Kidney Cancer (Renal Cell Carcinoma)
A "Low Shedder" Tumor: Limited MRD Detection with Selective Genotyping Utility
Clinical Overview
Renal cell carcinoma (RCC) represents approximately 90% of kidney cancers, with clear cell RCC (ccRCC) accounting for 75% of cases. Standard management includes surgical resection for localized disease, with surveillance for recurrence risk. Metastatic RCC is treated with systemic therapies including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and novel agents targeting the HIF-2α pathway (belzutifan).
Critical Challenge: RCC is classified as a "low shedder" tumor, with markedly lower ctDNA detection rates compared to other solid tumors. This biological characteristic fundamentally limits the clinical utility of ctDNA-based MRD detection in RCC, particularly in early-stage disease surveillance.
The "Low Shedder" Problem: Detection Rates by Stage
- Early-stage (pT1a): 20.8% ctDNA detection rate - insufficient for clinical surveillance
- Metastatic disease: 45-79% detection rate (study-dependent)
- Meta-analysis sensitivity: 33% overall - two-thirds of patients undetectable
- Clinical implication: Negative ctDNA result does NOT exclude disease or recurrence
Comparison to "High Shedders": Colorectal and lung cancers achieve 80-90% detection rates in early-stage disease, making RCC fundamentally different for MRD applications.
Why RCC is a Low Shedder: Multiple biological and anatomical factors contribute to poor ctDNA shedding:
- Pseudocapsule barrier: RCC tumors develop a fibrous pseudocapsule that may limit DNA release into circulation
- Hypoxic microenvironment: The hypoxic tumor microenvironment (driven by VHL loss and HIF activation) may reduce cell turnover and DNA shedding
- Low tumor cell turnover: RCC exhibits relatively slow proliferation compared to high-shedding cancers
- Rapid renal clearance: Kidneys continuously filter blood, potentially clearing cell-free DNA before systemic circulation and detection
ctDNA Testing Methodology
Two primary approaches are used for ctDNA detection in RCC, each with distinct workflows and clinical applications:
Tumor-Informed (Baseline-Based) Approach
Workflow: Uses a baseline sample (surgical tissue or pre-treatment blood draw) to identify the patient's specific mutations, then tracks those mutations at follow-up timepoints.
Advantages: Higher sensitivity when ctDNA is present; targeted tracking of known mutations improves detection.
Limitations: Requires baseline tissue or blood sample; still constrained by RCC's inherently low shedding rates.
Tumor-Agnostic (No Baseline) Approach
Workflow: Tests directly at surveillance timepoints without prior baseline profiling, screening for common RCC mutations using fixed gene panels.
Advantages: No tissue required; can be performed at any timepoint; useful when tissue unavailable.
Limitations: Lower sensitivity than tumor-informed approach; must detect mutations "blind" without knowing patient-specific profile.
Critical Reality Check
Both approaches are constrained by RCC's low shedding biology. Even with tumor-informed methods achieving the highest possible sensitivity, the 20.8% detection rate in pT1a disease renders MRD surveillance clinically unreliable for most early-stage patients. The methodology matters less than the tumor biology.
MRD Detection: Clinical Utility and Limitations
Clinical Context: Following surgical resection of localized RCC, approximately 20-40% of patients develop recurrence within 5 years. The question is whether ctDNA can detect recurrence earlier than imaging surveillance (CT/MRI every 3-12 months depending on risk).
