Is post-operative immunohistochemistry (IHC) recommended after Neoadjuvant Anthracycline-based Chemotherapy (NACT) in breast cancer patients?

Post-Operative IHC Assessment After NACT in Breast Cancer

Routine post-operative IHC reassessment of hormone receptors (ER/PR) and HER2 is not currently recommended as standard practice after neoadjuvant chemotherapy, but should be strongly considered in specific clinical scenarios where results would directly alter adjuvant treatment decisions. 1, 2

Current Guideline Recommendations

The International Working Group on pathologic evaluation of post-neoadjuvant specimens provides clear guidance on when IHC reassessment is warranted 1:

Mandatory Reassessment Scenarios

• Clinical trial protocols requiring retesting - IHC reassessment should be included in clinical trial protocols to gather high-quality data clarifying the significance of receptor status changes on outcomes 1

Strongly Consider Reassessment When:

• Negative or equivocal pretreatment core biopsy results - Meta-analyses report mean discordance rates of 13-18% for ER, 26-32% for PR, and 6-9% for HER2 between pre- and post-NACT specimens 1
• Insufficient invasive tumor on pretreatment biopsy or DCIS only - The pretreatment specimen may not have adequately sampled the invasive component 1
• Biopsy performed at another institution - Quality control and verification of initial results 1
• Heterogeneous tumor or multiple tumors with different morphologies - Intratumoral heterogeneity may result in sampling differences 1
• No response to therapy - Unexpected lack of response may prompt reassessment to verify initial receptor status 1

Clinical Significance of Receptor Changes

Frequency of Changes

• ER status changes: 5-23% of cases show alterations after NACT 2
• PR status changes: More frequent at 14.5-67% of cases, with decreases commonly observed 2, 3
• HER2 status changes: Less frequent, with loss more common than gain; higher change rates occur with IHC compared to in situ hybridization and following HER2-targeted therapy 2
• Triple-negative subtype: Most stable molecular subtype 2
• Combined ER and HER2-positive cancers: Show highest rate of receptor change 2

Prognostic Implications

• ER-negative status (both pre- and post-NACT) is significantly associated with worse locoregional recurrence, distant metastasis, and overall survival 4
• PR expression decreases after NACT and should be interpreted carefully, as chemotherapy tends to reduce expression 3
• Ki-67 index decreases after NACT, particularly in hormone receptor-positive and HER2-enriched subtypes, but not consistently in triple-negative subtype 3

Alternative to IHC: Tumor-Infiltrating Lymphocytes (TILs)

The International Immuno-Oncology Biomarker Working Group recommends H&E-based TIL assessment over IHC for post-NACT evaluation as the preferred method for risk stratification. 1

Why H&E TIL Assessment is Preferred Over IHC:

• Technically more feasible - Requires less biological tissue and no additional processing beyond routine pathology 1
• No additional technical standardization required - Unlike IHC which requires additional processing and standardization 1
• Strong biological relevance - TIL counts correlate well with immune gene expression in neoadjuvant studies 1
• Always available - H&E slides are routinely prepared without block recollection 1
• Prognostic value established - Particularly in triple-negative breast cancer with residual disease 1, 5

TIL Prognostic Data in Residual Disease:

• High TILs (>60% stromal TILs) in post-NACT residual TNBC tumors show significantly improved 5-year outcomes: metastasis-free survival 81.5% vs 46% (HR 0.24) and overall survival 91% vs 55% (HR 0.19) 1
• Each 10% TIL increment provides 21% relative reduction in risk of metastasis and death 1
• Greatest prognostic power in patients with large residual tumor burden (node-positive and/or residual tumor >2 cm) 1

Practical Clinical Algorithm

When to Perform Post-NACT IHC:

1. Always reassess if:

   • Required by clinical trial protocol 1
   • Conversion would change adjuvant therapy decisions (e.g., initiating endocrine or anti-HER2 therapy) 1, 2

2. Strongly consider reassessing if:

   • Initial biopsy was negative/equivocal for ER, PR, or HER2 1
   • Insufficient tissue on pretreatment biopsy 1
   • External biopsy without verification 1
   • Unexpected lack of response to therapy 1

3. Do not routinely reassess if:

   • Adequate pretreatment biopsy with clear positive results 1, 2
   • Results would not alter management 2

Important Caveats:

• If HER2 status is reassessed and found discordant, retesting should be performed with both immunohistochemistry and in situ hybridization 1
• Loss of HER2 amplification following neoadjuvant trastuzumab has been associated with worse outcomes 1
• Post-treatment Ki67 correlates with long-term outcome but is not routinely recommended due to lack of standardization 5
• Most guidelines do not currently recommend routine retesting, but the evidence base is evolving 2

Residual Cancer Burden (RCB) System

The American College of Pathologists and International Working Group recommend the RCB system as the preferred quantification method for residual disease in clinical trials, which does not require IHC but incorporates tumor dimensions, cellularity, and nodal status 5, 1