INSUFFICIENT EVIDENCE FOR GENE EXPRESSION PROFILES

"Insufficient Evidence" for Tumor Gene-Expression Profile Products in Breast Cancer

January 22, 2008 — There is insufficient evidence to make a recommendation either for or against the use of 3 tumor gene-expression profile products to improve outcomes in defined populations of women with breast cancer, concludes a working group supported by the US Centers for Disease Control and Prevention (CDC).

The Evaluation of Genomic Applications in Practice and Prevention working group outlines its views in the January issue of Genetics in Medicine.

The group evaluated 3 products: MammaPrint (Agendia), Oncotype DX (Genomic Health), and the Breast Cancer Gene Expression Ratio Assay — known as the Quest H:I Ratio test (developed by Quest Laboratories, based on technology from AviaraDx). All claim to provide prognostic information (about recurrence and survival rates) in specific populations of women with early-stage breast cancer and to identify women most likely to benefit from chemotherapy.

The group found no evidence of clinical utility for the MammaPrint and Quest H:I ratio tests, and inadequate evidence for Oncotype DX. All of these technologies have potential for both benefit and harm, they point out, and there is currently insufficient data to confidently estimate these risks and benefits. "No firm guidance can be given to clinicians" until results from ongoing clinical trials are available, they add.

In a disclosure, the CDC emphasizes that although it provides support, including staff, the working group is independent, and its recommendations should not be construed as official positions of the United States Department of Health and Human Services CDC.

Key Question in Breast Cancer Treatment

A key question about the management of breast cancer is whether or not to use adjuvant chemotherapy, the group comments. Although chemotherapy reduces the annual odds of recurrence and death for many women, especially those with estrogen receptor (ER)-negative breast cancer, the size of the benefit varies and it can be quite small in women with node-negative, ER-positive, and tamoxifen-treated breast cancer, it points out. And of course, the benefit needs to be weighed against harm from adverse drug events.

This is where the gene-expression profiling tests fit in, with their claims to provide prognostic information and to identify women most likely to benefit from chemotherapy.

However, the 3 tests differ from one another:

• MammaPrint is a 70-gene profile custom microarray, approved in the United States in 2007 for use as a prognostic test alongside other clinicopathologic factors. It tests for 70 cancer-related and about 1800 normative genes, and is intended for use in women 61 years or younger with primary invasive breast cancer (stage I or II) who are lymph-node negative and have an ER-positive or ER-negative tumor of 5 cm or less. Results are reported as low or high risk for developing distant metastases at 10 years without adjuvant treatment.
• Oncotype DX is intended for use with other conventional risk-assessment approaches (e.g., tumor staging/grading, analysis of other markers) to predict the likelihood of distant breast cancer recurrence in women of any age with newly diagnosed stage I or II breast cancer (lymph node-negative and ER-positive) who will be treated with tamoxifen. It analyses the expression of 21 genes, 16 cancer-related and 5 normative. Results are reported as low, high, or intermediate risk of developing distant recurrence at 10 years after 5 years of tamoxifen.
• The Quest H:I Ratio test was originally developed to go beyond the current clinical standard (e.g., estrogen-/progesterone-receptor status) to predict tumor recurrence risk in women taking tamoxifen monotherapy for whom alternative therapies (e.g., aromatase inhibitors, chemotherapy) might be considered. It measures the ratio of the expression of the homeobox gene B-13 (HOXB13) and the interleukin-17B-receptor gene (IL17BR), and claims to provide a "continuous marker of recurrence in untreated ER-positive/node-negative patients." Results are reported as a normalized H:I expression ratio along with a categorization of low or high risk for breast cancer recurrence at 5 years.

One of the issues that the working group examined was clinical utility, which it defines as the likelihood that using a gene-expression profiling test to guide management in patients with diagnosed early-stage cancer will significantly improve health-related outcomes. It was assessed by investigating the balance between benefits (reduced adverse events due to low-risk women avoiding chemotherapy) and harms (cancer recurrence that may have been prevented) associated with use of the test, and how that compares with the use of alternative management strategies.

The group found no evidence for either MammaPrint or the Quest H:I Ratio test showing the affect these tests have on clinical outcomes. For Oncotype DX, the group found some data suggesting that results from the test influence patient–clinician decision making, but this came from a retrospective analysis of 1 group of a prospective clinical trial (J Clin Oncol 2006;24:3726-3734). The group states that this "study design was not optimal, and prospective confirmation of these findings is needed."

Ongoing Trials

Two prospective randomized trials are currently in progress: the TAILORx trial with Oncotype DX is being conducted by the US National Cancer Institute; and the MINDACT trial with MammaPrint is being conducted by the European Organisation for Research and Treatment of Cancer. It might take some time before the results from these trials are available (results from TAILORx are not expected until 2013, and from MINDACT until about 2011).

But until the data from these trials are available, "no firm guidance can be given to clinicians on how the MammaPrint and Oncotype DX results can be acted upon," the group concludes.