • Basic Facts About Glioma.

The translating project was made possible through a grant from Janirve Foundation. The free publications can be ordered by calling (800) 253–6530 or sending an e-mail to familysupport@pbtfus.org.

© 2006 Lippincott Williams & Wilkins, Inc.
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