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Genetic alterations affect everolimus benefit in breast cancer

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Mutation profile needs further study

Failure of single genetic alterations, such as PIK3CA-activating mutations, to predict everolimus benefit likely reflects the fact that there are other, independent ways of activating the mTOR pathway. So maybe pathway activation is what we should be looking at, not necessarily gene mutations.

Are we going to do anything different in clinic tomorrow as a result of these findings when it comes to using everolimus? No, we are still going to select therapy based on clinical criteria of acquired resistance to previous nonsteroidal aromatase inhibitors. Perhaps in the future, we will continue to do more work because we may be still able to develop that mutation profile that perhaps will spare some patients the treatment because there are other drugs that they can benefit from.

Dr. Stephen R.D. Johnston is a professor of breast cancer medicine at the Royal Marsden Hospital in London. He was the invited discussant of the research. Dr. Johnston disclosed that he is a consultant to AstraZeneca, GlaxoSmithKline, and Roche/Genentech, and that he receives honoraria from GlaxoSmithKline and Novartis.


 

AT THE ASCO ANNUAL MEETING 2013

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

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