Mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2 mutated metastatic breast cancer

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Published: 11 Jun 2019
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Dr Adrienne Waks - Dana-Farber Cancer Institute, Boston, USA

Dr Adrienne Waks speaks to ecancer at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting about the mechanisms of resistance to platinum-based chemotherapy or PARP inhibitors in patients with BRCA1/2 mutated, metastatic breast cancer.

Dr Waks explains the preliminary findings of this study, in which 50 percent of patients acquired resistance as their tumours were no longer a BRCA1/2 mutant.

The protein RAD51 was also investigated as a potential biomarker, to determine the potency of BRCA1/2.

Dr Waks discusses the feasibility of implementing these techniques in the clinic, along with further work that will need to be carried out.
 

This programme has been supported by an unrestricted educational grant from Pfizer.

Our abstract basically takes advantage of the fact that as an institution we have collected a large, many hundred, patient cohort of patients with metastatic breast cancer. Most of them have hormone receptor positive metastatic breast cancer but there is also some triple negative breast cancer there. So we were interested within that large cohort of identifying patients who have a mutation in either BRCA1 or BRCA2, so the main breast cancer susceptibility genes that we all think of, and were exposed to treatment with either a PARP inhibitor or a platinum type of chemotherapy, which are types of medicines that are particularly targeted for effectiveness in a BRCA1 or BRCA2 mutant patient. We picked out eight of those patients from the large cohort of patients with metastatic breast cancer and we did sequencing on tumour samples that were available both after the patient had acquired resistance to the PARP inhibitor or the platinum therapy, and some time point before that at the time when the patient was initially sensitive to the PARP inhibitor or the platinum therapy as  a way of basically trying to look in the genome for reasons that these patients who initially responded to these targeted therapies would have initially responded and then subsequently become resistant.

It’s a small cohort, again it’s eight patients, so they are certainly findings that need to be looked at in larger cohorts but what we found is that in four of eight patients, so 50% of the patients, it looked like the patients acquired resistance to the therapy because their cancer cells found a way to become no longer BRCA mutant. So they developed what’s called a reversion, meaning that they acquired a secondary alteration in BRCA1 or BRCA2 genes such that instead of being BRCA deficient in the way that they had been at the beginning when they were responding to the therapy they ended up being BRCA intact and therefore they weren’t susceptible to the therapy anymore and so they progressed and had to move on to a different treatment. So that’s what we found in four of the eight patients.

Then in two of the eight patients we found evidence in the sequencing results that they may have acquired resistance to the PARP inhibitor or the platinum by increasing a part of DNA repair processes called end resection. So that finding was interesting and potentially important to us because it maybe points to another mechanism, another aspect of biology, that you could target in combination with the PARP inhibitor or the platinum in order to prevent or overcome resistance from developing to the original therapy. Because, of course, what we ultimately care about is not just figuring things out in the DNA sequence of tumours but actually being able to use that to figure out why therapies stop working and then make them work better for our patients.

Currently in the clinic, especially I can speak mostly to breast cancer because I’m a breast cancer doctor, in breast cancer our use of PARP inhibitors and platinums in patients who are BRCA1 or 2 mutant is relatively recent. So the first two PARP inhibitor drugs were actually both FDA approved in breast cancer in 2018. So in breast cancer I would say that we haven’t had a lot of insights, at least not breast cancer specific insights, into why resistance develops and how to manage it. So honestly we manage those patients in the way that we manage other metastatic breast cancer patients which is that, based on their disease status and their clinical status at the time of disease progression, you decide from the menu of options what treatment makes sense to use next. But I think up to this point we’ve been lacking ideas about exactly how to think about why they became resistant so that we could be rational in what treatments we use next, which is definitely still a work in progress. But that’s what we’re working towards.

Another thing that was exciting in our results and another thing that we looked into, again these are preliminary results, it’s a cohort of eight patients, but we looked at the use of the biomarker called RAD51. RAD51 is a protein that’s involved in DNA damage repair by homologous recombination so it’s basically in the same pathway as BRCA1 and BRCA2. What we found, and what others have found as well and we corroborate, is that you can use the presence or the absence of RAD51 as a marker of whether BRCA1 or 2 is working or is not working in a given tumour and whether the DNA damage repair pathway of homologous recombination is working or is not working in a given tumour.

The exciting thing that we found is that you can determine that by doing a simple stain for RAD51. So I’m just grabbing results from sequencing tumours, that takes months, then you have to analyse it, that’s obviously not going to be deployable in real time, at least not in 2019 in the clinic. But something like RAD51 staining where you just have one slide, you do a simple brown stain then you look for the presence or absence of a marker, that’s something that we could really deploy in the clinic and our results suggested that maybe that’s a meaningful clinical marker that can predict response or resistance.

What are the next steps for this research?

The main thing is that it needs to be looked at in larger cohorts and it needs to be replicated and taken further because our results are exciting and we’re hoping that they ultimately translate into benefit for patients in helping these two classes of therapies work better in patients with BRCA1 or 2 mutations. But it’s an eight patient cohort and certainly we need larger cohorts of patients who are participated broadly in clinical trials of PARP inhibitors or platinums, cohorts from other institutions and we need to do similar analyses both of genomics and of RAD51 in those bigger cohorts.