DISSECTING GENOMIC TUMOR HETEROGENEITY IN PATIENTS WITH RECURRENT INTRAHEPATIC CHOLANGIOCARCINOMA: IMPLICATIONS FOR NOVEL THERAEUTIC STRATEGIES
Hauke Lang1, Fabian Bartsch1, Janine Baumgart*1, Beate Straub1, Jens U. Marquardt2
1General, Visceral and Transplantation Surgery, Universitatsmedizin der Johannes Gutenberg-Universitat Mainz, Mainz, Rheinland-Pfalz, Germany; 2Universitatsklinikum Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany
Background
Complete resection, often including extended resections, is the only curative treatment option for Intrahepatic cholangiocarcinoma (ICC). However, tumor recurrence is common and associated with dismal clinical outcome. Molecular analysis might facilitate to improve patient selection and identify patients at increased risk for tumor recurrence. We performed comparative molecular analyses of molecular features in primary and recurrent ICC specimens.
Methods
From 01/2008 through 12/2017 a total of 208 patients underwent exploration for ICC. Further follow-up was performed and in case of tumor recurrence repeated resection was discussed and performed in selected patients. A total of 45 lesions from 15 patients undergoing resection for recurrence underwent high resolution next-generation targeted sequencing of all lesions to dissect genetic features and clonal evolution of different lesions as well as recurrent tumors.
Results
In total 145 (resection rate 69.7%) resections with curative intention were performed. Recurrence rate was 67.6% (98/145). Recurrence were intrahepatic in 43 (43.9%), extrahepatic in 25 (25.5%) and combined intra- and extrahepatic in 29 (29.6%) patients. Selected patients with isolated intrahepatic recurrence were candidates for repeated resection. All of the investigated patients received tumor resection for at least one tumor recurrence. Five patients underwent surgery for second and one for third tumor recurrence. Median time to recurrence of the entire resection group was 7.7 months while the subgroup of patients who underwent repeated resection had a median time to recurrence of 14.4 months. Median overall survival was 17.9 months for the entire resection cohort and 34.7 months for the repeated resection group. On the molecular level, the spectrum of genetic alterations was similar among patients with and without recurrence. Among patients with recurrent resections, primary tumors and matched recurrent lesions shared genetic alterations in key molecules resembling TP53, KRAS, IDH1, EGFR in each patient. However, several alterations resembling oxidative stress response, oncogenic signaling as well as angiogenesis, e.g. in KEAP1, VEGFB, BAP1 or KIT detected in multifocal cancers were only present in individual lesions. Interestingly, these alterations could subsequently be detected in matched recurrent lesions suggesting adverse molecular features.
Conclusions
Key oncogenic alterations are preserved in multifocal as well as recurrent ICC. However, inter- tumoral heterogeneity is highly variable among patients. Individual molecular alterations contribute to genetic landscape of recurrent tumors. Thus, analyses of single lesion may not completely recapitulate genomic features of recurrent ICC. These observations might have considerable implications for targeted treatment approaches as well as in particular for patient selection before surgery.
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