Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker

Chae, Hee Dong; Kim, Deokhoon; Yoo, Changhoon; Kim, Kyu-Pyo; Jeong, Jae Ho; Chang, Heung-Moon; Lee, Sang Soo; Park, Do Hyun; Song, Tae Jun; Hwang, Shin; Kim, Ki‐Hun; Song, Gi‐Won; Ahn, Chul Soo; Lee, Jae Hoon; Hwang, Dae Wook; Kim, Song Cheol; Jang, Se Jin; Hong, Seung‐Mo; Kim, Tae Won; Ryoo, Baek‐Yeol

doi:10.1016/j.ejca.2019.07.022

Cited by 63 publications

(68 citation statements)

References 32 publications

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“…At the single-gene level, our results showed better PFS in patients with ERBB2, LRP1B, and PKHD1 alterations. Consistent with previous reports, 34,35 we also found higher prevalence of ERBB2 alterations in patients with GCs than in ICCs. Yet the functional significance of ERBB2 missense mutations identified in our study cohort remained unclear.…”

Section: Discussionsupporting

confidence: 93%

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Wei

Wu³

et al. 2020

Clinical & Translational Med

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Background While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. Methods The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next‐generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. Results Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109; 95% CI, 0∼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation‐related indicators. NGS profiling of the available tumor tissues, revealed largely non‐overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06‐1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02‐1.19; P = .04), or PKHD1 (HR < 0.01; 95% CI, 0‐Inf; P = .04) showed strong association with increased progression‐free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK‐RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02‐0.63; P = .003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P = .032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7‐88.5; P < .001; 9p Del; HR = 4.88 × 109; 95% CI, 0‐Inf; P < .001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05‐1.17; P = .057). Conclusion Our study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification.

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Section: Discussionsupporting

confidence: 93%

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Wei

Wu³

et al. 2020

Clinical & Translational Med

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“…Other potential targets for future "Precision Medicine" strategies involve chromatin remodelling genes (ARID1, BAP1 and PBRM1) or DNA damage repair aberrations. [74][75][76] There has been some pre-clinical and early clinical research targeting BRAF and RNF43 mutations, as well as HER2 (also known as ERBB2). [77][78][79] In addition, some tumour-agnostic targets such as NTRK may also play a role for a small proportion of patients with biliary tract tumours (3%).…”

Section: Current Genetic Landscape and Actionable Aberrationsmentioning

confidence: 99%

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

Lamarca

Barriuso

McNamara

et al. 2020

Journal of Hepatology

240

221

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The prognosis for patients with biliary tract cancers (cholangiocarcinoma and gallbladder cancer) is poor, while the incidence of these cancers is increasing. Most patients are diagnosed with advanced disease when treatment options are limited to palliative approaches, mainly focused on chemotherapy. In recent years, novel treatment targets of relevance to biliary tract cancers, mainly present in patients with intrahepatic cholangiocarcinoma, have been identified and are rapidly changing the field. These include fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH)-1 and-2 mutations which are each present in around 10-20% of patients with intrahepatic cholangiocarcinoma. In addition, inhibition of other pathways/molecules is currently being explored, including human epidermal growth factor receptor (HER) family members, the Wnt pathway, neurotropic tyrosine kinase receptor (NTRK) fusions and BRAF mutations. The IDH1 inhibitor ivosidenib has already been tested in a phase III clinical trial in pretreated cholangiocarcinoma and showed benefit in terms of progression-free survival. Multiple FGFR inhibitors have consistently shown high response rates in phase II/III trials, especially for patients harbouring FGFR2 fusions. Herein, we provide an overview of the status of targeted therapies in biliary tract cancers, discussing the current clinical development of IDH and FGFR inhibitors in detail, as well as reviewing current caveats and future steps.

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“…The role of DDR alterations is still widely unknown in BTC and only few data about their clinical impact are currently available [ 51 ]. However, germline or somatic BRCAm are being increasingly reported due to the possibility to identify a distinct subgroup of carriers that may benefit from a personalized treatment strategy [ 52 , 53 ]. Curiously, BRCAm in BTC have been observed more frequently as somatic rather than as germline mutations [ 54 ].…”

Section: Ddr Deficiency and Brcam In Btcmentioning

confidence: 99%

“…Patients with BRCAm are predisposed for BTC, as BRCA1/2 alterations have been associated with early onset BTC [ 51 , 52 , 53 , 54 ]. More specifically, data from the early 2000s by the Breast Cancer Linkage Consortium (BCLC) suggested that BRCA2- carriers had higher relative risk (RR) of developing BTC than patients affected by infection with liver parasites, hepatitis C virus, and hepatitis B virus (RR 4.97, 95% confidence interval (CI) 1.50–16.52) [ 67 ].…”

Section: Ddr Deficiency and Brcam In Btcmentioning

confidence: 99%

PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block?

et al. 2020

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Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1–7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9–63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients.

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Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker

Cited by 63 publications

References 32 publications

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block?

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