Publications by authors named "Oluwadara Coker"

2 Publications

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Comprehensive Clinical and Molecular Characterization of -Mutant Colorectal Cancer.

JCO Precis Oncol 2021 6;5. Epub 2021 Apr 6.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population.

Methods: We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics.

Results: Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. p.G12C demonstrated higher rates of basal EGFR activation compared with nonG12C. When compared with an internal cohort of nonG12C, p.G12C patients had worse OS.

Conclusion: PFS is poor for patients with p.G12C metastatic colorectal cancer. OS was worse in p.G12C compared with nonG12C patients. Our data highlight the innate resistance to chemotherapy for p.G12C patients and serve as a historical comparator for future clinical trials.
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April 2021

Clinical and Functional Characterization of Atypical / Mutations in Metastatic Colorectal Cancer.

Clin Cancer Res 2021 Jun 11. Epub 2021 Jun 11.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Mutations in () predict lack of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). However, it is unclear if all mutations have similar impact, and atypical mutations beyond those in standard guidelines exist.

Experimental Design: We reviewed 7 tissue and 1 cell-free DNA cohorts of 9,485 patients to characterize atypical variants. Using an cell-based assay (functional annotation for cancer treatment), Ba/F3 transformation, and xenograft models of transduced isogenic clones, we assessed signaling changes across mutations.

Results: exon 2, extended , and atypical mutations were noted in 37.8%, 9.5%, and 1.2% of patients, respectively. Among atypical variants, L19F, Q22K, and D33E occurred at prevalence ≥0.1%, whereas no codon 117/146 and only one codon 59 mutation was noted. Atypical mutations had worse overall survival than wild-type mCRC (HR, 2.90; 95% confidence interval, 1.24-6.80; = 0.014). We functionally characterized 114 variants with the FACT assay. All exon 2 and extended mutations appeared activating. Of 57 atypical variants characterized, 18 (31.6%) had signaling below wild-type, 23 (40.4%) had signaling between wild-type and activating control, and 16 (28.1%) were hyperactive beyond the activating control. Ba/F3 transformation (17/18 variants) and xenograft model (7/8 variants) validation was highly concordant with FACT results, and activating atypical variants were those that occurred at highest prevalence in clinical cohorts.

Conclusions: We provide best available evidence to guide treatment when atypical variants are identified. L19F, Q22K, D33E, and T50I are more prevalent than many guideline-included variants and functionally relevant.
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June 2021