Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva

Howitt, Brooke E.; Sun, Heather H.; Roemer, Margaretha G.M.; Kelley, Alyssa; Chapuy, Bjoern; Aviki, Emeline; Pak, Christine J.; Connelly, Courtney; Gjini, Evisa; Shi, Yunling; Lee, Larissa; Viswanathan, Akila; Horowitz, Neil S.; Neuberg, Donna; Crum, Christopher P.; Lindeman, Neal; Kuo, Frank C.; Ligon, Azra H.; Freeman, Gordon J.; Hodi, F. Stephen; Shipp, Margaret A.; Rodig, Scott J.

doi:10.1001/jamaoncol.2015.6326

Cited by 119 publications

(105 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Howitt et al have investigated the status of genes encoding PD-1 ligands in cervical SCC. They have found co-gain or co-amplification of CD274 and PDCD1LG2, coding PD-L1 and PD-L2, in a significant number of cervical SCCs [36]. In a recent study of cervical SCC, patients with diffuse expression of PD-L1 were also found to have significantly worse disease-free and disease-specific survival as compared to those with only marginal PD-L1 expression [10].…”

Section: Discussionmentioning

confidence: 99%

Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas

2017

View full text Add to dashboard Cite

BackgroundThe programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) immune regulatory axis has emerged as a promising new target for cancer therapeutics, with lasting responses seen in the treatment of metastatic renal and lung carcinomas, as well as melanomas. As tumor surface expression of PD-L1 has been found to correlate with objective responses to anti-PD-L1 immunotherapies, we investigated the expression of PD-L1 in human cervical tumors and provide an adopted scoring system for the systematic evaluation of PD-L1 staining.MethodsImmunohistochemical staining for PD-L1 expression was performed on a tissue microarray of 101 normal and neoplastic cervical tissues. Neoplastic cores were divided into three groups: squamous cell carcinoma, adenosquamous carcinoma, and endocervical adenocarcinoma. PD-L1 expression was scored based on an adopted scoring system accounting to percentage and intensity of positivity, and results provided alongside available clinical and demographic data.ResultsOverall, PD-L1 was positive in 32 of 93 (34.4%) cervical carcinomas. Subcategorically, PD-L1 was positive in 28 of 74 (37.8%) squamous cell carcinomas, two of seven (28.6%) adenosquamous carcinomas, and two of 12 (16.7%) endocervical adenocarcinomas. It was negative in six benign cervical tissues.ConclusionsThis study shows a significant expression of PD-L1 in 34.4% of cervical carcinomas and no expression of PD-L1 in benign cervical tissues. These findings suggest a role for further investigation of anti-PD-L1/PD-1 immunotherapies in the treatment of PD-L1-positive cervical tumors. In addition, our adopted scoring system will facilitate more systematic correlations between tumor reactivity and response to treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas

2017

View full text Add to dashboard Cite

show abstract

“…Lastly, a genetic analysis of Howitt et al [63] identified the rational candidates who may benefit from therapies targeting PD-1 in cervical or vulvar squamous cell carcinoma (SCC) based on the expression of PD-L1. They suggested that alteration of 9p24.1 gene copy number results in increased PD-L1 expression in cervical and vulvar SCC.…”

Section: Immunotherapy Editing Immune System By Reengineering T-cellsmentioning

confidence: 99%

Major clinical research advances in gynecologic cancer in 2016: 10-year special edition

Suh

Kim

et al. 2017

J Gynecol Oncol

View full text Add to dashboard Cite

In 2016, 13 topics were selected as major research advances in gynecologic oncology. For ovarian cancer, study results supporting previous ones regarding surgical preventive strategies were reported. There were several targeted agents that showed comparable responses in phase III trials, including niraparib, cediranib, and nintedanib. On the contrary to our expectations, dose-dense weekly chemotherapy regimen failed to prove superior survival outcomes compared with conventional triweekly regimen. Single-agent non-platinum treatment to prolong platinum-free-interval in patients with recurrent, partially platinum-sensitive ovarian cancer did not improve and even worsened overall survival (OS). For cervical cancer, we reviewed robust evidences of larger-scaled population-based study and cost-effectiveness of nonavalent vaccine for expanding human papillomavirus (HPV) vaccine coverage. Standard of care treatment of locally advanced cervical cancer (LACC) was briefly reviewed. For uterine corpus cancer, new findings about appropriate surgical wait time from diagnosis to surgery were reported. Advantages of minimally invasive surgery over conventional laparotomy were reconfirmed. There were 5 new gene regions that increase the risk of developing endometrial cancer. Regarding radiation therapy, Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC)-3 quality of life (QOL) data were released and higher local control rate of image-guided adaptive brachytherapy was reported in LACC. In addition, 4 general oncology topics followed: chemotherapy at the end-of-life, immunotherapy with reengineering T-cells, actualization of precision medicine, and artificial intelligence (AI) to make personalized cancer therapy real. For breast cancer, adaptively randomized trials, extending aromatase inhibitor therapy, and ribociclib and palbociclib were introduced.

show abstract

“…To date, such amplifications have only been detected in small studies of head and neck squamous cell carcinoma, 14 cervical squamous cell carcinoma, 15 triple-negative breast cancer, 16-18 and non-small cell lung cancer. 19 Consistent with the aforementioned data on lymphomas, recent case reports found responses to PD-1 blockade in patients with PDL1 -amplified, microsatellite-stable colon cancer 20 and metastatic basal cell carcinoma, 21 suggesting the need for further interrogation of the potential utility of PDL1 amplifications as a biomarker for immune checkpoint blockade response.…”

mentioning

confidence: 99%

Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

et al. 2018

View full text Add to dashboard Cite

IMPORTANCE Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors. OBJECTIVES To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors. DESIGN, SETTING, AND PARTICIPANTS This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors. INTERVENTIONS Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade. MAIN OUTCOMES AND MEASURES The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS). RESULTS Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months). CONCLUSIONS AND RELEVANCE The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

show abstract

Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva

Abstract: Recurrent copy number gain of the genes encoding the PD-1 ligands provides a genetic basis for PD-L1 expression in a subset of cervical and vulvar SCCs and identifies a class of patients that are rational candidates for therapies targeting PD-1.

Cited by 119 publications

References 15 publications

Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas

Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas

Major clinical research advances in gynecologic cancer in 2016: 10-year special edition

Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

Contact Info

Product

Resources

About