What is the recommended treatment approach for HER2 (Human Epidermal growth factor Receptor 2)-positive invasive ductal carcinoma (IDC)?

HER2 Therapy for Invasive Ductal Carcinoma

Treatment Setting Determines Approach

For HER2-positive invasive ductal carcinoma, the treatment strategy depends critically on disease stage: early-stage disease requires dual HER2 blockade (trastuzumab plus pertuzumab) combined with chemotherapy for one year, while metastatic disease follows a sequential approach starting with trastuzumab, pertuzumab, and taxane as first-line therapy. 1, 2

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Early-Stage HER2-Positive IDC

Neoadjuvant Approach (Locally Advanced or High-Risk Disease)

• Administer trastuzumab, pertuzumab, and a taxane for 3-6 cycles preoperatively, followed by definitive surgery 1, 3
• The taxane component should be docetaxel 75-100 mg/m² every 3 weeks or weekly paclitaxel 80 mg/m² for 12 weeks 3
• Complete one full year (52 weeks) of trastuzumab-based therapy starting from neoadjuvant initiation 1, 4

Post-Neoadjuvant Management Based on Response

• If pathologic complete response (pCR) is achieved: Continue trastuzumab and pertuzumab to complete one year total, with no additional chemotherapy needed 1
• If residual invasive disease remains after neoadjuvant therapy: Switch to trastuzumab emtansine (T-DM1) for 14 cycles as adjuvant therapy, which reduces recurrence risk by 50% compared to continuing trastuzumab 5, 1
  • This recommendation is based on the KATHERINE trial showing invasive disease-free survival hazard ratio of 0.50 (95% CI 0.39-0.64) 5
  • If T-DM1 is unavailable, continue trastuzumab plus pertuzumab 1

Adjuvant-Only Approach (Operable Disease Without Neoadjuvant Therapy)

• Administer anthracycline-taxane chemotherapy combined with trastuzumab and pertuzumab for one year postoperatively 1, 4
• Standard regimen: Four cycles of doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² followed by paclitaxel with concurrent trastuzumab and pertuzumab 4
• Trastuzumab dosing: Initial 4 mg/kg loading dose, then 2 mg/kg weekly, or 8 mg/kg loading followed by 6 mg/kg every 3 weeks 6, 4
• Pertuzumab dosing: Initial 840 mg IV over 60 minutes, then 420 mg every 3 weeks 6

Radiation and Endocrine Therapy Sequencing

• Administer all chemotherapy before starting radiation therapy, but HER2-targeted therapy (trastuzumab/pertuzumab) continues during radiation 1
• Postmastectomy radiation is mandatory for T3 tumors, ≥4 positive nodes, or locally advanced disease 1, 3
• For hormone receptor-positive disease, start endocrine therapy after completing all chemotherapy (given sequentially, not concurrently), but it can be given concurrently with HER2-targeted therapy 1

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Metastatic HER2-Positive IDC

First-Line Treatment

• The standard first-line regimen is trastuzumab, pertuzumab, and a taxane unless contraindications to taxanes exist 7, 2
• Continue chemotherapy for approximately 4-6 months or until maximal response, then continue HER2-targeted therapy indefinitely until disease progression or unacceptable toxicity 7, 2
• If recurrence occurs >12 months after completing adjuvant trastuzumab, restart first-line therapy (trastuzumab, pertuzumab, taxane) 7, 1
• If recurrence occurs ≤12 months after completing adjuvant trastuzumab, proceed directly to second-line therapy 7, 1

Second-Line Treatment

• Trastuzumab deruxtecan (T-DXd) is the preferred second-line agent after progression on first-line HER2-targeted therapy 2
• If T-DXd is unavailable, use trastuzumab emtansine (T-DM1) 7, 2

Third-Line and Beyond

• If T-DM1 was not previously given, offer it at this stage 7, 2
• If pertuzumab was not previously given, it may be considered (weak evidence) 7
• After receiving both pertuzumab and T-DM1, options include lapatinib plus capecitabine, other chemotherapy combinations with trastuzumab, or lapatinib plus trastuzumab 7, 2

Hormone Receptor-Positive and HER2-Positive Disease

• HER2-targeted therapy plus chemotherapy remains the strongest evidence-based approach 7, 2
• In selected cases with low disease burden, significant comorbidities (such as contraindication to chemotherapy), or long disease-free interval, consider endocrine therapy plus trastuzumab or lapatinib 7, 2
• Endocrine therapy alone is only appropriate in highly selected cases with very low disease burden and significant contraindications to HER2-targeted therapy 7, 2

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Cardiac Monitoring Requirements

• Evaluate left ventricular ejection fraction (LVEF) prior to treatment initiation and every 3 months during HER2-targeted therapy 1
• Permanently discontinue trastuzumab if congestive heart failure develops or persistent/recurrent LVEF decline occurs 6, 4
• Avoid combining trastuzumab with anthracyclines due to 27% risk of cardiac dysfunction versus 8% with sequential therapy 1

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Critical Pitfalls to Avoid

• Never stop trastuzumab early—it must be completed for a full year (52 weeks) from the start of neoadjuvant or adjuvant therapy 1, 3
• Never discontinue HER2-targeted therapy when chemotherapy ends in the metastatic setting; continue until disease progression 7, 2
• Never give chemotherapy and endocrine therapy concurrently; they must be sequential with endocrine therapy starting after chemotherapy completion 1
• Never omit pertuzumab from the initial regimen in early-stage disease, as dual HER2 blockade provides 24% relative reduction in recurrence risk 1
• Never omit radiation therapy in T3N1 or higher disease, as postmastectomy radiation is mandatory for locoregional control 1, 3

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Special Consideration: Adjacent DCIS

• HER2-positive IDC with adjacent ductal carcinoma in situ (DCIS) shows lower response rates to neoadjuvant chemotherapy and trastuzumab compared to pure IDC 8
• However, complete eradication of adjacent DCIS is frequently observed (50.8% of cases) with standard HER2-targeted therapy 8
• The presence of adjacent DCIS is an independent negative predictor of pathologic complete response (odds ratio 0.42,95% CI 0.2-0.9) 8