Purpose: Bladder cancer is the sixth most common human cancer. Most cases are early-stage tumors known as papillary non-muscle invasive bladder cancer (NMIBC). After resection, 60-70% of NMIBCs recur locally, and ~15% progress to muscle invasion and metastasis. There is an unmet need for a biomarker to stratify tumors on their likelihood of recurrence. Such a biomarker could make it possible to identify those patients most likely to benefit from adjuvant intravesical therapy such as BCG. Furthermore, lower-risk patients could become eligible for less frequent post-resection surveillance by cystoscopy than the extremely intensive current standard of care. We recently identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence that STAG2 mutant tumors may recur less frequently than STAG2 wild-type tumors. Here we report a STAG2 biomarker study using an independent cohort of clinically annotated papillary NMIBC tumors.
Experimental Design: We identified all cases of papillary NMIBC treated at the Lombardi Comprehensive Cancer Center prior to 2013. STAG2 immunohistochemistry was performed and correlated with time to recurrence. This assay is particularly robust because (i) it utilizes a monoclonal antibody whose epitope is in the extreme carboxyl-terminus of STAG2, and ~85% of tumor-derived mutations of STAG2 are truncating; (ii) STAG2 is on the X-chromosome, so only a single mutation is required for complete gene inactivation; and (iii) STAG2 is among the most abundant proteins in the human proteome.
Results: 52% of NMIBC tumors with STAG2 expression recurred, whereas only 25% of NMIBC tumors with loss of STAG2 expression recurred (p=0.017). Multivariate analysis identified STAG2 as the only significant independent predictor of recurrence (p=0.050). The relative risk of recurrence for patients with STAG2-expressing tumors was 2.408 times the risk for patients with STAG2-negative tumors.
Conclusions: Here we demonstrate that a simple, robust assay for identifying STAG2-mutant tumors stratifies patients into two groups: (i) patients with retention of STAG2 expression (wild-type), ~52% of whom will recur; and (ii) patients with loss of STAG2 expression, of whom only ~25% will recur. Of note, STAG2 expression status, unlike pathologic grade–the current standard–was a significant predictor of recurrence. This information could help physicians make more informed decisions about the need for adjuvant immunotherapy/chemotherapy and also help inform the frequency of post-resection surveillance needed for individual patients. In conclusion, STAG2 is a simple, powerful, and potentially useful biomarker for prediction of recurrence in papillary NMIBC.
Citation Format: Alana Lelo, Brent T. Harris, Deborah L. Berry, Krysta Chaldekas, Anagha Kumar, David Solomon, Jeffry Simko, Pritish Bhattacharyya, Ciaran Mannion, Jung-Sik Kim, George Philips, Todd Waldman. STAG2 as a biomarker for prediction of recurrence in papillary non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1558.
