Updated October 2025
Precision Oncology
Genetic Testing and Targeted Therapy in Solid Tumors
Comprehensive genomic profiling (CGP) in advanced solid tumors increases identification of actionable alterations and facilitates matched targeted therapy, improving clinical trial matching and enabling tumor-agnostic strategies. Evidence supports first-line integration of CGP in many metastatic settings, utilization of basket and umbrella trial designs, and broader panels to expand therapeutic opportunities. Real-world data linkage refines prognostic gene discovery and outcomes benchmarking.
Clinical question
How should genetic testing be integrated into the care pathway of patients with advanced solid tumors to optimize selection of targeted therapies and clinical trial options?
GenomicsTargeted TherapyBasket TrialsUmbrella TrialsComprehensive Genomic ProfilingPrecision MedicineSolid Tumors
Key points
First-line CGP can guide therapy in advanced disease
A large cohort supports early CGP to identify clinically actionable variants, increase matched therapy use, and inform trial enrollment [1].
Adaptive trial designs accelerate access
Basket and umbrella trials efficiently test molecularly targeted agents across histologies or subtypes, with regulatory guidance supporting their use [2].
Broader panels expand opportunities
Broad panels identify more actionable alterations than limited assays, increasing chances for matched therapy or trial assignment [6].
Linking genomics to outcomes
Integration of genomic profiles with real‑world clinical data enables survival analyses to prioritize cancer genes and refine precision oncology strategies [5].
Implementing Genetic Testing to Drive Targeted Therapy
Operational steps to integrate comprehensive genomic profiling and translate findings into clinical action.
1
Select the right test and timing
Prioritize first‑line comprehensive genomic profiling (tumor and/or plasma) in metastatic/recurrent solid tumors where targeted options exist. Evidence supports early profiling to maximize matched therapy opportunities [1].
2
Maximize sample quality
Ensure adequate tumor cellularity and recent biopsy; consider reflex liquid biopsy for low-yield tissue or to detect resistance mechanisms. Re-biopsy upon progression to capture emergent drivers.
3
Interpret and tier alterations
Use standardized actionability tiers and consider tumor‑agnostic biomarkers (e.g., MSI‑H, TMB‑high, NTRK fusions) alongside histology‑specific drivers. Broader panels increase detection of clinically actionable variants [6].
4
Match to therapy or trial
Prioritize FDA‑approved targeted agents when on‑label; otherwise, pursue molecularly matched trials (basket/umbrella). FDA guidance supports these designs for efficient evaluation of biomarker‑defined cohorts [2].
5
Leverage data integration
Incorporate real‑world outcomes linked to genomics to refine prognostic expectations and therapy selection where randomized evidence is lacking [5].
6
Reassess and adapt
At progression, repeat profiling to identify resistance mutations or pathway bypass; consider trial enrollment targeting acquired mechanisms.
High‑Value Targets and Clinical Signals in Solid Tumors
Representative examples where genetic testing directly informs targeted therapy or trial selection.
Tumor-agnostic markers
NTRK fusions → TRK inhibitors; durable responses across histologies
MSI‑H/dMMR → immune checkpoint inhibitors
TMB‑high → ICI consideration (context‑dependent)
RET, BRAF V600E in multiple histologies → matched inhibitors via basket trials [2]
Common histology‑specific drivers
NSCLC: EGFR, ALK, ROS1, BRAF V600E, METex14, RET, NTRK, KRAS G12C, HER2
Breast: ERBB2 amplification/mutations, PIK3CA, ESR1, BRCA1/2 (PARP)
CRC: RAS WT for anti‑EGFR, BRAF V600E (combo targeted), MSI‑H
Melanoma: BRAF V600, KIT subsets
GIST: KIT/PDGFRA
Cholangiocarcinoma: IDH1, FGFR2 fusions
Prostate: HRR genes (PARP), MSI‑H
Brain and rare tumors
CGP can recharacterize diagnoses and identify actionable alterations in CNS tumors; supports biomarker‑stratified trials [4]
Reclassification via CGP can alter management trajectories [3]
Pitfalls and limitations
Low tumor purity/old blocks reduce sensitivity; consider liquid biopsy
Variants of uncertain significance are common—avoid overinterpretation
Not all detected alterations are druggable; evidence strength varies
Access and turnaround times can delay decisions; plan early
What the Evidence Suggests
Strength and directionality of current evidence across key domains.
First-line CGP utility
Cohort data show increased identification of actionable drivers and treatment guidance when CGP is used up‑front in advanced solid tumors [1]
Real‑world genomic–outcome linkage strengthens prognostic and therapeutic inference [5]
Broad vs limited panels
Broader panels yield more actionable findings and matched therapy opportunities than limited assays, especially for rare fusions or alterations [6]
Operational Tips for Clinics
Key steps to streamline precision oncology workflows.
1
Build a testing algorithm
Default to CGP for advanced disease; add liquid biopsy reflex. Define histology‑specific minimal markers if CGP unavailable.
2
Create a molecular tumor board
Standardize interpretation, tier evidence, and align on actionable thresholds; track outcomes to build a local learning system [5].
3
Map trials and access
Maintain real‑time lists of basket/umbrella trials and molecular eligibility; preauthorize common targeted agents and testing.
4
Close the loop
Document biomarker, actionability, therapy decision, response, and subsequent resistance findings to inform future care.
References
Source material
Primary literature that informs this article.
First-Line Genomic Profiling in Advanced Solid Tumors for ...
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New clinical trial design in precision medicine
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Tumor diagnosis recharacterization enabled by ...
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Comprehensive genetic profiling and molecularly guided ...
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Insights for precision oncology from the integration of ...
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Broad versus limited gene panels to guide treatment in ...
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Molecular targeted therapy for pancreatic adenocarcinoma
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Multifaceted perspectives of detecting and targeting solid ...
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The Molecular Basis of Cancer and the Development ...
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Personalized medicine: An alternative for cancer treatment
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Molecular profiling of advanced solid tumors and patient ...
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NCT02465060 | Targeted Therapy Directed by Genetic ...
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