Comprehensive genomic profiling of recurrent endometrial cancer: Implications for selection of systemic therapy

Emily N Prendergast; Laura L Holman; Annie Y Liu; Tiffany S Lai; Maira P Campos; Jacquline N Fahey; Xiaoyan Wang; Nabilah Abdelaal; Jian Yu Rao; Julia A Elvin; Kathleen M Moore; Gottfried E Konecny; Joshua G Cohen

doi:10.1016/j.ygyno.2019.06.016

Comprehensive genomic profiling of recurrent endometrial cancer: Implications for selection of systemic therapy

Gynecol Oncol. 2019 Sep;154(3):461-466. doi: 10.1016/j.ygyno.2019.06.016. Epub 2019 Jun 27.

Affiliations

¹ University of California Los Angeles, Division of Gynecologic Oncology, Los Angeles, CA, USA.
² Stephenson Oklahoma Cancer Center, Division of Gynecologic Oncology, Oklahoma City, OK, USA.
³ University of California Los Angeles, Division of Hematologic Oncology, Los Angeles, CA, USA.
⁴ University of California Los Angeles, Division of General Medicine and Health Services Research, USA.
⁵ University of California Los Angeles, Department of Pathology, Los Angeles, CA, USA.
⁶ Foundation Medicine, Inc., 150 Second Street, Cambridge, MA, USA.
⁷ University of California Los Angeles, Division of Gynecologic Oncology, Los Angeles, CA, USA; University of California Los Angeles, Division of Hematologic Oncology, Los Angeles, CA, USA. Electronic address: gkonecny@mednet.ucla.edu.

Abstract

Objectives: To assess whether comprehensive genomic profiling (CGP) in the setting of routine clinical care allows molecular classification of recurrent endometrial cancer (EC) into the four Cancer Genome Atlas (TCGA) categories: POLE ultramutated, microsatellite instable, copy-number low, and copy-number high and whether this approach can identify genomic alterations (GAs) which inform treatment decisions.

Methods: Archival tissues from 74 patients diagnosed with recurrent EC were prospectively analyzed using hybrid-capture-based genomic profiling. Tumor mutational burden and microsatellite instability were measured. Clinically relevant GAs (CRGAs) were defined as GAs associated with targeted therapies available on-label or in mechanism-driven clinical trials.

Results: Using POLE mutational analysis, mismatch repair status, and p53 mutational analysis as surrogate for 'copy-number' status CGP segregated all cases into four TCGA molecular subgroups. While recurrent serous ECs were predominantly copy-number high, we found no clear prevalence of a specific molecular subtype in endometrioid, clear cell or undifferentiated tumors. Every tumor sample had at least one GA and 91% (67/74) had at least one CRGA. In this series 32% (24/74) of patients received a matched therapy based on the results of CGP. Objective responses to the matched therapy were seen in 25% (6/24) of patients with an additional 37.5% (9/24) achieving stable disease leading to a clinical benefit rate of 62.5% with a median treatment duration of 14.6 months (range 4.3-69 months).

Conclusions: CGP allows molecular classification of EC into four TCGA categories and allows identification of potential biomarkers for matched therapy in the setting of routine clinical care.

Keywords: Comprehensive genomic profiling; Endometrial cancer; Next generation sequencing; Targeted therapy.

MeSH terms

Adult
Aged
Aged, 80 and over
DNA Mutational Analysis
Endometrial Neoplasms / drug therapy*
Endometrial Neoplasms / genetics*
Endometrial Neoplasms / pathology
Female
High-Throughput Nucleotide Sequencing
Humans
Microsatellite Instability
Middle Aged
Neoplasm Recurrence, Local / drug therapy*
Neoplasm Recurrence, Local / genetics*
Neoplasm Recurrence, Local / pathology
Neoplasm Staging
Retrospective Studies

Grants and funding

UG1 CA233193/CA/NCI NIH HHS/United States