Genomics May Provide New Insight Into Bladder Cancer Treatments

Genomics May Provide New Insight Into Bladder Cancer Treatments

Dr. David J. McConkey speaks during the Education Session “Expanding the Actionable Landscape: Bladder Cancer Genomics.”
Dr. MinYuen Teo speaks during the Education Session “Expanding the Actionable Landscape: Bladder Cancer Genomics.”
In patients with upper tract urothelial carcinoma (UC) or who have early onset bladder cancer, screening for Lynch syndrome and germline testing is highly recommended, according to panelists at the Clinical Science Symposium “Expanding the Actionable Landscape: Bladder Cancer Genomics,” on June 2.

The session featured four abstracts on the genomic revolution in bladder cancer, for which David J. McConkey, PhD, of Johns Hopkins School of Medicine, served as the discussant.

MinYuen Teo, MB, MRCP, of Memorial Sloan Kettering Cancer Center, discussed Abstract 4509, which found that DNA damage repair (DDR) gene alterations appear to be associated with overall response to PD-1/PD-L1 blockade of 72% and improved progression-free survival (PFS) and overall survival (OS).

“DDR alterations were seen in 49% of patients, and deleterious DDR alterations were seen in 27.5% of the patients,” Dr. Teo said.

The retrospective study included prospectively treated patients from three separate immunotherapy clinical trials, with the primary endpoint of objective response rate based on RECIST criteria and secondary endpoints of PFS and OS. Of the potential 51 patients for analysis, 44 (86.3%) were male, 37 (72.5%) had their primary tumor in the bladder, and 39 (76.5%) harbored visceral metastatic disease.

Half of the patients harbored DDR alterations, with a total of 73 mutations among them; 14 of those patients had deleterious DDR alterations, with a total of 24 mutations among them.

“DDR alterations are associated with PD-1/PD-L1 blockade response,” Dr. Teo said. “DDR alterations were associated with more responses at 72%, and the presence of deleterious DDR was also associated with a higher response rate at 78.6%.”

The presence of any DDR alteration was strongly associated with superior PFS (hazard ratio [HR] 0.27, 95% CI [0.13, 0.57]; p < 0.001) and OS (HR 0.30, 95% CI [0.13, 0.70]; p < 0.001); the median was not reached for patients with DDR alterations. For deleterious DDR alterations, a large effect size with HR in the range of 0.4 to 0.5 was observed, favoring superior PFS (HR 0.42, 95% CI [0.17, 1.03]; p = 0.058) and OS (HR 0.49, 95% CI [0.18, 1.29]; p = 0.129).

Cancer-Predisposing Germline Mutations

Dr. Maria I. Carlo speaks during the Education Session “Expanding the Actionable Landscape: Bladder Cancer Genomics.”
Germline genetic mutation prevalence is substantially higher than expected in patients with UC, Maria I. Carlo, MD, of Memorial Sloan Kettering Cancer Center, said during her presentation of Abstract 4510. Further, mismatch repair (MMR) and DDR are the most frequent mutations and may have a role in the pathogenicity of the disease.

In their analysis of 113 patients with UC seen in genitourinary medical oncology or urology, the group performed next-generation sequencing of both somatic and germline DNA using the Clinical Laboratory Improvement Amendments–certified MSK-IMPACT platform covering at least 341 genes. In these patients, the primary malignancy site was bladder/urethra (67%), upper tract (31%), or both/unknown (2%). No mutations were found in 78%, but of the 22% with germline mutations, most were high penetrance (> 60%) and “are mostly in DDR genes other than mismatch repair,” Dr. Carlo said. Of those patients with mutations, 11% had early-onset disease (younger than age 45 at diagnosis).

The group then evaluated loss of heterozygosity (LOH) in patients with germline DDR mutations and found LOH in tumors in 25% of cases.

The American College of Medical Genetics and Genomics (ACMG) and National Comprehensive Cancer Network (NCCN) currently do not have recommendations for genetic screening in bladder primaries or Lynch-associated cancer recommendations for renal pelvis/ureter primaries.

“This is a striking finding,” Dr. Carlo said. “Current ACMG and NCCN genetic testing criteria would miss 50% of cases,” as 83% of the moderate-penetrance genes and 25% of the high-penetrance genes would not meet testing criteria.

Dr. Gopa Iyer speaks during the Education Session “Expanding the Actionable Landscape: Bladder Cancer Genomics.”

MMR Detection

An MSI-Sensor score of 10 or more has a predictive value of greater than 90% for MMR-deficient (MMR-D) UC using the MSK-IMPACT, and these patients have a “very high likelihood” of Lynch syndrome, Gopa Iyer, MD, of Memorial Sloan Kettering Cancer Center, said (Abstract 4511). Almost 11,000 tumors containing high mutation burden have been identified across cancers, including bladder cancer, according to Dr. Iyer, and of those tumors, 13% have an MMR deficiency signature.

