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

Written by: Patrick Hensley, MD, Urologic Oncologist at the University of Kentucky (@pjhensley11) with Ashish Kamat, MD, Urologic Oncologist at MD Anderson Cancer Center (@UroDocAsh) during the 2022 Bladder Cancer Advocacy Network Think Tank (#BCANTT22) Wednesday Aug 3 – Friday Aug 5, 2022 


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