Teaching pack: Diagnostics & Biomarkers

Pathology and immunohistochemistry remain the foundation. Layered on top: comprehensive genomic profiling (DNA and RNA), liquid biopsy for circulating tumour DNA, minimal residual disease monitoring, multi-cancer early detection, spatial and single-cell profiling, and AI read-outs of slides and scans.

• Active surveillance: For low-risk prostate cancer, monitoring with PSA, MRI, and repeat biopsy instead of treating, because most such cancers never cause harm.
• BH3 profiling (functional apoptosis testing): A lab test that measures how close a leukaemia cell is to self-destructing, and which survival protein is holding it back, to predict response to venetoclax-type drugs.
• Biobanking and tissue procurement: Freezers full of consented tumour samples with matched clinical data, which every biomarker and drug programme depends on.
• Breath and volatile-organic-compound detection: Smelling cancer: measuring the trace chemicals a tumour puts into exhaled breath.
• Cancer variant knowledgebases and molecular tumour boards: Curated databases that say what each mutation means for treatment, and the expert meetings that use them to decide on therapy.
• cfDNA fragmentomics: Fragmentomics reads the sizes and positions of DNA fragments in blood, not the mutations. Cancer cells die messily and leave a recognisable fragmentation pattern.
• Circulating tumour HPV DNA (ctHPV-DNA): A blood test that detects fragments of the virus DNA shed by HPV-positive throat cancers, to confirm diagnosis, track response, and catch recurrence early.
• Clinical NGS bioinformatics and variant interpretation: Software that turns raw sequencer output into a report of which mutations matter and which drugs they point to.
• Companion diagnostics: The test that decides whether a specific drug is right for you, approved together with the drug.
• Comprehensive genomic profiling: Sequencing hundreds of cancer genes at once from a biopsy to find the mutations a drug can target.

• TAILORx (phase 3, n=10,273): Invasive disease-free survival at 9 years (RS 11-25): 83.3% vs 84.3%, HR 1.08
• IMvigor011 (phase 3, n=761): Disease-free survival (ctDNA-positive, randomised): 9.9 months vs 4.8 months, HR 0.64
• SANO (phase 3, n=274): Overall survival at 2 years (non-inferiority): pending
• SERENA-6 (phase 3, n=315): Progression-free survival: 16 months vs 9.2 months, HR 0.44
• PRECISION (phase 3, n=500): Detection of clinically significant cancer: 38% vs 26%
• NHS-Galleri (phase 3, n=142,000): Stage III–IV incidence, 12 prespecified cancers (primary): Not met: no statistically significant reduction within one year of the last screen; a fall in stage IV was offset by a rise in stage III.

1. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
2. What is the first FDA-cleared AI pathology tool that predicts treatment benefit, and in which cancer?
   Answer

   ArteraAI Prostate (de novo authorisation, August 2025) predicts prognosis and benefit from short-term androgen deprivation with radiotherapy in localised prostate cancer.
3. What was the first cancer drug approved on the basis of a blood test for leftover disease?
   Answer

   Atezolizumab for ctDNA-positive muscle-invasive bladder cancer after cystectomy (IMvigor011, using Signatera), approved Q2 2026; DFS HR 0.64, OS HR 0.59.
4. Can a blood test decide who needs chemotherapy after colon cancer surgery?
   Answer

   Yes in stage II: the DYNAMIC trial used ctDNA to guide adjuvant chemotherapy, halving its use (15% vs 28%) with non-inferior recurrence-free survival (93.5% vs 92.4% at two years).
5. What is the Galleri test and where does it stand with the FDA?
   Answer

   GRAIL's methylation-based multi-cancer early detection blood test for more than 50 cancers; PMA submitted January 2026 on PATHFINDER 2 and NHS-Galleri data, FDA advisory committee 23 September 2026. NHS-Galleri missed its primary stage III-IV reduction endpoint (stage IV fell ~14%).
6. What is positive predictive value and why does it matter for a cancer screening blood test?
   Answer

   The chance that a positive result is truly cancer. With a low-prevalence disease even a highly specific test yields many false positives; Galleri's PPV in PATHFINDER 2 was around 40-60%, so roughly half of positives lead to a diagnostic workup that finds no cancer.