Cytoreductive surgery, systemic treatment, genetic evaluation, and patient perspective in a young adult with metastatic renal cell carcinoma
Authors: Edouard H. Nicaise, Ahmet Yildirim, Swapnil Sheth, Ellen Richter, Mani A. Daneshmand, Shishir K. Maithel, Kenneth Ogan, Mehmet A. Bilen, Viraj A. Master
Journal: CA A Cancer Journal for Clinicians (2024)

A man aged 41 years who had a past medical history significant for bilateral lower extremity varicosities and a prior 20-pack-year smoking history reported several days of fatigue to his primary care physician. His family history was notable for metastatic kidney cancer in his father. On laboratory testing, he was anemic (hemoglobin, 11.2 g/dL), with iron studies suggestive of iron-deficiency anemia. He denied any melena, hematochezia, or hematuria and underwent a full workup, including colonoscopy and capsule endoscopy, which were negative for sources of occult bleeding. The patient eventually underwent computed tomography (CT) scans of the chest, abdomen, and pelvis, which demonstrated a large, heterogeneously enhancing right renal mass measuring 9.5 × 8.2 × 6.8 cm with tumor thrombus invasion of the right renal collecting system, right renal vein, and inferior vena cava (IVC) above the hepatic veins. In addition, there was a pulmonary nodule in the left lower lobe measuring 0.8 cm, which was believed to be concerning for metastatic disease and subcentimeter retroperitoneal lymph nodes. One month later, he proceeded with a CT-guided biopsy of the pulmonary nodule at an outside hospital, with pathology revealing metastatic renal cell carcinoma (RCC). The tumor cells were positive for PAX8 and CAIX and negative for TTF1, which were suggestive of clear cell RCC (ccRCC) histology. He proceeded with a fluorodeoxyglucose F18 positron emission tomography (PET) scan for further evaluation, which demonstrated abnormal uptake in the right renal mass, a soft tissue mass in the IVC, and several small pulmonary nodules in bilateral lower lobes. His Eastern Cooperative Oncology Group (ECOG) performance status was 0. The patient was started on nivolumab plus ipilimumab (3 mg/kg and 1 mg/kg every 3 weeks, respectively), both of which are immune checkpoint inhibitors (ICIs), for intermediate-risk, metastatic RCC (according to the International Metastatic Renal Cell Carcinoma Database Consortium [IMDC] risk model) by an outside medical oncology team before presentation at Emory University Hospital. After completing four cycles of combination immunotherapy, the patient was re-evaluated for potential cytoreductive surgery. He underwent magnetic resonance imaging (MRI) of the abdomen and pelvis for presurgical planning, most importantly as it related to the extent of the caval thrombus. The right renal mass was unchanged in size (8.8 × 6.3 × 8.7 cm); however, there was progression of the IVC tumor thrombus up to the right atrium, along with multiple (>10) new arterially enhancing lesions in the liver measuring up to 1.4 cm, compatible with metastasis (Figure 1). Transesophageal echocardiogram showed a large mass in the right atrium originating from the IVC; however, right ventricular size and function were normal, and the left ventricular ejection fraction was 60%. (A,B) T1-weighted, arterial phase and postcontrast magnetic resonance images of the renal mass with supradiaphragmatic TT. (C) This scan also shows multiple enhancing liver metastases. (D) A transesophageal echocardiogram at preoperative admission demonstrates an inferior vena cava TT located 1 cm from the TV and RV, within the RA. RA indicates right atrium; RV, right ventricle; TT, tumor thrombus; TV, tricuspid valve. In April 2022, after a multidisciplinary genitourinary tumor board, the consensus was to proceed with the surgery because >90% of the patient's disease resided within the kidney and thrombus. A cytoreductive right radical nephrectomy and IVC tumor thrombectomy with concurrent right adrenalectomy were performed by a multidisciplinary team of urology, surgical oncology, and cardiothoracic surgery. The kidney measuring >10 cm was excised, and the right renal vein was longitudinally divided, leaving the tumor thrombus transfixed within the renal vein stump and the IVC. Median sternotomy with cardiopulmonary bypass was not performed