Homologous Recombination Deficiency May Be Linked to Bladder Cancer Recurrences

Hristos Kaimakliotis, MD

Hristos Kaimakliotis, MD

Cell cycle progression (CCP) and homologous recombination deficiency (HRD) may be linked to bladder cancer recurrences and pathologic complete responses, according to Hristos Kaimakliotis, MD.

In an interview withTargeted Oncology, Kaimakliotis, assistant professor of urology, Indiana University School of Medicine, discusses a recent study looking at the correlations between CCP and HRD scores and recurrences, the utilization of these scores in other cancer types, as well as the future use of molecular sequencing in bladder cancer.

TARGETED ONCOLOGY:Can you tell us about your recent presentation on cisplatin neoadjuvant chemotherapy in bladder cancer?

Kaimakliotis:

I recently presented data on a study looking at cell cycle progression and homologous recombination assays, along with a mutational analysis of a set of genes that we thought were important drivers in bladder cancer. So essentially looking at the efficacy, or if we could predict the response, of cisplatin neoadjuvant chemotherapy in bladder cancer. There is clinical trial evidence to show that cisplatin is efficacious in bladder cancer, and trying to identify patients who would respond to cisplatin is of great interest.

There is a great push to identify markers to predict cisplatin response, and cell cycle progression and homologous recombination have been implicated in DNA repair pathways. These could also be a predictor of tumor behavior. So we sought to assess the utility of CCP and HRD assays and cisplatin neoadjuvant chemotherapy.

We found that a higher CCP, or cell cycle progression score, and a high homologous recombination deficiency score was associated with pathologic complete responses. The higher the homologous recombination deficiency score, the lower the patient's risk was for recurrence. With regards to mutational analysis, we found that P53 and RB1 mutations were associated with pathologic complete responses, and on a multi-variable analysis when assessing for pathologic complete responses, we found that the most important variable was the RB1 mutation. We adjusted for CCP and HRD scores separately.

With our analysis, assessing the risk of recurrence, we found that homologous recombination deficiency was associated with decreased risk of recurrence even with adjusting for pathologic complete responders. So we believe that RV1 could be used to predict chemosensitivity, and that predictive ability can be improved when adding a CCP or HRD score to the analysis, and perhaps can identify patients who will respond to cisplatin chemotherapy. The homologous recombination assay can then be used to predict the risk of recurrence in patients who have already undergone cystectomy after cisplatin neoadjuvant chemotherapy.

TARGETED ONCOLOGY:Are any of these assays being utilized in any other way now?

Kaimakliotis:

The CCP assay is used and validated in breast and ovarian cancer to predict cisplatin sensitivity. It has also been used in prostate cancer to try and figure out which patients will have more aggressive tumors, or which patients can be placed under active surveillance. Homologous recombination assay is currently being used in breast and ovarian cancer as well to asses the response to cisplatin therapy.

TARGETED ONCOLOGY:What are the next steps in validation?

Kaimakliotis:

We're looking forward to validating prospective patients, and also using a larger assay of genes that have been shown by other researchers to be implicated in cisplatin response. Researchers from Fox Chase have shown that other gene mutations such as ATM and RB1 have been implicated in response, and researchers from MD Anderson have shown that there may be a molecular signature that may be able to predict chemoresistance to cisplatin. So in combination with those, along with the CCP and HRD assay, we look forward to trying to put together a more robust assay to predict response.

TARGETED ONCOLOGY:Do you see molecular sequencing as the future of where bladder cancer is going?

Kaimakliotis: