How We Approach Complex Cases
A step-by-step walkthrough of the structured framework we apply to the most difficult molecular cases, so you know exactly what you're getting — and why — before you submit.
A tumor's molecular profile is often clear and clean; most of the time, the report and the decision line up. The hard cases are the ones where they don't.
A driver alteration with no matched drug. Findings that conflict across tests. A low variant allele frequency where it's unclear whether it's signal or noise. A rare fusion the report flags but doesn't put in context. A profile that quietly changes the diagnosis itself. These are the cases where a structured second opinion matters most — not because the test was wrong, but because interpreting what to do next is where clinical judgment lives. This page explains exactly how we work through such a case step by step, so you know what you're getting before you submit.
Complex cases are not solved by intuition. They are solved by applying the same rigorous sequence to every report, and then layering expert clinical judgment on top of it.
One disciplined framework, every time
Complex cases are not solved by intuition. They are solved by applying the same rigorous sequence to every report, then layering expert clinical judgment on top of it. We do not skip steps because a case looks familiar, and we do not add steps because it looks intimidating.
The framework below is what every case passes through, and it is what produces the structured IYGAS report you ultimately receive.
Seven steps, applied in sequence
The same sequence runs on every report before any conclusion is drawn — from reconstructing the clinical picture to assembling the final deliverable.
1Reconstruct the clinical picture first
Before reading a single variant, we reconstruct the patient's clinical context: tumor type and histology, stage, prior treatment lines and response, current performance status, and the specific question the case is asking.
A molecular finding carries an entirely different meaning in a treatment-naive patient than in one who has progressed through three lines. When key data are missing, we state this explicitly rather than assuming it.
2Reread the molecular data — not just the report summary
A genomic report's front-page summary is a starting point, not a conclusion. We go back to the underlying data and interpret it ourselves:
- VAF and clonality — is an alteration clonal (likely driving the tumor) or subclonal (likely a passenger or an emerging resistant clone)? This distinction changes whether an alteration should be targeted at all.
- Tumor purity — low purity can suppress VAF and cause real alterations to be under-called. We account for this before drawing conclusions.
- DNA versus RNA coverage — some fusions are reliably captured only by RNA-based testing. If the panel design could have missed something clinically important, we flag it.
3Grade every alteration by evidence tier
Every reported alteration is graded using established frameworks (the AMP / ASCO / CAP tiering system), so that the word "actionable" carries a specific meaning rather than functioning as a marketing label.
We separate alterations with strong, tumor-matched evidence from those with weaker, off-label, or purely investigational support, and in the final recommendation we never let a low-evidence finding take precedence over a high-evidence one.
4Build the treatment decision matrix
Once alterations are classified, we match them against the patient's actual treatment situation: what is appropriate now (first line), what should be held in reserve (second line and beyond), and what the sequencing should be.
The goal is a strategy, not a list of mutations. A biomarker with no appropriate matched therapy is documented exactly that honestly: a finding to monitor, not a treatment to chase.
5Assess immunotherapy eligibility and resistance strategy
We evaluate immunotherapy-related signals together rather than in isolation, and we think one step ahead: if a targeted approach is chosen, what is the most likely resistance mechanism, and what does that mean for monitoring and the next line?
Planning for resistance before it emerges is part of the recommendation, not an afterthought.
6Match carefully against clinical trials and off-label opportunities
Where standard options are limited, we identify relevant clinical trials and document credible off-label rationales with their evidence levels stated explicitly.
We are deliberately cautious here: an off-label idea is presented as an option with its supporting evidence stated, never as an established standard.
7Deliver a structured IYGAS report
Everything above is brought together in a single structured report: clinical context, genomic and biomarker profile, VAF/clonality interpretation, tiered classification, treatment decision matrix, immunotherapy and resistance assessments, trial matches, and a clear physician consultation outcome.
The goal is that another oncologist, or a tumor board, can read it and understand not only what we recommend, but why we recommend it.
What makes this different from an automated report?
Commercial genomic profiling answers the question "which alterations are present?" extremely well. The real hard question is not an algorithm's output — it is a piece of clinical judgment:
"Given this particular patient, what should happen next, and why?"
This judgment — applied through a consistent framework and documented transparently — is what we add. When two experts can reasonably reach different conclusions from the same profile, the value lies in making the reasoning visible and defensible.
The cases that benefit most
The cases that benefit most from this approach tend to share a pattern:
- A rare or non-canonical alteration
- Conflicting or ambiguous findings
- A borderline VAF
- A profile that doesn't fit the expected diagnosis
- A patient who has exhausted standard options and needs a reliable next step
If a case feels like it falls between guidelines rather than inside one, a structured second opinion is usually worth the time it takes.
This content is for educational purposes only. It does not constitute individual medical advice and does not replace the judgment of the treating physician.
Submit a case for expert molecular evaluation
NGS Advisory reviews your existing NGS report against current guidelines, clarifies the exact variant and its actionability for your tumor type, and provides a structured, calibrated second opinion.