TCHP Remains the Preferred Neoadjuvant Regimen for High-Risk HER2+ Early Breast Cancer
For high-risk HER2-positive early breast cancer (tumors ≥2 cm or node-positive), TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) is the preferred neoadjuvant regimen over TDXd-THP, as TCHP is guideline-endorsed with robust clinical trial data demonstrating superior pathological complete response rates and established long-term outcomes, while TDXd (trastuzumab deruxtecan) lacks neoadjuvant approval and supporting evidence in this setting. 1, 2
Why TCHP is the Standard of Care
Guideline Endorsement and Evidence Base
NCCN explicitly lists TCHP as a "preferred regimen" for neoadjuvant treatment of stage II-III HER2-positive breast cancer, based on multiple high-quality trials 1, 2
ESMO guidelines recommend neoadjuvant chemotherapy with dual HER2 blockade (pertuzumab-trastuzumab) as the preferred option for clinical stage II-III HER2-positive disease, with either anthracycline-taxane or taxane-carboplatin backbones 1
The American College of Surgeons considers neoadjuvant chemotherapy with dual HER2 blockade standard for high-risk patients (tumors ≥2 cm and/or positive lymph nodes) 2
Superior Pathological Complete Response Rates
TCHP achieved the highest pCR rate of 66.2% among three pertuzumab-containing regimens tested in the TRYPHAENA trial 2, 3
The NeoSphere study demonstrated that pertuzumab-trastuzumab with docetaxel resulted in a pCR rate of 45.8%, significantly higher than trastuzumab with docetaxel alone (29%, p=0.0063) 1, 2
Real-world data confirms TCHP achieves pCR rates of 60-63%, substantially higher than historical controls with single-agent trastuzumab 3
Established Safety Profile and Long-Term Outcomes
TCHP demonstrates excellent tolerability with minimal grade 3-4 toxicities, no febrile neutropenia, and no congestive heart failure in multiple studies 4, 5
After median follow-up of 48.5 months, the anthracycline-free TCH regimen (without pertuzumab) showed disease-free survival of 84.6%, distant disease-free survival of 87.2%, and overall survival of 91% 4
The anthracycline-free approach avoids significant cardiac toxicity while maintaining efficacy comparable to anthracycline-containing regimens 4, 6
Why TDXd-THP is Not Appropriate
Lack of Neoadjuvant Approval and Evidence
Trastuzumab deruxtecan (TDXd) has no FDA approval or guideline endorsement for neoadjuvant treatment of early breast cancer - it is currently approved only for metastatic HER2-positive disease after prior anti-HER2 therapies 1
No published clinical trials have evaluated TDXd in the neoadjuvant setting for early breast cancer, making its efficacy and safety profile unknown in this context
The KRISTINE trial attempted de-escalation with T-DM1 (another antibody-drug conjugate) plus pertuzumab versus standard chemotherapy, but T-DM1-based regimen produced significantly lower pCR rates (44.4% vs 55.7%, p=0.016) and higher risk of event-free survival events (HR 2.61) 7, 2
Critical Safety Concerns in the Neoadjuvant Setting
The KRISTINE trial showed 15 pre-surgical locoregional progression events with T-DM1 plus pertuzumab versus 0 with standard chemotherapy, demonstrating the risk of inadequate disease control with antibody-drug conjugates alone 7, 2
Complete withdrawal of taxanes from neoadjuvant regimens is not recommended as standard practice for HER2-positive patients, and should only be considered in clinical trials 2
Post-Neoadjuvant Management Algorithm
If Pathological Complete Response is Achieved
Complete 1 year total of trastuzumab-based therapy (18 cycles total including neoadjuvant period) 1, 2, 8
Continue pertuzumab plus trastuzumab if node-positive at initial diagnosis (category 1 recommendation) 1, 8
If Residual Invasive Disease Remains
Switch to adjuvant T-DM1 for up to 14 cycles, which decreases risk of recurrence or death by 50% 1, 8
This is the only established role for an antibody-drug conjugate in the treatment algorithm for early HER2-positive breast cancer 1, 9
Critical Pitfalls to Avoid
Never omit pertuzumab in high-risk patients (stage II-III disease), as dual HER2 blockade is superior to single-agent trastuzumab with meaningful clinical benefit 1, 8
Never combine trastuzumab/pertuzumab with anthracyclines concurrently due to significant cardiac toxicity risk 1, 8
Never use investigational agents like TDXd outside of clinical trials in the neoadjuvant setting, as inadequate disease control could compromise surgical outcomes and long-term survival 7, 2
Ensure regular cardiac monitoring (before, during, and following therapy) with LVEF evaluation every 3 months during treatment 1, 8