Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE- Mutant Uterine Carcinosarcoma.

Autor:	Bhangoo MS; Division of Hematology Oncology, Scripps Clinic, La Jolla, California, USA., Boasberg P; The Angeles Clinic and Research Institute, Los Angeles, California, USA., Mehta P; Department of Radiology, The Angeles Clinic and Research Institute, Los Angeles, California, USA., Elvin JA; Foundation Medicine, Inc., Cambridge, Massachusetts, USA., Ali SM; Foundation Medicine, Inc., Cambridge, Massachusetts, USA., Wu W; Department of Pathology, John Wayne Cancer Institute, Providence Saint John's Medical Center, Los Angeles, California, USA., Klempner SJ; The Angeles Clinic and Research Institute, Los Angeles, California, USA sklempner@theangelesclinic.org.; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Jazyk:	angličtina
Zdroj:	The oncologist [Oncologist] 2018 May; Vol. 23 (5), pp. 518-523. Date of Electronic Publication: 2018 Jan 31.
DOI:	10.1634/theoncologist.2017-0342
Abstrakt:	Gynecologic carcinosarcomas, previously known as malignant mixed Müllerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase ɛ ( POLE ), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE -endometrioid cases, our patient harbored alterations in PIK3CA , ARID1A , and PTEN and was microsatellite stable, with appreciable tumor-infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma. Key Points: Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis.Inactivating DNA polymerase ɛ ( POLE ) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition.To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma.This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors. Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article. (© AlphaMed Press 2018.)
Databáze:	MEDLINE
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