because the cardiothoracic surgeon determined that it was possible to obtain proximal control of the IVC through an abdominal transdiaphragmatic intrapericardial window. Once the porta hepatis, contralateral renal vein, and proximal and distal IVC were controlled and clamped, the vena cava was opened, and all tumor thrombus was excised and cleared with no evidence of retained thrombus at the end of the case. He was discharged home on postoperative day 14. Final pathology demonstrated ccRCC, nuclear grade 3, measuring 7.6 cm in greatest dimension. The tumor invaded the renal vein and sinus fat with no evidence of tumor necrosis, direct adrenal invasion, sarcomatoid, or rhabdoid features. The thrombus was positive for carcinoma, and the final IVC margin was negative. Pathologic stage classification (the American Joint Committee on Cancer's AJCC Cancer Staging Manual, eighth edition) was pT3cN0 given supradiaphragmatic extension of the IVC tumor thrombus with no metastatic lymph nodes (n = 0 of 8 interaortocaval nodes). His status remained clinical M1 given the known pulmonary metastasis at diagnosis and the evolution of liver metastases. Kidney cancer is the seventh most common malignancy in the United States, with an estimated 81,800 new cases to be diagnosed in 2023, of which 16% and 15% will present with regional lymph node spread or distant metastatic disease, respectively.1 Our patient at the time of surgery demonstrated two unique sites of metastatic disease along with a stable supradiaphragmatic tumor thrombus, in which we decided to proceed with cytoreductive nephrectomy (CN). The role of debulking or CN in patients with metastatic RCC (mRCC) has been widely debated but was initially supported according to four primary observations: (1) the rare, but reported, spontaneous regression of metastatic lesions after nephrectomy2, 3; (2) ex vivo evidence of the primary tumor inducing immune system dysregulation and suppression4-6; (3) poor primary tumor response to historical cytokine therapy (i.e., interferon-α2b [IFN-α2b], interleukin-2)7-9; and (4) two early randomized trials, as discussed below. The earliest major evidence in support of CN was provided by two randomized phase 3 studies published in 2001 (n = 331 participants combined) examining the objective response rate (ORR) and median overall survival (OS) between IFN therapy alone versus upfront CN followed by IFN therapy.10, 11 No difference in the ORR was observed; however, OS was prolonged in a combined analysis (7.8 vs. 13.6 months for IFN alone vs. upfront CN, respectively; p = .002).10, 11 Upfront CN remained the standard of care in appropriately selected patients, although the advent of targeted therapy in mRCC questioned its continued role. The CARMENA study, published in 2018 (ClinicalTrials.gov identifier NCT00930033), concluded that monotherapy with sunitinib, a monoclonal antibody tyrosine kinase inhibitor (TKI) targeting the vascular endothelial growth factor receptor (VEGFR), versus CN was noninferior (OS, 18.4 vs. 13.9 months); however, the study was limited by low accrual (n = 450 of 576 goal enrollment), crossover between treatment arms, failure to receive intended treatment, and greater inclusion of patients who had IMDC high-risk disease and were unlikely to benefit from surgery.12 The SURTIME trial, published in 2019 (ClinicalTrials.gov identifier NCT01099423), sought to determine when CN should occur relative to induction therapy. Limited by low accrual (n = 99 of 458 goal enrollment), the primary analysis included an intention-to-treat, 28-week progression-free rate, which showed no difference between deferred and upfront CN (43% vs. 42%, respectively; p = .61).13 However, the OS hazard ratio (HR) of deferred CN was 0.57 (95% confidence interval [CI], 0.35–0.94) with a median OS of 32.4 versus 15.0 months for upfront CN.13 Despite the limitations, these results suggested that upfront systemic therapy could confer a survival advantage to select patients presenting with mRCC. In 2015, the first ICI received approval for treatment in mRCC, with nivolumab plus ipilimumab becoming frontline treatment in 2018. However, CN decision making was guided by studies featuring earlier or historical classes of therapy. In 2020, Singla et al. used the National Cancer