During its annual meeting, the American Association for Cancer Research (AACR) announced that a scientific report describing a drug targeting the unprecedented genomic sequencing of 14 metastatic triple-negative breast cancers was the most cited study in the year of 2013 of any paper published that year by Molecular Cancer Therapeutics, AACR’s journal.
This study revealed drugs that target very difficult-to-treat metastatic triple-negative breast cancer (TNBC) thanks to genomic sequencing. “Genome and transcriptome sequencing in prospective triple negative breast cancer uncovers therapeutic vulnerabilities” was conducted by the Translational Genomics Research Institute (TGen) and US Oncology Research with support from Life Technologies Corporation.
TGen, US Oncology Research and Baylor University Medical Center researchers discovered relevant recurring mutations and other alterations in over 12 genes in patients treated at Baylor University Medical Center at Dallas. Furthermore, they managed to identify mutations that were never seen before in metastatic TNBC, crossing it with sequencing data to select specific therapeutic protocols according to the genetic profile of each patient.
“The nature of this disease cried out for innovative research techniques such as whole genome sequencing coupled with new tools for data analysis,” explained David Craig, co-lead author, the TGen’s Deputy Director of Bioinformatics.
Researchers found that the most frequently mutated gene among tumors was TP53, a tumor suppressor gene, along with anomalies in CTNNA1 (detected in 2 of 6 African American patients), another tumor suppressor gene. Alterations were also found in the ERBB4 gene, which is known to be involved in mammary-gland maturation during lactation and pregnancy but that was not linked to metastatic TNBC before.
Each tumor was unique in terms of genome, however, the majority contained modifications in 1 or 2 of the RAS/RAF/MEK/ERK and PI3K/AKT/MTOR pathways. Through targeted therapy aimed at these specific pathways, antitumor responses could be achieved in several cases.
“The fact that this study has been cited more often than any other in Molecular Cancer Therapeutics that year is a testament to strong interest the oncology community has in understanding the molecular basis of metastatic TNBC, and in the hypothesis that targeting specific mutations in patients’ TNBCs will improve patients’ outcomes,” noted Joyce O’Shaughnessy, study’s co-lead author.
Metastatic TNBC is a very aggressive type of breast cancer without expression of the estrogen receptor, HER-2 or progesterone receptor, which are the most successfully bio-markers targeted in this type of malignancy. This cancer has a poor prognosis with a median survival rate of 1 year and is responsible for 1 in each 4 deaths of breast cancer patients.
“This study continues to stand as a great example of molecular medicine in practice. The results have provided novel and interesting clues into breast cancer biology and into the promise and challenges of precision medicine,” noted John Carpten, TGen’s representative.