Alteration type

2. No biomarker in the text (classic chemotherapy, anti-angiogenesis without biomarker gating) → biomarker_name="none", alteration_type="none", biomarker_detail="n/a", diagnostic_criterion="n/a", scoring_system="n/a", test_method=[] (empty list — no diagnostic test applies). Flag "no-biomarker" and "non-targeted-therapy".

2a. A hereditary tumour syndrome named as the population (von Hippel-Lindau disease, neurofibromatosis type 1, tuberous sclerosis complex) is a clinical diagnosis, not a biomarker: biomarker_name="none", alteration_type="none", scoring_system="n/a", test_method=[]. Put the syndrome into tumor_type (e.g. "VHL disease-associated renal cell carcinoma") and patient_eligibility, and flag "no-biomarker" but NOT "non-targeted-therapy". Record a germline biomarker only when the text names the alteration itself (e.g. "germline BRCA1/2 mutations").

3. Primary negative biomarker (e.g. cetuximab RAS wild-type) → alteration_type="wild-type-required", biomarker_detail="RAS wild-type". When the absence of several alterations is the main requirement ("no sensitising EGFR mutations, or ALK, ROS1 or RET genomic tumour aberrations"), name all of them in biomarker_name joined by "/" ("EGFR/ALK/ROS1/RET"). Secondary negative (e.g. HER2-negative on a PD-L1 indication) → keep primary biomarker, append "; HER2-negative" to biomarker_detail, flag "multi-biomarker".

5b. HER2 protein status is an IHC score: scoring_system="IHC-score", and diagnostic_criterion gives the standard definition (EU SmPC section 4.2), even when the text names only the category:
    - HER2-positive / "HER2 overexpression or HER2 gene amplification" → "IHC 3+ or IHC 2+/ISH-positive" (keep stricter wording the text gives, e.g. "IHC 3+").
    - HER2-low → "IHC 1+ or IHC 2+/ISH-negative".
    - HER2-ultralow → "IHC 0 with membrane staining (faint, incomplete, ≤10% of tumour cells)".
    "HER2-low or HER2-ultralow" stays one row with both definitions. HER2 (ERBB2) mutation → alteration_type="mutation", scoring_system="n/a". A secondary "HER2-negative" does not change scoring_system.

6. "PD L1" / "PD-L1" are the same — use "PD-L1". PD-L1 scoring_system mapping by SmPC phrasing:
    - "tumour cell PD-L1 expression ≥ X%" / "PD-L1 expression in tumour cells ≥ X%" / "TPS ≥ X" / "tumour proportion score ≥ X%" → scoring_system="TPS" (Tumor Proportion Score = % PD-L1+ tumor cells, pembrolizumab/nivolumab).
    - "combined positive score ≥ X" / "CPS ≥ X" → scoring_system="CPS".
    - "PD-L1 positive immune cells ≥ X%" / "tumour-infiltrating immune cells covering ≥ X%" / "IC ≥ X" → scoring_system="IC" (Immune Cell score, atezolizumab SP142).
    - "TC ≥ X%" / "PD-L1 stained tumour cells ≥ X%" as the SP142-style tumour-cell leg paired with an IC leg → scoring_system="TC" (atezolizumab tumour-cell score, distinct from TPS).
    - "TAP score ≥ X%" / "tumour area positivity ≥ X%" / "PD-L1 expression with a TAP score ≥ X%" → scoring_system="TAP" (tislelizumab SP263).
    - A PD-L1 percentage that names no cells or score ("PD-L1 expression ≥ 1%", "tumours expressing PD-L1 ≥ 1%", "PD-L1 positive cells ≥ X%") → scoring_system="TPS" (tumour-cell expression, as in the pivotal trials). Exception: for atezolizumab (SP142 assay) such a percentage refers to tumour-infiltrating immune cells → scoring_system="IC", unless the text names tumour cells.
    - PD-L1 below a threshold ("tumour cell PD-L1 expression < 1%") is still a PD-L1 expression result → alteration_type="overexpression", with the threshold in diagnostic_criterion.

7. Gene symbols uppercase (BRAF, EGFR, ERBB2). Use "PD-L1" (protein) not CD274. An HLA type is a germline genotype, never a mutation: "HLA-A*02:01-positive" → biomarker_name="HLA-A*02:01", alteration_type="overexpression", biomarker_detail="HLA-A*02:01-positive", scoring_system="n/a", test_method=["molecular"]. Hormone receptors are proteins measured by IHC: "hormone receptor-positive" → biomarker_name="HR", "oestrogen receptor-positive" → "ER", progesterone receptor → "PR"; use "ESR1" only for ESR1 mutations.

17. MMR / MSI alteration_type disambiguation. The text can present MMR/MSI status in two framings, and both carry clinical meaning but the enum forces a single choice:
    - Protein-loss framing ("deficient mismatch repair (dMMR)", "loss of MLH1/MSH2/MSH6/PMS2", "MMR protein loss by IHC") → biomarker_alteration_type="loss".
    - MSI framing ("microsatellite instability-high (MSI-H)", "MSI by PCR/NGS" alone, no mention of MMR protein loss) → biomarker_alteration_type="MSI".
    - When the SmPC uses BOTH framings together ("dMMR or MSI-H", "mismatch repair deficient or microsatellite instability high", "MMR deficient / MSI high") → prefer biomarker_alteration_type="loss". Rationale: the primary molecular defect is MMR protein deficiency; MSI-H is the downstream consequence. Pathology labs diagnose this most commonly by IHC for MMR protein loss, so "loss" better captures the diagnostic workflow implied by the indication.