Database to identify surgical candidates diagnosed with metastatic ccRCC who had only received ICI induction.14 Those authors analyzed OS stratified by CN with ICI therapy versus ICI monotherapy. Patients who underwent surgery had significantly better OS (HR, 0.23; 95% CI, 0.15–0.37; median, not reached vs. 11.6 months; p < .001).14 Furthermore, the authors examined the role of upfront versus deferred CN. Of the 221 patients who underwent surgery, 24 received upfront ICI therapy, with one death at the 21-month mark. Notably, there were no differences in the rates of positive surgical margins, readmission, or prolonged length of stay. In addition, two patients with initial clinical stages of cT3a and cT2b achieved a complete pathologic response of the primary tumor, and pathologic downstaging of the primary tumor was observed twice as often with upfront induction.14 By using the IMDC, which is a prospectively maintained retrospective, multicenter database, Bakouny et al. identified 4639 eligible patients with mRCC who were treated with ICI or targeted therapy, with approximately one half of both cohorts having undergone upfront CN.15 In multivariable analyses, CN before treatment initiation was associated with significantly better OS in both the ICI-treated (HR, 0.61; 95% CI, 0.41–0.90; p = .013) and targeted therapy (HR, 0.72; 95% CI, 0.67–0.78; p < .001) groups.15 Although observational, these multicenter studies using comprehensive cancer databases support the contemporary role of CN; however, patient selection and timing remain controversial. In addition, ongoing phase 2 and 3 randomized clinical trials will help provide the strongest evidence that CN provides a survival benefit in the modern era of immunotherapy. There are four ongoing studies (Figure 2: NORDIC-SUN [ClinicalTrials.gov identifier NCT03977571], Cyto-KIK [ClinicalTrials.gov identifier NCT04322955], PROBE [ClinicalTrials.gov identifier NCT04510597], and SEVURO-CN [ClinicalTrials.gov identifier NCT05753839]), which began enrollment between June 2020 to July 2023 and are estimated to end by 2026 to 2027. In sum, they will answer whether CN should remain standard of care in appropriately selected patients with mRCC, and if so, how surgical timing, upfront versus deferred, affects outcomes. Descriptive summary of study designs for ongoing trials examining the efficacy of cytoreductive nephrectomy, including Nordic-Sun (Clinicaltrials.gov identifier NCT03977571), Cyto-KIK (Clinicaltrials.gov identifier NCT04322955), PROBE (Clinicaltrials.gov identifier NCT04510597), and SEVURO-CN (Clinicaltrials.gov identifier NCT05753839). ccRCC indicates clear cell renal cell carcinoma; CN, cytoreductive nephrectomy; ECOG, Eastern Cooperative Oncology Group; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IO, immuno-oncology agent; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; RCC, renal cell carcinoma, RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1; TKI, tyrosine kinase inhibitor; TRAEs, treatment-related adverse events. In 2023, Abel and colleagues proposed the Selection for Cytoreductive Nephrectomy (SCREEN) score as a prognostic model to improve upfront CN selection. By using relevant clinical and radiographic data from 914 patients who underwent upfront CN from 2006 to 2017, those authors identified seven independently predictive variables (three or more metastatic sites, total metastatic tumor burden ≥5 cm, bone metastasis, systemic symptoms, low serum hemoglobin, low serum albumin, and neutrophil/lymphocyte ratio ≥4) of first-year mortality.16, 17 The SCREEN score demonstrated greater predictive accuracy for mortality (area under the curve analysis, 0.76 vs. 0.55) compared with the IMDC model (<1 year from diagnosis to systemic therapy, poor performance status, low serum hemoglobin, high serum calcium, high neutrophil count, and high platelet count).16 In addition, sarcopenia—or low skeletal muscle mass—has become a prognostic factor of interest concerning RCC treatment. Sarcopenia is prevalent in 29%–48% of patients presenting for CN and is associated with receipt of neoadjuvant systemic therapy and higher risk disease.18, 19 The median OS in patients with sarcopenia was significantly reduced (7.0–15.0 months), and the inclusion of systemic markers of