Well, I guess to answer the question exactly in the post-CDK4-6 inhibitor setting, the strongest results I think we might have seen would be for the PI3 kinase inhibitor like alpelisib, and we’re still waiting for inavolisib comparison to that drug, where there was a PFS and a trend towards an overall survival advantage and important to say that both Finerenone and Capivasertib 291 neither showed an overall survival advantage for AKT and Ambition so probably going with Inavolisib looks the more sort of promising way to go there however if you take a patient from beginning, then probably looking at giving inavolisib with palbociclib, and aromatase inhibitor from the beginning, as in an AVO 120 trial, is probably the best option for somebody with these mutations that was both a progression-free survival of 10 months and a significant overall survival of 7 months...
Well, I guess to answer the question exactly in the post-CDK4-6 inhibitor setting, the strongest results I think we might have seen would be for the PI3 kinase inhibitor like alpelisib, and we’re still waiting for inavolisib comparison to that drug, where there was a PFS and a trend towards an overall survival advantage and important to say that both Finerenone and Capivasertib 291 neither showed an overall survival advantage for AKT and Ambition so probably going with Inavolisib looks the more sort of promising way to go there however if you take a patient from beginning, then probably looking at giving inavolisib with palbociclib, and aromatase inhibitor from the beginning, as in an AVO 120 trial, is probably the best option for somebody with these mutations that was both a progression-free survival of 10 months and a significant overall survival of 7 months. So I think the full answer for a patient is to treat at first line with a triplet rather than waiting to second line where we’ve seen less promise. The two basic mutations that we always want to know about at some stage are ESR1, the estrogen receptor mutations, and they tend to evolve through treatment. So something like 5% of patients have them in their primary but it builds up to anything up to forty percent as treatment goes along and that leads to resistance to aromatase inhibitors in particular so and the problem there is we kind of need to monitor that all the way along as has recently been done in the Serena 6 looking study looking for the appearance of ESR1 mutations and switching to a SERD-based drug. From the PI3 kinase point of view, the evidence suggests that most of those mutations are there at the beginning, that it’s there in the primary, it’s one of the primary drivers, causes the breast cancer to form in the first place, and so we can really measure that, probably should measure that at the beginning if we’re going to measure that, so we know what we’re dealing with from the outset. So two different answers for two different mutations. We then have a suite of other mutations that are emerging in significance, many of which, such as BRCA, you can measure from the beginning, but as we learn more, there may be more call for looking for the evolution of new mutations or selective clones.
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