Trastuzumab
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
- Trastuzumab
- Trastuzumab: From HER2-Positive Breast Carcinoma to Progesterone-Receptor Positive Breast Cancer
Trastuzumab: From HER2-Positive Breast Carcinoma to Progesterone-Receptor Positive Breast Cancer
One-Sentence Summary
Trastuzumab is a HER2-targeted antibody originally used to treat HER2-positive breast carcinoma. The TxGNN model predicts it may be effective for progesterone-receptor positive breast cancer, with 14 clinical trials and 20 publications currently supporting this direction. Most of this evidence reflects the already-established HER2-positive population, so the benefit is expected only in tumours that are both PR-positive and HER2-positive.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | HER2-positive breast carcinoma (the Singapore licence records contain no indication text) |
| Predicted New Indication | Progesterone-receptor positive breast cancer |
| TxGNN Prediction Score | 99.90% |
| Evidence Level | L1 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 11 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, trastuzumab is an antibody directed against HER2. Its efficacy in HER2-positive breast carcinoma is established, and mechanistically it may be applicable to the HER2-positive subset of PR-positive breast cancers.
A proportion of PR-positive breast cancers also overexpress HER2 (the HER2+/HR+ group). The approved HER2-positive indication therefore already overlaps with this population. Benefit is expected only in HER2-positive tumours, not in HER2-negative PR-positive disease.
Endocrine therapy is typically combined with HER2-directed treatment in this group. Crosstalk between HER2 and hormone receptor signalling is a recognised resistance mechanism, which is why combination approaches are being tested.
Other predicted indications in the same analysis:
- PR-negative breast cancer (score 99.90%, L1): trastuzumab works through HER2 blockade, so benefit applies only to HER2-positive patients and not to triple-negative disease. Phase 3 evidence exists, mostly in HER2-positive patients.
- Luminal A or B breast tumour (L1): evidence is from the literature only, with no trials listed under this term. Luminal B HER2-positive tumours respond to trastuzumab, but Luminal A tumours are generally HER2-negative.
- Normal breast-like subtype (L4, Hold): this subtype is generally HER2-low or HER2-negative, so there is little rationale. The one listed trial tests a different agent.
- Six rare tumour types (L5, Hold): these have model predictions only, with no clinical or literature support. They are malignant cutaneous granular cell tumour, ectomesenchymoma, human herpesvirus 8-related tumour, middle ear neuroendocrine tumour, kidney pelvis sarcomatoid transitional cell carcinoma, and prostatic urethra urothelial carcinoma. HER2 overexpression occurs in some urothelial carcinomas, so those two have a plausible rationale.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01275677 | Phase 3 | Completed | 3270 | Adjuvant chemotherapy with or without trastuzumab in node-positive or high-risk node-negative breast cancer |
| NCT04629846 | Phase 3 | Completed | 517 | QL1209 (pertuzumab biosimilar) vs pertuzumab, each with trastuzumab and docetaxel, in HER2-positive, ER/PR-negative breast cancer |
| NCT00053339 | Phase 3 | Withdrawn | 0 | Trastuzumab with or without tamoxifen in HR-positive, HER2-positive metastatic disease; no patients enrolled, so no evidence |
| NCT00194779 | Phase 2 | Completed | 50 | Neoadjuvant chemotherapy regimen in HER2-positive breast cancer |
| NCT01750073 | Phase 2 | Completed | 92 | Neoadjuvant paclitaxel and cyclophosphamide with or without trastuzumab |
| NCT00134680 | Phase 2 | Completed | 33 | Letrozole plus trastuzumab in ErbB2-positive, ER and/or PR-positive metastatic breast cancer |
| NCT04886531 | Phase 2 | Recruiting | 30 | Pre-operative neratinib, endocrine therapy and trastuzumab in ER-positive, HER2-positive cancers |
| NCT02260531 | Phase 2 | Completed | 36 | Cabozantinib alone or with trastuzumab in breast cancer brain metastases |
| NCT04334330 | Phase 2 | Unknown | 34 | Palbociclib, trastuzumab, pyrotinib and fulvestrant in ER/PR-positive, HER2-positive brain metastases |
