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, Streptomyces peucetius (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 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 Qu et al, 2001 Anthracyclines have multiple mechanisms of action: Topo II  is only one of them …

5. What is the role of anthracyclines in the adjuvant chemotherapy of primary breast cancer?

6. Oxford Overview, 2000 Anthracyclines vs. CMF unselected node positive breast cancer Absolute differences in mortality is 3% at 5 years and 4% at 10 years

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

8. EBCTCG Meta - analysis 2005-06 Breast cancer mortality 10 0 5 0 5 0 5 50 0 40 30 20 Anthra 31.0% Taxane 25.9% % + SE 10-y gain 5.1% p < 0.00001 15.3 12.8 10-y gain 4.3% p < 0.00003 10y gain 4.2% p < 0.00001 Years CMF 31.3% Anthra 27.0% Control 36.4% CMF 32.2% 20.5 17.8 19.9 16.5 Peto et al. 2007 No Chemo < CMF < Anthra < Taxanes

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. Cochrane Review 2008 A taxane containing regimen should be considered for women with moderate to high risk of recurrence following assessment of their individual risk of recurrence and comorbidities Taxanes for adjuvant treatment Taxanes for adjuvant treatment of early breast cancer

11. Summary from 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. Should we use Anthracyclines in the Adjuvant Therapy of Breast Cancer according to HER2 and Topo2A expression?

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

16. 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

17. The Role of Anthracyclines from Adjuvant to Metastatic from Metastatic to Adjuvant

18. Do anthracyclines work in the metastatic setting?

19. Principles of Chemotherapy for Metastatic Breast Cancer EFFICACYTOXICITY (RR, TTP, OS) (QoL, non-Hem and Hem. toxicity) Evaluation of the Therapeutic Index Not cure in the vast majority of patients

20. The Goals o improve quality of life o prolong life o prevention and palliation of symptoms o cure Principles of Chemotherapy for Metastatic Breast Cancer o prolong life o improve quality of life

21. Selection of Chemotherapy for Metastatic Breast Cancer Risk of recurrence or death Benefit from treatment Toxicities Tumor biology Comorbidities Optimal treatment selection

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

26. Anthracyclines as single agents or in combination chemotherapy? Selection of Chemotherapy for Metastatic Breast Cancer

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

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

35. Sparano, J. A. et al. J Clin Oncol; 27:4522-4529 2009 CONSORT diagram International, phase III randomized study 751 patients were randomly assigned to receive either : docetaxel 75 mg/m 2 docetaxel 75 mg/m 2 (n = 373) or PLD 30 mg/m 2 followed by docetaxel 60 mg/m 2 PLD 30 mg/m 2 followed by docetaxel 60 mg/m 2 every 21 days (n = 378) and continued until disease progression or prohibitive toxicity.

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

37. Adverse Events

38. there is the agreement that, at least in the presence of: 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: o rapid clinical progression o life-threatening visceral metastases o 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 European School of Oncology - Metastatic Breast Cancer Task Force -

39. 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