Teaching pack: Early Detection & Screening

Population screening (mammography, colonoscopy, low-dose CT, HPV testing, PSA) has proven mortality benefit in several cancers. Blood-based multi-cancer early detection (MCED) and risk-adapted AI screening aim to extend this to cancers with no screening today.

• Breath and volatile-organic-compound detection: Smelling cancer: measuring the trace chemicals a tumour puts into exhaled breath.
• 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.
• Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood): Finding and removing polyps before they become cancer. Colonoscopy prevents cancer; stool and blood tests catch it early and get more people screened.
• Colposcopy and excisional treatment (LEEP/LLETZ, cone): Looking at the cervix with a magnifier after a positive screen, then removing the abnormal patch with an electric wire loop in a clinic visit.
• Dermoscopy, total-body photography & AI skin analysis: Magnified skin imaging and whole-body photo mapping, increasingly read by algorithms, to find melanoma early and avoid unnecessary biopsies.
• DNA methylation profiling: Reading chemical tags on DNA that reveal a cell's identity, used to classify brain tumours and to detect cancer in blood.
• Endoscopic resection (EMR / ESD): Removing very early cancers of the oesophagus or stomach from the inside with an endoscope, so the organ is kept intact.
• HCC surveillance in cirrhosis (ultrasound + AFP): People with cirrhosis or chronic hepatitis B get a liver ultrasound and a blood test every six months so cancer is caught while it is still curable.
• High-risk pancreatic surveillance (CAPS / PRECEDE): Yearly MRI or endoscopic ultrasound for people with inherited risk, which catches pancreatic cancers while they are still operable.
• HPV DNA testing and self-sampling: A swab tested for the virus that causes cervical cancer, more accurate than the Pap smear and doable at home.

• Early detection roadmap: organ screening → blood tests for many cancers · Organ-specific screening proven (historic)
• Early detection roadmap: organ screening → blood tests for many cancers · cfDNA and methylation science (historic)
• Early detection roadmap: organ screening → blood tests for many cancers · Pivotal trials and first approvals (current)
• Early detection roadmap: organ screening → blood tests for many cancers · Decision and integration (emerging)
• Early detection roadmap: organ screening → blood tests for many cancers · Speculative (speculative)
• Paths to cures: interception, eradication, control · What already prevents cancer (historic)
• Paths to cures: interception, eradication, control · Vaccinating and monitoring people who do not yet have cancer (emerging)
• Paths to cures: interception, eradication, control · Removing every cell, and knowing that you did (current)
• Paths to cures: interception, eradication, control · Killing the last cell, wherever it is hiding (emerging)
• Paths to cures: interception, eradication, control · Living with cancer as a chronic disease (current)
• Paths to cures: interception, eradication, control · Steering resistance instead of waiting for it (emerging)
• Radical oncology: what could change the war by 2035 · Ideas already being tested against a control arm (current)
• Radical oncology: what could change the war by 2035 · Living drugs, logic gates, and designed proteins reach decision points (emerging)
• Radical oncology: what could change the war by 2035 · Radiation and radiopharmaceuticals get a second act (emerging)
• Radical oncology: what could change the war by 2035 · Monitoring becomes continuous and selection becomes spatial (emerging)
• Radical oncology: what could change the war by 2035 · Writing to the genome and the epigenome inside a tumour (speculative)
• Radical oncology: what could change the war by 2035 · Treating the soil rather than the seed (speculative)

• NLST & NELSON (low-dose CT screening) (phase 3, n=53,454): NLST: relative reduction in lung cancer mortality: 20%
• 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.
• PATHFINDER 2 (phase observational, n=35,878): Cancer signal detected: 0.93%
• UKCTOCS (phase 3, n=202,638): Ovarian and tubal cancer mortality reduction (multimodal vs none): 4%

1. What single change would most improve outcomes across all cancers, and what evidence supports it?
   Answer

   Prevention and early detection: HPV vaccination has driven cervical cancer toward elimination in vaccinated cohorts, tobacco control and screening (mammography, colonoscopy, low-dose CT) have proven mortality benefits, and early-stage disease is where surgery cures; MCED blood tests aim to extend this but are unproven.
2. 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%).
3. 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.
4. What is the readout calendar event on 23 September 2026?
   Answer

   The FDA advisory committee (Molecular and Clinical Genetics Panel) reviewing GRAIL's Galleri multi-cancer early detection PMA.