Mechanisms of resistance in triple negative breast cancer

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Published: 24 Mar 2017
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Prof Sherene Loi - Peter MacCallum Cancer Centre, Melbourne, Australia

Prof Loi speaks with ecancer at 2017 St. Gallen International Breast Cancer Conference about the oncogenic pathways upregulated in triple negative breast cancer, which can be highly resistant to chemotherapy.

She highlights how genome sequencing has unveiled a patchwork of heterogeneity in tumours, with gene replication and a varied sea of clonotypes which leave targeted or immune therapies unable to deliver significant damage.

Prof Loi hopes that further understanding of these mechanisms will aid in developing combinations of therapies for the disease.

At this meeting I’m giving a talk about the mechanisms of resistance to chemotherapy in triple negative breast cancer. We’ve known for a long time that triple negative breast cancer has the worst outcome relative to other breast cancer subtypes and while we’ve made significant improvements in survival in ER positive and HER2 positive breast cancer we’ve really stalled in our treatment of triple negative breast cancer. It continues to have very poor survival with the highest rate of death compared to ER positive breast cancer, 6-8 times in the first two years after diagnosis.

So is this very resistant to chemo?

The patients, a minority of patients do respond very well to chemo but particularly those with large tumour burden or lots of lymph nodes involved at diagnosis they seem to relapse and die relatively quickly with a median survival of metastatic disease of triple negative breast cancer about one year. So we’ve really made very little impact into our treatment of that particular breast cancer subtype.

What are these means for resistance?

With the advent of new sequencing technologies and genomic technologies we’ve begun to understand really now the complexity and unstable genomes that triple negative breast cancers have. Their chromosomes are completely deranged, often genome doubling, aneuploidy, chromosomal gains and losses. This contributes to this phenotype of high levels of oncogenic signalling and this ability to upregulate some oncogenic signalling pathways and multiple oncogenic pathways as well as abnormal DNA damage response allows triple negative breast cancer to grow, to become resistant to chemotherapy and basically resistant to our current means of treating these patients which is still traditional chemotherapy.

The other thing that we’ve begun to understand with using sequencing technologies is the mutational profile of triple negative breast cancer. So it’s very diverse; some triple negative breast cancers have many mutations, others have few, but the common theme is that these mutations are subclonal in that they’re not present in 100% of cells but only in a minority of cells. So this means that targeted therapy is probably going to have little efficacy in triple negative breast cancer because if you target one mutation then the other clone will just grow out. So we’re dealing with genomic instability, chromosomal instability and this all probably contributes to a phenotype of immune invasion. We know that in triple negative breast cancer that the immune infiltrate is strongly prognostic so this suggests that activation of the immune response is important for patients with triple negative breast cancer and patients with low levels of this infiltrate do really poorly. It’s probably a combination of the genomic instability, these upregulation oncogenic pathways as well as certain mutations that downregulate and suppress the immune response and this contributes to this whole phenotype of a very aggressive disease.

So basically the way forward is trying to understand this a little bit more, so more collection of tumours, particularly patients who don’t respond well to neoadjuvant chemotherapy, and trying to understand the molecular mechanisms of resistance. This is likely to involve combinations, so combinations of new potent agents, combinations with chemo, combinations with immunotherapy and that hopefully will make an impact in triple negative breast cancer.