inflammation can be further used to risk stratify surgical candidates.18, 19 Given the complicating factor of a supradiaphragmatic caval tumor thrombus with our patient, it is important to discuss the role and timing of cytoreductive surgery and systemic therapy in these scenarios. In a single-site series from 1991 to 2003, 33 patients with mRCC and concomitant tumor thrombus (renal vein, n = 21 [64%]; infradiaphragmatic IVC, n = 10 [30%]; supradiaphragmatic IVC, n = 2 patients [6%]) underwent upfront CN.20 Compared with CN in patients without tumor thrombus (n = 23), there was no difference in median OS (10.6 [tumor thrombus] vs. 12.2 [nonthrombus] months; p = .76); however, the 2-year and 5-year OS rates were 24.1% and 4%, respectively.20 In a more contemporary (2000–2014), expansive, multicenter study, Abel et al. evaluated prognostic factors for OS after CN in 417 patients who had mRCC with venous tumor thrombus. Of these, 122 patients (32%) died within 270 days of surgery, with IVC thrombus above the diaphragm as one of the primary independent factors predictive of worsened OS (9.2 vs. 21.7 months; p = .0165).21 Furthermore, these findings were echoed in a 2019 study analyzing 2736 patients who had mRCC with tumor thrombus from the National Cancer Database.22 In a matched Kaplan–Meier analysis, CN improved the median OS versus nonsurgical management in patients who had a thrombus isolated to the renal vein (HR, 0.43; 24.0 vs. 9.2 months; p < .01) or below the diaphragm (HR, 0.68; 22.3 vs. 11.5 months; p = .03); however, this survival benefit was lost in patients who had a supradiaphragmatic IVC thrombus (HR, 0.58; 13.1 vs. 10.3 months; p = .33).22 In addition, CN was used less frequently with thrombus-level progression (80.0%–69.6%), although patients who had a tumor thrombus were still more likely to undergo CN than those who had mRCC without a concomitant thrombus.22 Cytoreductive surgery for patients who have mRCC with an IVC tumor thrombus below the diaphragm appears to be safe and imparts a survival benefit; however, the management of a supradiaphragmatic thrombus requires further clarification. Rationale for upfront CN in this setting can be attributed to increased concern for a catastrophic tumor thromboembolism resulting in sudden cardiopulmonary collapse. Upfront combination immunotherapy has been shown to significantly reduce tumor volume in up to one third of patients with mRCC, which could be an enticing preoperative option for a supradiaphragmatic tumor thrombus.23 Concerning our patient, he had received four cycles of nivolumab plus ipilimumab before surgery; and, although the tumor thrombus failed to regress, it remained stable without progression or signs of friability leading to acute thromboembolism during 6 months on therapy. He safely underwent CN with a normal perioperative course without a delay in systemic therapy, although the tumor thrombus does become more densely adherent in the IVC with ICI therapy. Tumor thrombus adherence to the intraluminal IVC may be associated with ICI-induced tumor cell necrosis and surrounding fibrosis, which can be identified on final pathology; however, adherence is not always found in thrombi even with a complete pathologic response after neoadjuvant ICI therapy.24-27 This potential consequence is important when discussing surgical options for the patient, primarily with regard to the need for more extensive IVC resection and complex reconstruction with or without cardiopulmonary bypass. Our patient underwent repeat imaging of the chest, abdomen, and pelvis at 6 weeks postoperatively, which demonstrated an increase in the size and number of hepatic metastases in addition to several enhancing metastatic pulmonary nodules. Because of disease progression with ICI combination therapy, subsequent treatment options were discussed. The patient started ICI/TKI combination therapy with lenvatinib plus pembrolizumab (20 mg orally once daily and 200 mg intravenously every 3 weeks) in June 2022. Throughout the combination therapy, the patient experienced grade 1 abdominal pain, grade 2 mouth sores, grade 2 palmoplantar erythrodysesthesia, grade 2 hypothyroidism, and grade 1 fatigue, most likely attributed to new-onset hypothyroidism. This prompted a nutrition consult, and the sores were