Adjuvant therapy in early breast cancer

Transcription

1 Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania Centro di Riferimento Regionale per la diagnosi e la terapia dei tumori del colon-retto. D.A. 26/10/2012 G.U.R.S. del 14/12/2012 parte I, n 53 Adjuvant therapy in early breast cancer Roberto Bordonaro Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania Siracusa, 6 giugno 2014

2 Historycal background Halstedian conception of loco-regional preminent High demolitive surgery (Radical mastectomy or modified and extended radical mastectomy ) diffusion of breast cancer (1894) Local relapses usually not exceed 5 per cent But overall survival at 5 years of about 12 per cent Characteristics of the patients 10-years overall survival from surgery (%) Node negative 75 Node positive 30 Fischer, 1978

3 Bonadonna s CMF data. Relapse-free-survival Overall survival median Observation time = 28.5 years. H.r. for RFS = 0.71 (r ; p = 0.005) in favour of CMF H.R. for OS = 0.79 (r ; p = 0.04) in favour of CMF

4 EBCTCG meta-analysis Meta-analysis of 194 controlled randomized studies. Clinical and demographic data Primary end-points: - Time to first relapse - Mortality (overall) - Cancer-specific mortality - Cause-specific mortality - Seconda cancer s occurence The Lancet, 2005

5 EBCTCG Meta-analysis Breast cancer mortality Taxanes > Anthra. > CMF > No Chemo y gain 4.3% (SE 1.0) Lorank 2p < y gain 4.3% (SE 1.0) Lorank 2p < y gain 5.1% (SE 1.6) Lorank 2p < Control 36.4% CMF 31.3% Anthr. 31.0% % + SE CMF 32.2% Anthr. 27.0% Taxane 25.9% 0 Years Years Years Death rates (% / year: total rate in women without recurrence) & logrank analyses Peto R on behalf of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Presented at SABCS 2007, December 13, San Antonio, TX.

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7 SAME non-taxane CHT DIFFERENT non-taxane CHT

8 SAME non-taxane CHT SAME non-taxane CHT DIFFERENT non-taxane CHT

9 Signal transduction pathways in breast cancer cells

10 Signal transduction pathways in breast cancer cells

11 Risk Reduction in Early Breast Cancer in Estrogen Receptor Positive Patients DFS OS EBCTCG,Lancet 1998

12 Ais as adjuvant therapy in early breast cancer: an update. Study ATAC IES ABCSG 8 ARNO 95 ITA MA17 BIG1-98 SAMPLE DESIGN OF THE STUDY T x 5aa vs. A x 5 aa vs. T + A x 5 aa T x 5 vs. T x 2/3 E x 3/2 T x 5 vs. T x 2 A x 3 T x 5 vs. T x 2/3 A x 3/2 T x 5 Placebo vs. T x 5 L x 5 T x 5 vs. L x 5 vs. T-L vs- L-T CHARACTERISTICS OF THE PATIENTS N0 = 61% HR + = 84% N0 = 51% HR + = 81% N0 = 74% HR + = 96% N+ = 100% HR + = 86% N0 = 50% HR + = 98% N0 = 57% HR+ = 99% median FOLLOW-UP (years) DFS IMPROVEMENT (%) DFS ABSOLUTE DIFFERENCES % 4.7 % 3.5 % 5.3 % 5 % 3.4 %

13 EGF receptors and their ligands. Ligandi: EGF TGF- Anfiregulina Betacellulina HB-EGF Epiregulina Neureguline NRG2 NRG3 Eregulina Betacellulina HER1/EGFR erbb1 HER2 erbb2 neu HER3 erbb3 HER4 erbb4 Salomon D, et al. Crit Rev Oncol Hematol 1995;19: ; Woodburn JR. Pharmacol Ther 1999;82:241 50

14 Adjuvant Trials of Trastuzumab >13,000 Women With HER2 3+ or FISH+ Early Breast Cancer Trastuzumab upfront Trastuzumab after AC x 3 months Trastuzumab after chemo-rt Anthra Anthra + HERC BCIRG 006 FINHER No Anthra NSABP B31 NCCTG N9831 HERA All trials strongly positive at median follow-up times of months Anthra 68% Anthra + Tax 24% No Anthra 6%

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16 Competing causes of mortality Age 50 years and ER+ Probability Breast cancer deaths Other deaths Time from diagnosis (years) Hanrahan et al. J Clin Oncol 2007; 25:

17 women living after a diagnosisi of breast cancer

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20 Stop your movement spheres of the sky, do not come midnight, do not come Lucifer. J W von Goethe, 1808

21 The price of success: Ovarian failure Bone loss Weight gain Neuropathy Cardiac dysfunction Neurocognitive dysfunction Second malignancies

22 Ovarian failure. Premature menopause Infertility Sexual dysfunction In most cases chemo-induced amenorrhea is transient and a normal ovarian funciton return within a few months from the end of therapy; A subset of patients will develope permanent ovarian failure; Also for patient who regain menses there s a high risk of develope premature menopause subsequently.

23 Bone loss. Long-time survivors breast cancer patients frequently develope bone loss; Prolonged exposition to Ais and/or premature menopause are the main risk factors; Screening patients every 1 2 yeras by dual-energy X-ray absorptionmetry is recommended

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25 On average, cognitive deficits observed in patients with previous exposure to chemo fro BC are SMALL IN MAGNITUDE and limited to domains of VERBAL ABILITY and VISUOSPATIAL ABILITY.

26 Anthra-induced cardiac dysfunction. Late onset Tends to irreversibility Related to cumulative doses Congestive hearth failure in BC patients (%) Age (years) Anthra-based chemo Non-anthra based chemo

27 Risk of CHF NYHA Class 3-4 Cardiotoxicity Issues With Trastuzumab 4 3 A = adriamycin H = trastuzumab D = docetaxel P = paclitaxel AC AC PH 2.4 PH DCH 0.3 AC AC P H 1.4 H 0.5 AC DH BCIRG No 006 trastuzumab FINHER N-9831 N-9831 HERA BCIRG006 NSABP B31 CHF: congestive heart failure; NYHA: New York Heart Association.

28 Trastuzumab-induced cardiac dysfunction. Early onset (during exposure to the drug); Reversible; Cardiac-medications-sensitive; No dose-related

29 OLDER AGE, HYPERTENSION, LOW BASELINE LVEF, HIGH BODY MASS INDEX

30 Second malignancies. Mainly AML or MDS Topo II-isomerase agents Within 5 years from drug exposure May not be preceded by MDS Abnormal cytogenetics of 11q23 ALERT for GF to mantain doseintensity Alkylators (mainly Cyclophosphamide) Usually more than 5 years later than chemo May be preceded by MDS Abnormalities of chromosome 5 and 7 on older BC-pts (m Age 76) H.r. = 1.53 (p = 0.005); but low absolute risk respcet to notchemo-tretaed ones)

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33 Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania Centro di Riferimento Regionale per la diagnosi e la terapia dei tumori del colon-retto. D.A. 26/10/2012 G.U.R.S. del 14/12/2012 parte I, n 53 Adjuvant therapy in early breast cancer Roberto Bordonaro Struttura Complessa di Oncologia Medica ARNAS Garibaldi Catania Siracusa, 6 giugno 2014