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OLD AND NEW ANTHACYCLINES: A STILL VALID OPTION IN BREAST CANCER TREATMENT True : Clara Natoli

OLD AND NEW ANTHACYCLINES: A STILL VALID OPTION IN BREAST CANCER TREATMENT True : Clara Natoli. Anthracyclines are actually the most discussed drugs in breast cancer treatment. Anthracyclines.

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OLD AND NEW ANTHACYCLINES: A STILL VALID OPTION IN BREAST CANCER TREATMENT True : Clara Natoli

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  1. OLD AND NEW ANTHACYCLINES: A STILL VALID OPTION IN BREAST CANCER TREATMENT True: Clara Natoli

  2. Anthracyclines are actually the most discussed drugs in breast cancer treatment

  3. Anthracyclines FarmItalia Research developed anthracyclines in 1960s. They are derivatives of soil microbe, Streptomycespeucetius(rhodomycin), taken at Castel Del Monte, near Andria. Doxorubicin was approved by FDA in 1974. The first trial of epirubicin in humans was published in 1980. Upjohn applied for approval by the FDA in node- positive breast cancer in 1984, but was turned down because of lack of data. However, epirubicin was licensed for use in Europe from around this time. Patent protection for epirubicin expired in August 2007.

  4. Anthracyclines Proposed Mechanisms of Action Qu et al, 2001 • Inhibition of DNA and RNA synthesis by multiple mechanisms, including: • Inhibition of topoisomerase II preventing the relaxing of supercolied DNA, thus blocking trascription and replication • Single strand DNA breakage • Intercalation between DNA base pairs • Inhibition of proteasome function • Chelation of divalent cations • Production of iron-mediated free O2 radicals able to damage DNA and cell membranes • Inhibition of angiogenesis Anthracyclines have multiple mechanisms of action: TopoIIa is only one of them …

  5. What is the role of anthracyclines in the adjuvantchemotherapy ofprimarybreastcancer?

  6. Oxford Overview, 2000 Anthracyclines vs. CMF unselectednode positive breastcancer Absolute differences in mortality is 3% at 5 years and 4% at 10 years

  7. Role of the Taxanes O O OH HO O OH O O H O H NH O NH O O H O O O O O O OH O OH OH OH O O O O Paclitaxel Docetaxel

  8. 5 10 5 10 5 10 EBCTCG Meta - analysis 2005-06Breast cancer mortality No Chemo < CMF < Anthra < Taxanes 10y gain 4.2% p < 0.00001 10-y gain 4.3% p < 0.00003 10-y gain 5.1% p < 0.00001 50 Control36.4% CMF31.3% Anthra 31.0% 40 30 CMF32.2% 20.5 % + SE 19.9 Anthra27.0% 20 15.3 Taxane25.9% 17.8 16.5 12.8 10 0 0 0 0 Years Peto et al. 2007

  9. Even if taxanes are superior to anthracyclines, it makes sense to try to combine them with anthracyclines, since neither group of drugs is effective in more than a minority of breast cancer patients • their mechanisms of action are different • they show noncross-resistance

  10. Taxanes for adjuvant treatment of early breast cancer Cochrane Review 2008 A taxanecontainingregimenshouldbeconsideredfor women with moderate to high riskofrecurrencefollowingassessmentoftheirindividualriskofrecurrence and comorbidities

  11. Summaryfrom ASCO 2009

  12. Safety of Anthracyclines: Cardiotoxicity • Clinical CHF is rare (< 1%) • In EBCTCG analysis, mortality from heart disease was 0.08% vs 0.06% per year[1] • Decrease risk by screening patients 1. EBCTCG. Lancet. 2005;365:1687-1717.

  13. ShouldweuseAnthracyclines in the AdjuvantTherapyofBreastCanceraccordingto HER2 and Topo2A expression?

  14. We must still identify reliable predictors of benefit and resistance to individual drugs to reach the objective of personalized therapy

  15. We believe that … … anthracyclines should still be used in adjuvant chemotherapy (including HER2-positive tumors) because there is insufficient evidence to date supporting the efficacy of alternative regimens

  16. The RoleofAnthracyclines fromMetastatictoAdjuvant fromAdjuvanttoMetastatic

  17. Do anthracyclines work in the metastaticsetting?

  18. PrinciplesofChemotherapy forMetastaticBreastCancer EFFICACY TOXICITY (RR, TTP, OS) (QoL, non-Hem and Hem. toxicity) Evaluationof the TherapeuticIndex Not cure in the vast majority of patients

  19. PrinciplesofChemotherapy forMetastaticBreastCancer • The Goals • improve quality of life • prolong life • prevention and palliation of symptoms • cure • prolong life • improvequalityof life

  20. SelectionofChemotherapy forMetastaticBreastCancer Benefit from treatment Riskofrecurrence or death Optimal treatment selection Toxicities Tumorbiology Comorbidities

  21. Cardiotoxocity is a major clinical handicap limiting the cumulative dose of doxorubicin and epirubicin in the metastatic setting

  22. SelectionofChemotherapy forMetastaticBreastCancer Anthracyclines as single agents or in combination chemotherapy?

  23. Efficacy data from randomized studies with mandated crossover in the monotherapy arm * * * * * Cardoso et al, J Natl Cancer Inst 2009;101:1174–1181

  24. … conventional anthracyclines are limited by cardiac toxicity • PLD has comparable efficacy and significantly improved safety profile compared with conventional doxorubicin in MBC1 • Significantly less cardiotoxicity • Less nausea/vomiting, alopecia, and myelosuppression Pegylated Liposomal Doxorubicin (PLD) 1O’Brien et al. Ann Oncol. 2004;15:440-449.

  25. CONSORT diagram International, phase III randomized study 751 patientswere randomly assigned to receive either : docetaxel 75 mg/m2(n = 373) or PLD 30 mg/m2 followed by docetaxel 60 mg/m2every 21 days (n = 378) and continueduntil disease progression or prohibitive toxicity. Sparano, J. A. et al. J Clin Oncol; 27:4522-4529 2009

  26. Time to progression for PLD plus docetaxel and docetaxel groups Sparano, J. A. et al. J Clin Oncol; 27:4522-4529 2009

  27. AdverseEvents

  28. European School of Oncology - Metastatic Breast Cancer Task Force - • Even if no consensus exists and both combination and sequential single-agent chemotherapy are reasonable options as first-line systemic therapy, there is the agreement that, at least in the presence of: • rapid clinical progression • life-threatening visceral metastases • the need for rapid symptom and/or disease control • combination chemotherapy, possibly including anthracyclines and taxanes, should be the first choice Cardoso et al, J Natl Cancer Inst 2009;101:1174–1181

  29. Summary • Anthracycline-based regimens are still a standard of care for breast cancer treatment • Retreatment of MBC is effective and PLD is rational choice for retreatment of patients who have received previous anthracyclines • There is currently insufficient evidence: • To replace anthracycline-based adjuvant chemotherapy with non-anthracycline-based regimens • To support the use of biomarkers HER2 and Topo II to select chemotherapy regimens

  30. Grazie per l’attenzione

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