Detection Performance: Stage-Dependent Limitations
| Stage | ctDNA Detection Rate | Clinical Utility | Recommendation |
|---|---|---|---|
| pT1a (Small, localized) |
20.8% | Insufficient sensitivity for surveillance | Continue standard imaging surveillance |
| pT1b-pT3 (Locally advanced) |
Variable (limited data) | Likely <40% based on meta-analysis | Imaging remains gold standard |
| Metastatic | 45-79% | Better detection, but still misses 21-55% | May complement imaging; cannot replace |
| Meta-analysis (All stages) |
33% | Two-thirds of patients undetectable | ctDNA negative ≠ no recurrence |
Prognostic Value: When ctDNA is Detected
Despite low detection rates, when ctDNA is detected, it carries strong prognostic significance:
Hazard Ratios for Recurrence (ctDNA+ vs ctDNA-):
- HR 2.9-18.0 for disease recurrence (study-dependent, confidence intervals not consistently reported)
- Interpretation: Detectable ctDNA associates with 2.9 to 18-fold increased risk of recurrence
- Clinical limitation: Wide HR range reflects heterogeneous studies and small sample sizes
- Key problem: High false-negative rate (67% undetectable) limits clinical actionability
Lead Time: Earlier Detection Before Imaging
In patients with detectable ctDNA who develop recurrence, ctDNA can provide advance warning:
- Lead time: 13.6 weeks (3.4 months) before radiographic detection
- Clinical benefit uncertain: Whether 3.4-month lead time improves outcomes is unproven
- Applies to minority: Only relevant for the ~33% of patients with detectable ctDNA
Clinical Limitations: When NOT to Use ctDNA MRD Testing in RCC
ctDNA MRD Testing is NOT Recommended for:
- Early-stage (pT1a) surveillance: 20.8% detection rate too low; continue standard imaging
- Replacing imaging surveillance: ctDNA negative does NOT rule out recurrence (67% false-negative rate)
- Determining adjuvant therapy eligibility: No prospective data showing ctDNA-guided adjuvant decisions improve outcomes
- Stopping imaging in ctDNA-negative patients: Unacceptably high risk of missing recurrence
- As sole monitoring tool: Must always be combined with imaging surveillance, never replace it
ctDNA MRD Testing May Be Considered for:
- High-risk patients (pT3-pT4, node-positive): Higher detection rates in advanced disease; still investigational
- Clinical trial enrollment: Stratification or exploratory endpoints in trials
- Complementary data point: Alongside imaging in metastatic patients on therapy, understanding limitations
Bottom Line: For most RCC patients, imaging surveillance remains the gold standard. ctDNA MRD detection is limited by RCC's low shedding biology and should not replace or reduce standard imaging protocols.
Genotyping: Molecular Profiling for Treatment Selection
Clinical Context: While MRD detection is limited, ctDNA genotyping can provide molecular information to guide treatment selection in metastatic RCC. Multiple therapeutic options now exist (TKI monotherapy, immunotherapy combinations, TKI+immunotherapy, HIF-2α inhibitors), and molecular biomarkers may help optimize treatment choice.
Detection Rates: Plasma vs Tissue
Genotyping also faces detection challenges due to low ctDNA shedding:
| Gene | Tissue Detection | Plasma Detection | Concordance Challenge |
|---|---|---|---|
| VHL | 59% | 18% | Low plasma shedding misses 70% of VHL mutations |
| BAP1 | 10-15% (tissue studies) | 8.7% | Reasonably concordant given low prevalence |
| PBRM1 | 30-40% | Variable (limited data) | Likely under-detected in plasma |
Clinical Implication: Plasma genotyping will miss the majority of VHL mutations and likely underdetect PBRM1. Tissue genotyping remains the gold standard for comprehensive molecular profiling.
1. VHL Mutations: HIF-2α Pathway Targeting
Biological Context: VHL (Von Hippel-Lindau) is the canonical tumor suppressor in clear cell RCC. VHL loss leads to HIF-2α accumulation, driving angiogenesis, proliferation, and the characteristic "clear cell" histology.
