How does Immunohistochemistry (IHC) inform chemotherapy decisions in cancer treatment?

IHC's Role in Guiding Chemotherapy Decisions

Immunohistochemistry should NOT be used to guide specific chemotherapy regimen selection in breast cancer, but it remains essential for determining HER2 status to identify patients eligible for HER2-targeted therapies like trastuzumab. 1

Critical Distinction: Diagnostic vs. Predictive Use

Where IHC IS Essential

HER2 Testing for Targeted Therapy Eligibility

• IHC is the primary method for determining HER2 status, which directly determines eligibility for trastuzumab (Herceptin) and other HER2-targeted agents. 1, 2
• HER2 IHC 3+ indicates HER2-positive disease and qualifies patients for trastuzumab-based therapy, with demonstrated improvements in disease-free survival (HR 0.48) and overall survival in both adjuvant and metastatic settings. 2
• A new clinical threshold exists: HER2 IHC 1+ or IHC 2+/ISH not-amplified (previously considered "HER2-negative") now qualifies patients for trastuzumab deruxtecan based on the DESTINY-Breast04 trial. 1
• This represents a treatment eligibility criterion rather than a true predictive biomarker threshold—patients with IHC 0 were excluded from the trial and remain ineligible. 1

ER/PR Testing for Endocrine Therapy

• ER and PR status by IHC determines eligibility for endocrine therapy (tamoxifen, aromatase inhibitors), which is fundamental to breast cancer treatment decisions. 1, 3

Where IHC Should NOT Be Used

Chemotherapy Regimen Selection - Strong Recommendations Against:

• Ki-67 (MKI67 protein) by IHC should NOT be used to guide adjuvant chemotherapy decisions due to lack of reproducibility across laboratories and insufficient predictive value. 1

• TOP2A protein expression or gene amplification should NOT be used to select anthracycline-based chemotherapy despite extensive study—results have been controversial and biologically inconsistent. 1

• Microtubule-associated protein Tau (MAP-Tau) should NOT be used to guide taxane (paclitaxel) selection—while prognostic, it is not predictive of paclitaxel benefit and lacks reproducibility. 1

• HER1/EGFR expression should NOT be used to guide taxane selection despite some evidence of paclitaxel benefit—insufficient reproducibility in clinical laboratories. 1

• Tumor-infiltrating lymphocytes (TILs) should NOT be used to guide chemotherapy decisions in any breast cancer subtype, despite prognostic value in HER2+ and triple-negative disease. 1

• IHC4 (a four-marker immunohistochemical panel) should NOT be used to guide adjuvant systemic chemotherapy decisions in ER/PR-positive, HER2-negative breast cancer. 1

Lung Cancer: Where IHC Plays a Different Role

In non-small cell lung cancer (NSCLC), IHC serves primarily for histologic subtyping rather than direct chemotherapy selection:

• A limited two-marker panel (TTF-1 and p40) is recommended for NSCLC subtyping to distinguish adenocarcinoma from squamous cell carcinoma, which indirectly affects treatment as pemetrexed is contraindicated in squamous histology. 4

• ALK IHC with validated assays may be used directly to prescribe ALK inhibitors without molecular confirmation. 4

• PD-L1 IHC is essential for selecting patients for immune checkpoint inhibitor therapy using drug-specific companion diagnostics (22C3 for pembrolizumab, 28-8 for nivolumab, SP142 for atezolizumab). 4

Key Clinical Pitfalls

Common Misuses to Avoid:

1. Do not use IHC markers beyond ER/PR/HER2 to make chemotherapy decisions in breast cancer—the 2016 ASCO guidelines provide strong recommendations against most IHC-based predictive markers due to insufficient evidence quality and lack of reproducibility. 1

2. Distinguish between prognostic and predictive markers—many IHC markers (Ki-67, TILs, MAP-Tau) have prognostic value but do not predict benefit from specific chemotherapy regimens. 1

3. For HER2 testing, carefully distinguish IHC 0 from IHC 1+ when considering trastuzumab deruxtecan eligibility—examine at 40x magnification and consider second pathologist review for borderline cases. 1

4. Recognize that HER2 IHC 2+ requires ISH confirmation before determining HER2-positive status for traditional trastuzumab therapy, but HER2 IHC 2+/ISH not-amplified now qualifies for trastuzumab deruxtecan. 1

Evidence Quality Considerations

The ASCO 2016 guidelines represent the highest-quality evidence for breast cancer biomarkers, with evidence-based recommendations carrying intermediate to high evidence quality. 1 The consistent message across multiple guideline sections is that most IHC markers beyond ER/PR/HER2 lack sufficient reproducibility in clinical laboratories to guide therapy selection, even when they show promise in research settings with optimized conditions. 1

The 2023 ASCO-CAP HER2 guideline update represents the most recent high-quality evidence, establishing new clinical thresholds for HER2-low disease based on treatment availability rather than biological distinctions. 1