Sumanta K Pal1, Guru Sonpavde2, Neeraj Agarwal3, Nicholas J Vogelzang4, Sandy Srinivas5, Naomi B Haas6, Sabina Signoretti7, Bradley A McGregor8, Jeremy Jones9, Richard B Lanman10, Kimberly C Banks10, Toni K Choueiri8. 1. Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Electronic address: spal@coh.org. 2. Division of Hematology & Oncology, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL, USA. 3. Division of Medical Oncology, Department of Internal Medicine, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA. 4. Department of Medical Oncology, Nevada Comprehensive Cancer Center, Las Vegas, NV, USA. 5. Department of Medicine, Stanford University, Stanford, CA, USA. 6. Division of Hematology/Medical Oncology, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. 7. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 8. Department of Medical Oncology, Dana-Farber Cancer Institute/Brigham and Women's Cancer Center, Boston, MA, USA. 9. Department of Cancer Biology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. 10. Department of Medical Affairs, Guardant Health, Inc., Redwood City, CA, USA.
Abstract
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.
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.
Authors: Marco Calandri; Giulia Siravegna; Andrea Veltri; Bruno C Odisio; Steven M Yevich; Giuseppe Stranieri; Carlo Gazzera; Scott Kopetz; Paolo Fonio; Sanjay Gupta; Alberto Bardelli Journal: Eur Radiol Date: 2020-03-19 Impact factor: 5.315