Selected predictive biomarkers for VEGF inhibitors in the treatment of metastatic RCC as highlighted by Dr. Choueiri are as follows:1
Dr. Choueiri notes that there are several considerations to understand regarding circulating biomarkers. With regards to systemic therapy, for the VEGF-TKI’s it is likely a bit too late to consider biomarkers, however, for immunotherapy, it is not too late to explore biomarkers. A biomarker of interest may be related to the pathway involved and could include plasma proteins, for example, sVEGF, sVEGFR2, and sPDL1. On the other hand, a biomarker may be a measure of disease, for example circulating tumor cells or circulating tumor DNA. Dr. Choueiri suggests that for circulating biomarkers plasma proteins should be used for anti-angiogenic and circulating tumor DNA should be used for immunotherapy.
Work initially presented at the GU ASCO 2020 annual meeting looked at the plasma protein sPDL1 as a potential prognostic biomarker among 91 patients with metastatic RCC treated with nivolumab in the CheckMate 009 trial. Several notable findings from this study included baseline sPDL1 and on-therapy increase in sPDL1 being associated with progressive disease, and tumor PD-L1 not being associated with clinical outcomes. Additionally, there was a disparate association of immune gene expression in sPDL1 compared to tissue PDL1, in that sPDL1 may be produced by different mechanisms (ie. transcriptional versus post-transcriptional).
Perhaps it is possible that liquid biopsies/circulating tumor DNA can identify microscopic disease. In a study led by Dr. Monty Pal and Dr. Choueiri, they assessed circulating tumor DNA profile in a cohort of 220 metastatic RCC patients, and to assess changes across patients receiving first-line and later lines of therapy.2 Genomic alterations were detected in 78.6% of patients, with the most frequent alterations in the overall cohort including TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). The highest disparity in genomic alteration frequencies in post-first-line versus first-line therapies were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%).
As such, increasing p53 and mTOR pathway (eg, NF1, PIK3CA) alterations in post-first-line patients with first-line VEGF-directed therapy may underlie mechanisms of resistance.
Recent work has also assessed the sensitivity of cancer detection for plasma cell-free DNA variant analysis and cell-free methylated DNA immunoprecipitation sequencing in RCC. Lasseter and colleagues found that among 40 metastatic RCC patients, cell-free DNA variant analysis detected 21 candidate variants in 11 patients (28%).3 In 34 metastatic RCC patients undergoing cell-free methylated DNA immunoprecipitation sequencing, cell-free DNA variant analysis identified variants in 7 (21%), while cell-free methylated DNA immunoprecipitation sequencing detected all metastatic RCC cases (100% sensitivity) with 88% specificity in 34 control subjects.
Dr. Choueiri concluded his presentation highlighting ongoing work in his lab and with other collaborators at the Dana Farber Cancer Institute, as well as collaborators at the University of Toronto. This group has developed cell-free methylated DNA immunoprecipitation high-throughput sequencing, which requires <1cc of tissue and 1-10ng of cell free DNA. This technique is able to detect CpG island methylation changes, is tissue and tumor-specific, and is very accurate (92-98% detection rate) and very sensitive.
Presented by: Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md duringthe 2021 European International Kidney Cancer Symposium (EIKCS), April 23-24, 2021
- Sonpavde G, Choueiri TK. Precision medicine for metastatic renal cell carcinoma. Urol Oncol. 2014 Jan;32(1):5-15.
- Pal SK, Sonpavde G, Agarwal N, et al. Evolution of Circulating Tumor DNA Profile from First-line to subsequent therapy in metastatic renal cell carcinoma. Eur Urol. 2017 Oct;72(4):557-564.
- Lasseter K, Nassar AH, Hamieh L, et al. Plasma cell-free DNA variant analysis compared with methylated DNA analysis in renal cell carcinoma. Genet Med. 2020 Aug(8):1366-1373.