Allen Gown

gownIHC to determine PD-L1 expression in non-small cell lung and other tumors as a predictor of patient response to drugs targeting immune checkpoints: The rationale, predictive value, confusion and potential of companion diagnostics

The PD-1/PD-L1 interaction is an example of an “immune checkpoint” that under physiologic conditions is a negative feedback loop repressing cytotoxic immune response. However, when hijacked by tumor cells expressing PD-L1, these latter cells can block tumor cell killing by host cells. Drugs targeting either PD-1 or PD-L1 can help release this “brake” on the host immune response and have been demonstrated to show significant efficacy against a wide range of tumors.
A total of three different “immune checkpoint” drugs have been approved by the FDA in the US: two targeting PD-1 (pembrolizumab, nivolumab) and one targeting PD-L1 (atezolizumab). In a complex approval mechanism, all three of these drugs have been approved along with a [required] “companion” or [suggested] “complementary” diagnostic IHC test, with the requirement dependent upon the tumor type and the drug being entertained. Along with the publication of results of new clinical trials, the FDA has approved different drugs with different corresponding IHC, each using different antibodies with different cutoffs for different clinical applications. Interpretation of these studies is generally straightforward per published guidelines, although some unique features of the PD-L1 scoring systems can pose difficulties in interpretation. Compared with other companion diagnostics such as HER2 FISH and IHC for trastuzumab qualification, there are few published data on the effects of pre-analytical factors as well as the inter- and intra-observer variability in scoring results, especially in settings where the distinction of tumor from non-tumor (e.g., macrophages) elements can be challenging. Results of my laboratory’s experience in PD-L1 IHC testing in >2000 cases in the past year confirms and qualifies the clinical trial data on frequency of various levels of PD-L1 expression in non-small cell lung and other carcinomas, and highlights the ‘real world problems’ regarding this assessment. To address the complexity of multiple test platforms requiring multiple antibody kits and autostainer protocols, a number of published studies have documented high levels of concordance among some, but not all, of the IHC tests, and has highlighted the presence of some discordances in predictive scoring of existing PD-L1 IHC tests, further confused by the scoring of immune cell expression of PD-L1 in at least one application of one test. While in many tumors the efficacy of PD-L1 targeted drugs can be predicted by the results of IHC testing for PD-L1 expression, this is tumor-dependent and not absolute. Thus, the enthusiasm for the immune checkpoint targeted drugs has outstripped our ability to provide completely predictable companion diagnostics for these drugs, and more work needs to be done in identifying optimal IHC, and perhaps non-IHC, biomarkers.


Dr. Gown received his MD from the Albert Einstein College of Medicine of Yeshiva University, Bronx, NY in 1975, and then completed his Pathology Residency as well as Pathology Fellowship training at the University of Washington, Seattle, the latter under the aegis of Dr. Earl Benditt. Dr. Gown rose through the ranks to full Professor of Pathology and served as attending pathologist at the University of Washington Medical Center, where he developed and directed the immunohistochemistry (IHC) laboratory.  In 1997, Dr. Gown left the University of Washington to found PhenoPath, which has grown to become an internationally renowned specialty pathology reference laboratory.  Currently, Medical Director and Chief Pathologist at PhenoPath, Dr. Gown is a pathologist-scientist recognized as one of the world’s leading experts in the diagnostic and research applications of IHC.  He has developed numerous clinically important monoclonal antibodies employed in IHC laboratories around the world (HMB-45, OSCAR, etc.). Dr. Gown is a member of the editorial boards of many of the major pathology journals.  He is a Clinical Professor of Pathology at the University of British Columbia, Vancouver, BC, and an Affiliate Investigator in the Clinical Research Division of the Fred Hutchinson Cancer Research Center, Seattle, WA.  Dr. Gown continues to be at the forefront of clinical investigative studies employing IHC and other modalities with over 300 peer-reviewed publications and as a frequent presenter at national and international conferences.

Selected references

  1. Kandalaft PL, Gown AM, Isacson C. The lung-restricted marker napsin A is highly expressed in clear cell carcinomas of the ovary. Am J Clin Pathol, 142(6):830-6, 2014.
  2. Banet N, Gown AM, Shih IeM, Kay Li Q, Roden RB, Nucci MR, Cheng L, Przybycin CG, Nasseri-Nik N, Wu LS, Netto GJ, Ronnett BM, Vang R. GATA-3 expression in trophoblastic tissues: an immunohistochemical study of 445 cases, including diagnostic utility. Am J Surg Pathol, 39(1):101-8, 2015.

  3. Polley MY, Leung SC, Gao D, Mastropasqua MG, Zabaglo LA, Bartlett JM, McShane LM, Enos A, Badve SS, Bane AL, Borgquist S, Fineberg S, Lin MG, Gown AM, Grabau D, Gutierrez C, Hugh JC, Moriya T, Ohi Y, Osborne CK, Penault-Llorca FM, Piper T, Porter PL, Sakatani T, Salgado R, Starczynski J, Lænkholm AV, Viale G, Dowsett M, Hayes DF, Nielsen TO. An international study to increase concordance in Ki67 scoring. Modern Pathol, 28(6):778-86, 2015.

  4. Kandalaft PL, Gown AM. Practical Applications in Immunohistochemistry: Carcinomas of Unknown Primary Site. Arch Pathol Lab Med. 140(6): 508-23, 2016.

  5. Hwang HC, Sheffield BS, Rodriguez S, Thompson K, Tse CH, Gown AM, Churg A. Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens. Am J Surg Pathol. 40(1): 120-6, 2016.

  6. Gown AM, Fulton RS, Kandalaft PL. Markers of metastatic carcinoma of breast origin. A Review. Histopathology. 68(1): 86-95, 2016.

  7. Hwang HC1, Pyott S, Rodriguez S, Cindric A, Carr A, Michelsen C, Thompson K, Tse CH, Gown AM, Churg A. BAP1 Immunohistochemistry and p16 FISH in the Diagnosis of Sarcomatous and Desmoplastic Mesotheliomas. Am J Surg Pathol. 40(5): 714-8, 2016.

  8. Gown AM. Diagnostic Immunohistochemistry: What Can Go Wrong and How to Prevent It. Arch Pathol Lab Med. 140(9): 893-8, 2016.

  9. Sheffield BS, Fulton R, Kalloger SE, Milne K, Geller G, Jones M, Jacquemont C, Zachara S, Zhao E, Pleasance E, Laskin J, Jones SJ, Marra MA, Yip S, Nelson BH, Gown AM, Ho C, Ionescu DN. Investigation of PD-L1 Biomarker Testing Methods for PD-1 Axis Inhibition in Non-squamous Non-small Cell Lung Cancer. J Histochem Cytochem. 64(10): 587-600, 2016.

  10. Kandalaft PL, Simon RA, Isacson C, Gown AM. Comparative Sensitivities and Specificities of Antibodies to Breast Markers GCDFP-15, Mammaglobin A, and Different Clones of Antibodies to GATA-3: A Study of 338 Tumors Using Whole Sections. Appl Immunohistochem Mol Morphol. 24(9): 609-614, 2016.