The number of treatable tumor-specific molecular aberrations has grown substantially in the past decade, with a survival benefit obtained from matching biomarkers to therapies in several cancer types, such as breast, colon, and lung. Molecular diagnostic techniques have become fundamental in providing information about tumor diagnosis and prognosis as well as in driving therapeutic decisions in oncology practice.
The National Comprehensive Cancer Network guidelines state that molecular testing should be considered before the initiation of primary therapy. The introduction of next-generation sequencing to oncology practice has enabled a better understanding of genetic landscapes and promoted the identification of potential actionable genomic alterations, including in patients diagnosed with cholangiocarcinoma (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. A minority of patients with newly diagnosed CCA undergo comprehensive molecular profiling. Oncologists have been slow to incorporate these new tests effectively into routine patient care. More needs to be done, especially in educating oncology providers, to ensure that patients who can benefit from this technology receive the appropriate testing they need at the time that they are diagnosed.
Francesca Avogadri-Connors, PhD, QED Therapeutics, San Francisco, CA, and colleagues examined the list of 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.
The results were presented at the 2020 American Association for Cancer Research annual meeting. A comprehensive literature review and analysis of multiplatform genomic data from publicly available databases were used to conduct this analysis. 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 that were 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. The most common genomic alterations for each variant type were IDH1/2 mutations (10%-18%), FGFR2 fusions (10%-20%), and CDKN2A deletion (9%-20%).
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%). Of the 190 patients in the study, 3 (1.6%) patients were classified as microsatellite instability high.
Based on these data, 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. Tumor molecular phenotypes predict responses to targeted therapies, which may provide a rationale for a randomized umbrella clinical trial with multiple targeted treatment arms and a single shared control arm.
In an interview with CCA News, Dr Avogadri-Connors stated, “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.”
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