VHL Alterations in RCC:
- Prevalence: 80-90% of clear cell RCC harbor VHL alterations (somatic mutations, deletions, or hypermethylation)
- Plasma detection: Only 18% detected in plasma (vs 59% in tissue) - 70% false-negative rate
- Therapeutic target: Belzutifan (HIF-2α inhibitor) shows clinical efficacy in VHL disease-associated RCC
- Current indication: VHL disease (germline VHL mutations) with RCC not requiring immediate surgery
- Future direction: Trials testing belzutifan in sporadic ccRCC with VHL alterations
Clinical Trial Data (Belzutifan):
- Study population: VHL disease patients with RCC, pancreatic, or CNS hemangioblastomas
- RCC objective response rate: 49%
- Response duration: Durable responses (median not reached at time of publication)
- Safety: Anemia (most common adverse event, manageable); generally well-tolerated
Limitation: Low plasma VHL detection (18%) means tissue sequencing is essential for identifying belzutifan candidates. ctDNA genotyping will miss most VHL-altered patients.
Reference: Jonasch et al. N Engl J Med 2021;385:2036-2046
2. BAP1 Mutations: Prognostic and Predictive Biomarker
Biological Context: BAP1 (BRCA1-Associated Protein 1) is a tumor suppressor gene involved in chromatin remodeling and DNA damage repair. BAP1 loss is associated with aggressive disease but paradoxically enhanced immunotherapy response.
BAP1 in RCC:
- Prevalence: 10-15% of clear cell RCC
- Plasma detection: 8.7% (reasonably concordant given low prevalence)
- Prognostic impact: HR 18.88 for worse overall survival (BAP1-mutant vs wild-type)
- Tumor characteristics: Higher grade, more aggressive features, earlier metastasis
- Predictive value: Better response to immunotherapy combinations (nivolumab-ipilimumab, atezolizumab-bevacizumab)
- Mechanism: May create more immunogenic tumor microenvironment with increased immune infiltration
BAP1: Poor Prognosis but Immunotherapy Responsive
The BAP1 paradox illustrates precision oncology principles:
- Prognostic: BAP1 mutations confer dramatically worse outcomes (HR 18.88 for OS) - among the strongest prognostic markers in RCC
- Predictive: Despite poor prognosis, BAP1-mutant tumors show enhanced response to immunotherapy
- Clinical strategy: Identify BAP1-mutant patients as strong candidates for aggressive immunotherapy-based regimens
- Potential mechanism: BAP1 loss may increase neoantigen presentation and T-cell infiltration, creating "hot" tumors
Implication: BAP1 status can guide treatment selection, prioritizing immunotherapy combinations in this high-risk subset.
Reference: Hakimi et al. J Clin Oncol 2013;31:1466-1473
3. PBRM1 Mutations: TKI Sensitivity
Biological Context: PBRM1 (Polybromo-1) is a chromatin remodeling gene frequently mutated in clear cell RCC. PBRM1 status associates with TKI response and may guide first-line treatment selection.
PBRM1 in RCC:
- Prevalence: 30-40% of clear cell RCC
- Prognostic association: PBRM1 mutations generally associated with favorable prognosis
- TKI response: PBRM1-mutant tumors show longer PFS on sunitinib, pazopanib, and other VEGF-targeted TKIs
- Treatment implication: May favor TKI-based approaches over immunotherapy in first-line setting
- Mechanism: May indicate "angiogenesis-driven" tumor biology more responsive to VEGF inhibition
Clinical Application: In the current treatment landscape with multiple first-line options (TKI monotherapy, immunotherapy doublets, combination regimens), PBRM1 status can inform treatment selection. PBRM1-mutant patients may achieve excellent outcomes with TKI monotherapy, potentially sparing immunotherapy-related toxicity.
Reference: Hsieh et al. Eur Urol 2017;71:405-414
4. Tumor Mutational Burden (TMB): Not Validated in RCC
Important Negative Finding: Unlike other cancers where high TMB predicts immunotherapy response, RCC shows a paradoxical pattern:
TMB in RCC: Paradoxical Association
- Counterintuitive finding: Low TMB RCC may respond better to immunotherapy than high TMB RCC
- Hypothesis: RCC immunogenicity may be driven by factors other than mutation burden (e.g., angiogenesis, hypoxia-driven immune modulation)
- Clinical implication: Do NOT use TMB to exclude RCC patients from immunotherapy
- Current status: TMB not validated as predictive biomarker in RCC
Recommendation: TMB testing in RCC should be interpreted with caution and not used to guide treatment decisions.
