Topotecan
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Topotecan: From Ovarian Cancer to Female Breast Carcinoma
One-Sentence Summary
Topotecan is a topoisomerase I inhibitor chemotherapy, originally used for ovarian cancer and related ovarian tumours. The TxGNN model predicts it may be effective for Female Breast Carcinoma, with 3 clinical trials (all early-phase or combination studies) and 20 publications currently linked to this direction. Most of this evidence is indirect, so the prediction is best treated as a research question.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Ovarian cancer (including ovarian germ cell tumours, yolk sac tumour and related subtypes) |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 99.92% |
| Evidence Level | L3 |
| US Market Status | Cancelled only (no currently valid licences in the data compiled for this report) |
| Number of NDAs | 7 (3 NDAs and 4 ANDAs, all cancelled) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on the known drug class, topotecan inhibits topoisomerase I, causing DNA damage and replication-dependent cell death in rapidly dividing tumour cells. Its efficacy in ovarian cancer is established, and mechanistically it may be applicable to breast cancer.
Two lines of evidence support the link:
- A 2023 preclinical study (PMID 37987734) suggests that topoisomerase 1 inhibition causes aberrant R-loop accumulation and synthetic lethality in MYC-driven cancer. This may be relevant to MYC-high breast cancer subtypes such as triple-negative disease.
- Topotecan is a substrate of the BCRP/ABCG2 efflux transporter, which is expressed in breast cancer cells and may drive resistance. Several of the publications listed below address this.
This rationale rests on the class mechanism and preclinical data, not on direct clinical proof in breast cancer.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00006032 | Phase 2 | Terminated | Not reported | Intensive-dose topotecan, ifosfamide/mesna and etoposide (TIME) followed by autologous stem cell rescue in metastatic breast cancer. Topotecan’s individual contribution cannot be isolated. |
| NCT02419495 | Phase 1 | Terminated | 221 | Selinexor combined with several standard chemotherapies (topotecan among them) in advanced malignancies. Combination safety data only; no topotecan-specific breast cancer efficacy signal. |
| NCT06840886 | Phase 1 | Recruiting | 426 | First-in-human dose escalation and expansion study of PHST001 in advanced solid tumours. Link to topotecan is indirect and no results are available. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 9413954 | 1997 | Phase 2 | Br J Cancer | Continuous infusional topotecan in advanced breast cancer and NSCLC showed no evidence of increased efficacy |
| 11455218 | 2001 | Pilot study | Onkologie | Topotecan as primary chemotherapy for breast cancer brain metastases |
| 9425961 | 1997 | Review | Semin Oncol | Potential role of topotecan in advanced breast cancer |
| 37987734 | 2023 | Preclinical | Cancer Res | Topoisomerase 1 inhibition promotes R-loop accumulation and synthetic lethality in MYC-driven breast cancer models |
| 10472342 | 1999 | Preclinical | Anticancer Res | Xenograft comparison; irinotecan and doxorubicin regressed breast lines, and topotecan was also tested |
| 10930538 | 2000 | Preclinical | Biochem Pharmacol | BCRP expression in topotecan-resistant MCF7 breast carcinoma cells |
| 15836850 | 2005 | Preclinical | J Surg Res | Effect of quercetin on topotecan cytotoxicity in MCF-7 and MDA-MB-231 cells |
| 25236865 | 2015 | Review | AAPS J | BCRP/ABCG2 drug transport; topotecan is a substrate |
| 21514634 | 2011 | Phase 2 | Gynecol Oncol | Lapatinib plus topotecan in platinum-resistant ovarian cancer, testing BCRP efflux blockade (indirect) |
| 39013199 | 2024 | Expert consensus | Rev Colomb Obstet Ginecol | Management of advanced epithelial ovarian cancer (indirect) |
US Market Information
All 7 US authorisations are currently cancelled. The approved indication text is not available in the data compiled for this report.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA020671 | HYCAMTIN (Novartis) | Injection, powder, lyophilized, for solution | Not available (cancelled) |
| NDA020981 | HYCAMTIN (Sandoz) | Capsule | Not available (cancelled) |
| NDA200582 | Topotecan (Hospira) | Injection, solution, concentrate | Not available (cancelled) |
| ANDA091089 | Topotecan Hydrochloride (Fresenius Kabi) | Injection, powder, lyophilized, for solution | Not available (cancelled) |
| ANDA204406 | Topotecan (Accord Healthcare) | Injection | Not available (cancelled) |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (topoisomerase I inhibitor, camptothecin derivative) |
| Myelosuppression Risk | High (myelosuppression is the main dose-limiting toxicity; the knowledge graph lists neutropenia, thrombocytopenia, anaemia and agranulocytosis as contraindication-related conditions) |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | CBC with differential, liver and renal function; monitor for diarrhoea and respiratory symptoms |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
- Contraindication-related conditions (from the drug-disease knowledge graph, not label text): thrombocytopenia, neutropenia, agranulocytosis, anaemia (including macrocytic anaemia), interstitial lung disease, pulmonary fibrosis (including post-inflammatory), diarrhoeal disease, and impaired renal function.
- Drug Interactions: 100 interactions were identified. Major-level interactions include:
- Deferiprone
- Samarium (153Sm) lexidronam
Moderate-level interactions include:
- Eliglustat
- Rolapitant
- Iobenguane (I-131)
- Palifermin
- Strontium chloride Sr-89
- Ibritumomab tiuxetan
Several are agents that also suppress bone marrow, so additive myelosuppression is a concern. Other listed interactions are minor or of unknown severity (for example levofloxacin, caffeine, ondansetron and proton pump inhibitors).
Please refer to the package insert for full warnings and precautions, as label text was not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The TxGNN score is very high (99.92%), but the supporting clinical data are weak: the only breast cancer trials are terminated, early-phase or combination studies, and the one relevant phase 2 publication found no evidence of increased efficacy. Evidence is mainly preclinical, review and indirect. With all US licences cancelled and label safety data missing, the prediction is best treated as a research question.
To proceed, the following is needed:
- Dedicated, topotecan-specific clinical data in breast cancer, with attention to MYC-high and triple-negative subtypes
- Detailed mechanism of action data to strengthen the mechanistic link
- Full package insert warnings and contraindications
- Clarification of current US regulatory status, since all licences are cancelled
- Safety monitoring plan for myelosuppression, pulmonary toxicity and diarrhoea in breast cancer populations
Other predictions: The next-ranked prediction, adult germ cell tumour (score 99.57%, evidence level L2), is clinically closer to topotecan’s existing ovarian germ cell indication, but its trial and literature evidence mostly concerns neuroblastoma, glioma and retinoblastoma. The testicular yolk sac tumour pattern predictions (ranks 3–10, score 99.49%) have no trials or literature and are on Hold.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.