Urothelial carcinoma is the 5th most common cancer in the United States and the 9th most common cause of cancer worldwide.1 Upper tract urothelial carcinomas (UTUCs) are a rare subset of urothelial carcinoma (UC) that occur in the renal pelvis and/or ureter, and represent approximately 5% of total urothelial carcinomas.2 UTUC and UC share a similar histologic appearance, both are more common in men (3:1), and both are associated with smoking. However, there are some significant differences as well. UTUC is different at a molecular, anatomic, and clinical level.3,4 Unlike UC, UTUC is highly associated with Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), and harbors unique molecular signatures, such as FGFR3 mutations.5–8 UTUC is the 3rd most common Lynch syndrome associated cancer after colon and endometrial cancer.9 The tight anatomic constraints of the upper GU tract make UTUCs more challenging to biopsy, grade, and stage, and they require different treatments.3 Cisplatin-based chemotherapy is the standard of care for muscle invasive bladder UC, but treatment of UTUC usually requires nephroureterectomy, and the resulting loss of renal function may preclude treatment with the standard cisplatin-based chemotherapy because of its known nephrotoxicity.10 New treatment modalities, such as immune checkpoint inhibitors (ICIs) are a viable, non-chemotherapeutic option. ICIs are becoming more common in the treatment of many types of cancer and PD-L1 expression has been shown in some tumor types to be predictive of response to ICI therapy.
Currently, the United States Food and Drug Administration (FDA) has approved PD-L1 companion diagnostic testing, to qualify patients for treatment with pembrolizumab (Keytruda®, Merck, Kenilworth, NJ, USA), using PD-L1 clone 22C3 (Dako, Agilent, Santa Clara, CA, USA) and atezolizumab (Tecenriq®, Genentech, South, San Francisco, CA, USA), using PD-L1 clone SP-142 (Ventana, Roche, Basel, Switzerland).11,12 A third immune checkpoint inhibitor, durvalumab (Imfinzi®, AstraZeneca, Cambridge, UK) has also been approved for use in the setting of urothelial carcinoma, but the associated PD-L1 clone, SP-263 (Ventana, Roche, Basel, Switzerland) currently has no PD-L1 companion diagnostic testing approval.13 Finally, nivolumab (Opdivo®, Bristol-Myers Squibb, New York, NY, USA) has similarly been approved for use in this setting, but the associated PD-L1 clone, 28 − 8 (Dako, Agilent, Santa Clara, CA, USA) also currently has no companion diagnostic approval.14
Patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy can qualify for monotherapy treatment with pembrolizumab, atezolizumab, or nivolumab. Each of these immune checkpoint inhibitors was FDA approved following a phase 3 clinical trial, and each trial utilized a specific PD-L1 clone, scoring system and expression cutoff value. The PD-L1 testing that accompanies each of these drugs, therefore must use a specific clone, scoring system, and cutoff, and is selected based on which drug is intended for use in the patient. Pembrolizumab requires the use of the 22C3 clone, and requires a combined positive score (CPS) of ≥ 10.11,15 A CPS refers to the sum of positive viable tumor cells (showing membranous staining, irrespective of intensity and completeness) plus the positive, tumor associated lymphocytes and macrophages (membranous or cytoplasmic staining irrespective of intensity) over the total number of tumor cells, multiplied by 100. Qualifying for atezolizumab requires the SP-142 clone, and utilizes an immune cell score (IC) of ≥ 5% of the tumor area, meaning greater than 5% of the tumor area showing positive staining within the immune cells (not the tumor cells).16 Treatment with nivolumab does not require a companion diagnostic test, however, a complementary diagnostic test is available that utilizes the 28 − 8 clone and a tumor proportion score (TPS) of ≥ 1%. TPS is defined as the percentage of tumor cells showing membranous staining (complete or incomplete) at any level of intensity. The variety of PD-L1 antibody clones, scoring systems, and cutoffs used in the clinical trials and in the current literature illustrate the complex nature of PD-L1 testing in general.
Because immune checkpoint inhibitor therapy in UC is quite recent, and given the relative rarity of UTUC, little is known about the prognostic utility of PD-L1 in UTUC, or the status of PD-L1 expression in UTUC in general. UTUC-specific prognostic and predictive models are needed. The aims of this study are to investigate the performance of different FDA-approved PD-L1 clones, and explore any possible association between PD-L1 expression and clinicopathologic features of upper urothelial tract urothelial carcinomas.