treated with magic mouthwash containing nystatin, diphenhydramine, and dexamethasone. In September 2022, given progressive fatigue and palmoplantar erythrodysesthesia, lenvatinib was held for a few days with significant improvement. Decision was then made to proceed with a lenvatinib dose reduction to 14 mg instead of 20 mg. In addition, 50 mcg of levothyroxine was also prescribed for hypothyroidism because of an increasing trend in the thyroid-stimulating hormone level. Follow-up imaging in August 2022 and December 2022 demonstrated a partial response, with a decrease in the size and number of pulmonary nodules and stable hepatic metastases. In March 2023, the surveillance scans showed disease progression with increased size of pulmonary nodules; innumerable, new, enhancing liver lesions; and a new acetabular lesion compatible with osseous metastasis. The patient was referred to radiation oncology and completed stereotactic body radiation therapy to the acetabular lesion (30 grays in 10 fractions), in May 2023 with no complications. stereotactic body radiation therapy has demonstrated superiority to standard multifraction radiotherapy for pain management secondary to nonspine osseous metastatic disease.28 In addition, denosumab injections were prescribed to prevent and reduce the risk of skeletal-related events.29 In April 2023, the patient was started on the subsequent therapy option, lenvatinib plus everolimus, which he tolerated with a partial response until disease progression, including new contralateral renal metastases in August 2023. Soon after, he started on a clinical trial evaluating the efficacy of a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Kidney Cancer for subsequent therapy options for relapsed or stage IV ccRCC are dichotomized based on prior therapy received: ICI pretreated or ICI naive.30 The available options for second-line treatment along with supporting evidence are listed in Table 1 for patients who received prior ICI therapy.30-48 Each regimen described has its respective benefits and weaknesses, including the strength of the evidence; however, decision making should first assess individual patient-dependent features. When the patient first progressed after surgery, the decision was made to start him on combination pembrolizumab plus lenvatinib. Given the patient's presenting history, having first received induction therapy at an outside hospital, along with the development of hepatic metastases, the medical oncology team agreed to proceed with lenvatinib plus pembrolizumab. The regimen of lenvatinib plus pembrolizumab was first evaluated in the phase 1/2 study, KEYNOTE-146 (ClinicalTrials.gov identifier NCT02501096), which assessed efficacy and safety in patients who had either treatment-naive or previously treated mRCC. The primary end point, the ORR at week 24, was 72.7% (n = 16; 95% CI, 49.8%–89.3%) for treatment-naive patients, 41.2% (n = 7; 95% CI, 18.4%–67.1%) for previously treated ICI-naive patients, and 55.8% (n = 58; 95% CI, 45.7%–65.5%) for ICI-pretreated patients. In the ICI-pretreated group, the median duration of response was 12.5 months (range, 9.1–17.5 months), and the median OS had not yet been reached, with a median follow-up time of 16.6 months (range, 12.8–20.0 months). Among patients who had previously received ipilimumab plus nivolumab, the reported ORR was 61.5% (n = 24; 95% CI, 44.6%–76.6%). Adverse effect (AE) profiles and rates were similar across cohorts.49 Subsequently, CLEAR, a phase 3, open-label, randomized study (ClinicalTrials.gov identifier NCT02811961), compared lenvatinib plus pembrolizumab or lenvatinib plus everolimus versus sunitinib alone for upfront management in patients who had treatment-naive, metastatic ccRCC.31 The primary end point of the study, PFS, was significantly longer in patients who received lenvatinib plus pembrolizumab (23.9 months) than in those who received lenvatinib plus everolimus (14.7 months) or sunitinib (9.2 months). The secondary end point, OS, was only longer when lenvatinib plus pembrolizumab was compared with sunitinib (HR, 0.66; 95% CI, 0.49–0.88; p = .005).31 These studies established lenvatinib plus pembrolizumab as both a frontline regimen for newly metastatic ccRCC and a recommended option after disease progression with