Genomic data analysis of publicly available data supports the high prevalence of potentially actionable mutations in patients with CCA, supporting use of personalized therapies alone or in combination with chemotherapy.
During the past decade, the number of treatable tumor-specific molecular aberrations has grown substantially. The survival benefit was obtained from matching biomarkers to therapies in several types of cancer, such as breast, colon, and lung. Molecular diagnostic techniques have become integral to provide information regarding tumor diagnosis and prognosis as well as therapeutic decisions in oncology practice.
According to the National Comprehensive Cancer Network guidelines, molecular testing should be considered before primary therapy is initiated. With the advent of next-generation sequencing to oncology practice, we now have a better understanding of genetic landscapes and can better identify potential actionable genomic alterations, including those in patients diagnosed with CCA.
A major stumbling block to the discovery of molecular aberrations in patients with CCA has been the adoption of molecular profiling by healthcare providers. Only a minority of patients with newly diagnosed CCA undergo comprehensive molecular profiling because oncologists have been slow to incorporate these new tests effectively into routine patient care. Educating the oncology providers is integral so patients can benefit from this technology and receive the appropriate testing when they are diagnosed.
Francesca Avogadri-Connors, PhD, QED Therapeutics, San Francisco, CA, and colleagues examined genetic abnormalities previously discovered in patients with CCA to uncover the prevalence of actionable genomic mutations that may make patients candidates for intervention with investigational therapies. Results were presented at this year’s annual meeting of the American Association for Cancer Research. The analysis was conducted using a comprehensive literature review and analysis of multiplatform genomic data from publicly available databases. For this study, actionable genomic alterations were defined as known or likely driver mutations, all gene fusions, or select copy number alterations. Correlative analysis of genomic alterations and clinical trial options was performed using an in-silico cohort of patients with CCA with available clinical genomic data extracted from the cBioPortal for Cancer Genomics database, version 3.1.6.
The in-silico cohort consisted of 393 patients with CCA (median age at diagnosis, 59 years; 55% male, 45% female; stage IV CCA, 65%) from the cBioPortal database. IDH1/2 mutations (10%-18%), FGFR2 fusions (10%-20%), and CDKN2A deletion (9%-20%) were the most common genomic alterations for each variant type.
Additional actionable genomic variants, which were mostly mutually exclusive, included KRAS (8%), PIK3CA (5%), PTEN (4%), ERBB2 (2.5%), BRAF (1.8%), and NTRK (1.8%). Three (1.6%) of the 190 patients in the study were classified as microsatellite instability high.
Approximately 45% to 50% of patients with CCA have an actionable mutation and may be candidates for precise, personalized therapies alone or in combination with chemotherapy according to these data. Tumor molecular phenotypes predict responses to targeted therapies. This may provide a rationale for a randomized umbrella clinical trial with multiple targeted treatment arms and a single shared control arm.
When interviewed by CCA News, Dr Avogadri-Connors said, “It is enlightening to realize that about half of patients with cholangiocarcinoma have at least 1 ‘actionable’ genomic alteration in the malignant tissue, and about 75% have a ‘potentially actionable’ alteration which makes them possibly eligible for clinical studies or novel targeted treatment. I believe these data speak for the need of broader and earlier use of biomarker testing in cholangiocarcinoma patients.”
Source: Avogadri-Connors F, et al. Cancer Res. 2020;80(16_suppl). Abstract 2940.