# Source screening: PMID 41212147 (T-DXd resistance — HER2 loss/binding)

**Agent:** kestrel (Evidence synthesis)  
**Mission scope:** HER2-positive breast cancer residual disease, resistance, toxicity, and access  
**Work type:** source-screening  
**Screened:** 2026-09-23 (Asia/Karachi / PKT)  
**Round:** 1491764  

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## 1. Record identity

| Field | Value |
|-------|-------|
| PMID | `41212147` |
| DOI | `10.1158/2159-8290.CD-25-0647` |
| PMCID | `PMC12631751` |
| Title | Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding. |
| Journal | Cancer discovery |
| Pub date | 2026 Feb |
| Authors (first 10) | Chen Wanyi; Gupta Avantika; Mai Nicholas; Nag Sharanya; Lau Joshua S; Singh Sukrit; Chodera John D; Liu Bo; de Stanchina Elisa; Pareja Fresia |
| Publication types | Journal Article |
| PubMed | https://pubmed.ncbi.nlm.nih.gov/41212147/ |
| DOI link | https://doi.org/10.1158/2159-8290.CD-25-0647 |
| PMC | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12631751/ |

**Provenance:** NCBI `efetch` (first PubmedArticle only).  
**Integrity:** SHA-256(TITLE+PMID+ABSTRACT)=`df5a18f15a5336a8f51f501dd4afdf2a263e75242cd62c6ed3e57686d769123e` · SHA-256(efetch XML bytes)=`2a69c254a154c6cba9d5ba5383b6f8867a2f5c1bf9367a95b39c0693a5525479`  

Bibliographic screening only. Not medical advice.

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## 2. What the record is

Peer-indexed **Journal Article** (Cancer Discovery) on **mechanisms of clinical resistance to trastuzumab deruxtecan (T-DXd)** in breast cancer, including HER2-positive and HER2-low metastatic disease.

Abstract-bound findings (not living-paper standards until extraction + review):
- Paired pre/post–T-DXd specimens: **49%** major HER2 decrease at progression; among those, **52%** complete HER2 loss.
- Isogenic models: HER2 decrease → reduced T-DXd internalization ↑ IC50.
- Validated **ERBB2** mutations at trastuzumab-binding interface (**V597M**, **P593R**) promoting T-DXd resistance.
- Exploratory overcoming strategy: low-dose T-DXd + TROP2-directed ADC combinations to deliver DXd more uniformly after HER2 loss.

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## 3. Scope decision

**IN SCOPE — `adc-resistance` (primary); secondary clinical-evidence / residual-disease-adjacent biomarker biology.**

Rationale: Directly addresses a named MUSE pillar (ADC resistance) with patient-specimen molecular evidence and binding-site mutations relevant to HER2-targeted ADC failure after T-DXd.

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## 4. Screening decision

**INCLUDE for full-text structured extraction** → section **`adc-resistance`**.

Extraction targets: cohort size/lines of therapy; assay for HER2 (IHC/ISH/RNA); definition of “major decrease”; mutation calling; model IC50 methods; any clinical outcomes tied to HER2-loss; TROP2 combo data limitations (preclinical vs clinical).

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## 5. Limitations

- Abstract-only this pass (full text/PMC needed for tables).
- HER2-low included in framing — keep HER2-positive subset explicit at extraction.
- Combination TROP2 ADC note is mechanistic/hypothesis-generating in abstract — not a care recommendation.
- Catalogue metadata alone is never accepted evidence.

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*kestrel · round 1491764 · bibliographic screening only*