TY - JOUR
T1 - HER2+ endometrioid endometrial cancer possesses distinct molecular and immunologic features associated with a more active immune microenvironment and worse prognosis
AU - Bruce, Shaina F.
AU - Wu, Sharon
AU - Ribeiro, Jennifer R.
AU - Farrell, Alex
AU - Oberley, Matthew J.
AU - Winer, Ira
AU - Erickson, Britt K.
AU - Klc, Tenley
AU - Jones, Nathaniel L.
AU - Thaker, Premal H.
AU - Powell, Matthew A.
N1 - Funding Information:
AF, MJO, SW, and JRR are employees of Caris Life Sciences. MAP receives consulting fees from Glaxo Smith Klein/Tesaro, Merck, AstraZeneca, Clovis Oncology, SeaGen, and Eisai. BKE receives consulting fees from Signatera and travel support from GOG Foundation to attend annual meetings. PHT's institution received grants or contracts from Merck and Glaxo Smith Klein. PHT participates in data safety monitoring boards or advisory boards for Eisai, Clovis Oncology, AstraZeneca, Glaxo Smith Klein, Aadi Pharmaceuticals, Novocure, Mersana, Celsion, Seagen, Agenus, Immunogen, Merck, and Iovance, and has stock/stock options with Celsion. PHT has a leadership role in the Association of Community Cancer Centers.
Publisher Copyright:
© 2023
PY - 2023/5
Y1 - 2023/5
N2 - Objective: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. Methods: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. Results: HER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. Conclusions: HER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.
AB - Objective: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. Methods: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. Results: HER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. Conclusions: HER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.
KW - Endometrioid endometrial cancer
KW - HER2
KW - Immunotherapy
KW - Microsatellite instability
KW - Molecular profiling
KW - Tumor immune microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85151475729&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2023.03.008
DO - 10.1016/j.ygyno.2023.03.008
M3 - Article
C2 - 37003074
AN - SCOPUS:85151475729
SN - 0090-8258
VL - 172
SP - 98
EP - 105
JO - Gynecologic oncology
JF - Gynecologic oncology
ER -