Title: CANONIC ANKI / ABOPM Foundation Deck
Tags: GOLD SILVER biomarker_interp vus_discussion staging_debate BRONZE acmg_debate guideline_drift methods

Q: ypN0 after KEYNOTE-522 NAC — escalating to T-DM1 per KATHERINE, holding at pembro continuation, or watchful surveillance? Tumor board tonight.
A: Marcus Freeman · Attending · Genomic pathology · PharmGKB CPIC contributor
Our tumor board moved to (a) pembro continuation as the default in mid-2024 after the 2-yr DFS data held up in the node-positive pCR subset. The KATHERINE-style T-DM1 argument only makes sense for HER2+ residual disease by design; you'd be stretching the indication for TNBC ypT0N0 with retroactive axillary micromet. @alexa_park the nuance in your case is whether the 'micrometastatic focus' on the original axillary path was true residual disease or a clipped-node artifact. We've had two cases where surgical path re-review downgraded the finding. Worth a call to path before the board. #staging_debate
Priya Chen · Resident · Molecular pathology PGY-3 · ABOPM candidate
Molecular pathology resident here — would also flag that the 2025 KEYNOTE-522 update explicitly allowed continued pembro in the pCR node-positive subset based on exploratory analyses, but NCCN has not yet moved the recommendation from category 2A to category 1. Version drift means institutional practice is ahead of the written guideline for this exact scenario.
Thread: @alexa_park · Contributors: @marcus_freeman, @priya_chen · Origin: https://onconex.ai/onconex/community/seed-onco-eng-01

Q: MSI-H vs TMB-H — when they disagree, which drives therapy?
A: AI note — cites the primary sources.
NCCN Endometrial v3.2024; Marabelle A Lancet Oncol 2020; ESMO Precision Medicine WG 2020. Pearl: dMMR (IHC MSH2/MSH6/MLH1/PMS2 loss) is the pathology-first surrogate for MSI-H — in endometrial it is now standard universal screening per NCCN.
Marcus Freeman · Attending · Genomic pathology · PharmGKB CPIC contributor
Agree — MSI-H is the stronger driver. TMB-H pembrolizumab approval (KEYNOTE-158) was controversial because of cross-histology variability; some cancer types (melanoma, NSCLC) respond better than others at same TMB. ESMO 2020 precision medicine recommendations downweight TMB-H outside MSI-H + checkpoint-native histologies. Reference: Marabelle A et al Lancet Oncol 2020 (KEYNOTE-158).
Thread: @alexa_park · Contributors: @canonic, @marcus_freeman · Origin: https://onconex.ai/onconex/community/onco-bio-03

Q: Grammar demo — #staging_debate with @idrdex + @CANONIC summon
A: AI note — cites the primary sources.
AJCC 8th ed. (2018) formalized the Y-prefix for post-neoadjuvant pathologic staging and explicitly allows reporting the pre-treatment clinical stage (cTNM) alongside the post-treatment pathologic stage (ypTNM) when they diverge. NCCN Breast Cancer v4.2025 follows this convention — the pathologic ypN drives the adjuvant decision tree (escalation per KATHERINE / CREATE-X when residual disease, de-escalation when pCR), while the clinical cN remains in the registry record for epidemiologic continuity. Most NCI-designated centers now include a discordance field in their pathology report. Discuss with your tumor-board chair before clinical action. — @CANONIC · governed AI layer · sources: AJCC 8th ed., NCCN v4.2025, KATHERINE (von Minckwitz NEJM 2019), CREATE-X (Masuda NEJM 2017).
Thread: @abopm-community · Contributors: @canonic · Origin: https://onconex.ai/onconex/community/seed-grammar-demo-01

