AZIENDA OSPEDALIEROUNIVERSITARIA DI MODENA Evoluzione del trattamento del

AZIENDA OSPEDALIERO-UNIVERSITARIA DI MODENA Evoluzione del trattamento del tumore mammario: dalla ricerca alla clinica Nonantola, 18 Novembre, 2011 Pier. Franco 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

Cancer Mortality in women - Italy Annual cancer mortality / 100, 000 women, ages 35– 69* 70 60 50 ITALY Breast 1951– 2001 Stomach Uterus Adj HT Screening Adj. Chemo. Rx 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 5 y 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 Chemo. Rx vs no Chemo. Rx 10 y Breast Cancer Mortality Patients # N+ 10 y 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 Chemo. Rx (33, 084 pts; 82% N+) 5 y 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: – 1 st generation: CMF, AC – 2 nd generation: FAC, FEC, DC, AC/P – 3 rd generation: FEC/D, AC/w. P, dd. AC/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 5 y; LHRH agonists for 2 -5 y; Tam+LHRH – Post-menopause: AI for 5 y; either sequence of Tam/AI for 5 y – Extended adjuvant AI after 5 y 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

HER 2+ Early Breast Cancer Median follow-up (HR) HERA 1 year (0. 54) HERA 2 years (0. 64) N 9831 AC-T-H 1. 5 years (0. 87) Combined analysis 2 years (0. 48) BCIRG 006 AC DH 2 years (0. 61) 2 years (0. 67) BCIRG 006 DCarbo. H 3 years (0. 42) Fin. HER 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

N 9831 - 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 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 HER 2+ EBC • Treatments of proven efficacy: – Any chemotherapy followed by trastuzumab for 1 y – AC-TH followed by trastuzumab up to 1 y – TCH followed by trastuzumab up to 1 y • Evidence and Recommendations: – Trastuzumab for 1 y reduces the risk of relapse by 25 -50% – Trastuzumab administered concomitantly to chemotherapy and up to 1 y 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 HER 2+ tumors

Genomic assays to predict clinical outcome C Sotiriou & L Pusztai

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

Genomic Health Web Site (november 2011) • Oncotype. Dx 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 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 P 2 -09 -06.

IHC 4 score vs GHI-RS Predicted TTDR for a 13. 9% >65 ys patient with node 13. 4% neg, 1 -2 cm 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 IHC 4 and GHI-RS scores for different G, Nodal status for a woman >65 yrs with a 1 -2 cm 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 HER 2+ tumors

High Risk of Recurrence for Patients with HER 2+, Node -negative Tumors 1 cm or Smaller • • • N=965, 10% HER 2+ tumors More T 1 a than T 1 b were HER 2+ (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

HER 2+ EBC patients Adjuvant trastuzumab trials vs Modena Cancer Registry (B 31/N 9831/HERA/Fin. Her/BCIRG 006/PACS 04) Modena Cancer Registry Age (median) 49 59 > 60 y % ~ 16 43. 9 T 1 % 44. 5 71. 9 N 0 % 21 57. 9 T 1 N 0 % ~ 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 T 1 N 0 HER 2+ EBC • Prognosis of small, N 0, HER 2+ 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 HER 2+ 15 -20% Triple negative 15%

Breast Cancer Diseases – 201… ER+ 65 -75% PI 3 Kmut 10% HER 3+ IGFR 1+ All Breast Cancers HER 2+ 15 -20% p 95+ 4% P 53 mut 30 -40 % Triple negative 15% BRCAMut 8% FGFR 1 Ampl 8% PTENloss 30 -50%

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

New agents for the breast cancer molecular subtypes ER+ 65 -75% HER 2+ 15 - 20 % Triple negative 15% m. TOR inhibitors PI 3 K inhibitors Lapatinib Neratinib Pertuzumab TDM-1 Anti. HER 2 combinations Trastuzumab + m. TORi New cytotoxics (eribulin, ixabepilone, vinflunine) Platinum salts Bevacizumab PARP inhibitors Anti. EGFR (Cetuximab, erlotinib) Anti androgens

Neo-Adjuvant: A Faster Approach Number of Patients Efficacy Endpoint Primary analysis Adjuvant Neo-adjuvant thousands hundreds DFS p. CR 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

HER 2+ EBC RCTs of PCT + dual anti. HER 2 blockade Trial pts # Regimen p. CR % (breast & N) Neo-ALLTO 1 455 w. Pac+T/L/TL 20 /27. 6/46. 9* Neo. Sphere 2 417 DT/DTP/TP/DP 21. 5/39. 3*/11. 2/17. 7 Cher. Lob 3 121 T = trastuzumab L = Lapatinib P = Pertuzumab w. P-FECT/L/TL 25. 7/27. 8/43. 1* * p value < 0. 05 1 Baselga J et al, SABCS 2010; 2 Gianni L et al, SABCS 2010; 3 Guarneri V et al, ASCO 2011 43

ALTTO study design: use of lapatinib in adjuvant setting for Erb. B 2 -positive breast cancer 1 Completion of all (neo) adjuvant anthracyclinebased chemotherapy (≥ 4 cycles) No taxane Design 2 Concomitant paclitaxel Randomisation Surgery Trastuzumab 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 NCT 00490139

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 HER 2+ Anti. HER 2 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