Letrozole
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
Letrozole: From Breast Cancer Endocrine Therapy to Female Breast Carcinoma
One-Sentence Summary
Letrozole is an oral aromatase inhibitor that lowers estrogen production, and it is already marketed in Singapore for hormone-driven breast cancer. The TxGNN model predicts it may be effective for female breast carcinoma, which is an established use of the drug, not a new one. This direction is supported by 40 clinical trials and 19 publications listed for this prediction, including several large Phase 3 trials.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available (the Singapore licence records contain no indication text); the predicted indication is breast cancer, the drug's established use |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 99.98% |
| 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, letrozole is a non-steroidal aromatase inhibitor. It blocks the conversion of androgens to estrogens, which lowers estrogen-driven growth signalling in hormone receptor-positive breast cancer.
The predicted indication is therefore consistent with how the drug is already used. Phase 3 data (MONALEESA-2, PALOMA-2, COMPLEEMENT-1) support letrozole as the endocrine backbone in combination with CDK4/6 inhibitors. Because this is an established, marketed use, it is not a repurposing candidate in the strict sense. The prediction mainly confirms current practice.
Other predictions in the data are weaker. They include:
- Hormone-resistant breast carcinoma (L2), a research question where benefit would come from combinations.
- Bilateral breast carcinoma (L3), a research question supported only by indirect evidence.
- Estrogen-receptor negative breast cancer, nipple carcinoma, breast fibrocystic disease, benign mammary dysplasia and Ehrlich tumor carcinoma (all L4–L5, Hold). For ER-negative disease, the high score is not backed by direct clinical evidence.
Clinical Trial Evidence
The data list 40 trials for this prediction. The ten most relevant are shown below.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02941926 | Phase 3 | Completed | 3246 | Ribociclib + letrozole in HR+/HER2- advanced breast cancer; large safety and efficacy dataset |
| NCT02600923 | Phase 3 | Completed | 131 | Palbociclib + letrozole in postmenopausal HR+/HER2- advanced breast cancer |
| NCT01740427 | Phase 3 | Completed | 666 | PALOMA-2: palbociclib + letrozole vs placebo + letrozole, first-line |
| NCT00382070 | Phase 3 | Unknown | 3966 | Five years of extended letrozole vs placebo after prior hormonal therapy |
| NCT03425838 | Phase 3 | Active, not recruiting | 1050 | SONIA: CDK4/6 inhibitor with an aromatase inhibitor first-line vs second-line |
| NCT00908531 | Phase 3 | Terminated | 123 | Letrozole before surgery vs surgery first; low power |
| NCT04584853 | Phase 3 | Active, not recruiting | 123 | POETIC-A: adjuvant endocrine therapy ± abemaciclib after 2-week aromatase inhibitor window |
| NCT04272801 | Phase 2 | Active, not recruiting | 84 | Pre-operative endocrine therapy in older women to inform radiation decisions |
| NCT01439711 | Phase 2 | Completed | 108 | Neoadjuvant letrozole in ER+ ductal carcinoma in situ |
| NCT00688909 | Phase 4 | Completed | 261 | Rheumatological tolerability of letrozole after anastrozole intolerance |
Literature Evidence
The data list 19 publications for this prediction. The ten most relevant are shown below, with RCTs first.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 35263519 | 2022 | RCT | N Engl J Med | Overall survival with ribociclib + letrozole in advanced breast cancer |
| 29718092 | 2018 | RCT | Ann Oncol | MONALEESA-2 updated efficacy, safety and biomarker results |
| 30632023 | 2019 | RCT | Breast Cancer Res Treat | PALOMA-2 extended follow-up; palbociclib + letrozole prolonged progression-free survival (HR 0.58) |
| 36243120 | 2022 | Review | Life Sci | Letrozole pharmacology, toxicity and therapeutic uses |
| 17912633 | 2007 | Review | Breast Cancer Res Treat | Discovery and mechanism of action of letrozole |
| 20095792 | 2010 | Review | Expert Opin Drug Metab Toxicol | Letrozole pharmacology and clinical efficacy and safety |
| 17544670 | 2007 | Review | Breast | Extended adjuvant letrozole and the MA-17 trial |
| 12113048 | 2002 | Review | Expert Rev Anticancer Ther | Letrozole shown superior to tamoxifen first-line in metastatic disease |
| 19250202 | 2009 | Review | Ann N Y Acad Sci | Aromatase inhibitors in a preclinical model of postmenopausal breast cancer |
| 35464999 | 2022 | Comparative study | Comput Math Methods Med | Tamoxifen followed by letrozole vs letrozole alone |
Singapore Market Information
All 11 registrations are valid, single-ingredient, oral film-coated tablets (2.5 mg). The licence records contain no approved indication text.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN09915P | Femara Tablet 2.5 mg (Novartis) | Tablet, film coated | Not stated in licence record |
| SIN14565P | Letrozole Sandoz Film Coated Tablets 2.5 mg | Tablet, film coated | Not stated in licence record |
| SIN13916P | Letrozole Mevon Tablets 2.5 mg | Tablet, film coated | Not stated in licence record |
| SIN14406P | Lotuserm Film-Coated Tablets 2.5 mg | Tablet, film coated | Not stated in licence record |
| SIN15739P | Zatrolex Film-Coated Tablet 2.5 mg | Tablet, film coated | Not stated in licence record |
Six other registrations are not listed: Letara, Letrocord, Letrovitae, Lebreta, Letero and Lentronat.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Hormonal (endocrine) antineoplastic agent, non-steroidal aromatase inhibitor; not a conventional cytotoxic |
| Myelosuppression Risk | Low; please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Low |
| Monitoring Items | Please refer to the package insert; bone health and liver function are relevant given the knowledge-graph signals below |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
Package insert warnings and contraindications were not available in the data compiled for this report.
- Disease-level contraindication signals (knowledge graph, not label text): liver failure, cirrhosis of liver, osteoporosis, postmenopausal osteoporosis, hyperbilirubinemia, hereditary hyperbilirubinemia, Gilbert syndrome and cerebrovascular disorder.
- Drug Interactions: The interaction query found 100 records. Most are of unknown severity. The only one rated Moderate is aprepitant. Others in the sample include calcitriol, glimepiride, metformin, simvastatin, prednisone, omeprazole, pantoprazole, lansoprazole, famotidine and morphine.
Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Multiple completed Phase 3 trials and RCT publications support letrozole-based endocrine therapy in HR+ breast cancer. The drug is already marketed in Singapore with 11 valid registrations. This is confirmation of an established use, not a new repurposing opportunity, and the package insert safety review is still outstanding.
To proceed, the following is needed:
- Singapore package insert warnings and contraindications (a blocking gap for safety screening)
- Detailed mechanism of action data from DrugBank
- Approved indication text for the Singapore licences
- Bone-health and liver-function monitoring plan, given the knowledge-graph contraindication signals
- Restriction of use to hormone receptor-positive disease, since ER-negative evidence is indirect
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.