Clinical Summary
Renal cell carcinoma is a "low shedder" tumor with fundamental biological constraints on ctDNA detection. These limitations must be understood before considering ctDNA testing in RCC patients.
| Application | Detection/Utility | Clinical Recommendation |
|---|---|---|
| MRD: Early-stage (pT1a) | 20.8% detection | NOT recommended - continue imaging surveillance |
| MRD: Meta-analysis (all stages) | 33% sensitivity | Insufficient for clinical use; high false-negative rate |
| MRD: Metastatic | 45-79% detection | Investigational; may complement imaging but cannot replace |
| Prognostic (when detectable) | HR 2.9-18 for recurrence | Strong association, but limited by low detection rate |
| Lead time | 13.6 weeks (3.4 months) | Early detection, but benefit on outcomes unproven |
| VHL genotyping | 18% plasma (vs 59% tissue) | Tissue preferred; misses 70% of VHL mutations in plasma |
| BAP1 genotyping | 8.7% plasma; HR 18.88 worse OS | Strong prognostic marker; identifies immunotherapy candidates |
| PBRM1 genotyping | 30-40% prevalence; TKI sensitivity | May guide TKI vs immunotherapy selection |
Evidence-Based Recommendations
Current Clinical Practice:
- Surveillance: Continue standard imaging protocols; ctDNA cannot replace imaging
- Molecular profiling: Tissue sequencing remains gold standard; plasma genotyping complementary when tissue unavailable
- Treatment selection: Consider BAP1 (immunotherapy) and PBRM1 (TKI) status when available
- Risk stratification: Use established clinical risk scores (UISS, SSIGN); ctDNA not validated for adjuvant decisions
Future Directions:
- Improved detection methods: Ultra-sensitive assays may improve detection rates
- Prospective trials: Needed to determine if ctDNA-guided decisions improve outcomes
- Biomarker refinement: Identifying which RCC subtypes shed more ctDNA
- Multimodal approaches: Combining ctDNA with other biomarkers (CTCs, exosomes, imaging)
Bottom Line: RCC is a "low shedder" with 20.8% detection in pT1a disease and 33% meta-analysis sensitivity across stages. These rates are insufficient for MRD surveillance, and imaging remains the clinical standard. When ctDNA is detectable, it provides prognostic value (HR 2.9-18 for recurrence) and can enable genotyping for treatment selection, but clinicians must understand that negative ctDNA does NOT exclude disease. Molecular profiling is best performed on tissue, with plasma genotyping missing 70% of VHL mutations (18% plasma vs 59% tissue detection). BAP1 mutations (8.7% plasma detection) confer dramatically worse prognosis (HR 18.88 for OS) but predict immunotherapy response, illustrating the potential value of genotyping when ctDNA is detectable. For now, ctDNA in RCC remains investigational, with limited clinical utility outside research settings.
References
- Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med 2021;385:2036-2046.
- Hakimi AA, Ostrovnaya I, Reva B, et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res 2013;19:3259-3267.
- Hsieh JJ, Chen D, Wang PI, et al. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol 2017;71:405-414.
- Pal SK, Sonpavde G, Agarwal N, et al. Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Eur Urol 2017;72:557-564.
- Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol 2020;17:271-291.
- Belderbos BPS, Hijmering-Kappelle JM, Grunwald V, et al. Low prevalence of circulating tumor DNA in early-stage clear cell renal cell carcinoma. Eur Urol Oncol 2021;4:975-978.
Evidence summary as of January 2026 | Document Version: 2.0