Dharmesh Gopalakrishnan

Next-generation sequencing (NGS) of cell-free circulating tumor DNA and tumor tissue in patients with advanced urothelial cancer: a pilot assessment of concordance

Background Advances in cancer genome sequencing have led to the development of various next-generation sequencing (NGS) platforms. There is paucity of data regarding concordance of different NGS tests carried out in the same patient. Methods Here, we report a pilot analysis of 22 patients with metastatic urinary tract cancer and available NGS data from paired tumor tissue [FoundationOne (F1)] and cell-free circulating tumor DNA (ctDNA) [Guardant360 (G360)]. Results The median time between the diagnosis of stage IV disease and the first genomic test was 23.5 days (0-767), after a median number of 0 (0-3) prior systemic lines of treatment of advanced disease. Most frequent genomic alterations (GA) were found in the genes TP53 (50.0%), TERT promoter (36.3%); ARID1 (29.5%); FGFR2/3 (20.5%), PIK3CA (20.5%) and ERBB2 (18.2%). While we identified GA in both tests, the overall concordance between the two platforms was only 16.4% (0%-50%), and 17.1% (0%-50%) for those patients (n = 6) with both tests conducted around the same time (median difference = 36 days). On the contrary, in the subgroup of patients (n = 5) with repeated NGS in ctDNA after a median of 1 systemic therapy between the two tests, average concordance was 55.5% (12.1%-100.0%). Tumor tissue mutational burden was significantly associated with number of GA in G360 report (P < 0.001), number of known GA (P = 0.009) and number of variants of unknown significance (VUS) in F1 report (P < 0.001), and with total number of GA (non-VUS and VUS) in F1 report (P < 0.001). Conclusions This study suggests a significant discordance between clinically available NGS panels in advanced urothelial cancer, even when collected around the same time. There is a need for better understanding of these two possibly complementary NGS platforms for better integration into clinical practice.

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA

Biomarker‐guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell‐free circulating DNA (cfDNA) next‐generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook

Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC.

Prognostic Factors and Risk Stratification in Invasive Upper Tract Urothelial Carcinoma

Micro‐Abstract Upper tract urothelial carcinoma is a rare disease and most of the treatment guidelines are extrapolated from urothelial carcinoma of the bladder. In this retrospective study, we were able to identify baseline features, treatment patterns, and prognostic factors, which could be used in risk stratification, management decision‐making, and disease‐specific clinical trial design. Background: Upper tract urothelial carcinoma (UTUC) accounts for approximately 5% of all urothelial cancers. Because of similarities in morphology and histology between UTUC and urothelial carcinoma of the bladder, most treatment guidelines used for UTUC are extrapolated from the urothelial bladder carcinoma setting. With the emergence of new treatment modalities, such as immunotherapy, UTUC‐specific prognostic and predictive models are needed. Patients and Methods: A retrospective study of 454 UTUC patients who received surgery at Cleveland Clinic (1995‐2014) was conducted. Univariable and multivariable analysis (MVA) was used to identify independent predictors of progression‐free survival (PFS) and overall survival (OS). Results: Two hundred eighty‐six patients with invasive UTUC were identified with pT1, pT2, pT3, and pT4 in 93 (33%), 51 (18%), 126 (44%), and 16 (6%), respectively. Most patients (76%) had laparoscopic nephroureterectomy, 14% had positive invasive surgical margins, and 22% had multifocal tumors. All patients had urothelial carcinoma as primary histology, 93 of 183 (51%) with available follow‐up data had disease recurrence. Estimated median PFS was 17.2 months (95% confidence interval [CI], 13.1‐39.3). In MVA, pT stage (P = .0005), positive margins (P = .04), and age older than 70 years (P = .002) independently correlated with PFS. Overall, 101 patients (37%) of 272 patients with available data died with estimated median OS of 64.5 months (95% CI, 39.3‐107.4); median follow‐up was 39.5 (range, 0.3‐186) months in patients alive and recurrence‐free at last follow‐up. In MVA, lymphovascular invasion (P = .005), tumor size (P = .0005), age (P = .005), and pT stage (P = .03) independently predicted OS. Using these factors, 3 prognostic groups for PFS and 2 for OS were identified. Conclusion: Clinical‐pathological parameters can be prognostic in UTUC and might inform clinical trial design and decision‐making.

Effect of Switching Systemic Treatment After Stereotactic Radiosurgery for Oligoprogressive, Metastatic Renal Cell Carcinoma

Background We assessed the clinical outcomes of patients with oligoprogressive renal cell carcinoma (mRCC) treated with stereotactic radiosurgery (SRS), stratified by changing or continuing systemic treatment. Patients and Methods Ninety‐five consecutive patients with clear cell mRCC who had undergone SRS to the central nervous system (CNS) or spine during systemic treatment were divided into 3 cohorts: those who continued the same systemic therapy (STAY), those who changed systemic treatment after SRS (SWITCH), and patients with progression outside the SRS sites, who also changed systemic treatment (PD‐SYS). The primary outcome was treatment duration after SRS, defined as the interval between SRS and discontinuation of the current systemic therapy for the STAY group and discontinuation of the first subsequent therapy in the SWITCH and PD‐SYS groups. Results Local control with SRS was achieved in 85% of the patients. The most common systemic treatment at SRS included anti–vascular endothelial growth factor (67%), mammalian target of rapamycin (14%), and programmed cell death protein 1 inhibitors (9%). The median treatment duration for the STAY group was 5.2 months (95% confidence interval [CI], 3.5‐6.9) compared with 5.0 months (95% CI, 4.3‐5.7) for the SWITCH group (P = .549) and 3.1 months (95% CI, 1.7‐4.5) for the PD‐SYS group (P = .07, compared with all other patients). No difference in median overall survival was found for the STAY and SWITCH groups (24.2 vs. 27.1 months; P = .381) but was significantly longer than that for the PD‐SYS group (P = .025). Conclusion The decision to continue the same systemic therapy at SRS to treat CNS or spinal lesions did not compromise the clinical outcomes of patients with oligoprogressive mRCC. Micro‐Abstract Stereotactic radiosurgery (SRS) can be used to treat metastatic renal cell carcinoma (mRCC) when progression involves a limited number of metastases. In the present retrospective study of consecutive patients with oligoprogressive mRCC, the decision to continue with the same systemic therapy after SRS did not compromise treatment duration or overall survival. Medical treatment decisions should be individualized according to tolerance of the existing regimen, progressive disease outside sites of SRS, and patient access to subsequent therapies.

Evaluation of prognostic factors in upper tract urothelial carcinoma (UTUC).

372 Background: UTUC is relatively rare (5-10% of UC). Limited data on prognostic factors is available. Methods: A retrospective study of UTUC patients (pts) who had surgery (1995-2014) at Cleveland Clinic (n = 454) was conducted. Univariable (UVA) and multivariable (MVA) analysis (proportional hazards) with a stepwise selection algorithm (p = .10 and .05, as criteria for entry and retention in the model) was used to identify independent predictors of recurrence-free survival (RFS) and overall survival (OS). Results: 192 pts with invasive high grade UTUC were identified; median age at resection was 72; 69% men. 72% of pts had laparoscopic and 17% open nephrouretectomy, 23% had +ve margins (including bladder/ureter cuff), 22% had multifocal tumor. Median tumor size 3.5 cm (0.2-12); 70% had tumors < 5 cm; 65% pT3, 8% pT4 stage; among pts with lymph node (LN) dissection, 25% had +ve LN. All but 3 pts (2 sarcomatoid, 1 small cell) had primarily UC; 28% mixed UC histology; 40% CIS, 54% confirmed lymphovascular...