Biochemical screening for early detection of:

• Prostatic cancer
• Colorectal cancer
• DPYD deficiency
• Alzheimer disease

Biochemical tumour markers in blood:

• Biochemical — measured by laboratory assays
• Elevated in patients with tumour
• Related to total tumour burden ^[1]

The key nuance the lecturer raises: "To what extent is this true?" — meaning tumour markers are imperfect. They can be elevated in benign conditions, they are not always proportional to tumour burden, and they have variable sensitivity and specificity. This is why most tumour markers are NOT suitable as stand-alone screening tests.

Are there non-biochemical markers? Yes — genetic markers:

• Cytogenetic markers (e.g., Philadelphia chromosome in CML)
• Plasma nucleic acid (e.g., circulating tumour DNA, ctDNA)
• Specific mutations (e.g., EGFR in lung cancer)
• Genomic changes (e.g., microsatellite instability)

What can we do with tumour markers?

1. Screening
2. Diagnosis
3. Determine modality of treatment
4. Monitoring disease progression
5. Detection of relapse
6. Prognostication

Why this ordering matters: Most tumour markers are better at monitoring/relapse detection than at screening. Screening requires very high sensitivity and specificity in a low-prevalence population — most tumour markers fail this bar.

• Suspected medullary thyroid carcinoma → Calcitonin, [Procalcitonin]
• Suspected hepatocellular carcinoma → Alpha-fetoprotein

Serial monitoring examples:

• CA-125 in ovarian cancer
• CEA in colon cancer / lung cancer
• Thyroglobulin in differentiated thyroid carcinoma

The principle here: after definitive treatment (e.g., surgery), the tumour marker should fall to baseline. A subsequent rise indicates relapse. This requires serial measurements, not one-off values.

Prostate cancer is very common:

• Worldwide incidence: 1.6M per year
• Deaths: 366k per year
• American lifetime risk of disease: 16%
• Risk of dying from prostate cancer: 2.9%

The large gap between the 16% lifetime risk of diagnosis and 2.9% risk of dying highlights a critical screening dilemma: many prostate cancers are clinically indolent. Over-detection leads to over-treatment (radical prostatectomy, radiotherapy) with associated morbidity (incontinence, erectile dysfunction) in men who may never have died from their cancer. This is why PSA screening remains controversial.

• Prostate-specific antigen = Human kallikrein 3
• Serine protease (an enzyme)
• Complexed with serum anti-proteases: α1-anti-chymotrypsin, α2-macroglobulin

PSA is prostate-specific but NOT prostate-cancer-specific ^[3]. It is also elevated in:

• Benign prostatic hyperplasia (BPH)
• Prostatitis
• Prostatic infarction
• Acute urinary retention
• Prostate manipulation (biopsy, TURP, DRE — though DRE causes only minimal transient elevation)
• Ejaculation (returns to normal within 48 hours)
• Cycling/perineal trauma

Serum PSA levels:

• < 4 ng/mL: negative (Sn = 78%, Sp = 33%)
• > 10 ng/mL: positive (Sn ~40%, Sp ~90%)
• 4–10 ng/mL: troublesome ("grey zone")
• AUC = 0.58 — it's not a very good test

Why is the 4–10 ng/mL zone problematic? In this range, roughly 20–25% of men actually have prostate cancer ^[3]. That means 75–80% of men in this zone who undergo biopsy have a negative result — a lot of unnecessary invasive procedures.

phi = p2PSA / free PSA × √PSA

phi is superior to %p2PSA, %freePSA, and PSA for diagnosis of prostate cancer, but is fairly expensive ^[1]

It takes 10 years on average to develop from adenomatous polyp to invasive carcinoma

This long preclinical window (the adenoma-carcinoma sequence) is what makes colorectal cancer an ideal candidate for screening — there is ample time to detect and remove polyps before they become malignant.

Polyps:

• Adenomatous vs hyperplastic
• Small vs large

Adenomatous polyps are the precancerous ones. Hyperplastic polyps are generally benign (though sessile serrated adenomas, a subtype, can also progress). Larger polyps and villous histology carry higher malignant potential.

