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Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations

Citation

Almquist, Daniel et al. (2020), Assessment of clinical outcomes with immune checkpoint inhibitor therapy in melanoma patients with CDKN2A and TP53 pathogenic mutations, Dryad, Dataset, https://doi.org/10.5061/dryad.m0cfxpp0g

Abstract

Background: Somatic CDKN2A and TP53 mutations are recurrent events in melanoma, occurring in 13.3% and 15.1% of cases respectively and are associated with poorer outcomes. It is unclear what effect somatic CDKN2A and TP53 mutations have on the clinical outcomes of patients treated with checkpoint inhibitors. Methods: All patients with cutaneous melanoma or melanoma of unknown primary who received checkpoint inhibitor therapy and underwent genomic profiling with the 50-gene Mayo Clinic solid tumor targeted cancer gene panel were included. Patients were stratified according to the presence or absence of mutations in BRAF, NRAS, CDKN2A, and TP53. Patients without mutations in any of these genes were termed quadruple wild type (Quad WT ). Clinical outcomes including median time to progression (TTP), median overall survival (OS), 6-month and 12-month OS, 6-month and 12-month without progression, ORR and disease control rate (DCR) were analyzed according to the mutational status of CDKN2A, TP53 and Quad WT . Results: A total of 102 patients were included in this trial of which 14 had somatic mutations of CDKN2A (CDKN2A mut ), 21 had TP53 mutations (TP53 mut ), and 12 were Quad WT . TP53 mut , CDKN2A mut and Quad WT mutational status did not impact clinical outcomes including median TTP, median OS, 6-month and 12-month OS, 6-month and 12-month without progression, ORR and DCR. There was a trend towards improved median TTP and DCR in CDKN2A mut cohort and a trend towards worsened median TTP in the Quad WT cohort. Conclusion: Cell cycle regulators such as TP53 and CDKN2A do not appear to significantly alter clinical outcomes when immune checkpoint inhibitors are used.

Methods

Study Population/Study Design:

This is a retrospective study which was approved by Mayo Clinic IRB(16-005168). No consent was needed as information was obtain anonymously. This study was conducted in accordance with principles for human experimentation as defined in the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. No participating physicians have conflicts of interest to declare.  The Mayo Clinic IRB waived the requirement for informed consent since the data was analyzed anonymously. Patients were identified from all three Mayo Clinic campuses (Minnesota, Arizona and Florida). Patients with a diagnosis of metastatic or unresectable cutaneous melanoma or melanoma of unknown primary whose tumors were analyzed with our 50 gene Solid Tumor Targeted Cancer Gene Panel were included. Patients who received an immune checkpoint inhibitor at any point during their treatment course were included. However, data associated with the first immunotherapy regimen and overall patient outcomes were evaluated for this analysis. Response to targeted therapy, chemotherapy and subsequent lines of immunotherapy treatments were collected but are not the focus of this study. This study allowed for treatment with cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors, PD-1 inhibitors, or combinations that included either a PD-1 inhibitor or CTLA-4 inhibitor.

The objective of this study is to investigate the impact of the presence of CDKN2A mutations (CDKN2Amut), TP53 mutations (TP53mut) and quadruple wild type (QuadWT) mutational status on clinical outcomes in patients who received immune checkpoint inhibitors. Patients who did not carry TP53, CDKN2A, NRAS or BRAFv600 mutations were termed QuadWT. The primary endpoint measured was median time-to-progression (TTP) with secondary endpoints including the percentage of participants without progression at 6 and 12 months, median overall survival (OS), OS at 6 and 12 months, disease control rate (DCR) and overall response rate (ORR) to immunotherapy. Response rates were assessed using available CT or MRI imaging and their associated reports. Calculations were based on the best overall response using the immune related response criteria (irRC) and were categorized as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Pathologic tumor characteristics, patient demographic and clinical details were also collected by chart review.

Genomic Profiling:

The Solid Tumor Targeted Cancer Gene Panel is a 50 gene panel that evaluated the following genes: ABL1, AKT1, ALK, APC, ATM, BRAF, CDH11, CKDN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53 and VHL. This is a laboratory-developed  test using Research Use Only reagents.  Extracted DNA from the clinical specimen is fragmented, adapter ligated, and a sequence library of fragments is prepared using a custom capture hybridization method. Individual patient samples are indexed for identification and the library is sequenced on an Illumina platform. Sequence data are processed through the Mayo Clinic Clinical Genome Sequencing Lab bioinformatics pipeline and a variant call file is generated for final analysis and reporting(Unpublished Mayo method). This testing is clinically available through Mayo Clinic.

Usage Notes

The Solid Tumor Targeted Cancer Gene Panel is a 50 gene panel that evaluated the following genes: ABL1, AKT1, ALK, APC, ATM, BRAF, CDH11, CKDN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53 and VHL. This is a laboratory-developed  test using Research Use Only reagents.  Extracted DNA from the clinical specimen is fragmented, adapter ligated, and a sequence library of fragments is prepared using a custom capture hybridization method. Individual patient samples are indexed for identification and the library is sequenced on an Illumina platform. Sequence data are processed through the Mayo Clinic Clinical Genome Sequencing Lab bioinformatics pipeline and a variant call file is generated for final analysis and reporting(Unpublished Mayo method). This testing is clinically available through Mayo Clinic.

 

Funding

None, Award: None