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🚨 Protocol Update Alert: IHC CAP Guidelines

It’s time to update your immunohistochemistry (IHC) protocols!
The latest CAP March 2025 update introduces key changes to HER2 testing, including new classifications for Low HER2 and Ultra-Low HER2.

These refinements aim to improve diagnostic precision and align pathology reporting with the latest HER2-targeted therapies.

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🧬 Before the Update: Traditional HER2 Classification

Previously, HER2 status was determined using IHC and ISH, with categories as follows:

• Score 0: No staining (HER2-negative)
• Score 1+: Faint, incomplete staining (HER2-negative)
• Score 2+: Weak-to-moderate, complete staining (Equivocal → ISH tested)
• Score 3+: Strong, complete staining (HER2-positive)

Key Points :

• HER2 status was classified as:
  • Positive (3+)
  • Equivocal (2+)
  • Negative (0 / 1+)
• IHC 0 and 1+ were both considered HER2-negative
• Therapeutic implications were limited to HER2-positive cases only

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CAP March 2025 Update: Expanded HER2 Spectrum

The new 2025 guidelines introduce refined categories recognizing Low HER2 and Ultra-Low HER2 expression.

Updated IHC Interpretation:

• Score 0 (NULL): No staining
• Score 0 (ULTRA-LOW): ≤10% of cells with faint, incomplete membrane staining
• Score 1+: Faint/incomplete staining in >10% of cells
• Score 2+: Weak to moderate complete staining (ISH negative = HER2-Low)
• Score 3+: Strong, complete staining (HER2-positive)

Key Updates:

• 🧩 Recognition of Low HER2 and Ultra-Low HER2 subcategories
• 🔍 Updated interpretation for IHC 1+ and IHC 0 with faint staining
• 🧠 Alignment with evolving HER2-directed therapies

This nuanced classification better captures tumors that may benefit from newer HER2-targeted drugs—even when they’re not “HER2-positive” by traditional criteria.

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💡 Clinical Pearl: Insights from DESTINY-Breast04 & 06 Trials

Recent trials have shown that HER2-Low and even HER2-Ultra-Low breast cancers may respond to therapies such as trastuzumab-deruxtecan (T-DXd).

Subcategory	IHC Pattern	Description
HER2-null	IHC 0	No staining
HER2-ultra-low	IHC 0 (<1+)	Faint, incomplete staining in ≤10% of tumor cells
HER2-low	IHC 1+ or 2+ / ISH-negative	Incomplete to moderate staining

Clinical Impact:

• HER2-Low = IHC 1+ or 2+ / ISH-negative
• HER2-Ultra-Low = IHC 0 (pattern 0+) with faint staining in ≤10% of cells
• These subtypes may qualify for trastuzumab-deruxtecan in metastatic disease
• True IHC 0 (no staining) remains excluded from eligibility

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