immunotherapy. However, the CONTACT-03 trial (ClinicalTrials.gov identifier NCT04338269) has questioned the subsequent use of immunotherapy in patients previously treated with ICIs. In that study, patients received atezolizumab (PD-L1 antibody) plus cabozantinib versus cabozantinib monotherapy, although, no differences in PFS or OS were observed after a median follow-up of 15.2 months.50 In addition, the ongoing phase I TiNivo-2 trial (ClinicalTrials.gov identifier NCT04987203), which is evaluating tivozanib plus nivolumab versus tivozanib alone in ICI-pretreated patients, will help define the role of immunotherapy in ICI-pretreated patients. After disease progression on immune-targeted and VEGF-targeted therapy, multiple options were considered, including cabozantinib or lenvatinib plus everolimus. Cabozantinib monotherapy had been evaluated in the phase 3 METEOR trial as a second-line option after VEGF-targeted therapy (ClinicalTrials.gov identifier NCT01865747). Compared with everolimus, cabozantinib prolonged PFS (7.4 vs. 3.9 months; HR, 0.51; 95% CI, 0.41–0.62; p < .0001) and resulted in a higher ORR (17% vs. 3%; p < .0001).32, 33, 51 In a phase 2 trial, investigators compared lenvatinib, everolimus, and the combination of these two in patients who had received one prior VEGF-targeted therapy. The primary end point of the study, PFS, was significantly prolonged in those who received lenvatinib plus everolimus compared with those who received everolimus alone (14.6 vs. 5.5 months).34 This provided the supporting evidence for subsequent use in our patient. Although lenvatinib and cabozantinib share similar drug profiles, given the patient's prior treatment response and tolerability with lenvatinib, we agreed to proceed with lenvatinib plus everolimus as opposed to challenging with cabozantinib as a new agent. Currently, there is no direct comparison between cabozantinib and lenvatinib plus pembrolizumab or other options, although one ongoing trial is evaluating lenvatinib plus everolimus versus cabozantinib for second-line or third-line treatment of metastatic ccRCC (ClinicalTrials.gov identifier NCT05012371). Combination therapy with two different drug classes requires tailored management of AEs. In the CLEAR trial, AEs of any grade led to the interruption of lenvatinib, pembrolizumab, or both medications in 78.4% of cases.31 In Figure 3, treatment-related AEs associated with ICI or TKI therapy in mRCC are classified and visualized. The recommended process to evaluate which component of combination therapy is likely responsible is to first hold the TKI and see whether symptoms resolve. Depending on the AE and the severity of the AE, initial management can vary as listed: supportive measures, dose reduction, or holding oral medications and one or more infusion cycles. The timeframe of the AEs can also provide insight when determining the cause. The AEs from TKIs are typically present earlier in the course of treatment, and they tend to be milder compared with the AEs from ICIs. Immune-related AEs commonly have higher grades and often present several weeks after the initiation of treatment.52, 53 To illustrate recommended management, we can take diarrhea as an example because it is the most common AE in patients who receive combination therapy and can be attributed to either ICIs or TKIs.31, 35, 36 Our approach to diarrhea begins with grading and ruling out an infectious etiology. Concomitant symptoms with diarrhea can indicate a causal agent: TKI-related diarrhea often presents with flatulence, bloating, and small, frequent stools; whereas immune-related diarrhea often presents with cramping and watery stools.52 Grade 1 diarrhea can be managed with supportive measures and follow-up; persistent or intolerable diarrhea may require TKI dose reduction. Grade 2 diarrhea requires holding the TKI, oral/intravenous hydration, and close monitoring. If symptoms are persistent or intolerable, then holding the ICI and initiating short-course steroid therapy are reasonable. Grade 3–4 diarrhea will most likely be secondary to immune-related colitis and requires inpatient admission, intravenous steroids, and temporary ICI discontinuation. Our patient experienced hypothyroidism, which could have been induced by either TKI or ICI therapy, and also