Radiological: Barium enema; CT colonoscopy Biochemical: Faecal occult blood (different types); Faecal DNA Endoscopic: Flexible sigmoidoscopy; Colonoscopy; Capsule endoscopy Combinations

EGTM guideline — Recommended: CEA

• Prognosis
• Surveillance following resection
• Monitoring therapy in advanced disease Faecal occult blood tests: Screening > 50 years of age DNA tests not recommended at present ^[1]

Key concept: CEA is NOT used for screening of colorectal cancer. It is used for prognosis, post-operative surveillance (serial measurements to detect recurrence), and monitoring response to treatment in advanced disease. This is a common exam trap.

The lecture includes slides about the HK situation (slides 36–37). Key points:

• Colorectal cancer is the most common cancer in Hong Kong (by incidence) and second most common cause of cancer death
• The government-funded screening programme targets ages 50–75
• Uses quantitative FIT as first-line test
• Positive FIT → colonoscopy subsidy provided

This section discusses dihydropyrimidine dehydrogenase (DPD/DPYD) deficiency in the context of 5-fluorouracil (5-FU) and capecitabine toxicity. The slide references the paper: Tong CC, Lam CW, et al. A Novel DPYD Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive DPYD Genotype Screening. Front Oncol. 2018 ^[1].

5-Fluorouracil (5-FU) is a fluoropyrimidine antimetabolite used in the treatment of colorectal cancer, breast cancer, head and neck cancers, and others. It works by inhibiting thymidylate synthase (blocking DNA synthesis) and incorporating into RNA.

DPD (dihydropyrimidine dehydrogenase) is the rate-limiting enzyme in the catabolism (breakdown) of 5-FU. Over 80% of administered 5-FU is broken down by DPD in the liver. The gene encoding DPD is DPYD.

If a patient has a DPYD deficiency (heterozygous or homozygous pathogenic variant), they cannot metabolize 5-FU efficiently → accumulation of active drug → severe and potentially fatal toxicity:

• Severe mucositis
• Myelosuppression (neutropenia, thrombocytopenia)
• Diarrhoea
• Hand-foot syndrome
• Neurotoxicity
• Death (in severe cases)

Pre-emptive DPYD genotype screening is advocated before prescribing fluoropyrimidines

This fits under pharmacogenomic screening — testing a patient's genetic makeup before starting a drug to predict toxicity and guide dose adjustment.

Key DPYD variants tested:

• DPYD*2A (IVS14+1G>A, c.1905+1G>A) — splice site variant, most common in Caucasians
• DPYD*13 (c.1679T>G)
• c.2846A>T
• HapB3 (c.1236G>A)
• Novel variants — the cited paper from Prof Lam's group identified a novel variant in a Hong Kong patient

Management based on genotype:

• Homozygous or compound heterozygous for loss-of-function variants → avoid fluoropyrimidines entirely (use alternative regimen)
• Heterozygous for one variant → reduce dose by 25–50% and monitor closely
• Wild type → standard dosing

The lecture slide 39 shows a pathway diagram: "Disorders of the metabolism of purines, pyrimidines and nucleotides." DPYD deficiency falls under pyrimidine catabolism disorders. Dihydropyrimidine dehydrogenase converts uracil and thymine to their dihydro forms as the first step of degradation. When this enzyme is deficient:

• Endogenously: usually mild/asymptomatic (may cause childhood seizures, intellectual disability in homozygotes)
• Pharmacologically: catastrophic when exposed to 5-FU

April 1906 — the first histopathological findings of Alzheimer's disease reported by Dr. Alois Alzheimer

• Presented "peculiar severe disease process of the cerebral cortex" in the 37th Meeting of South-West German Psychiatrists

1. Amyloid-beta (Aβ) — forms extracellular amyloid plaques

   • Derived from cleavage of Amyloid Precursor Protein (APP) by β-secretase and γ-secretase
   • Aβ42 is the most pathogenic form (more prone to aggregation)

2. Tau — forms intracellular neurofibrillary tangles (NFTs)

   • Tau is a microtubule-associated protein that stabilises neuronal cytoskeleton
   • In AD, tau becomes hyperphosphorylated → detaches from microtubules → aggregates into paired helical filaments → NFTs

The lecture includes a slide showing the "Schematic representation of tau proteins" ^[1].

