Gene Testing to Determine Chemotherapy Need

What is the problem and what is known about it so far?
Women with estrogen receptor positive (ER+) breast cancer and negative lymph nodes (LN-) who have been treated with tamoxifen (a hormonal therapy) have a very low risk of their cancer returning somewhere throughout the body. Only 15% of these women have recurrence at 10 years, however there is no way to predetermine which women fit into this category. Therefore, most women with ER+/LN- breast cancer treated with tamoxifen run the risk of being over-treated with chemotherapy; however, if chemotherapy were not used in this group of women some would run the risk of being under-treated.

Why did the researchers do this particular study?
This study seeks to find genes within breast cancer cells that could help select which women with tamoxifen- treated ER+/LN- breast cancer that are at greater risk of recurrence and would therefore benefit from additional chemotherapy.

Who was studied?
Patients investigated in this study were women enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial* who were diagnosed with ER+/LN- breast cancer. These women were treated with breast removal and tamoxifen hormonal therapy and followed for a period of at least 10 years.

How was the study done?
21 genes were selected which in previous studies had been found to be closely associated with recurrence of breast cancer. The genes found in a patient’s breast cancer cells were used to calculate a recurrence score (RS); which then determined low, medium and high risk of recurrence for each patient. The researchers then examined how good the RS was for accurately predicting recurrence of breast cancer when compared to other traditionally accepted predictors of breast cancer recurrence.

What did the researchers find?
RS proved to be a more accurate predictor of which women with tamoxifen-treated ER+/LN- breast cancer would have recurrence over a 10-year period than other indicators of recurrence risk, including patient age, tumor size/grade, presence of estrogen/progesterone receptors, or excess of the HER2 gene**. Overall 7% of patients in the Low-Risk Group had recurrence at 10 years compared to 30% of patients in the High Risk Group.

What were the limitations of the study?
This study does not demonstrate whether the genes used in the calculation of the RS are associated with recurrence because they describe the biology of the tumor, or because they predict responsiveness to tamoxifen, or both. As all women in the study were treated with tamoxifen, the findings cannot be used to distinguish which women would and would not benefit from tamoxifen therapy.

What are the implications of the study?
If the tumor cells of women with tamoxifen treated ER+/LN- are analyzed using the RS, physicians could more accurately decide which group of women are more likely to develop recurrence and therefore benefit from additional chemotherapy to prevent recurrent disease. Tumor gene analysis is a promising technology that could be a better predictor of breast cancer recurrence in individual patients than other currently accepted criteria.

*The NSABP B-14 trial was a clinical trial carried out to study the use of tamoxifen in ER+/LN- breast cancer between 1982-1988. Patients were randomly assigned to be placed in the group of patients receiving tamoxifen versus the group of patients receiving a placebo. The two groups were then compared to determine if the tamoxifen group had an increase risk of developing endometrial cancer when compared to the group that received the placebo. This key study demonstrated that there was an increase risk of endometrial cancer with tamoxifen use, but that the benefits of the drug greatly outweighed this risk.

**HER2 is a proto-oncogene found to be over-expressed in Breast Cancer and associated with a poorer prognosis.

Summarized by Vanetta Levesque, MD, General Surgery Residency, Fletcher Allen Health Care.
Summarized from "A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer". Paik S. et al., New England Journal of Medicine December 2004, Volume 351, Number 27, pages 2817-2826.