Metastatic Thymoma Harboring a Deleterious BRCA2 Mutation Derives Durable Clinical Benefit from Olaparib

Abstract

Thymomas comprise a group of rare epithelial neoplasms of the anterior mediastinum. Whereas localized disease carries a favorable prognosis, the majority of patients with metastatic thymomas experience progression or recurrence over a 10-year period. Although targeted therapies have become standard of care in many malignancies, no clinically actionable mutations have consistently been identified in metastatic thymomas.Here, we describe a patient with an aggressive thymoma complicated by extensive pleural metastases. Over a 16-year period, she progressed on multiple treatment regimens. To identify additional treatment options, tissue from a pleural metastasis was sent for next-generation sequencing, revealing mutations in BRCA2, tyrosine kinase 2, and SET domain containing 2. Based on supporting evidence for poly (ADP-ribose) polymerase (PARP) inhibition in other BRCA-mutated tumors, the patient was started on the PARP inhibitor olaparib. She derived significant clinical benefit from treatment, with imaging showing overall stabilization of her disease. Here, we review the genotyping results of her tumor and discuss the functional and clinical significance of the mutations in her cancer as well as implications for managing patients with advanced BRCA-mutant thymomas. The Oncologist 2020;25:301-305 KEY POINTS• Targeted therapy has yet to enter the standard clinical management of metastatic thymomas.• Patients with BRCA2-mutant thymomas may benefit from poly (ADP-ribose) polymerase inhibition.

Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

“…Thus, initial trials were based on the hypothesis that inhibiting the repair of single stranded breaks will cause synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination 40 . As discussed, this approach has shown tremendous efficacy in several BRCA -mutant cancers, including those of the breast, ovary, prostate, colon, thymus, and pancreas 10,13,42 . Olaparib became the first FDA-approved PARP inhibitor based on results from Study 19, a randomized, placebo-controlled trial in ovarian cancer showing an improvement in both progression-free and overall survival 43 .…”

“…The use of PARP inhibitors in these patients limits their ability to undergo single stranded break repair, leading to the accumulation of DNA damage and eventually cell death 6,7 . This approach has shown clinical efficacy in the management of BRCA -mutated breast, ovarian, pancreas, and prostate cancers [8][9][10][11] , and more recently glioblastoma multiforme and metastatic thymomas 12,13 .…”

The Never-Ending History of Octreotide in Thymic Tumors: A Vintage or A Contemporary Drug?

“…This preliminary evidence was confirmed in a phase II study from the French RYTHMIC network enrolling 51 patients, which reported a disease control rate as high as 88% [17]. The search for an actionable mutation in thymoma led to the treatment of a patient with a pathogenetic BRCA mutation with the PARP inhibitor olaparib, which achieved a significant clinical benefit [103].…”

Mediastinal thymoma in a patient with previous rectal and breast cancers: A report of a case with multiple primary cancers and review of literature

“… 15 , 16 A case of thymoma was reported by Principe et al, which was accompanied by deleterious BRCA2 mutation, a gene mostly seen in breast cancer but proven unrelated to colorectal cancer. 17 Also, another case of thymoma was reported by Tampellini et al, which was accompanied by Lynch syndrome. 18 In another case series, three patients with a family history of upper aero‐digestive tract squamous carcinoma developed MPC, suggesting an inherited predisposition.…”

“…Genetic predisposition plays an important role in presenting cancer in individuals, 14 and there are known inherited cancer syndromes that are caused by single or multiple gene mutations 15,16 . A case of thymoma was reported by Principe et al, which was accompanied by deleterious BRCA2 mutation, a gene mostly seen in breast cancer but proven unrelated to colorectal cancer 17 . Also, another case of thymoma was reported by Tampellini et al, which was accompanied by Lynch syndrome 18 .…”