| NCT02152943 | Phase 1 | Completed | 37 | Everolimus, letrozole and trastuzumab in HR-positive, HER2-positive advanced cancers |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 32353342 | 2020 | RCT (phase 2) | Lancet Oncol | monarcHER: abemaciclib plus trastuzumab with or without fulvestrant vs trastuzumab plus chemotherapy in HR-positive, HER2-positive advanced breast cancer |
| 16236738 | 2005 | RCT | N Engl J Med | Adjuvant chemotherapy with or without trastuzumab in operable HER2-positive breast cancer |
| 26874901 | 2016 | RCT (phase 3) | Lancet Oncol | ExteNET: neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer |
| 27179402 | 2016 | Phase 2 RCT | Lancet Oncol | NeoSphere 5-year analysis of neoadjuvant pertuzumab and trastuzumab in HER2-positive breast cancer |
| 31410192 | 2019 | Multi-cohort study | Theranostics | Molecular features and trastuzumab responsiveness of ER+/PR+/HER2+ (triple-positive) breast cancer |
| 21151204 | 2011 | Review | Nat Rev Clin Oncol | HER2 and hormone receptor-positive breast cancer: combining aromatase inhibitors with anti-HER2 therapy |
| 35640077 | 2022 | Guideline | J Clin Oncol | ASCO guideline update on systemic therapy for advanced HER2-positive breast cancer |
| 39631485 | 2024 | Review | Pharmacol Res | Targeted and cytotoxic inhibitors in breast cancer, by HER2, HR, ER and PR status |
| 15894097 | 2005 | Meta-analysis | Lancet | Overview of randomised trials of chemotherapy and hormonal therapy in early breast cancer |
| 40339592 | 2025 | Phase 2a | Lancet Oncol | Zanidatamab plus palbociclib and fulvestrant in HR-positive, HER2-positive metastatic breast cancer |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14867P | Herceptin Solution for Injection 600mg/5ml | Injection, solution | Not stated in the licence records |
| SIN11028P | Herceptin Powder for Injection 440 mg/vial | Injection, powder, for solution | Not stated in the licence records |
| SIN15839P | Herzuma 440mg | Lyophilised powder for infusion | Not stated in the licence records |
| SIN16206P | Kanjinti 150 mg/vial | Injection, powder, for solution | Not stated in the licence records |
| SIN16247P | Phesgo 1200 mg/600 mg / 15 ml | Injection, solution (subcutaneous) | Not stated in the licence records |
There are 11 valid registrations in total, all single-ingredient products. They include the originator and several biosimilars (Herzuma, Kanjinti, Trazimera, Trazher) as well as the Phesgo subcutaneous formulation.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (HER2-directed monoclonal antibody), not a conventional cytotoxic |
| Myelosuppression Risk | Low as a single agent; it may add to the myelosuppression of combined chemotherapy |
| Emetogenicity Classification | Low |
| Monitoring Items | Cardiac function (LVEF) before and during treatment, CBC when combined with chemotherapy, infusion-related reactions |
| Handling Protection | Please refer to the package insert warnings and precautions |
Cardiotoxicity is a recognised concern (see PMID 17687157 in the compiled literature).
Safety Considerations
- Drug Interactions: 94 interactions were identified, with the main ones below.
- Major: deferiprone, samarium (153Sm) lexidronam, adalimumab, baricitinib.
- Moderate: paclitaxel, warfarin, dicoumarol, zidovudine, chloramphenicol, roflumilast, palifermin, azathioprine, alemtuzumab, anakinra, canakinumab, alefacept, strontium chloride Sr-89, and some vaccines (tetanus toxoid, anthrax).
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Large Phase 3 and Phase 2 trials support trastuzumab in HER2-positive breast cancer, including HR-positive disease. The new indication largely overlaps with the approved population, so the evidence is strong, but only for HER2-positive tumours. One Phase 3 trial of trastuzumab with tamoxifen in this group was withdrawn without enrolling anyone.
To proceed, the following is needed:
- Restriction of use to patients confirmed HER2-positive, with PR status as a stratifier.
- Package insert warnings and contraindications from the HSA, which are currently missing.
- Mechanism of action data to be added.
- Cardiac monitoring and drug interaction review, especially for co-medications with major interactions.
- Confirmation of the approved indication wording on the Singapore licences.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.