had palmoplantar erythrodysesthesia; however, these resolved with supplemental levothyroxine and a lenvatinib dose reduction, respectively. No additional grade 3–4 toxicities were reported. Summary of immune checkpoint inhibitor-specific, TKI-specific, and shared adverse events. TKI indicates tyrosine kinase inhibitor. In June 2022, our patient was additionally referred to Genetic and Molecular Medicine to evaluate for an underlying predisposition to the development of RCC given his multiple risk factors (age, disease progression, family history). Early onset kidney cancer is defined as diagnosis at age 46 years or younger, which has been shown to best balance the sensitivity and specificity of identifying an RCC-related genetic syndrome.54 Over the past 20 years, the incidence of RCC in young adults has continued to rise, with an annual percent increase of 5% since 2000 bringing the age-standardized incidence to 0.8 per 100,000 person-years in 2016.55, 56 In addition, there is a greater prevalence of pathogenic germline variants in genes associated with RCC and other cancer predispositions among patients who have early onset kidney cancer.57 Furthermore, Santos et al. and Carlo et al. observed a high prevalence (range, 1.4%–5.5%) of germline mutations, both among patients with locally advanced RCC and among those with mRCC, in RCC-predisposition genes (fumarate hydratase [FH], von Hippel –Lindau [VHL], BRCA1 associated protein-1 [BAP1], succinate dehydrogenase [SDH], and mesenchymal epithelial transition [MET]), especially for non-ccRCC versus ccRCC (11.7% vs. 1.7% [p = .001]; 6.4% vs. 0.4% [p = .0025]).58, 59 Up to 10% of patients with non-ccRCC had a mutation with potential to direct systemic therapy, which suggests a benefit of germline testing in this group.59 Secondary to the patient's age (41 years) and disease progression at presentation, there were clear indications for genetic referral according to a clinical consensus statement and the NCCN Guidelines.30, 60, 61 Table 2 lists the key criteria for genetic testing and counseling in affected individuals along with an overview of hereditary syndromes associated with RCC. Diagnosed at age 46 years or younger Bilateral or multifocal renal masses (synchronous or metachronous) One or more first-degree or second-degree relative with RCC Personal history that suggests a genetic syndrome Tumor with any of the following histologic characteristics: Multifocal papillary HLRCC-associated/FH-associated BHDS-related (multiple chRCC, oncocytoma, or oncocytic hybrid) AML of the kidney and one additional TSC criterion SDH-deficient RCC Because no other findings specific to a hereditary kidney cancer syndrome were present, multicancer panel gene testing was ordered.60, 62 Biomarkers can be crucial when tailoring treatment for patients with cancer, although further investigation is required to identify those pertinent to mRCC, especially among the young adult population. No germline variants were detected, including those associated with RCC syndromes. However, a next-generation sequencing test was also performed, including genetic and immunochemistry testing of primary tumor tissue, which detected multiple pathogenic variants in the VHL (exon 3|p.E186), BAP1 (exon 15|p.N645fs), MTOR (exon 43|p.T1977R), and ARID2 (exon 4|p.N132fs and exon 8|p.S261) genes in our patient. The VHL mutation now carries a therapy association after US Food and Drug Administration approval of the HIF-2α inhibitor belzutifan in 2021 for patients who have neoplasms associated with VHL disease. This decision was based on the phase 1/2 belzutifan (MK-6482; formerly PT-2977) trials, which demonstrated an ORR of 49% in patients who had advanced, pretreated RCC, with only nine patients (15%) experiencing grade 3 treatment-related AEs.37, 38 At the 36-month interim analysis, 62% of patients remained on treatment, with an updated ORR of 64%, a median time to response of 11.1 months, and the median duration of response not yet reached.63 Unfortunately, neither of those studies specified patients who had somatic VHL mutations. However, in the ongoing, open-label, phase 2 LITESPARK-003 study (ClinicalTrials.gov identifier NCT03634540), which is examining belzutifan plus cabozantinib as second-line treatment for all patients w