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BAP1 Treatment

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BAP1 Treatment

Treatment of BAP1-TPDS tumours:

There are currently no unique treatment options available to BAP1-TPDS  patients for their tumours. Furthermore, tumours within the spectrum are some of the most deadly malignancies.

  • Uveal melanoma (UM): Commonly treated locally if small with brachytherapy (application of radioactive plaque to lesion[j2] ). Unfortunately, BAP1 mutated UM tumoursare of the highest risk group for poor prognosis1. Currently there are no  effective treatments for metastatic UM; worldwide there has been case reports of immunotherapy in two patients related to a germline mutation in the MBD4 gene producing positive responses 2.
  • Mesothelioma: Commonly treated with pemetrexed and a [j3] platinum based chemotherapy drug with limited effectiveness. Overwhelminglypatients with mesothelioma do not survive past 5 years. There has been a report of BAP1 germline carriers have extended survival3 but is thought to be limited to pleural mesothelioma without asbestos exposure. This survival benefit is not seen in peritoneal mesothelioma patients which constitutes ~50% of mesothelioma patients who carry BAP1 germline variants. There is currently trials showing positive results with immunotherapy (durvalumab) plus chemotherapy4 and the NCI [j4] is enrolling patients for a trial (https://clinicaltrials.gov/ct2/show/study/NCT03531840) with a PARPi[j5]  (olaparib) which is postulated that it may show some effectiveness in carriers.
  • Cutaneous Melanoma (CM): Locally treated with wide-local excision of lesions, this is commonly sufficient in disease management. Metastatic melanoma is the poster child of immunotherapy and is commonly treated with either single or combination of PD-1/CTLA-4 inhibitors.
  • Renal Cell Carcinoma (RCC): Early diagnosis of RCC can allow for curative partial/radical nephrectomy, shown to be very successful in disease management 5. Generally metastatic disease is treated with a tyrosine kinase inhibitor (TKI) as a monotherapy or in combination,  modestly effective, at best. Unfortunately, the BAP1-TPDS has been linked mainly with clear cell RCC and been linked with mainly poor prognosis 6-8.
  • Meningioma: If the most common, Grade I tumour can be cured through complete surgicalexcision. However, there has been some evidence that BAP1 mutated meningiomas are more commonly high grade and of the rhabdoid subtype 9.
  • Cholangiocarcinoma: Can be treated through multiple methods but as following the theme of the BAP1-TPDS, BAP1-mutant cholangiocarcinoma is thought to be an aggressive subtype 10.
  • Basal Cell Carcinoma (BCC): Normally treated by wide[j6] -local excision and very rarely metastasizes.
  • BAP1-inactivated melanocytic tumours (BIMTs): Benign lesions originally characterized on BAP1 germline variant carriers 11. The transformation potential of these lesions is unknown and it is recommended that they are treated as for other highly suspicious lesions.

1-Jovanovic, P. et al. Ocular melanoma: an overview of the current status. International journal of clinical and experimental pathology 6, 1230-1244 (2013).

2-Rodrigues, M. et al. Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Nature communications 9, 1866, doi:10.1038/s41467-018-04322-5 (2018).

3-Baumann, F. et al. Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis 36, 76-81, doi:10.1093/carcin/bgu227 (2015).

4-Nowak, A. K. et al. DREAM: A phase II study of durvalumab with first line chemotherapy in mesothelioma—First results. Journal of Clinical Oncology 36, 8503-8503, doi:10.1200/JCO.2018.36.15_suppl.8503 (2018).

5-Bianchi, M. et al. Conditional survival after nephrectomy for renal cell carcinoma (RCC): changes in future survival probability over time. BJU international 111, E283-289, doi:10.1111/bju.12115 (2013).

6-Hakimi, A. A. et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clinical cancer research : an official journal of the American Association for Cancer Research 19, 3259-3267, doi:10.1158/1078-0432.ccr-12-3886 (2013).

7-Kapur, P. et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal cell carcinoma: a retrospective analysis with independent validation. The Lancet. Oncology 14, 159-167, doi:10.1016/S1470-2045(12)70584-3 (2013).

8-Gossage, L. et al. Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes, chromosomes & cancer 53, 38-51, doi:10.1002/gcc.22116 (2014).

9-Shankar, G. M. et al. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro-oncology, doi:10.1093/neuonc/now235 (2016).

10-Al-Shamsi, H. O. et al. BRCA-associated protein 1 mutant cholangiocarcinoma: an aggressive disease subtype. Journal of gastrointestinal oncology 7, 556-561, doi:10.21037/jgo.2016.03.05 (2016).

11-Wiesner, T. et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nature genetics 43, 1018-1021, doi:10.1038/ng.910 (2011).