Targeting <scp><i>BRCA</i>‐mutant</scp> biliary tract cancer: Current evidence and future perspectives

Li, Xinyu; Chen, Jiaqi; Aisa, Adilai; Ding, Yu; Zhang, Ding; Yuan, Ying

doi:10.1111/1751-2980.13168

Cited by 4 publications

(6 citation statements)

References 94 publications

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“…In particular, known pathogenic mutations in the BRCA2 gene were found in two iCCA samples that were analyzed with the Illumina TruSight Tumor 170 kit. Recently, it was suggested that BTCs with mutations in BRCA1/2 genes may benefit from therapy with poly(ADPribose) polymerase inhibitors (PARPi) [62,63]. Pathogenic MLH1 mutations were observed in another two iCCA cases; interestingly, only one of these cases was MSI-positive, as determined by the pentaplex PCR panel.…”

Section: Discussionmentioning

confidence: 99%

Molecular Analysis of Biliary Tract Cancers with the Custom 3′ RACE-Based NGS Panel

Mitiushkina,

Tiurin,

Anuskina

et al. 2023

Diagnostics

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The technique 3’ rapid amplification of cDNA ends (3′ RACE) allows for detection of translocations with unknown gene partners located at the 3′ end of the chimeric transcript. We composed a 3′ RACE-based RNA sequencing panel for the analysis of FGFR1–4 gene rearrangements, detection of activating mutations located within FGFR1–4, IDH1/2, ERBB2 (HER2), KRAS, NRAS, BRAF, and PIK3CA genes, and measurement of the expression of ERBB2, PD-L1, and FGFR1–4 transcripts. This NGS panel was utilized for the molecular profiling of 168 biliary tract carcinomas (BTCs), including 83 intrahepatic cholangiocarcinomas (iCCAs), 44 extrahepatic cholangiocarcinomas (eCCAs), and 41 gallbladder adenocarcinomas (GBAs). The NGS failure rate was 3/168 (1.8%). iCCAs, but not other categories of BTCs, were characterized by frequent FGFR2 alterations (17/82, 20.7%) and IDH1/2 mutations (23/82, 28%). Other potentially druggable events included ERBB2 amplifications or mutations (7/165, 4.2% of all successfully analyzed BTCs) and BRAF p.V600E mutations (3/165, 1.8%). In addition to NGS, we analyzed microsatellite instability (MSI) using the standard five markers and revealed this event in 3/158 (1.9%) BTCs. There were no instances of ALK, ROS1, RET, and NTRK1–3 gene rearrangements or MET exon 14 skipping mutations. Parallel analysis of 47 iCCA samples with the Illumina TruSight Tumor 170 kit confirmed good performance of our NGS panel. In conclusion, targeted RNA sequencing coupled with the 3′ RACE technology is an efficient tool for the molecular diagnostics of BTCs.

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Section: Discussionmentioning

confidence: 99%

Molecular Analysis of Biliary Tract Cancers with the Custom 3′ RACE-Based NGS Panel

Mitiushkina,

Tiurin,

Anuskina

et al. 2023

Diagnostics

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“…Genomic instability from BRCA mutations has been significantly associated with higher tumor mutational burden (TMB), regardless of deficient or proficient mismatch repair (dMMR or pMMR) [ 121 ]. Given that BRCA mutations are often associated with dMMR/MSI-H, the combination of PARPi + ICI could aid in the prevention of PARPi resistance and improve outcomes [ 124 ]. This combination is currently being studied in advanced BTC in the phase II trial combining rucaparib (PARPi) with nivolumab after proven platinum sensitivity (no radiographic or clinical progression after 4–6 months of platinum-based systemic chemotherapy), the results of which are anticipated in 2024 [ 125 ].…”

Section: Advanced Stage Diseasementioning

confidence: 99%

Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma

Wheless,

Agarwal,

Goff

et al. 2024

Curr. Treat. Options in Oncol.

