Biomarkers may be predictive of patient response to bladder cancer treatments

“Our work indicates that these genetic signatures may prove to be tremendously valuable in predicting immunotherapy response in patients with bladder cancer, but also other tumor types," says Dan Theodorescu, MD, PhD.

Investigators from Cedars-Sinai Cancer Center in Los Angeles, California have implicated DDR1 and DDR2 genetic biomarkers in determining whether patients with bladder cancer will respond to anti-PD-1 and PD-L1 immune checkpoint therapies (ICTs).1

A prior study from Theodorescu et al found that DDR2 contributed to anti-PD-1 resistance in animals with various types of cancer.2 For the current study, investigators looked at the DDR gene family again, but in human participants, by analyzing mRNA expressions and gene signatures.

“Our work indicates that these genetic signatures may prove to be tremendously valuable in predicting immunotherapy response in patients with bladder cancer, but also other tumor types. We will continue investigating these biomarkers with the goal of bringing them into clinical use and improving patient outcomes,” senior author Dan Theodorescu, MD, PhD, the director of Cedars-Sinai Cancer Center, said in a news release about the results.3

The study authors investigated the impact of DDR1 and DDR2 on patients with bladder cancer receiving anti-PD-1/L1 immunotherapy by analyzing mRNA expressions of the biomarkers and deriving gene signature scores from transcriptome analysis. The mRNA expressions and gene signature scores were then evaluated using 2 different datasets: BCa The Cancer Genome Atlas (TCGA) program (n = 259) and the IMvigor210 clinical trial (NCT02951767) (n = 298).

Study findings showed that DDR2-high BCa had indications of a T-cell-inflamed phenotype, whereas DDR1-high BCa exhibited a non–T-cell-inflamed phenotype. Tumors with a high level of DDR1 or DDR2 in the IMvigor210 cohort had poor rates of overall survival (OS), but high DDR2 levels indicated a poorer rate of OS (HR = 1.56 95% CI, 1.20-2.06, P < .001) and progression-free survival (HR = 1.77 95% CI, 1.05-3.00, P = .047).

The DDR1 and DDR2 markers were found to be mutually exclusive. Further, high DDR1 tumors were found to be “cold,” meaning they block immune cells from infiltrating, and high DDR2 tumors were found to be “hot,” meaning that immune cells are usually able to infiltrate to the core of the tumor.

Investigators also found an association between 4 gene signatures modulated by DDR1 and DDR2 biomarkers and a response to immunotherapy in patients with cancer.

“We found that these gene signatures were clearly associated with response to immunotherapy in bladder cancer and lung cancer tumors in multiple patient groups,” said first author Sungyong You, PhD, a computational biologist at Cedars-Sinai Cancer Center.

According to Theodorescu, the next step would be to validate the findings in a prospective clinical trial. “This could yield new tools that allow clinicians to determine pre-treatment whether given patients will likely respond to anti-PD-1/PD-L1 therapy. They can then proceed with anti-PD-1/PD-L1 therapy for those patients who will derive the most benefit, and offer alternative therapies for patients not likely to respond, improving outcomes for all,” Theodorescu said.

References

1. You S, Kim M, Hoi XP, et al. Discoidin domain receptor-driven gene signatures as markers of patient response to anti-PD-L1 immune checkpoint therapy. J Natl Cancer Inst. Published online August 3, 2022. doi:10.1093/jnci/djac140

2. Tu MM, Lee FYF, Jones RT, et al. Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy. Sci Adv. 2019;5(2):eaav2437. doi:10.1126/sciadv.aav2437

3. Genetics may predict bladder cancer immunotherapy response. News release. Cedars-Sinai. August 3, 2022. Accessed October 6, 2022. https://www.newswise.com/articles/genetics-may-predict-bladder-cancer-immunotherapy-response?sc=sphr&xy=10016681