Il trattamento sistemico (neo)-adiuvante

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1 II SESSIONE: TERAPIA DELLA MALATTIA IN FASE PRECOCE Il trattamento sistemico (neo)-adiuvante Stefania Gori U.O.C. Oncologia Medica Cancer Care Center Sacro Cuore-Don Calabria Negrar- VERONA Presidente eletto AIOM

2 PDTA tumore della mammella- R.O.V. VM Postchirurgica

3 Terapia sistemica adiuvante: definizione e scopi La terapia sistemica adiuvante o precauzionale è il trattamento medico che viene somministrato DOPO il trattamento chirurgico con l obiettivo di distruggere eventuali micrometastasi sistemiche e, quindi, di aumentare le probabilità di GIUARIGIONE della donna

4 Terapia sistemica adiuvante: dati della letteratura I dati derivanti da metanalisi e da studi randomizzati di fase III evidenziano una significativa riduzione del rischio di recidiva e di morte ( sia x BC sia globale) con: la polichemioterapia, la terapia endocrina, la terapia biologica (trastuzumab nei tumori HER2+),

5 Terapia sistemica adiuvante La decisione di quale o quali terapie utilizzare nella singola paziente richiede una attenta valutazione di: -fattori prognostici, che definiscono l entità del rischio di ripresa; -fattori predittivi di risposta ai trattamenti (ER, HER2); -benefici attesi dal trattamento (in termini di percentuale di beneficio assoluto) ed effetti collaterali attesi; -comorbidità della paziente; -attesa di vita; -preferenza della paziente.

6 Valutare entità del rischio: Fattori prognostici standard stato linfonodale (N-; N+ e numero LN+) dimensioni del tumore grado istologico tipo istologico* attività proliferativa (Ki67/Mib1) invasione vascolare peritumorale stato recettoriale ormonale (ER; PgR) e livelli dei recettori stato HER2 età della paziente profili di espressione genica, qualora disponibili *Prognosi eccellente: ca.tubulare, ca.mucinoso, ca. adenoido-cistico,cribriforme invasivo Linee Guida AIOM 2009

7 PDTA tumore della mammella- R.O.V. VM Postchirurgica

8 Linea Guida 2015 QUALE TERAPIA MEDICA ADIUVANTE?

9 Chemioterapia adiuvante

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11 Bonadonna G, NEJM % 5.3% p< % 8.8%

12 Bonadonna G, NEJM 1976

13 Treatment outcome in the first randomised CMF study after a median observation of 28.5 years RELAPSE-FREE SURVIVAL after surgery alone (179 pts) vs CMF (207 pts) HR 0.71 (95% CI ) p=0.005 OVERALL SURVIVAL after surgery alone (179 pts) vs CMF (207 pts) HR 0.79 (95% CI ) p=0.04 Bonadonna G et al, BMJ 2005

14 Metanalisi Il vantaggio della metanalisi è quello di stimare l effetto medio dei diversi trattamenti disponibili e di valutare se questo effetto differisce in particolari sottogruppi di pazienti. Metanalisi di Oxford o Metanalisi dell Early Breast Cancer Trialists Collaborative Group

15 CMF > Control Anthra > CMF A+Taxane > Anthra EBCTCG meta-analysis, Lancet 2012

16 E1199 trial

17 JCO 2015

18 Schemi CMF Like CMF classico; CMF endovena Schemi con antracicline e senza taxani AC/EC A/E CMF CAF; CEF Canadese FAC;FEC Schemi con Taxani con o senza antracicline AC/EC paclitaxel settimanale FEC paclitaxel settimanale AC docetaxel FEC 100 docetaxel TAC TC (docetaxel-ciclofosfamide) AC/EC paclitaxel dose dense SCHEMI di CHEMIOTERAPIA Schemi con trastuzumab AC/EC paclitaxel e trastuzumab AC/EC docetaxel e trastuzumab TCH (docetaxel-carboplatino-trastuzumab) T-Ciclo H (docetaxel-ciclofosfamide-trastuzumab) Paclitaxel-Trastuzumab Chemioterapia Trastuzumab Linea Guida 2015

