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Evoluzione del trattamento del tumore mammario: dalla ricerca alla clinica Nonantola, 18 Novembre, 2011 PierFranco Conte Dipartimento di Oncologia, Ematologia.

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Presentation on theme: "Evoluzione del trattamento del tumore mammario: dalla ricerca alla clinica Nonantola, 18 Novembre, 2011 PierFranco Conte Dipartimento di Oncologia, Ematologia."— Presentation transcript:

1 Evoluzione del trattamento del tumore mammario: dalla ricerca alla clinica Nonantola, 18 Novembre, 2011 PierFranco Conte Dipartimento di Oncologia, Ematologia e Malattie dell’ Apparato Respiratorio Università di Modena e Reggio Emilia AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA

2 –Where we are now –How we got here –Standard of Care for EBC –Remaining questions –The Challenges ahead The Conquest of Breast Cancer: a few more steps ahead….

3 TRENDS IN MORTALITY FROM BREAST CANCER IN SELECTED COUNTRIES: AGE-STANDARDISED RATE (W) PER 100,000

4 –Where we are now –How we got here –Standard of Care for EBC –Remaining questions –The Challenges ahead The Conquest of Breast Cancer: a few more steps ahead….

5 P Autier et al; BMJ 2011 Breast cancer mortality in three pairs of countries (North Ireland vs Rep. of Ireland, the Netherlands vs Belgium and Sweden vs Norway) from 1989 to 2006 Countries in each pair had similar healthcare services, but differing implementation of mammography screening, with a gap of about years No correlation between the introduction of screeening and reduction in breast cancer mortality The steepest fall in mortality observed was among the women under 50 who had not been invited for screening Screening did not play a direct role in the reductions of breast cancer mortality Improvements in adjuvant treatment may be a more plausible explanation. Breast cancer mortality in neighbouring European countries with different levels of screening but similar access to treatment: trend analysis of WHO mortality database

6 Cancer Mortality in women - Italy Adj HT Screening Annual cancer mortality / 100,000 women, ages 35–69* *Mean of annual rates in the component 6-year age groups Source: WHO mortality and UN population estimates ITALY 1951–2001 Breast Stomach Uterus Lung AdjChemoRx

7 EBCTCG META-ANALYSIS Adjuvant chemotherapy versus no treatment 5-y absolute DFS gain with polychemotherapy: % in N+ pt under 50 y - 9.9% in N- pt under 50 y - 5.9% in N+ pt aged y - 5.3% in N- pt aged y Lancet 365: 1687, N N+ < 50 N-< 50 N+

8 EBCTCG META-ANALYSIS ER + EBC: Tamoxifen for 5y EBCCTG, Lancet 2011 At 15 yrs, Tamoxifen increases DFS by 13.2% and OS by 9.2%

9 –Where we are now –How we got here –Standard of Care for EBC –Remaining questions –The Challenges ahead The Conquest of Breast Cancer: a few more steps ahead….

10 1990 on: increasing use of anthracyclines 2000 on: increasing use of taxanes increasing use of aromatase inhibitors 2005 on: increasing use of trastuzumab Adjuvant Treatment of EBC: Refinement of Standard of Care

11 Anthra-based ChemoRx vs no ChemoRx 10 y Breast Cancer Mortality Patients#N+10y gainRRp all857582% < < 55 y280870% y537388% < ER-poor207673% ER % < ER+& <55 y158277% ER+ & y357890% EBCTCG 2011 in press

12 Anthra + Taxane vs non Taxane ChemoRx (33,084 pts; 82% N+) RR 5 y gain p recurrence < BC mortality EBCTCG Meta-analysis EBCTCG 2011 in press

13 Adjuvant Chemotherapy for EBC Regimens of proven efficacy: –1 st generation: CMF, AC –2 nd generation: FAC, FEC, DC, AC/P –3 rd generation: FEC/D, AC/wP, ddAC/P,TAC Evidence and Recommendations: –Anthracycline/taxane based regimens provide meaningful DFS and OS benefit –Sequential anthracycline/taxane are NOT inferior and more tolerable than combined regimens –The most effective schedules are 3-weekly docetaxel and weekly paclitaxel –TC x 4 is superior to AC x 4 (this is NOT one of the most active regimen and should be considered only when anthracyclines are contraindicated)

14 1990 on: increasing use of anthracyclines 2000 on: increasing use of taxanes increasing use of aromatase inhibitors 2005 on: increasing use of trastuzumab Adjuvant Treatment of EBC: Refinement of Standard of Care

15 Meta- Analysis of adjuvant trials of AIs vs Tamoxifen M Dowsett et al, JCO 2010 UP-FRONT : two trials (ATAC, BIG 01-98) 9,856 patients 8 y gain = 3.9 % in DFS, 0.5 % in OS

16 M Dowsett et al, JCO 2010 SWITCH : four trials (ARNO, IES, ITA, ABCSG VIII) 9,015 patients 6 y gain = 3.6 % in DFS, 1.7 % in OS Meta- Analysis of adjuvant trials of AIs vs Tamoxifen

17 Predictors of Early Distant Metastasis Patients treated with tamoxifen at greatest risk for distant metastasis, within the first 2.5 years –Age  75 years –Tumors  2 cm –Grade  2 –  1 node involved –Lymphovascular invasion –Not screen detected Mansell J et al. Breast Cancer Res Treat 2008; Dec 27 [Epub ahead of print].

