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Tests could save some breast cancer patients from chemotherapy

From the October ACP Observer, copyright 2007 by the American College of Physicians.

By Lola Butcher

Molecular diagnostic tests have the potential to spare some breast cancer patients the burden of chemotherapy and its side effects after lumpectomy or mastectomy, allowing physicians and patients to decide whether it's appropriate based on the estimated risk of recurrence.

A Genomic Health scientist reviews a sample slide to ensure that the tissue sample is suitable for the Oncotype DX assay.


A Genomic Health scientist reviews a sample slide to ensure that the tissue sample is suitable for the Oncotype DX assay.



Two tests—Oncotype DX (Genomic Health Inc.) and MammaPrint (Agendia)—measure the expression of certain genes in a patient's tumor tissue and estimate the likelihood of cancer recurrence. MammaPrint, the first complex genetic test to go through the formal FDA approval process, received marketing approval in February 2007 but has not yet been released for sale in the U.S. Oncotype DX, which is currently available, operates under government rules that allow tests developed and performed at a single lab to be sold without FDA approval.

"MammaPrint and Oncotype DX are a step in the right direction to help us define which patients would benefit from chemotherapy and which patients would do fine with hormonal therapy alone," said Neelima Denduluri, MD, a medical oncologist and breast cancer researcher at the National Cancer Institute.

The two tests measure different sets of genes—MammaPrint uses 70 genes, while Oncotype DX uses 21. Oncotype DX analyzes preserved tumor tissue that is fixed in formalin and embedded in paraffin and develops a recurrence score—a number between 1 and 100 that predicts the likelihood of cancer recurring within 10 years of initial diagnosis. It is currently covered by Medicare and a number of large private insurers.

MammaPrint, which is available in the Netherlands, assesses the global gene expression of live tumor samples using DNA microarrays and puts women into risk categories based on the results. Both tests target women with lymph-node-negative, hormone-receptor-positive breast cancer, and MammaPrint is also validated in estrogen-receptor-negative patients.

About 125,000 women each year, or roughly half of all newly diagnosed breast cancer patients, would be candidates for the tests, said Joseph A. Sparano, MD, director of the Breast Evaluation Center at Montefiore-Einstein Cancer Center in New York City. Of those, 80% to 85% could be adequately treated with adjuvant hormone therapy, but physicians historically have been unable to identify those individuals, according to a study in the August 2006 issue of Community Oncology.

Physicians and patients frequently rely on "better safe than sorry" thinking and opt to add chemotherapy, said Dr. Sparano. "We unnecessarily treat the majority of women."

The mid-level conundrum

More studies are under way to help physicians interpret test results. Particularly difficult for physicians is deciding what to recommend to patients whose recurrence score is in the intermediate risk range—defined by Oncotype DX as between 18 and 30.

The recurrence score helps inform many but not all treatment decisions, said Dr. Denduluri of the National Cancer Institute.

"In a trial of Oncotype DX, patients with a high recurrence score had a much higher chance of having their tumor come back if they received hormonal therapy alone, and a lower chance of recurrence if they received both chemotherapy and hormones," she said. Patients with a low recurrence score did equally well with or without chemotherapy.

Dr. Sparano, who wrote about an ongoing Oncotype DX trial in the August 2006 issue of Community Oncology, said midlevel scores for that test present a conundrum.

"For the one-third to one-half of patients where the result is in the extreme range, either very high or very low, it can provide clear direction about what treatment choice to make," he said. "The problem is we are not exactly sure what to do with the mid-range score."

A trial for Oncotype DX will attempt to answer that question. The ongoing TAILORx—Trial Assigning IndividuaLized Options for Treatment (Rx)—which is sponsored by the NCI, is enrolling up to 12,000 women over three years and looking primarily at mid-range patients.

MammaPrint, which gives either a high-risk or low-risk score, is also undergoing study through the Microarray In Node negative Disease may Avoid ChemoTherapy, or MINDACT, trial, which started in Belgium earlier this year. This study is a prospective validation trial for MammaPrint, as outcomes in patients whose treatment is guided by the test will be compared with those of patients in a control arm whose tumors are assessed by traditional methods.

Because the molecular profile tests look at an individual patient, they are more precise than the results of Adjuvant Online! (www.adjuvantonline.com), a widely used tool that incorporates information about the patient, the tumor and treatment options under consideration to estimate the benefit of therapy.

Currently, molecular tests are most typically used in conjunction with Adjuvant Online! rather than in place of it. They are currently being used primarily by oncologists, but Dr. Sparano forecasts that general internists eventually may use molecular tests to determine whether a patient should be referred to a medical oncologist.

"If the test gave a low recurrence score it would be reasonable to prescribe endocrine therapy and only refer the patient for chemotherapy if she has a high recurrence score," he said.

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