BCAN TT 2022: Defining the Clinical Impact and Molecular Drivers of “Secondary” Muscle-Invasive Bladder Cancer

(UroToday.com) Dr. Eugene Pietzak, MD is a urologic oncologist at the Memorial Sloan Kettering Cancer Center in New York, NY. He is the recipient of the 2021 BCAN Young Investigator Award for his research focused on molecular characterization of tumors which have progressed through intravesical BCG therapy to muscle-invasive disease.

BCG is the longstanding reference standard intravesical therapy for intermediate and high risk NMIBC. An estimated 10-30% of patients will exhibit therapeutic BCG failure and progress “secondary” MIBC. While these patients are conventionally managed with standard of care cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy, it has been hypothesized that their tumor biology and susceptibility to systemic cytotoxic therapy may be inherently different compared to treatment-naïve patients with primary or “de novo” MIBC.

Level 1 evidence from randomized trials attributes a 5-7% survival advantage 5-years post radical cystectomy for patients treated with neoadjuvant chemotherapy. The therapeutic efficacy of neoadjuvant chemotherapy in secondary MIBC after BCG failure has been characterized by conflicting results from single institution series.

Dr. Pietzak and his colleagues had investigated biologic differences in tumors induced by BCG which could account for differing response to cisplatin. In a 2017 European Urology publication, they identified that alterations in ERCC2, a DNA damage response element involved in nucleotide excision repair, is associated with favorable recurrence-free survival compared with wildtype ERCC2. This formulated the hypothesis that mutations in DNA damage response genes lead to higher tumor mutational burden and portend therapeutic sensitivity to BCG. They then hypothesized that BCG treatment places selection pressure on tumors to express ERCC2 wildtype clones which may contribute to cisplatin resistance.

The investigators interrogated these hypotheses in a 2019 European Urology publication in which secondary MIBC patients exhibited worse outcomes with neoadjuvant chemotherapy. Secondary MIBC tumors were characterized by a relative paucity of cisplatin-sensitizing ERCC2 alterations (0% in secondary tumors compared to 17% in primary MIBC).

The first Aim of Dr. Pietzak’s YIA proposal was to prospectively validate these findings and further characterize both germline and somatic ERCC2 gene alterations in secondary MIBC. Prospective validation was performed in an intent-to-treat cohort using the MSK-IMPACT sequencing platform.

Indeed, the investigators observed lower incidence of ERCC2 gene alterations in secondary MIBC tumors compared primary MIBC, consistent with their initial hypothesis. These findings are incorporated into the Alliance A031701 bladder preservation trial, amongst others, which stratify patients to bladder preservation if they achieve pathologic downstaging and express sensitizing DDR mutations, including ERCC2.

In a recently published Clinical Cancer Research report, Dr. Pietzak and his colleagues characterized germline mutations in 214 MSKCC patients with NMIBC. They identified pathogenic or likely pathogenic germline mutations in 10% of patients, with the vast majority being mutations in DNA damage response genes. These germline mutations were exclusive to high-grade tumors. They were, however, not predictive of BCG therapeutic response.

The investigators further studied the tumor immune microenvironment as it relates to BCG therapeutic response. In a recent Clinical Cancer Research publication, they performed molecular characterization of NMIBC. While UROMOL molecular subtype was not predictive of BCG response, the tissue microenvironment was a promising predictive biomarker, with the possibility of therapeutic targeting of immunologically “cold” tumors to modulate sensitivity to BCG.

While others have descriptively investigated differences in neoadjuvant chemotherapy response prior to radical cystectomy between primary and secondary MIBC, Dr. Pietzak and his colleagues have described a compelling biologic difference in cisplatin-sensitizing DNA damage response gene alterations. These findings provide insight into BCG therapeutic response and genetic alterations induced by BCG therapy, and have significant clinical applicability as we tailor sequencing of definitive therapy in these distinctly different patient populations.

Presented by: Dr. Eugene Pietzak, MD a urologic oncologist at the Memorial Sloan Kettering Cancer Center in Manhattan, NY

1. Pietzak EJ, Bagrodia A, Cha EK, Drill EN, Iyer G, Isharwal S, Ostrovnaya I, Baez P, Li Q, Berger MF, Zehir A, Schultz N, Rosenberg JE, Bajorin DF, Dalbagni G, Al-Ahmadie H, Solit DB, Bochner BH. Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. Eur Urol. 2017 Dec;72(6):952-959. doi: 10.1016/j.eururo.2017.05.032. Epub 2017 Jun 3. PMID: 28583311; PMCID: PMC6007852.
2. Hensley PJ, Bree KK, Campbell MT, Alhalabi O, Kokorovic A, Miest T, Nogueras-Gonzalez GM, Gao J, Siefker-Radtke AO, Guo CC, Navai N, Dinney CP, Kamat AM. Progression of Disease after Bacillus Calmette-Guérin Therapy: Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy. J Urol. 2021 Nov;206(5):1258-1267. doi: 10.1097/JU.0000000000001943. Epub 2021 Jun 29. PMID: 34184926.
3. Pietzak EJ, Zabor EC, Bagrodia A, Armenia J, Hu W, Zehir A, Funt S, Audenet F, Barron D, Maamouri N, Li Q, Teo MY, Arcila ME, Berger MF, Schultz N, Dalbagni G, Herr HW, Bajorin DF, Rosenberg JE, Al-Ahmadie H, Bochner BH, Solit DB, Iyer G. Genomic Differences Between "Primary" and "Secondary" Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy. Eur Urol. 2019 Feb;75(2):231-239. doi: 10.1016/j.eururo.2018.09.002. Epub 2018 Oct 2. PMID: 30290956; PMCID: PMC6339572.
4. Pietzak EJ, Whiting K, Srinivasan P, Bandlamudi C, Khurram A, Joseph V, Walasek A, Bochner E, Clinton T, Almassi N, Truong H, de Jesus Escano MR, Wiseman M, Mandelker D, Kemel Y, Zhang L, Walsh MF, Cadoo KA, Coleman JA, Al-Ahmadie H, Rosenberg JE, Iyer GV, Solit DB, Ostrovnaya I, Offit K, Robson ME, Stadler ZK, Berger MF, Bajorin DF, Carlo M, Bochner BH. Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer. Clin Cancer Res. 2022 Jul 14:ccr.22.1006. doi: 10.1158/1078-0432.CCR-22-1006. Epub ahead of print. PMID: 35833951.
5. Damrauer JS, Roell KR, Smith MA, Sun X, Kirk EL, Hoadley KA, Benefield HC, Iyer G, Solit DB, Milowsky MI, Kim WY, Nielsen ME, Wobker SE, Dalbagni G, Al-Ahmadie HA, Olshan AF, Bochner BH, Furberg H, Troester MA, Pietzak EJ. Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer. Clin Cancer Res. 2021 Aug 15;27(16):4599-4609. doi: 10.1158/1078-0432.CCR-21-0205. Epub 2021 Jun 11. PMID: 34117034; PMCID: PMC8416390.