The MMR pathway corrects base mismatches that occur during DNA replication; microsatellite instability (MSI) is a diagnostic hallmark of MMR-D tumors, Dr. Iyer said. MMR deficiency can predict response to immune checkpoint blockade (ICB). As such, the goal of this study was to define the mutation burden and response to ICB among patients with MMR-D UC.

In this analysis of 424 patients, 337 (79%) were diagnosed with bladder 
cancer, and 87 (21%) with upper tract UC; 25% had been treated with ICB. The MSI-Sensor score assessed the number and length of microsatellites within targeted sequencing regions. The score determines the fraction of unstable sites in a tumor compared with the number of normal sites. An MSI-high score was defined as 10 or higher, an MSI-indeterminate score as 3 to 10, and an MSI-stable score as less than 3.

“A high MSI-Sensor score is associated with an increased mutation burden,” Dr. Iyer said. Further, the MSI-Sensor score is associated with Lynch syndrome. Patients with an MSI-high score all had disease responses to immunotherapy; three patients with Lynch syndrome had disease responses to ICB.

“Although rare, MMR-D UC is characterized by a high mutation load, strong association with Lynch syndrome, and durable responses to ICB, similar to what we have found in colon cancer,” Dr. Iyer continued. He recommends patients with an MMR-D signature be genetically tested for Lynch syndrome, and that ICB be considered in the early treatment course of patients with MMR-D metastatic UC.

The data suggest that “MSI-high UC is chemotherapy-resistant yet exquisitely sensitive to ICB,” Dr. Iyer said.

Subclonal Mutational Heterogeneity and Survival

Dr. David Liu speaks during the Education Session “Expanding the Actionable Landscape: Bladder Cancer Genomics.”
Intratumoral heterogeneity can be used to predict survival in some patients with cisplatin-resistant muscle-invasive bladder cancer (MIBC) and could potentially identify a high-risk subset of patients who might benefit from more aggressive intervention, according to David Liu, MD, MS, MPH, of Dana-Farber Cancer Institute, who presented Abstract 4512. This may be particularly true for post-treatment patients.

Outcomes for patients with MIBC treated with neoadjuvant cisplatin-based chemotherapy are mixed, with a complete response between 30% and 40% and a residual resistance of 60% to 70%.

Because tumor heterogeneity already is associated with survival in other contexts, Dr. Liu asked if genomic features could be used to risk-stratify patients with resistant disease. His group sequenced and analyzed tissue from 30 patients with chemotherapy-resistant MIBC pre- and post-treatment with neoadjuvant cisplatin-based chemotherapy.

Matched pre- and post-treatment tumor samples were obtained from 30 patients who had gross residual disease (< pT2) at cystectomy.

An increased proportion of subclonal mutations in post-treatment tumors was associated with worse OS (HR 1.86, 95% CI [1.12, 3.06]; p = 0.036), and the pre-treatment proportion of subclonal mutations was only borderline statistically significant (HR 1.48, 95% CI [0.99, 2.20]; p = 0.088). In addition, the total number of inferred tumor subclones in pre- or post-treatment tumors (or both) was associated with OS (HR 1.60; 95% CI [1.05-2.43]; p = 0.004).

Dr. Bishoy Faltas speaks during the Education Session “Expanding the Actionable Landscape: Bladder Cancer Genomics.”
“This means that each 10% increase in subclonal [proportion] is associated with a 6% increase in mortality,” Dr. Liu said. “Interestingly, pre- and post-treatment heterogeneity are not statistically significantly correlated, suggesting that both pre- and post-treatment heterogeneity provide prognostic information.” The number of subclones is associated with OS as well. Each additional subclone is associated with a 60% increase in mortality rate, he said.

Specifically, the researchers observed amplification of cell-cycle–related genes (E2F3, JUN) in a resistant post-treatment tumor, but also observed biallelic loss of FBXW7 in a resistant post-treatment tumor, and amplification of a chromosomal segment containing PD-L1/PD-L2/JAK2 in a resistant post-treatment tumor “that may have existed in a pre-treatment subclone,” Dr. Liu said.

Looking to the Future

Discussant Bishoy M. Faltas, MD, of Weill Cornell Medicine, said the four presentations can be discussed in terms of their germline mutation and somatic mutation findings. With those findings, the questions become about the relationship between germline mutations and UC, whether somatic mutations can predict a response to immunotherapy in UC, and whether tumor heterogeneity can shape the response to systemic therapy. The somatic mutation rate is almost two orders of magnitude higher than the germline mutation rate, he said.

“This speaks to the privileged status of germline genomic integrity and the great lengths to which an organism will go to protect germline DNA from mutations,” he said. “UC tumor heterogeneity and evolution are major biologic barriers to durable clinical responses.”

Calling the future “bright” for bladder cancer research, Dr. Faltas said now is “the first time in almost 30 years where we’ve hit the trifecta—new insights lead to more effective therapies, new therapies lead to improved clinical outcomes, and new investigations, like those presented here today, lead to more innovation.”

–Michelle Dalton, ELS