Q: BRCA2 c.6405_6409delTCAAA — LP or VUS?
A: AI note — cites the primary sources.
Richards S et al Genet Med 2015 (ACMG/AMP); Abou Tayoun AN et al Hum Mutat 2018 (PVS1 refinement). The 2018 PVS1 refinement explicitly addresses frameshifts distal to the last 50bp of the penultimate exon — invoke PVS1 strong not moderate when NMD-predicted.
Alexa Park · Fellow · Heme/Onc · breast focus
PVS1 applies (frameshift in canonical transcript, no predicted rescue isoform) + PM2_supporting (gnomAD absent). That gets you LP per ACMG/AMP 2015 rules (2 moderate-strong lines of evidence). You do not need functional data for a clean PVS1 call. Reference: Richards S et al Genet Med 2015;17:405.
Thread: @marcus_freeman · Contributors: @alexa_park, @canonic · Origin: https://onconex.ai/onconex/omicschat/community/omics-vus-01

Q: HRD score interpretation — BRCA vs genomic scar signatures
A: AI note — cites the primary sources.
NCCN Ovarian Cancer v2.2024; González-Martín NEJM 2019; Myriad myChoice CDx package insert. Note: the HRD cutoff 42 is assay-specific — FoundationOne CDx HRD+ uses a different threshold. Cross-platform comparison is not validated.
Marcus Freeman · Attending · Genomic pathology · PharmGKB CPIC contributor
HRD status is validated for first-line maintenance decisions in ovarian HGSC but not for subsequent lines. SOLO-1 (BRCA+) + PAOLA-1 (HRD+/BRCA-) + PRIMA (HRD+) are the three pivotal trials. HRD+/BRCA- benefits less than BRCA+ but benefits more than HR-proficient. Reference: González-Martín A et al NEJM 2019 (PRIMA); Ray-Coquard I et al NEJM 2019 (PAOLA-1).
Thread: @alexa_park · Contributors: @canonic, @marcus_freeman · Origin: https://onconex.ai/onconex/community/onco-bio-02

Q: TP53 c.743G>A p.Arg248Gln — how to weigh recurrent vs segregation
A: AI note — cites the primary sources.
ClinGen TP53 VCEP Specifications v1.4.0 (2023); Giacomelli AO et al Nat Genet 2018; Kato S et al PNAS 2003. Residents should note: the ClinGen VCEP framework is now the authoritative source for TP53 germline classification, superseding older ACMG-generic approaches.
Thread: @marcus_freeman · Contributors: @canonic · Origin: https://onconex.ai/onconex/omicschat/community/omics-vus-03

Q: mCODE FHIR rollout across 51 hospitals next quarter — looking for operational lessons from centers that have done this
A: Alexa Park · Fellow · Heme/Onc · breast focus
@devon_khan MD Anderson enforced mCODE at BOTH the registry AND tumor-board-documentation level — we learned fast that registry-only enforcement creates a shadow dataset that the clinical team doesn't trust. On the free-text-to-mCODE gap: we built a 'rescue' templated prompt in our EHR that fires on tumor-board note save and asks the clinician to map the free-text problem list to the mCODE disease primary code. Adoption was 40% at launch, 82% at month 6, stable at 91% after the first accreditation review. The reason: clinicians stopped trusting the registry numbers and started trusting the mCODE-structured ones. About 15% of our cancer types needed custom extensions — we pushed them upstream to the mCODE working group and landed 3 in STU4.
Thread: @devon_khan · Contributors: @alexa_park · Origin: https://onconex.ai/onconex/community/seed-onco-eng-02

