Clinical data have revealed the remarkable potential for T-cell-modulating agents to induce potent and durable responses in a subset of cancer pts. Biomarker-driven selection would minimize unnecessary exposure of pts to life-threatening immune-related toxicities and reduce the financial costs of these expensive agents. Genomic profiling of tumor samples of pts who achieved extreme responders (> 1year) may help identifying predictive biomarkers.
We analyzed formalin fixed paraffin embedded (FFPE) tissue from pts with refractory solid tumors extreme responders (> 1 year) to PD1 inhibition. A platinum refractory, bladder pt (#1), having PR lasting 18-months (m), still on treatment; one TNBC (#2, in 3th line) with PR lasting 24-m, one bladder pt (#3, in 4th line), achieving PR lasting 14-m were analyzed. Genomic profiling using Foundation Medicine T5a test was performed in a CLIA-certified lab (Foundation Medicine, Inc.).
CREBBP alterations were found in extreme responders. Pt #1 presented a frame shift mutation R1443fs*10 involving the domain for histone acetylation; pt #2 had a frame shift mutation E649*5 in the KIX, KID binding domain; pt #3 harbored a mutation in the splice site 1941 + 1G > A for the transcriptional adaptor zinc finger 2. Additional mutations are described in the Table below.
|CREBBP||R1443fs*10||E649fs*5||splice site 1941 + 1G > A|
Present genomic analyses revealed CREBBP alterations in extreme responders to PD1 inhibition independently by the tumor type. CREBBP is ubiquitously expressed and it is known to play many different roles in immune response. Functionally, the described mutations could impair histone acetylation and transcriptional regulation of CREBBP targets. This association deserves validation in a wider anti-PD1 treated cohort of pts but it suggests that CREBBP mutations could have a potential role as predictive biomarker for immunological treatments.
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All authors have declared no conflicts of interest.