Author Manuscript Published OnlineFirst on May 26, 2015; DOI: 10.1158/2326-6066.CIR-15-0043 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Differential expression of PD-L1 between primary and metastatic sites in clear cell Renal Cell Carcinoma Marcella Callea1, Laurence Albiges2, Mamta Gupta3,8, Su-Chun Cheng4,8, Elizabeth M. Genega5, André P. Fay2, Jiaxi Song1, Ingrid Carvo1, Rupal S. Bhatt6,8, Michael B. Atkins7, F. Stephen Hodi2, Toni K. Choueiri2,8, David F. McDermott6,8, Gordon J. Freeman2, Sabina Signoretti1,2,8
1
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
2
Department of Medical Oncology and 4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School Boston, MA 3
Department of Pathology and 6Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 5
Department of Pathology, Tufts Medical Center, Boston, MA
7
Georgetown-Lombardi Comprehensive Cancer Center, Washington DC
8
Kidney Cancer Program, Dana-Farber Harvard Cancer Center, Boston, MA
Corresponding Author: Sabina Signoretti M.D. Department of Pathology, Brigham and Women's Hospital 75 Francis Street, Thorn Building 504A Boston, MA 02115 617-525-7437 (phone) 617-264-5169 (fax) [email protected] Conflict of interest statement: MC, MG, SC, EMG, APF, JS, IC, RSB, DFM: No disclosures. LA disclosed: consulting or advisory role to Pfizer, Novartis, Sanofi, Amgen; Research funding: Pfizer, Novartis. MBA disclosed: consulting or advisory role to Merck, BMS, Genentech, Novartis, GSK, Neostem, Alkermes, X4Pharma, Amgen; Expert testimony: BMS. FSH disclosed: research support from Bristol-Myers Squibb to institution; Consultant to Merck, Novartis; Clinical trial support to institution from BristolMyers Squibb, Merck, Genentech. TKC disclosed: consulting or advisory role to Pfizer, GSK, Novartis, Merck and Bayer; Research funding: Pfizer, GSK, Novartis, BMS, Merck, Exelixis, Roche, Astra Zeneca, Tracon. GJF has patents/pending royalties on the PD-1 pathway from Bristol-Myers-Squibb, Roche, Merck, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, and Novartis. GF has served on advisory boards for CoStim, Novartis, Roche, and Bristol-MyersSquibb. SS serves as consultant for AstraZeneca, Merck, and Verastem. 1
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Author Manuscript Published OnlineFirst on May 26, 2015; DOI: 10.1158/2326-6066.CIR-15-0043 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abstract: 245 /250 word limit Main text: 3276/5000 word limit Number of tables and figures: 7/7 (4 tables, 2 figures, 2 supplemental tables)
2
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Author Manuscript Published OnlineFirst on May 26, 2015; DOI: 10.1158/2326-6066.CIR-15-0043 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abstract PD-L1 expression in primary clear cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved.
Areas with
predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using Hscore. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11/53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (p=0.51). Tumor cell PD-L1 positivity was associated with higher T stage (p=0.03) and higher Fuhrman Nuclear Grade (FNG) (p
Differential expression of PD-L1 between primary and metastatic sites in clear cell Renal Cell Carcinoma Marcella Callea1, Laurence Albiges2, Mamta Gupta3,8, Su-Chun Cheng4,8, Elizabeth M. Genega5, André P. Fay2, Jiaxi Song1, Ingrid Carvo1, Rupal S. Bhatt6,8, Michael B. Atkins7, F. Stephen Hodi2, Toni K. Choueiri2,8, David F. McDermott6,8, Gordon J. Freeman2, Sabina Signoretti1,2,8
1
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
2
Department of Medical Oncology and 4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School Boston, MA 3
Department of Pathology and 6Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 5
Department of Pathology, Tufts Medical Center, Boston, MA
7
Georgetown-Lombardi Comprehensive Cancer Center, Washington DC
8
Kidney Cancer Program, Dana-Farber Harvard Cancer Center, Boston, MA
Corresponding Author: Sabina Signoretti M.D. Department of Pathology, Brigham and Women's Hospital 75 Francis Street, Thorn Building 504A Boston, MA 02115 617-525-7437 (phone) 617-264-5169 (fax) [email protected] Conflict of interest statement: MC, MG, SC, EMG, APF, JS, IC, RSB, DFM: No disclosures. LA disclosed: consulting or advisory role to Pfizer, Novartis, Sanofi, Amgen; Research funding: Pfizer, Novartis. MBA disclosed: consulting or advisory role to Merck, BMS, Genentech, Novartis, GSK, Neostem, Alkermes, X4Pharma, Amgen; Expert testimony: BMS. FSH disclosed: research support from Bristol-Myers Squibb to institution; Consultant to Merck, Novartis; Clinical trial support to institution from BristolMyers Squibb, Merck, Genentech. TKC disclosed: consulting or advisory role to Pfizer, GSK, Novartis, Merck and Bayer; Research funding: Pfizer, GSK, Novartis, BMS, Merck, Exelixis, Roche, Astra Zeneca, Tracon. GJF has patents/pending royalties on the PD-1 pathway from Bristol-Myers-Squibb, Roche, Merck, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, and Novartis. GF has served on advisory boards for CoStim, Novartis, Roche, and Bristol-MyersSquibb. SS serves as consultant for AstraZeneca, Merck, and Verastem. 1
Downloaded from cancerimmunolres.aacrjournals.org on June 2, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 26, 2015; DOI: 10.1158/2326-6066.CIR-15-0043 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abstract: 245 /250 word limit Main text: 3276/5000 word limit Number of tables and figures: 7/7 (4 tables, 2 figures, 2 supplemental tables)
2
Downloaded from cancerimmunolres.aacrjournals.org on June 2, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on May 26, 2015; DOI: 10.1158/2326-6066.CIR-15-0043 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Abstract PD-L1 expression in primary clear cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved.
Areas with
predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using Hscore. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11/53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (p=0.51). Tumor cell PD-L1 positivity was associated with higher T stage (p=0.03) and higher Fuhrman Nuclear Grade (FNG) (p
