Open AccessNext‐Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma
Author(s) -
Ikeda Sadakatsu,
Tsigelny Igor F.,
Skjevik Åge A.,
Kono Yuko,
Mendler Michel,
Kuo Alexander,
Sicklick Jason K.,
Heestand Gregory,
Banks Kimberly C.,
Talasaz AmirAli,
Lanman Richard B.,
Lippman Scott,
Kurzrock Razelle
Publication year - 2018
Publication title -
the oncologist
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.176
H-Index - 164
eISSN - 1549-490X
pISSN - 1083-7159
DOI - 10.1634/theoncologist.2017-0479
Subject(s) - cdkn2a , pten , medicine , hepatocellular carcinoma , cancer research , palbociclib , sorafenib , oncology , cancer , biology , pi3k/akt/mtor pathway , genetics , metastatic breast cancer , apoptosis , breast cancer
Background Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood‐derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. Materials and Methods We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild‐type allele fraction was calculated. Results All patients (100%) had somatic alterations (median = 3 alterations/patient [range, 1–8]); median mutant allele fraction, 0.29% (range, 0.1%–37.77%). Mutations were identified in several genes: TP53 (57% of patients), CTNNB1 (29%), PTEN (7%), CDKN2A (7%), ARID1A (7%), and MET (7%); amplifications, in CDK6 (14%), EGFR (14%), MYC (14%), BRAF (7%), RAF1 (7%), FGFR1 (7%), CCNE1 (7%), PIK3CA (7%), and ERBB2/HER2 (7%). Eleven patients (79%) had ≥1 theoretically actionable alteration. No two patients had identical genomic portfolios, suggesting the need for customized treatment. A patient with a CDKN2A ‐inactivating and a CTNNB1 ‐activating mutation received matched treatment: palbociclib (CDK4/6 inhibitor) and celecoxib (COX‐2/Wnt inhibitor); des‐gamma‐carboxy prothrombin level decreased by 84% at 2 months (1,410 to 242 ng/mL [normal: ≤7.4 ng/mL]; alpha fetoprotein [AFP] low at baseline). A patient with a PTEN ‐inactivating and a MET ‐activating mutation (an effect suggested by in silico molecular dynamic simulations) received sirolimus (mechanistic target of rapamycin inhibitor) and cabozantinib (MET inhibitor); AFP declined by 63% (8,320 to 3,045 ng/mL [normal: 0–15 ng/mL]). Conclusion ctDNA derived from noninvasive blood tests can provide exploitable genomic profiles in patients with HCC. Implications for Practice This study reports that blood‐derived circulating tumor DNA can provide therapeutically exploitable genomic profiles in hepatocellular cancer, a malignancy that is known to be difficult to biopsy.