Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA 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 The Conquest of Breast Cancer: a few more steps ahead…. – Where we are now – How we got here – Standard of Care for EBC – Remaining questions – The Challenges ahead TRENDS IN MORTALITY FROM BREAST CANCER IN SELECTED COUNTRIES: AGE-STANDARDISED RATE (W) PER 100,000 http://globocan.iarc.fr/factsheets/cancers/breast.asp The Conquest of Breast Cancer: a few more steps ahead…. – Where we are now – How we got here – Standard of Care for EBC – Remaining questions – The Challenges ahead Breast cancer mortality in neighbouring European countries with different levels of screening but similar access to treatment: trend analysis of WHO mortality database • 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 10-15 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. P Autier et al; BMJ 2011 Annual cancer mortality / 100,000 women, ages 35–69* Cancer Mortality in women - Italy 70 60 50 ITALY Breast 1951–2001 Stomach Uterus Adj HT Screening AdjChemoRx 70 60 50 Lung 40 40 30 30 20 20 10 10 0 0 1950 1960 *Mean of annual rates in the component 6-year age groups 1970 1980 1990 2000 2010 Source: WHO mortality and UN population estimates EBCTCG META-ANALYSIS Adjuvant chemotherapy versus no treatment < 50 N- < 50 N+ 5-y absolute DFS gain with polychemotherapy: - 14.6% in N+ pt under 50 y 9.9% in N- pt under 50 y 5.9% in N+ pt aged 50-69 y 5.3% in N- pt aged 50-69 y 50-69 N- 50-69 N+ Lancet 365: 1687, 2005 EBCTCG META-ANALYSIS ER + EBC: Tamoxifen for 5y At 15 yrs, Tamoxifen increases DFS by 13.2% and OS by 9.2% EBCCTG, Lancet 2011 The Conquest of Breast Cancer: a few more steps ahead…. – Where we are now – How we got here – Standard of Care for EBC – Remaining questions – The Challenges ahead Adjuvant Treatment of EBC: Refinement of Standard of Care 1990 on: increasing use of anthracyclines 2000 on: increasing use of taxanes increasing use of aromatase inhibitors 2005 on: increasing use of trastuzumab Anthra-based ChemoRx vs no ChemoRx 10 y Breast Cancer Mortality Patients # N+ 10y gain RR p all 8575 82% 6.5 0.79 <0.00001 < 55 y 2808 70% 5.6 0.81 0.004 55-69 y 5373 88% 6.5 0.79 <0.00001 ER-poor 2076 73% 7.1 0.80 0.003 ER + 5433 86% 6.4 0.77 <0.00001 ER+& <55 y 1582 77% 5.6 0.83 0.05 ER+ & 55-69 y 3578 90% 6.0 0.78 0.0002 EBCTCG 2011 in press EBCTCG Meta-analysis Anthra + Taxane vs non Taxane ChemoRx (33,084 pts; 82% N+) 5y RR gain p recurrence 0.86 2.9 <0.00001 BC mortality 0.88 1.4 0.0001 EBCTCG 2011 in press Adjuvant Chemotherapy for EBC • Regimens of proven efficacy: – 1st generation: CMF, AC – 2nd generation: FAC, FEC, DC, AC/P – 3rd 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) Adjuvant Treatment of EBC: Refinement of Standard of Care 1990 on: increasing use of anthracyclines 2000 on: increasing use of taxanes increasing use of aromatase inhibitors 2005 on: increasing use of trastuzumab Meta- Analysis of adjuvant trials of AIs vs Tamoxifen UP-FRONT : • two trials (ATAC, BIG 01-98) • 9,856 patients • 8 y gain = 3.9 % in DFS, 0.5 % in OS M Dowsett et al, JCO 2010 Meta- Analysis of adjuvant trials of AIs vs Tamoxifen SWITCH : • four trials (ARNO, IES, ITA, ABCSG VIII) • 9,015 patients • 6 y gain = 3.6 % in DFS, 1.7 % in OS M Dowsett et al, JCO 2010 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]. 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 Adjuvant Treatment of EBC: Refinement of Standard of Care 1990 on: increasing use of anthracyclines 2000 on: increasing use of taxanes increasing use of aromatase inhibitors 2005 on: increasing use of trastuzumab HER2+ Early Breast Cancer Median follow-up (HR) HERA 1 year (0.54) HERA 2 years (0.64) N9831 AC-T-H 1.5 years (0.87) Combined analysis 2 years (0.48) BCIRG 006 ACDH 2 years (0.61) 2 years (0.67) BCIRG 006 DCarboH 3 years (0.42) FinHER VH / DH 4 years (0.86) PACS 04 0 Favours Herceptin 1 Favours no Herceptin 2 HR Piccart-Gebhart NEJM 2005; Romond NEJM 2005; Slamon SABCS 2006; Smith, Lancet 2007; Perez ASCO 2005; Joensuu NEJM 2006; Spielmann SABCS 2007 N9831- Sequential vs Concurrent Trastuzumab E Perez et al, JCO 2011 Slamon D et al. N Engl J Med 2011;365:1273-1283 BCIRG 006 - outcomes DFS Survival Arm Events # HR Events # HR AC-T 257 1 141 1 AC-TH 186 TCH 214 0.64 p< 0.001 0.75 p= 0.04 94 113 0.63 p< 0.001 0.77 p=0.04 Slamon D et al. N Engl J Med 2011;365:1273-1283 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?) The