Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma

Francesco Sabbatino; Luigi Liguori; Umberto Malapelle; Francesca Schiavi; Vincenzo Tortora; Valeria Conti; Amelia Filippelli; Giampaolo Tortora; Cristina R Ferrone; Stefano Pepe

doi:10.3389/fonc.2020.567289

Case Report: BAP1 Mutation and RAD21 Amplification as Predictive Biomarkers to PARP Inhibitor in Metastatic Intrahepatic Cholangiocarcinoma

Front Oncol. 2020 Nov 27:10:567289. doi: 10.3389/fonc.2020.567289. eCollection 2020.

Authors

Francesco Sabbatino^{1

2}, Luigi Liguori³, Umberto Malapelle⁴, Francesca Schiavi⁵, Vincenzo Tortora³, Valeria Conti^{1

6}, Amelia Filippelli^{1

6}, Giampaolo Tortora⁷, Cristina R Ferrone⁸, Stefano Pepe^{1

2}

Affiliations

¹ Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy.
² Oncology Unit, University Hospital San Giovanni di Dio e Ruggi D'Aragona, Salerno, Italy.
³ Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy.
⁴ Public Health, University of Naples "Federico II", Naples, Italy.
⁵ Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
⁶ Clinical Pharmacology and Pharmacogenetics Unit, University Hospital "San Giovanni di Dio e Ruggi D'Aragona", Salerno, Italy.
⁷ Oncologia Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica Del Sacro Cuore, Roma, Italy.
⁸ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Abstract

Introduction: Intrahepatic cholangiocarcinoma (ICC) is a rare hepatobiliary cancer characterized by a poor prognosis and a limited response to conventional therapies. Currently chemotherapy is the only therapeutic option for patients with Stage IV ICC. Due to the poor response rate, there is an urgent need to identify novel molecular targets to develop novel effective therapies. Precision oncology tests utilizing targeted next-generation sequencing (NGS) platforms have rapidly entered into clinical practice. Profiling the genome and transcriptome of cancer to identify potentially targetable oncogenic pathways may guide the clinical care of the patient.

Case presentation: We present a 56-year-old male patient affected with metastatic ICC, whose cancer underwent several precision oncology tests by different NGS platforms. A novel BAP1 mutation (splice site c.581-17_585del22) and a RAD21 amplification were identified by a commercial available platform on a metastatic lesion. No germline BAP1 mutations were identified. Several lines of evidences indicate that PARP inhibitor administration might be an effective treatment in presence of BAP1 and/or RAD21 alterations since both BAP1 and RAD21 are involved in the DNA repair pathway, BAP1 interacts with BRCA1 and BRCA1-mediated DNA repair pathway alterations enhance the sensitivity to PARP inhibitor administration. In this case, after failing conventional therapies, patient was treated with PARP inhibitor olaparib. The patient had a partial response according to RECIST criteria with an overall survival of 37.2 months from the time of diagnosis of his ICC. Following 11.0 months on olaparib treatment, sustained stable disease control is ongoing. The patient is still being treated with olaparib and no significant toxicity has been reported.

Conclusion: These findings have clinical relevance since we have shown PARP inhibitor as a potential treatment for ICC patients harboring BAP1 deletion and RAD21 amplification. We have also highlighted the utility of NGS platforms to identify targetable mutations within a cancer.

Keywords: BAP1; Poly ADP ribose polymerase (PARP) inhibitor; RAD21; cholangio carcinoma; olaparib; precision oncology.

Publication types

Case Reports