Differing Von Hippel Lindau Genotype in Paired Primary and Metastatic Tumors in Patients with Clear Cell Renal Cell Carcinoma

In sporadic clear cell renal cell carcinoma (CCRCC), the von Hippel Lindau (VHL) gene is inactivated by mutation or methylation in the majority of primary (P) tumors. Due to differing effects of wild-type (WT) and mutant (MT) VHL gene on downstream signaling pathways regulating angiogenesis, VHL gene status could impact clinical outcome. In CCRCC, comparative genomic hybridization analysis studies have reported genetic differences between paired P and metastatic (M) tumors. We thus sequenced the VHL gene in paired tumor specimens from 10 patients to determine a possible clonal relationship between the P tumor and M lesion(s) in patients with CCRCC. Using paraffin-embedded specimens, genomic DNA from microdissected samples (>80% tumor) of paired P tumor and M lesions from all 10 patients, as well as in normal tissue from 6 of these cases, was analyzed. The DNA was used for PCR-based amplification of each of the 3 exons of the VHL gene. Sequences derived from amplified samples were compared to the wild-type VHL gene sequence (GenBank Accession No. AF010238). Methylation status of the VHL gene was determined using VHL methylation-specific PCR primers after DNA bisulfite modification. In 4/10 (40%) patients the VHL gene status differed between the P tumor and the M lesion. As expected, when the VHL gene was mutated in both the P tumor and M lesion, the mutation was identical. Further, while the VHL genotype differed between the primary tumor in different kidneys or multiple metastatic lesions in the same patient, the VHL germline genotype in the normal adjacent tissue was always wild-type irrespective of the VHL gene status in the P tumor. These results demonstrate for the first time that the VHL gene status can be different between paired primary and metastatic tissue in patients with CCRCC

Meta-analysis on the association of VEGFR1 genetic variants with sunitinib outcome in metastatic renal cell carcinoma patients

VEGFR1 rs9582036 and rs9554320 were previously reported the association with sunitinib progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Hereafter, the association of both single nucleotide polymorphisms (SNPs) with PFS/OS was confirmed in two independent mRCC cohorts. The aim of the current study was to validate the associations of both SNPs with sunitinib outcome in three independent well-characterized cohorts (SUTOX, CCF and SOGUG) including 286 sunitinib-treated mRCC patients, as well as to perform a meta-analysis of current and published data combined. We found that rs9582036 and rs9554320 showed a significant association with sunitinib PFS in the CCF cohort (HR: 0.254, 95%CI: 0.092-0.703; P=0.008 and HR: 0.430, 95%CI: 0.200- 0.927

Association of single nucleotide polymorphisms in IL8 and IL13 with sunitinib-induced toxicity in patients with metastatic renal cell carcinoma

Purpose: Earlier, the association of single nucleotide polymorphisms (SNPs) with toxicity and efficacy of sunitinib has been explored in patients with metastatic renal cel

HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism

Clear cell renal cell carcinoma (ccRCC) is histologically defined by its lipid and glycogen-rich cytoplasmic deposits. Alterations in the VHL tumor suppressor stabilizing the hypoxiainducible factors (HIFs) are the most prevalent molecular features of clear cell tumors. The significance of lipid deposition remains undefined. We describe the mechanism of lipid deposition in ccRCC by identifying the rate-limiting component of mitochondrial fatty acid transport, carnitine palmitoyltransferase 1A (CPT1A), as a direct HIF target gene. CPT1A is repressed by HIF1 and HIF2, reducing fatty acid transport into the mitochondria, and forcing fatty acids to lipid droplets for storage. Droplet formation occurs independent of lipid source, but only when CPT1A is repressed. Functionally, repression of CPT1A is critical for tumor formation, as elevated CPT1A expression limits tumor growth. In human tumors, CPT1A expression and activity are decreased versus normal kidney; and poor patient outcome associates with lower expression of CPT1A in tumors in TCGA. Together, our studies identify HIF control of fatty acid metabolism as essential for ccRCC tumorigenesis

Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma

The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma

Fourth-Line Therapy in Metastatic Renal Cell Carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC)

Background: Fourth-line therapy (4LT) in the treatment of metastatic renal cell carcinoma (mRCC) varies significantly due to the lack of data and recommendations to guide treatment decisions. Objective: To evaluate the use and efficacy of 4LT in mRCC patients. Methods: The International mRCC Database Consortium (IMDC) dataset was used to identify patients with mRCC treated with 4LT. This is a multicenter, retrospective cohort study. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier curves. Patients were evaluated for overall response. The six prognostic variables included in the IMDC prognostic model were used to stratify patients into favorable-, intermediate- and poor-risk groups. Exploratory analyses were performed examining the elderly (>70 years old) and non-clear cell RCC subgroups. Proportional hazards regression modelling was performed adjusting these covariates by IMDC criteria measured at initiation of 4th line therapy. Results: 7498 patients were treated with first line targeted therapy and out of these 594 (7.9%) received 4LT. Everolimus was the most frequently used 4LT (16.8%). Sorafenib, axitinib, pazopanib, sunitinib and clinical trial drugs were also used in >10% of patients. The OS of patients on any 4LT was 12.8 months, with a PFS of 4.4 months. The overall response rate (ORR) was 13.7%. Favorable-risk patients using IMDC criteria (5%) displayed an OS of 23.1 months, intermediate-risk patients (66%) had an OS of 13.8 months and poor-risk patients (29%) had an OS of 7.8 (p 70 years and non-clear cell histology did not impact OS. Our study is limited by its retrospective design. Conclusions: 4LT use appears to have activity in mRCC patients. The IMDC continues to be of prognostic value in the fourth-line setting for OS. This study helps to set a benchmark for response rate and survival for which clinical trials can plan sample size calculations and aim to improve upon

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial

Background The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. Methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatmentnaive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intentionto-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. Findings Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2–34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3–not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55–0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7–18·9] vs 11·1 months [9·1–12·5]; 0·71 [0·60–0·84], p<0·0001). The most frequent (≥10% patients in either group) treatmentrelated grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. Interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19

Importance: Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2). Objective: To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer. Design, Setting, and Participants: This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease. Exposures: Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19. Main Outcomes and Measures: The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching. Results: After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42). Conclusions and Relevance: Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.450