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Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma
Sumanta K Pal1, Guru Sonpavde2, Neeraj Agarwal3
1Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Background:
Treatment of metastatic renal cell carcinoma (mRCC) typically entails mechanistically distinct agents across the first- and second-line setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile.
Objective:
To assess the ctDNA profile in a large cohort of mRCC patients, and to assess changes across patients receiving first-line and later lines of therapy.
Design, Setting, And Participants:
We obtained the ctDNA profile in mRCC patients who received ctDNA profiling as part of routine clinical care at progression using a 73-gene Clinical Laboratory Improvement Amendments-certified ctDNA platform.
Outcome Measurements And Statistical Analysis:
Genomic alterations (GAs) were pooled for the entire cohort. A comparison of first- and postfirst-line was performed with grouping based on conventional practice patterns (first-line regimens included sunitinib, pazopanib, and bevacizumab, and postfirst-line regimens included everolimus, axitinib, cabozantinib, and nivolumab).
Results And Limitations:
ctDNA clinical results from a nationwide cohort of 220 consecutive patients with mRCC were assessed (145 men, 75 women; median age: 63 yr, interquartile range: 57-70). GAs were detected in 78.6% of patients. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). Thirty-eight and 64 patients were coded as receiving first-line and later line agents, respectively. The highest disparity in GA frequencies in postfirst-line versus first-line were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%) while ARID1A was equivalent (13% vs 11%). Restricting the analysis to later lines versus first-line vascular endothelial growth factor inhibitors, these differences were even more prominent, particularly for TP53 (64% vs 31%) and NF1 (29% vs 4%).
Conclusions:
In the largest assessment of ctDNA-detected GAs prevalence in mRCC to date, the majority of patients demonstrated clinically and biologically relevant GAs. Increasing p53 and mechanistic target of rapamycin pathway (eg, NF1, PIK3CA) alterations in postfirst-line patients with first-line vascular endothelial growth factor-directed therapy may underlie mechanisms of resistance. Routine ctDNA assessment during the clinical course of mRCC patients may have therapeutic implications.
Patient Summary:
Collection of circulating tumor DNA is feasible in patients with metastatic renal cell carcinoma, and analysis of a large cohort demonstrates significant changes in circulating tumor DNA profile across patients' clinical course which may have therapeutic implications.
Insights
Circulating tumor DNA (ctDNA) analysis in metastatic renal cell carcinoma (mRCC) reveals significant genomic alterations, particularly TP53 and NF1, that emerge after first-line therapy. These findings suggest ctDNA monitoring may guide future mRCC treatment strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Metastatic renal cell carcinoma (mRCC) treatment involves distinct first- and second-line agents.
- Tumor genomic profiles evolve under therapeutic selective pressure.
- Circulating tumor DNA (ctDNA) offers a noninvasive method to track these genomic changes over time.
Purpose of the Study:
- To characterize the ctDNA profile in a large cohort of mRCC patients.
- To analyze changes in ctDNA profiles across different lines of therapy.
Main Methods:
- ctDNA profiling was performed on 220 mRCC patients using a 73-gene platform.
- Genomic alterations (GAs) were analyzed and compared between first-line and later-line treatment groups.
- Patients received standard first-line (sunitinib, pazopanib, bevacizumab) or later-line (everolimus, axitinib, cabozantinib, nivolumab) therapies.
Main Results:
- Genomic alterations were detected in 78.6% of mRCC patients.
- The most frequent GAs included TP53 (35%), VHL (23%), and EGFR (17%).
- Post-first-line therapy showed significantly higher frequencies of TP53 (49% vs. 24%) and NF1 (20% vs. 3%) alterations compared to first-line therapy.
Conclusions:
- The study represents the largest assessment of ctDNA-detected GAs in mRCC to date.
- Increasing TP53 and mTOR pathway alterations (e.g., NF1, PIK3CA) post-first-line therapy may indicate resistance mechanisms.
- Routine ctDNA assessment holds potential therapeutic implications for managing mRCC.