Certain tissue biomarkers may predict response to neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer, according to the findings of a study of Swedish patients published in European Urology.
The investigators assessed how molecular subtypes of tumors impact pathologic response and survival in 149 patients receiving preoperative cisplatin-based chemotherapy. In this retrospective study, patients were classified according to tumor transcriptomic profiling and immunostaining. For external validation, they compared a cohort treated with radical cystectomy (RC) alone and public data sets. The team identified an association between molecular subtypes on tissue specimens obtained during transurethral resection of bladder tumor and pathologic complete response (pT0).
Following NAC and RC, patients with genomically unstable (GU) and urothelial-like (UroC) tumors had higher proportions of complete pathologic response (52%) and (31%) compared with those who had basal/squamous subtypes (21%). In addition, GU tumors and UroC tumors were independently associated with 71% and 63% decreased risks for death, respectively, compared with basal/squamous tumors after adjusting for clinical stage.
“This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer,” the authors concluded. “Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.”
In an interview, corresponding author Gottfrid Sjödahl, MD, of the division of urological research and department of translational medicine at Lund University Cancer Center in Lund, Sweden, said, “We had no particular expectations going into this study, but we are encouraged by this indication that molecular subtypes may have a treatment predictive role in the neoadjuvant setting.”
This transcriptomic study is the second largest available in terms of number of patients treated with NAC. The current investigation has advantages over previous studies because of its consecutive design with uniform surgical parameters and inclusion criteria. Another strength was the use of a highly comparable reference cohort treated with RC alone.
“It would be useful to shift from highly selected retrospective to prospective study designs. It would also be very helpful if, like us, future studies applied the consensus molecular classification system for MIBC in addition to any other system,” Dr Sjödahl said.
Urologic oncologist Sam Kaffenberger, MD, of the University of Michigan Rogel Cancer Center in Ann Arbor, noted that NAC has been the standard of care for more than 15 years and it keeps improving in terms of how it is delivered. “However, there is a significant number who don’t respond. So, the ability to better identify the people who need adjuvant chemotherapy would be advantageous,” Dr Kaffenberger said. “Finding ways to better select patients who are at higher risk of benefiting from treatment is important. This paper adds to growing literature to support this.”
Suthee Rapisuwon, MD, a medical oncologist with Medstar Washington Hospital Center and Medstar Georgetown University Hospital in Washington DC, said the jury is still out as to whether the validation cohort in prospective clinical trials will demonstrate a similar benefit. However, there is a great need to avoid the toxicities of chemotherapy in patients who are not likely to benefit from it.
“Incorporation of tumor molecular proofing, both genomic and transcriptomic approaches, as potential biomarkers could serve as both prognostic and predictive markers in localized disease,” Dr Rapisuwon said. “We know that approximately up to 30% of patients who underwent neoadjuvant chemotherapy could have a pT0 disease at the time of cystectomy. This raises the question of which patients would benefit from neoadjuvant chemotherapy enough that their bladder could be spared.”
Having biomarkers to help in selecting the optimal treatment for a given patient would not only lower mortality, but also reduce treatment-related morbidities. Dr Rapisuwon said quality of life is an important factor that must be thoroughly considered. “There has been great enthusiasm in biomarker-driven treatment approaches,” Dr Rapisuwon said. “Previously studies have demonstrated that somatic DNA damage repair alteration is associated with improved outcomes in platinum-based chemotherapy in advanced urothelial cancer.”
Sjödahl G, Abrahamsson J, Holmsten K, et al. Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes. Eur Urol. 2021. Published online November 12, 2021. doi:10.1016/j.eururo.2021.10.035