18 Adjuvant Endocrine Therapy for HR+ EBC Treatments of proven efficacy: –Pre-menopause: Tamoxifen for 5y; LHRH agonists for 2-5y; Tam+LHRH –Post-menopause: AI for 5y; either sequence of Tam/AI for 5y –Extended adjuvant AI after 5y tamoxifen Evidence and Recommendations: –AIs provide a better DFS (OS gain ?) than Tamoxifen –Either sequence of Tam/Letrozole is not inferior to upfront Letrozole –Upfront AIs may be superior to sequential therapy in high risk pts –Extended adjuvant AIs may provide a DFS and OS gain in high risk pts

19 1990 on: increasing use of anthracyclines 2000 on: increasing use of taxanes increasing use of aromatase inhibitors 2005 on: increasing use of trastuzumab Adjuvant Treatment of EBC: Refinement of Standard of Care

20 012 HERA1 year (0.54) Combined analysis 2 years (0.48) Median follow-up (HR) Favours Herceptin Favours no Herceptin HR BCIRG 006 DCarboH 2 years (0.67) 2 years (0.61) BCIRG 006 AC  DH HERA 2 years (0.64) N9831 AC-T-H 1.5 years (0.87) PACS 04 FinHER VH / DH 3 years (0.42) 4 years (0.86) HER2+ Early Breast Cancer Piccart-Gebhart NEJM 2005; Romond NEJM 2005; Slamon SABCS 2006; Smith, Lancet 2007; Perez ASCO 2005; Joensuu NEJM 2006; Spielmann SABCS 2007

21 N9831- Sequential vs Concurrent Trastuzumab E Perez et al, JCO 2011

22 Slamon D et al. N Engl J Med 2011;365:

23 BCIRG outcomes Slamon D et al. N Engl J Med 2011;365: Arm DFSSurvival Events #HREvents #HR AC-T AC-TH p< p< TCH p= p=0.04

24 Adjuvant Trastuzumab for HER2+ EBC Treatments of proven efficacy: –Any chemotherapy followed by trastuzumab for 1y –AC-TH followed by trastuzumab up to 1y –TCH followed by trastuzumab up to 1y Evidence and Recommendations: –Trastuzumab for 1y reduces the risk of relapse by 25-50% –Trastuzumab administered concomitantly to chemotherapy and up to 1y is superior to sequential administration alone –TCH is less cardiotoxic than AC-TH (is it also equally effective?)

25 –Where we are now –How we got here –Standard of Care for EBC –Remaining questions –The Challenges ahead The Conquest of Breast Cancer: a few more steps ahead….

26 –Genomic assays to predict outcome and chemo- sensitivity of HR+ tumors –Trastuzumab for small, N-ve HER2+ tumors Adjuvant treatments of EBC Remaining questions

27 Genomic assays to predict clinical outcome C Sotiriou & L Pusztai

28 Benefit of Tamoxifen or Chemotherapy by RS Low Risk (RS<18) Int Risk (RS 18-30) High Risk (RS≥31) NSABP B-14 NSABP B-20

29 OncotypeDx testing requests: - more than 10,000 doctors - 55 countries - 175,000 patients Genomic Health Web Site (november 2011)

30 Meta-analysis: overall impact of RS on treatment decisions Treatment plan prior to Oncotype DX ® Treatment plan after RS 4% change 33% change Overall, the RS led to a 37% change in treatment decisions 33% from CT+HT  HT 4% from HT  CT+HT Overall, the RS led to a 37% change in treatment decisions 33% from CT+HT  HT 4% from HT  CT+HT CT + HT HT Hornberger J, et al. SABCS Poster P

31 IHC4 score vs GHI-RS Predicted TTDR for a >65ys patient with node- neg, 1-2cm poorly differentiated tumor receiving anastrozole. Kaplan Meyer curves for either the 25° or 75° percentile of each score. 13.9% 13.4% 9.2% 7.6% Predicted 9-year distant recurrence probabilities for 25° and 75° percentiles of the IHC4 and GHI-RS scores for different G, Nodal status for a woman >65yrs with a 1-2cm tumor receiving anastrozole. Cuzick J et al, JCO 2011

32 –Genomic assays to predict outcome and chemo- sensitivity of HR+ tumors –Trastuzumab for small, N-ve HER2+ tumors Adjuvant treatments of EBC Remaining questions

