|Gene Expression Profiles in Paraffin-Embedded Core Biopsy Tissue Predict Response to Chemotherapy in Women with Locally Advanced Cancer|
|Reviewer: Courtney L. Bui, M.D.|
|The Abramson Cancer Center of the University of Pennsylvania|
Author: Gianni L, Zambetti, K., et al.
Gene array and RT-PCR technology allows for the rapid evaluation of hundreds of individual genes that may play a role in predicting response to chemotherapy. Previously, such techniques were limited by the fact that fresh tissue was required for analysis, but recent studies have demonstrated that a sufficient amount of RNA can be extracted from paraffin-embedded samples.
Recently, Paik et al. (NEJM 251;27,2004) reported on the results of the Oncotype DX assay (Genomic Health). In that study of 250 potential candidate genes, the authors found 21 genes to be related to risk of recurrence in breast cancer patients. The study was designed to validate a previously established 21-gene RT-PCR assay. This assay is used as part of a recurrence score (RS) algorithm for node-negative, estrogen-receptor positive breast cancer patients who had been treated with Tamoxifen in the NSABP trial B-14. The results demonstrated that patients could be categorized as having a low, intermediate, or high risk for recurrence based on the RS resulting from this assay. The authors suggested that the RS can then be used to better select patients to receive chemotherapy, i.e.: to give chemotherapy to patients who have a sufficiently high risk of recurrence.
The present study examines 384 genes to determine whether any are associated with improved response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. The authors sought to determine whether a specific group of genes correlate with response to neoadjuvant doxorubicin and paclitaxel. These genes were then assessed in a separate cohort of patients to determine their response-discriminating value.
Methods of Milan Cohort
Results of Milan Cohort
Methods of MDACC Cohort
Results of MDACC Cohort
In the last few years, several papers have been published seeking a specific gene set that will predict for outcome or response to therapy in cancer patients. The Oncotype DX assay was tested in over 400 patients from three different populations, and further validated in the study referenced above. The current study is hypothesis- generating, but it is still too early to tell whether a subset of the 86 original genes is predictive for pathologic response. The original model was tested in 89 patients, of whom only 12% had a pCR. The authors state that with this low number, they would expect a 22% false discovery rate when testing 384 genes. It is encouraging that many of the genes also predicted for pCR in the MDACC cohort, and that the direction of effect was the same in all cases. The concept of choosing specific chemotherapy, or whether or not to give chemotherapy, based on certain genetic profiles is very interesting, and we will await further validation of this study in additional patient populations to determine its clinical applicability.