The lecture references the AD continuum concept:

This continuum is important because it shows that biochemical/imaging biomarkers change YEARS before clinical symptoms — creating a window for early detection (and potentially early intervention with emerging therapies like anti-amyloid antibodies).

The lecture references studies (Kivisäkk et al., Sci Rep 2024; Dulewicz et al., Int J Mol Sci 2022) on AD biomarkers:

CSF biomarkers (established):

• CSF Aβ42 — decreased (because Aβ42 is sequestered into plaques in the brain, less enters CSF)
• CSF total tau (t-tau) — increased (neuronal death releases tau)
• CSF phosphorylated tau (p-tau) — increased (reflects tangle pathology specifically)
• CSF Aβ42/Aβ40 ratio — decreased (more specific than Aβ42 alone)

Blood-based biomarkers (emerging):

• Plasma p-tau181, p-tau217, p-tau231 — highly promising; correlate with amyloid and tau PET
• Plasma Aβ42/Aβ40 ratio — decreased in AD
• Plasma GFAP (glial fibrillary acidic protein) — marker of astrocyte activation
• Plasma NfL (neurofilament light chain) — marker of neuronal injury (non-specific)

Stem: "A 70-year-old man presented with acute retention of urine. His serum total prostate specific antigen was 8 ng/mL (age-related cut-off: 6.5 ng/mL). For early detection of prostate cancer, which of the following tests should be added?"

• A. CA-125
• B. Free PSA only
• C. p2PSA and free PSA ✓
• D. p2PSA only

Answer: C — p2PSA and free PSA

Rationale: The PSA is in the grey zone (elevated but not grossly high). To improve diagnostic accuracy, the Prostate Health Index (phi) should be calculated. phi requires p2PSA, free PSA, and total PSA. Since total PSA is already measured, you need to add both p2PSA AND free PSA. Free PSA alone gives %free PSA (helpful but inferior to phi). p2PSA alone is insufficient without free PSA. CA-125 is for ovarian cancer — a clear distractor.

Discriminator: B vs C — phi is superior to %freePSA alone (directly stated on lecture slide). You need BOTH p2PSA and free PSA to calculate phi.

Stem: "A laboratory test for detecting a rare inherited metabolic disorder has a very high specificity but moderate sensitivity. Which of the following clinical scenarios BEST suits this test?"

• A. Confirmatory testing after a positive screening test ✓
• B. Initial screening for asymptomatic population
• C. Population-wide epidemiological studies
• D. Testing in emergency setting for rapid diagnosis

Answer: A — Confirmatory testing after a positive screening test

Rationale: High specificity = low false positive rate = good at ruling IN disease (few false positives). This makes it ideal for confirmatory testing (you've already identified high-risk individuals through a sensitive screening test; now you want to confirm true positives). For initial screening (option B), you want high sensitivity to catch as many cases as possible. This question tests screening principles directly relevant to this lecture.

Stem: "Radiographs are used for diagnosis of different kinds of diseases. Which of the following radiographic imaging methods is used for detecting breast abnormality?"

• A. Chest radiograph
• B. Fluoroscopy
• C. Mammogram ✓
• D. Radionuclide scan

Answer: C — Mammogram

Rationale: While not directly about biochemical screening, this tests the concept of screening modalities. Mammography is the standard imaging modality for breast cancer screening. This connects to the broader screening theme of this lecture.

HK's newborn screening programme (implemented 2015) uses dried blood spots for amino acids and acylcarnitines (tandem mass spectrometry) to detect 26 IEM conditions. Prior to 2015, cord blood TSH and G6PD screening had been in place for > 30 years. The principle is the same as this lecture's theme: biochemical screening for early detection — catching IEM before clinical symptoms manifest allows dietary/metabolic intervention to prevent intellectual disability and death.

The O&G block teaches screening principles through antenatal screening (thalassemia trait by MCV/Hb, syphilis by VDRL, Down syndrome by combined/quadruple tests, NIPT). The same sensitivity/specificity/PPV/NPV concepts apply directly.

Mammography screening for breast cancer is another major population screening programme. The BIRADS classification, age criteria, and the concept of false positives leading to unnecessary biopsies mirrors the PSA screening dilemma in prostate cancer.