Vivek Subbiah, Chief of Early-Phase Drug Development at the Sarah Cannon Research Institute, shared a post on X:
“Pleased to share our paper published in Journal of Clinical Oncology ASCO.
Please read the paper and tweetorial +share your thoughts
THREAD: Is It Time to Retire the Unified Cancer of Unknown Primary Concept in the Precision Oncology Era?
Our new commentary challenges a 50-year-old paradigm. Here’s why CUP isn’t one disease, it’s many:
CUP accounts for 2-5% of metastatic cancers. For decades, we’ve treated it as one disease: aggressive, unpredictable, treatment-resistant.
But here’s the problem: this classification was born from diagnostic limitations, not biological understanding.
Molecular profiling has shattered this myth. Gene expression studies identify putative primary sites in 80-90% of CUP cases. NGS reveals actionable mutations in 30-40%. These aren’t random—they mirror patterns in lung, GI, breast, ovarian cancers with KNOWN primaries.
The clinical evidence is compelling: Standard platinum-based chemo: 20-35% response rate, 9-12 months OS Molecularly-guided therapy: 35-55% response rate, >15 months OS We’re not dealing with one aggressive disease.
Two landmark trials changed the game:
- FUDAN-001: Gene expression-guided therapy → >40% response rate
- CUPISCO: Molecular profiling vs standard chemo → significant PFS benefit
Both showed what happens when we treat CUP as the heterogeneous entity it truly is.
Immunotherapy exposed the paradox even further: Overall CUP response to checkpoint inhibitors: 15-25% MSI-H/dMMR or TMB-high CUP: 40-50%.
This isn’t a single disease-it’s occult lung, GI, renal, and other cancers, each with different immunotherapy sensitivity.
We propose a new tiered classification:
- Tier 1A: Molecularly defined occult primaries → site-specific therapy
- Tier 1B: Actionable targets → targeted therapy/immunotherapy
- Tier 2: Ambiguous results → biomarker-driven approach
- Tier 3: True orphans → clinical trials
The hierarchy of decision-making:
- Identify actionable mutations and immunotherapy biomarkers
- FIRST Use tissue-of-origin when it expands treatment options
- Empiric approaches ONLY when molecular profiling yields nothing Molecular features, not anatomy, drive therapy.
Critics say: ‘Not all centers have molecular profiling access.’
Our response: Expand access to diagnostics, don’t perpetuate outdated classifications.
The technology exists. The evidence is clear. The question is implementation, not validity.
For patients, this matters deeply. A CUP diagnosis breeds uncertainty and therapeutic nihilism.
A molecularly-informed diagnosis–>even without knowing the anatomic primary–>offers precision, hope, and rational treatment options. We owe our patients this evolution.
CUP forces us to confront what’s true across ALL oncology: molecular heterogeneity transcends organ boundaries. By necessity, not choice, CUP shows us the future–>where biology, not anatomy, defines cancer. Read the full commentary.”
Title: Is It Time to Retire the Unified Cancer of Unknown Primary Concept in the Precision Oncology Era?
Authors: Vivek Subbiah and F. Anthony Greco
You can read the full article in the Journal of Clinical Oncology.
More posts featuring Vivek Subbiah.