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Primary versus Metastatic Intrahepatic CCA: A Comparative Comprehensive Genomic Profiling Study

2020 Year in Review: Cholangiocarcinoma — December 19, 2020

Comprehensive genomic profiling data indicate that genetic profile of primary intrahepatic CCA was significantly different from metastatic intrahepatic CCA, with different rates of potentially targetable genetic alterations.

To determine whether genetic alterations characteristic of intrahepatic CCA are different between primary tumor tissue and metastatic tissue, a comparative comprehensive genomic profiling (CGP) study was conducted on tumor archival tissue; results of this study were reported at the American Society of Clinical Oncology (ASCO) 2020 Gastrointestinal Cancers Symposium.

CGP was performed on 1268 formalin-fixed paraffin-embedded tumor samples of advanced-stage intrahepatic CCA, which included 1048 samples of primary CCA tissue and 220 samples from CCA metastatic lesions including from lymph nodes, soft tissues, peritoneum, lung/pleura, omentum, bone, gynecologic tract, brain, upper gastrointestinal tract, colon, bladder, abdomen, and adrenal sites. Sequencing was performed for up to 315 genes and introns from 28 genes commonly rearranged in cancer. Base substitutions, insertions, deletions, rearrangements, and copy number were assessed. TMB, MSI, and PD-L1 expression in tumor cells were determined.

Overall, genetic alterations per tumor sample were similar between the primary and metastatic CCA samples (4.2 and 4.3, respectively). MSI-high status (<1% in primary tumors and 1% in metastatic CCA), TMB status (median TMB, 2.5 in both cohorts), and PD-L1 IHC expression levels (high, 5% and 4%; low, 15% and 18%) were similar between the 2 cohorts. Similar profiles of biomarkers of resistance to immune-oncology drug such as PBRM, STK11, MDM2, and KEAP1 were noted.

Although the overall frequencies of untargetable genetic alterations were similar between the 2 cohorts, there were differences in the frequencies of potentially targetable genetic alterations. The frequency of KRAS mutations, particularly the potentially targetable KRAS G12C, was significantly higher in the metastasis cohort compared with the primary cohort (P = .001). Notably, the frequency of IDH1 (P = .001) and FGFR2 genetic alterations was lower in the metastatic cohort, which is in contrast to its enrichment in primary intrahepatic CCA. STK11 genetic alterations occurred more frequently in metastatic samples.

These results indicate that the genetic alteration profiles are significantly different between primary and metastatic intrahepatic CCA, particularly relating to KRAS, IDH1, and FGFR2 genes, which the authors concluded was suggestive of a non-intrahepatic CCA primary tumor and incorrect diagnosis of metastatic intrahepatic CCA.

Source: Ross GS, et al. J Clin Oncol. 2020;38(4_suppl). Abstract 578.

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