Conquest of Breast Cancer: a few more steps ahead…. – Where we are now – How we got here – Standard of Care for EBC – Remaining questions – The Challenges ahead Adjuvant treatments of EBC Remaining questions – Genomic assays to predict outcome and chemosensitivity of HR+ tumors – Trastuzumab for small, N-ve HER2+ tumors Genomic assays to predict clinical outcome C Sotiriou & L Pusztai Benefit of Tamoxifen or Chemotherapy by RS NSABP B-20 NSABP B-14 1.0 0.8 DRFS 0.6 Low Risk (RS<18) 0.4 0.2 Placebo Tamoxifen 0.0 0 2 4 6 8 10 12 14 16 Years 1.0 0.8 DRFS 0.6 Int Risk (RS 18-30) 0.4 0.2 Placebo Tamolxifen 0.0 0 2 4 6 8 10 12 14 16 Years 1.0 0.8 DRFS 0.6 High Risk (RS≥31) 0.4 0.2 Placebo Tamoxifen 0.0 0 2 4 6 8 Years 10 12 14 16 Genomic Health Web Site (november 2011) • OncotypeDx testing requests: - more than 10,000 doctors - 55 countries - 175,000 patients Meta-analysis: overall impact of RS on treatment decisions Treatment plan prior to Oncotype DX® Treatment plan after RS Treatment plan after RS 33% change 4% change CT + HT HT Overall, the RS led to a 37% change in treatment decisions • • 33% from CT+HT HT 4% from HT CT+HT Hornberger J, et al. SABCS 2010. Poster P2-09-06. IHC4 score vs GHI-RS Predicted TTDR for a 13.9% >65ys patient with node13.4% neg, 1-2cm poorly differentiated tumor 9.2% receiving anastrozole. 7.6% Kaplan Meyer curves for either the 25° or 75° percentile of each score . 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 Cuzick J et al, JCO 2011 anastrozole. Adjuvant treatments of EBC Remaining questions – Genomic assays to predict outcome and chemosensitivity of HR+ tumors – Trastuzumab for small, N-ve HER2+ tumors High Risk of Recurrence for Patients with HER2+, Node-negative Tumors 1 cm or Smaller • • • • • 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 95.8% 93.7% 86.4% 77.1% p<0.0001 RFS p<0.0001 DRFS Gonzalez-Angulo et al. J Clin Oncol 2009 BCIRG 006 – Subset analysis Supplement to: Slamon et al., NEJM 2011; 365:1273-83 HER2+ EBC patients Adjuvant trastuzumab trials vs Modena Cancer Registry (B31/N9831/HERA/FinHer/BCIRG006/PACS04) Modena Cancer Registry Age (median) 49 59 > 60 y % ~ 16 43.9 T1 % 44.5 71.9 N0 % 21 57.9 T1N0 % ~2 48.7 Characteristic Adjuvant trastuzumab trials 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 1998-2007 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 The Conquest of Breast Cancer: a few more steps ahead…. – Where we are now – How we got here – Standard of Care for EBC – Remaining questions – The Challenges ahead Breast Cancer Diseases – 2011 ER+ 65-75% All Breast Cancers HER2+ 15-20% Triple negative 15% Breast Cancer Diseases – 201… ER+ 65-75% PI3Kmut 10% HER3+ IGFR1+ All Breast Cancers HER2+ 15-20% p95+ 4% P53mut 30-40 % Triple negative 15% BRCAMut 8% FGFR1 Ampl 8% PTENloss 30-50% Clinical Genomics: The Next Frontier Stratton, Campbell and Futreal Nature 2009 PhRMA Report 2011, Medicines in development for cancer New agents for the breast cancer molecular subtypes ER+ 65-75% HER2+ 15- 20 % Triple negative 15% mTOR inhibitors PI3K inhibitors Lapatinib Neratinib Pertuzumab TDM-1 AntiHER2 combinations Trastuzumab + mTORi New cytotoxics (eribulin, ixabepilone, vinflunine) Platinum salts Bevacizumab PARP inhibitors AntiEGFR (Cetuximab, erlotinib) Anti androgens Neo-Adjuvant: A Faster Approach Number of Patients Efficacy Endpoint Primary analysis Adjuvant Neo-adjuvant thousands hundreds DFS pCR years after end of recruitment months after end of recruitment Biological Window No Yes Functional Imaging No Yes Sample Collection baseline multiple time points +++++ ++ Cost HER2+ EBC RCTs of PCT + dual antiHER2 blockade Trial pts # Regimen pCR % (breast & N) Neo-ALLTO1 455 wPac+T/L/TL 20 /27.6/46.9* NeoSphere2 417 DT/DTP/TP/DP 21.5/39.3*/11.2/17.7 CherLob3 121 T = trastuzumab L = Lapatinib P = Pertuzumab wP-FECT/L/TL 25.7/27.8/43.1* * p value < 0.05 1Baselga J et al, SABCS 2010; 2Gianni L et al, SABCS 2010; 3Guarneri V et al, ASCO 2011 43 ALTTO study design: use of lapatinib in adjuvant setting for ErbB2-positive breast cancer1 Trastuzumab Surgery Completion of all (neo) adjuvant anthracyclinebased chemotherapy (≥4 cycles) No taxane Design 2 Concomitant paclitaxel Randomisation Design 1 Lapatinib Trastuzumab Wash out Lapatinib 12 wks 6 wks 34 wks (12 wks) Lapatinib + trastuzumab 52 wks N = 8000 (2000 patients per treatment arm) 1. www.clinicaltrial.gov NCT00490139 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