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Opinion statementBiliary tract cancers are molecularly and anatomically diverse cancers which include intrahepatic cholangiocarcinoma, extrahepatic (perihilar and distal) cholangiocarcinoma, and gallbladder cancer. While recognized as distinct entities, the rarer incidence of these cancers combined with diagnostic challenges in classifying anatomic origin has resulted in clinical trials and guideline recommended strategies being generalized patients with all types of biliary tract cancer. In this review, we delve into the unique aspects, subtype-specific clinical trial outcomes, and multidisciplinary management of patients with extrahepatic cholangiocarcinoma. When resectable, definitive surgery followed by adjuvant chemotherapy (sometimes with selective radiation/chemoradiation) is current standard of care. Due to high recurrence rates, there is growing interest in the use of upfront/neoadjuvant therapy to improve surgical outcomes and to downstage patients who may not initially be resectable. Select patients with perihilar cholangiocarcinoma are being successfully treated with novel approaches such as liver transplant. In the advanced disease setting, combination gemcitabine and cisplatin remains the standard base for systemic therapy and was recently improved upon with the addition of immune checkpoint blockade to the chemotherapy doublet in the recently reported TOPAZ-1 and KEYNOTE-966 trials. Second-line all-comer treatments for these patients remain limited in both options and efficacy, so clinical trial participation should be strongly considered. With increased use of molecular testing, detection of actionable mutations and opportunities to receive indicated targeted therapies are on the rise and are the most significant driver of improved survival for patients with advanced stage disease. Though these targeted therapies are currently reserved for the second or later line, future trials are looking at moving these to earlier treatment settings and use in combination with chemotherapy and immunotherapy. In addition to cross-disciplinary management with surgical, medical, and radiation oncology, patient-centered care should also include collaboration with advanced endoscopists, palliative care specialists, and nutritionists to improve global patient outcomes.

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“…Breast cancer antigens 1/2 (BRCA1/2) are central enzymes in homologous recombination crucial for repairing double-strand breaks (DSB). In cells with BRCA1/2 mutations, the repair of DSB is inefficient, leading to the accumulation of gene alterations and carcinogenesis [195]. The treatment of tumors with BRCA1/2 mutation has been extensively studied in various solid tumors, such as breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.…”

Section: Targeting Braf Alterationsmentioning

confidence: 99%

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma

Heumann,

Albert,

Gülow

et al. 2024

Cancers

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We conducted a comprehensive review of the current literature of published data, clinical trials (MEDLINE; ncbi.pubmed.com), congress contributions (asco.org; esmo.org), and active recruiting clinical trains (clinicaltrial.gov) on targeted therapies in cholangiocarcinoma. Palliative treatment regimens were analyzed as well as preoperative and perioperative treatment options. We summarized the current knowledge for each mutation and molecular pathway that is or has been under clinical evaluation and discussed the results on the background of current treatment guidelines. We established and recommended targeted treatment options that already exist for second-line settings, including IDH-, BRAF-, and NTRK-mutated tumors, as well as for FGFR2 fusion, HER2/neu-overexpression, and microsatellite instable tumors. Other options for targeted treatment include EGFR- or VEGF-dependent pathways, which are known to be overexpressed or dysregulated in this cancer type and are currently under clinical investigation. Targeted therapy in CCA is a hallmark of individualized medicine as these therapies aim to specifically block pathways that promote cancer cell growth and survival, leading to tumor shrinkage and improved patient outcomes based on the molecular profile of the tumor.

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Targeting BRCA‐mutant biliary tract cancer: Current evidence and future perspectives

Cited by 4 publications

References 94 publications

Molecular Analysis of Biliary Tract Cancers with the Custom 3′ RACE-Based NGS Panel

Molecular Analysis of Biliary Tract Cancers with the Custom 3′ RACE-Based NGS Panel

Current Standards, Multidisciplinary Approaches, and Future Directions in the Management of Extrahepatic Cholangiocarcinoma

Current and Future Therapeutic Targets for Directed Molecular Therapies in Cholangiocarcinoma

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