8th European Breast Cancer Conference - March 21 - 24, Vienna

Triple negative advanced breast cancer treatment with PARP inhibitors

Dr Tim Yap - Royal Marsden Hospital, London, UK

Dr Yap, thank you very much indeed for giving us a little bit of time at this breast cancer meeting. You are a FLIMS alumnus, is that correct?

Yes, that is correct.

And, tell us a little bit about that?

So, the FLIMS workshop basically has been occurring for the past fourteen years; it’s an annual workshop on clinical trial design, that’s organised yearly in FLIMS in Switzerland and hence the name the FLIMS workshop. It’s organised jointly by AACR, ESMO, ECCO as well as ERTC and it’s actually a workshop I attended back in 2007.

It’s five days, isn’t it? It’s serious stuff.

Seven days, actually. It’s a very intense workshop whereby about 80 oncology trainees get to sit down and mingle very closely with faculty members. There’s a good ratio of maybe two trainees to one faculty member, so you get really intense training in actually writing and designing clinical trials. We’re all asked to write a concept sheet to bring there, and we’re expected to produce a full protocol at the end of the seven days. So essentially 24 hours a day writing protocols, talking trial design, there are didactic lectures, also interactive sessions, small group breakout sessions, and what was also very good was informal sessions with the faculty as well.

How did you get into medical oncology?

I did my SHO jobs in Oxford, where I did oncology there; that led to me working for Martin Gore at Marsden as an SHO and then I went on to work in the drug development unit with Stan Kaye and Johann de Bono, this is going back to 2006 now. And following that I went on to do my PhD in medical oncology, mainly based on a development pre-clinical pharmacology and clinical development of AKT inhibitors in cancers, and also design and conduct of a phase I trial. And following that, I’m basically now a specialist registrar, and I’m doing Professor Cunningham’s firm in GI cancers.

So, back to Oxford, what made you think about oncology as a career?

I’ve always wanted to do oncology. As a medical student I actually did a visiting clerkship, if you like, or an elective in the States in oncology and that really made my mind up, if you like.

So, it was at that level, even pre-graduation?

Oh yes, absolutely.

And you’re now an MD PhD?

In progress, yes.

Good. Well, that’s really interesting, and I know that the thousands of people who will be watching this programme will be interested in that as well. And you’re clearly enjoying it, and you’re not regretting the decision.

No, no, absolutely.

So tell us what you were talking about today. Now you’re coming back as an alumnus of FLIMS and you’re talking to the FLIMS folk, aren’t you? What were you talking about?

So this was actually a workshop organised by this FLIMS alumni club that was started about ten years ago by Jean-Charles Soria and we’re trying to more or less give back to the FLIMS workshop by reaching out to other people who haven’t actually gone to the actual workshop. My topic I was given today was to talk about PARP inhibitors and triple negative breast cancer, going with the theme of the meeting. The three main take home points from the talk today were firstly that synthetic lethality in tumours is a really important step forward in oncology.

What does that mean? Take it slowly, what does synthetic lethality mean?

So it actually describes the relationship between two different genes. So one gene is actually aberrant or abnormal, there is no impact on the cell viability, so the cell lives. However synthetic lethality describes the phenomenon in which the combination of the two abnormal genes, two mutated genes, will result in the lethality to the cells. So the cell actually dies, undergoes apoptosis and might potentially result in a selective targeting of the tumour.

You mean if you had a drug to target this synthetic lethality?

Exactly, and we have got preliminary results now from PARP inhibitors when given to patients with BRCA mutated tumours, including breast, ovarian and prostate cancers.

So, you were talking about triple negative and what’s that got to do with PARP inhibitors?

That’s a very good point. We’re trying to… I think the oncology field now is trying to see if it’s not just a boutique drug for BRCA mutated germline tumours, but also might have a wide application for sporadic cancers, which display something called the BRCAness phenomenon, and that was a term first coined by a paper from Nick Turner, Andrew Tutt and Alan Ashworth in Nature Cancer Reviews back in 2004. And that basically describes sporadic tumours, some non-germline tumours that share characteristics with germline BRCA1 or BRCA2 mutated cancers, meaning that the whole concept of synthetic lethality could actually be extended to apply to those other sporadic cancers, one of them being triple negative breast cancer.

I think one of the caveats to my talk, one of the main take home points, is that triple negative breast cancer is not a single disease. There are many subtypes within this breast cancer subtype, and we really need better predictive biomarkers really, to try and select for patients who will respond to these inhibitors.

It’s always dangerous when you see something defined by an absence of something. I’ve always been amused by the fact that non-small cell lung cancer meant a negative thing.

Yes.

It didn’t ever actually say what it was, it just said what it wasn’t. And that’s a little bit the issue with triple negative, and as breast cancer is opening up, presumably, how many different subsets will there be in triple negative, do you think?

I don’t know. I think that’s an excellent question. I think it’s yet to be determined.

Double figures?

Perhaps, but I think it really does depend on how we’re going to define those subtypes, and I think we’ll leave that to the experts really.

A different drug for each receptor, or what? What do you think?

I think we need to take a step back as well and look at what kind of treatments will be available. I think if we’re talking about the whole concept of tumour synthetic lethality, and what we’re really looking for are subtypes that have an aberrant homologous recombination pathway. And that’s a pathway which is an error-free DNA double strand repair pathway. Research has shown, from Alan Ashworth’s group, that combining tumours with those defects with a PARP inhibitor may actually result in efficacy to the tumour.

So, tell me about the PARP inhibitors. They are, again, a bit of a black box, aren’t they?

Well I think it’s still work in progress. I think when we ran the phase I trial, there was certainly preliminary evidence [??].

With which one?

This was the olaparib AstraZeneca compound. And we showed single agent activity in BRCA mutated ovarian, breast and prostate cancers. Since then there have been other PARP inhibitors, and I think the really important thing to remember is that all these different PARP inhibitors have very different inhibitory profiles, if you like. So they behave differently. And that has important implications, not just for toxicities but also for efficacy. I think recent papers have shown that the iniparib compound may actually work through independent mechanism other than PARP inhibition as well. But various other PARP inhibitors now such as from Merck, or other companies, are still undergoing clinical trials so I think we wait for those results.

But you’re optimistic about the future of PARP inhibitors?

Absolutely. I think cautious optimism is the way forward, really.

Having BRCAness is not a very great biomarker by the sound of it. Have you got a biomarker coming along?

I’m not involved directly in that field, but I know that is something that research is on-going on, and it’s going to be a very important assay that needs to be developed, essentially. But as you say, even if we do have that assay, it remains to see whether the anti-tumour efficacy with the BRCAness approach is going to be equivalent to the anti-tumour efficacy with germline BRCA mutated cancers.

That’s unbelievably clear, thank you very much indeed Dr Yap.