Q: Studying for boards — walk me through PM5 escalation when 3+ different pathogenic substitutions share the residue
A: AI note — cites the primary sources.
The ClinGen Sequence Variant Interpretation (SVI) working group's published recalibration of PM5 (Abou Tayoun et al., Hum Mutat 2018) established the general framework but explicitly did not set a numeric threshold for PM5_strong escalation. The field has converged, not via a single normative document but via accumulated gene-specific expert panels, on ≥3 different pathogenic substitutions at the same residue as the typical threshold for PM5_strong. Gene-specific panels matter: BRCA1/2 VCEP allows PM5_supporting for some cases, PM5_strong only with 3+ substitutions AND at least one with ClinVar review status 2+ stars. For board preparation, memorize 3+ as the modal answer and be prepared to defend PM5_moderate as the conservative default when the evidence is not clearly residue-wide. — @CANONIC · governed AI layer · sources: Abou Tayoun et al. Hum Mutat 2018 (PM5 recalibration), ClinGen BRCA1/2 VCEP Criteria v1.1.0, Ellard et al. Eur J Hum Genet 2019 (implementation framework). Not a substitute for your institution's variant-curation SOP.
Marcus Freeman · Attending · Genomic pathology · PharmGKB CPIC contributor
@priya_chen this is a good question and the answer in practice is less consensus than the literature pretends. Our lab's internal SOP requires ≥3 different pathogenic missense changes at the same residue AND at least one of them with ClinVar 2+ star review status for PM5_strong; we hold at PM5_moderate otherwise. The ClinGen SVI working group working document suggests ≥3 but calls it a 'starting calibration' — my read is the field is standardizing around 3 but nobody has written the definitive implementation paper yet. For boards I'd memorize 3+ as the modal answer but be prepared to defend PM5_moderate as the conservative default. Prep hack: the 2019 Ellard framework paper in Eur J Hum Genet walks through the exact calibration logic and is a common exam source. #acmg_debate
Alexa Park · Fellow · Heme/Onc · breast focus
From the clinical side — when our molecular pathology colleagues escalate to PM5_strong, that often flips our treatment-decision certainty from 'consider germline testing' to 'order germline testing now.' The calibration matters downstream. +1 to @marcus_freeman's 3-different-residue-changes rule — that's what I've seen at our NCI-designated tumor board as the de facto standard.
Thread: @priya_chen · Contributors: @alexa_park, @canonic, @marcus_freeman · Origin: https://onconex.ai/onconex/omicschat/community/seed-omics-eng-01

Q: MLH1 intronic +5G>A — computational vs functional evidence
A: AI note — cites the primary sources.
ClinGen InSiGHT MMR VCEP 2019; Jaganathan K et al Cell 2019 (SpliceAI). Splice-proximal variants (+5 position) warrant extra caution — SpliceAI has lower specificity for +5 than canonical +1/+2. Consider a minigene assay if RNA not available.
Marcus Freeman · Attending · Genomic pathology · PharmGKB CPIC contributor
SpliceAI 0.34 is below the typical 0.5 threshold for confident splicing prediction. Without RNA data, this stays VUS — but segregation in 3+ affecteds can pull PP1_strong, pushing to LP. Get the segregation data before the RNA assay. Reference: ClinGen InSiGHT MMR VCEP classification criteria 2019.
Thread: @priya_chen · Contributors: @canonic, @marcus_freeman · Origin: https://onconex.ai/onconex/omicschat/community/omics-vus-02

Q: NTRK fusion in tumor-agnostic context — larotrectinib indication
A: AI note — cites the primary sources.
NCCN Guidelines Occult Primary v1.2024; Drilon A et al NEJM 2018 (larotrectinib); Solomon JP Mod Pathol 2020. ABOPM exam note: the fusion gene-first approach (NTRK, ALK, RET, ROS1) requires biomarker literacy across all solid tumor histologies; precision oncology is no longer organ-specific.
Marcus Freeman · Attending · Genomic pathology · PharmGKB CPIC contributor
Key testing caveat: NTRK IHC has reasonable sensitivity but poor specificity for NTRK3; confirmation with FISH or RNA-seq is needed for fusion detection. DNA-based NGS misses intronic breakpoints — always pair with RNA-seq for fusion detection. Reference: Solomon JP et al Mod Pathol 2020 (NTRK testing recommendations).
Thread: @alexa_park · Contributors: @canonic, @marcus_freeman · Origin: https://onconex.ai/onconex/community/onco-bio-01

Q: DPYD pre-5FU genotyping — three-center implementation notes on the CPIC workflow (happy to answer questions)
A: Priya Chen · Resident · Molecular pathology PGY-3 · ABOPM candidate
@marcus_freeman the EHR critical-path point is gold. We have DPYD available as an orderable but nobody in the community practice is actually checking the report before signing the 5-FU order. Can I ask — did you run this past your P&T committee first or did you go through oncology service line? The governance bottleneck at our shop feels like it's going to be P&T. #methods
Thread: @marcus_freeman · Contributors: @priya_chen · Origin: https://onconex.ai/onconex/omicschat/community/seed-omics-eng-02