This week I want to blog about one of my specialty topics: cancer genetics. In particular, this blog post will focus on the use of genetic signatures – human genes that can be measured to predict cancer risk, cancer progression, or to personalize treatment. ChemotherapyAdvisor has published several news stories on the use of such genetic signatures as diagnostic and prognostic tools for the treatment of breast cancer.
In one study, a molecular signature was used to predict whether breast cancer patients will be sensitive to radiotherapy. A radiosensitivity molecular signature (RSI) was developed to measure the expression of a specific set of breast cancer-associated genes and determine changes in expression following radiotherapy. Patients for which RSI predicted radiosensitivity (RS) had improved survival rates when compared with radioresistant (RR) patients (95% vs. 75%, P = 0.0212). Equally important was the fact that this signature was specific to treatment with radiotherapy as no difference in RSI was found between RS and RS patients treated without radiotherapy (71% vs. 77%, P = 0.6744).
The most important observation in this study was that this RSI can predict the outcome of radiotherapy for human estrogen receptor (HER)-positive breast cancer patients (HR=2.64, P = 0.0085), allowing further personalization of therapy for this population.
Genetic signatures have also been used to predict the response to neoadjuvant therapy in breast cancer patients with aromatase inhibitors. In one study, the investigators examined gene mutations in tumor biopsies from patients with HER-positive breast cancer.
The investigators conducted a large genetic screen that resulted in the identification of 18 significantly mutated genes. When the investigators correlated these mutant genes with the histologic features of the associated tumors, they found that a mutated version of a gene called MAP3K1 was associated with “luminal A status, low-grade histology, and low proliferation rates,” whereas a mutated version of a gene called TP53 was associated with the opposite pattern. Another part of this genetic signature was the observation that a mutated version of a gene called GATA3 was associated with diminished tumor growth following treatment with aromatase inhibitors. This genetic signature predicted a breast cancer response to aromatase inhibitors.
With a 70-gene signature, the MammaPrint test is by far the largest prognostic genetic signature available for predicting response to breast cancer treatment. The authors of a presentation given during the 8th European Breast Cancer Conference in Vienna, Austria, on March 22, 2012, suggested that if this 70-gene signature were added to standard guidelines used to select patients for adjuvant systemic therapy, fewer patients would be selected for such therapy.
In this study, the genomic test was used on 427 patients with early breast cancer to predict the risk of metastasis in order to optimize and personalize chemotherapy. Based on the results of testing with MammaPrint, only 15% of 219 patients classified as “low risk” received adjuvant chemotherapy vs. 81% (169/208) classified as high-risk. The 5-year distant disease-free survival rate for “low risk” patients was 96% vs. 90% for the high-risk group.
“We believe that our results already show that the use of genomic tests is feasible and effective in clinical practice, and can help in decision-making,” concluded lead author Sabine Linn, MD, PhD, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Readers, what is your opinion on the use of the genetic signature for the prognosis and/or treatment of breast cancer?
What impact will genetic signature testing have on practice?