Wednesday, February 13, 2019

Better melanoma results with radiation BEFORE BRAFi (at least in this report)


What treatment to employ and the order in which to use them in melanoma care have long been discussed and examined, sometimes with horrible results.  Remember back in the day, when it was decreed that one had to take and FAIL ipi BEFORE being allowed to take anti-PD-1???  And then we learned that folks treated that way had a DECREASED response to anti-PD-1???!!!  Remember when we thought having radiation while on anti-PD-1 would cause untenable side effects?  But, instead we learned that radiation WITH anti-PD-1 provided better results than when either treatment was utilized alone??!!!  Progress, though ever so much slower than we want and need, continues to be made  regarding order of operation, thanks to amazing ratties and research.

Now, there's this:

Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma. Shannan, Matschke, Chauvistre, et al.  Eur J Cancer. 2019 Feb 2. 

Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common.  Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-na├»ve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance  between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death.  The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

So...in this retrospective analysis of 65 Stage IV melanoma patients, it appears that those who opted for radiation before BRAFi had a longer duration of response.  Small numbers, but something to think about.

For what it's worth.  Hang tough, ratties.  - c

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