One of the challenges of triple negative breast cancer is that it is defined by what it is not (ie ER/PR-, HER2-), rather than what it is. This broad subgroup of breast cancer is therefore more heterogeneous in nature than many people actually realise. It also means that unless we uncover the various driving mutations underlying it, we are sadly doomed to the world of repeatedly poor response rates. We can do better than this.
The other day I saw a new paper in the Journal of Clinical Investigation (open access) that caught my eye:
“Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies”
Researchers from Vanderbilt-Ingram cancer centre identified six different subtypes relating to this disease. Six!
They found the subtypes by looking at gene expression profiles in 21 different breast cancer sets and identified the triple negative cases (n=587). From these cases, cluster analysis identified the six TNBC subtypes. These subtypes included:
- two basal-like (BL1 and BL2)
- an immunomodulatory (IM)
- a mesenchymal (M)
- a mesenchymal stem–like (MSL)
- a luminal androgen receptor (LAR)
Here’s where it gets very interesting though – these newly identified subtypes are sensitive to different therapies:
“BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin.
M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor).
The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling.”
In other words, based on identifying a women with triple negative breast cancer’s precise subtype, they could be used as a potential biomarker for selection into appropriate clinical trials. By doing this we may be able to screen those women more likely to respond to a given therapy and then determine in randomised controlled clinical trials whether the molecular hypothesis is indeed correct before treatment in a broader population.
Many of you will no doubt be wondering how this relates to PARP inhibitors such as iniparib, which until recently were the hottest thing in breast cancer. The simple answer is, it doesn’t. None of the subtypes identified appear to have a known sensitivity to PARP inhibitors, that I know of. What is important is that new molecular subtypes have been identified and these appear to be sensitive to therapies either already available commercially or in clinical development for other tumour types.
Overall, this is an excellent and well designed study with the most useful and instructive findings. It’s like finding 6 needles in a haystack at once and will hopefully guide us in a much more focused way. I really do hope that clinical researchers respond quickly and get some new clinical trials going up and running soon with appropriate patient selection criteria in triple negative breast cancer.
We need more cowbell like this in cancer research. This is the stuff dreams are made of.
Lehmann, B., Bauer, J., Chen, X., Sanders, M., Chakravarthy, A., Shyr, Y., & Pietenpol, J. (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies Journal of Clinical Investigation, 121 (7), 2750-2767 DOI: 10.1172/JCI45014