33 High Risk of Recurrence for Patients with HER2+, Node-negative Tumors 1 cm or Smaller Gonzalez-Angulo et al. J Clin Oncol % 77.1% 95.8% 86.4% p< N=965, 10% HER2+ tumors More T1a than T1b were HER2+ (32.3 vs 43.9%) No patient got chemo or trastuzumab All tissues were reviewed and re-measured Median follow up: 6.2 yrs RFS DRFS

34 Supplement to: Slamon et al., NEJM 2011; 365: BCIRG 006 – Subset analysis

35 Characteristic Adjuvant trastuzumab trials (B31/N9831/HERA/FinHer/BCIRG006/PACS04) Modena Cancer Registry Age (median) 4959 > 60 y %~ T1 % N0 % T1N0 %~ HER2+ EBC patients Adjuvant trastuzumab trials vs Modena Cancer Registry Piccart N Engl J Med 2005; Romond N Engl J Med 2005; Joensuu N Engl J Med 2006; Slamon D, SABCS 2006; Spielmann M et al, SABCS 2007; Federico M, RTM

36 Adjuvant Trastuzumab for T1 N0 HER2+ EBC Prognosis of small, N0, HER2+ tumors is poorer Trastuzumab has shown efficacy in these patients Small, node negative tumors as well as elderly patients, are underepresented in clinical trials Cardiac safety and cardiac recovery in elderly patients treated with trastuzumab are basically unknown In these patients, competitive deaths are prevalent, and the decision to treat should be based on a careful evaluation of the risk/benefit ratio Trials designed for frail and low risk patients are warranted

37 –Where we are now –How we got here –Standard of Care for EBC –Remaining questions –The Challenges ahead The Conquest of Breast Cancer: a few more steps ahead….

38 All Breast Cancers ER % HER % Triple negative 15% Breast Cancer Diseases – 2011

39 All Breast Cancers ER % HER % Triple negative 15% HER3+ IGFR1+ p95+ 4% P53 mut % FGFR1 Ampl 8% PTEN loss 30-50% PI3K mut 10% BRCA Mut 8% Breast Cancer Diseases – 201…

40 Clinical Genomics: The Next Frontier Stratton, Campbell and Futreal Nature 2009 PhRMA Report 2011, Medicines in development for cancer

41 ER % mTOR inhibitors PI3K inhibitors New agents for the breast cancer molecular subtypes Lapatinib Neratinib Pertuzumab TDM-1 AntiHER2 combinations Trastuzumab + mTORi Triple negative 15% HER % New cytotoxics (eribulin, ixabepilone, vinflunine) Platinum salts Bevacizumab PARP inhibitors AntiEGFR (Cetuximab, erlotinib) Anti androgens

42 Neo-Adjuvant: A Faster Approach AdjuvantNeo-adjuvant Number of Patientsthousandshundreds Efficacy EndpointDFSpCR Primary analysisyears after end of recruitment months after end of recruitment Biological WindowNoYes Functional ImagingNoYes Sample Collectionbaselinemultiple time points Cost

43 43 HER2+ EBC RCTs of PCT + dual antiHER2 blockade Trialpts #RegimenpCR % (breast & N) Neo-ALLTO 1 455wPac+T/L/TL20 /27.6/46.9* NeoSphere 2 417DT/DTP/TP/DP21.5/39.3*/11.2/17.7 CherLob 3 121wP-FECT/L/TL25.7/27.8/43.1* * p value < 0.05T = trastuzumab L = Lapatinib P = Pertuzumab 1 Baselga J et al, SABCS 2010; 2 Gianni L et al, SABCS 2010; 3 Guarneri V et al, ASCO 2011

44 ALTTO study design: use of lapatinib in adjuvant setting for ErbB2-positive breast cancer 1 Surgery Completion of all (neo) adjuvant anthracycline- based chemotherapy (≥4 cycles) Design 1 No taxane Design 2 Concomitant paclitaxel (12 wks ) Trastuzumab Lapatinib Wash out Lapatinib Trastuzumab Lapatinib + trastuzumab Randomisation 12 wks 6 wks34 wks 52 wks N = 8000 (2000 patients per treatment arm) 1. NCT

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46 The Conquest of Breast Cancer: from Evidence Based to Personalized Medicine Breast Cancer mortality is declining because of earlier diagnosis and effective adjuvant treatments Randomized clinical trials have allowed to define the appropriate therapy for the average patient population The backbone of adjuvant treatments is based on the molecular characterization of the disease: HR+  Endocrine therapy HER2+  AntiHER2 therapy Triple negative  Chemotherapy Clinical genomics will allow to move forward personalized cancer medicine: More refined prognosticators  to spare unecessary therapy More reliable predictors of sensitivity  to administer individualized therapy More reliable predictors of resistance  to develop innovative therapies

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