Brooke E Howitt1, Heather H Sun1, Margaretha G M Roemer2, Alyssa Kelley1, Bjoern Chapuy2, Emeline Aviki3, Christine Pak1, Courtney Connelly1, Evisa Gjini4, Yunling Shi1, Larissa Lee3, Akila Viswanathan3, Neil Horowitz3, Donna Neuberg5, Christopher P Crum1, Neal L Lindeman1, Frank Kuo1, Azra H Ligon1, Gordon J Freeman6, F Stephen Hodi6, Margaret A Shipp6, Scott J Rodig7. 1. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts. 3. Departments of Obstetrics and Gynecology, Radiation Oncology, and Gynecological Oncology, Brigham and Women's Hospital, Boston, Massachusetts. 4. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. 6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 7. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts4The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract
IMPORTANCE: Patients with squamous cell carcinoma (SCC) of the cervix or vulva have limited therapeutic options, and the potential for immunotherapy for this population has not been evaluated. Recent trials suggest that tumors with a genetic basis for PD-1 (programmed cell death protein 1) ligand expression are highly sensitive to therapeutic antibodies targeting PD-1. OBJECTIVE: To determine the genetic status of CD274 (encoding PD-L1 [programmed cell death 1 ligand 1]) and PDCD1LG2 (encoding PD-L2 [programmed cell death 1 ligand 2]) in SCCs of the cervix and vulva and to correlate the findings with PD-L1 protein expression. DESIGN, SETTING, AND PARTICIPANTS: We performed fluorescence in situ hybridization (FISH) using probes targeting CD274, PDCD1LG2, and the centromeric portion of chromosome 9, and immunohistochemistry (IHC) using an antibody recognizing PD-L1 on formalin-fixed, paraffin-embedded (FFPE) biopsy specimens from 48 cervical SCCs and 23 vulvar SCCs. MAIN OUTCOMES AND MEASURES: Tumors were categorized according to the genetic abnormality in CD274 and PDCD1LG2 (coamplification > cogain > polysomy > disomy) as detected by FISH, and evaluated on a semiquantitative scale (modified H score, the product of the percentage of tumor cells with positive staining and the maximum intensity of positive staining) for PD-L1 protein expression as detected by IHC. RESULTS: Overall, 71 samples of FFPE tissue from cases of cervical SCCs (n = 48) and vulvar SCCs (n = 23) were retrieved from the archives of Brigham and Women's Hospital and included in this study. We observed cogain or coamplification of CD274 and PDCD1LG2 in 32 of 48 cervical SCCs (67%) and 10 of 23 vulvar SCCs (43%). Median PD-L1 protein expression was highest among tumors with CD274 and PDCD1LG2 coamplification and lowest among tumors with disomy. CONCLUSIONS AND RELEVANCE: 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.
IMPORTANCE: Patients with squamous cell carcinoma (SCC) of the cervix or vulva have limited therapeutic options, and the potential for immunotherapy for this population has not been evaluated. Recent trials suggest that tumors with a genetic basis for PD-1 (programmed cell death protein 1) ligand expression are highly sensitive to therapeutic antibodies targeting PD-1. OBJECTIVE: To determine the genetic status of CD274 (encoding PD-L1 [programmed cell death 1 ligand 1]) and PDCD1LG2 (encoding PD-L2 [programmed cell death 1 ligand 2]) in SCCs of the cervix and vulva and to correlate the findings with PD-L1 protein expression. DESIGN, SETTING, AND PARTICIPANTS: We performed fluorescence in situ hybridization (FISH) using probes targeting CD274, PDCD1LG2, and the centromeric portion of chromosome 9, and immunohistochemistry (IHC) using an antibody recognizing PD-L1 on formalin-fixed, paraffin-embedded (FFPE) biopsy specimens from 48 cervical SCCs and 23 vulvar SCCs. MAIN OUTCOMES AND MEASURES: Tumors were categorized according to the genetic abnormality in CD274 and PDCD1LG2 (coamplification > cogain > polysomy > disomy) as detected by FISH, and evaluated on a semiquantitative scale (modified H score, the product of the percentage of tumor cells with positive staining and the maximum intensity of positive staining) for PD-L1 protein expression as detected by IHC. RESULTS: Overall, 71 samples of FFPE tissue from cases of cervical SCCs (n = 48) and vulvar SCCs (n = 23) were retrieved from the archives of Brigham and Women's Hospital and included in this study. We observed cogain or coamplification of CD274 and PDCD1LG2 in 32 of 48 cervical SCCs (67%) and 10 of 23 vulvar SCCs (43%). Median PD-L1 protein expression was highest among tumors with CD274 and PDCD1LG2 coamplification and lowest among tumors with disomy. CONCLUSIONS AND RELEVANCE: 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.
Authors: Lada A Koneva; Yanxiao Zhang; Shama Virani; Pelle B Hall; Jonathan B McHugh; Douglas B Chepeha; Gregory T Wolf; Thomas E Carey; Laura S Rozek; Maureen A Sartor Journal: Mol Cancer Res Date: 2017-09-19 Impact factor: 5.852
Authors: Aaron M Goodman; David Piccioni; Shumei Kato; Amélie Boichard; Huan-You Wang; Garrett Frampton; Scott M Lippman; Caitlin Connelly; David Fabrizio; Vincent Miller; Jason K Sicklick; Razelle Kurzrock Journal: JAMA Oncol Date: 2018-09-01 Impact factor: 31.777