19 Terapia adiuvante ormonale

20 Linea Guida 2015

21 Lancet 1998: terza metanalisi dell EBCTCG relativa all ormonoterapia adiuvante

22 ER-positive was defined as at least 10 fmol ER per mg cytosol protein where quantitative measurements were available, but was otherwise accepted as reported. ECBTCG- Lancet 1998; 351:

23 ECBTCG- Lancet 1998; 351:

24 ECBTCG- Lancet 1998; 351: Recurrence as first event Mortality (death from any cause) 5.6% 10.9% Absolute risk reduction during 10 years, subdivided by TAM duration and by nodal staus (after exclusion of ER-poor tumors) In ER+ and ER untested pts (30,000): The absolute improvement in recurrence was greater during the first 5 yr; the improvement in survival grew steadily larger throught the first 10 yr (carry over effect). - The proportional mortality reductions were similar for pts with N+ and N- disease ( 25%), but the absolute mortality reductions were greater in Node+ pts. A N+: parità improvementdi in 10-yr riduzione OS: 10.9% (SD2.5) proporzionale (61.4% vs 50.5% survival; 2p del <.00001) rischio, la riduzione in termini assoluti è N-: improvement in 10-yr OS: 5.6% (SD 1.3) (78.9% vs 73.3% survival; 2p <.00001) maggiore nel gruppo di pazienti con iniziale rischio più elevato

25 TAMOXIFEN impact (each p< ) pts from 20 trials with 5y of TAM vs control (~ 80% of compliance) ECBTCG- Lancet 2011; 378:771-84

26 ER status was the only recorded factor importantly predictive of the proportional reductions. In ER+ disease, the PR measurements were not predictive of who would respond to TAM ECBTCG- Lancet 2011; 378:771-84

27 No chemotherapy N- N+ TAMOXIFEN impact by N status and CT Chemotherapy for all N- N+ ECBTCG- Lancet 2011; 378:771-84

28 Endocrine therapy in postmenopausal pts: strategies TAM Anastrozole Letrozole UP-FRONT ATAC- Anastrozole BIG Letrozole TAM Exemestane Anastrozole EARLY-SWITCH TAM IES- exemestane ARNO 95 ABCSG 8 anastrozole ITA TAM Aromatase inhibitor PLACEBO or nil LATE- SWITCH MA-17-Letrozole NSABP B33-Exemestane ABCSG 6a- Anastrozole

29 X Congresso Nazionale AIOM, Verona ottobre 2008 BREAST CANCER Adjuvant endocrine therapy in postmenopausal pts: AIs > TAM (DFS)

30 EBCTCG meta-analyses: 5 years AI vs 5 years TAM RECURRENCE BREAST CANCER MORTALITY EBCTCG- AI vs TAM in EBC. Lancet 2015

31 Adjuvant endocrine therapy in early breast cancer No of pts CT+ ET only CT HR+/N % 17% HR+/N % 23% Endocrine therapy was not prescribed HRunknown/ N+ or N % 49% Modified from Roila F et al, Ann Oncol 2003;14:843-8

32 Linea Guida 2015

33 BREAST CANCER Adjuvant hormonal therapy Premenopausal HR+ EBC: TAM vs TAM+OS

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35 SOFT trial- Pagani O et al- NEJM 2014

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37 BREAST CANCER Adjuvant hormonal therapy Premenopausal HR+ EBC: TAM+OS vs AI+OS

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39 Exemestane+OFS Improved DFS Presented By Olivia Pagani at 2014 ASCO Annual Meeting

40 Women Who Did Not Receive Chemotherapy Presented By Olivia Pagani at 2014 ASCO Annual Meeting

41 BREAST CANCER Adjuvant hormonal therapy ER+ EBC: after 5y-TAM

42 Linea Guida 2015

43 10-yr Tamoxifen (ATLAS) Recurrence Breast Cancer Mortality Absolute reduction: 3.7% Absolute reduction: 2.8% Recurrence and BC mortality by treatment allocation for 6846 women with ER-positive disease Davies C et al, Lancet 2013; 381:

44 10-yr Tamoxifen (ATLAS) At 15 years, absolute reduction in: Recurrence 3.7% Mortality 2.8% Relative Risk of Endometrial Cancer = 1.74 (3.1% vs 1.6%; mortality: 0.4% vs 0.2%, with an absolute mortality increase 0.2%) Relative Risk of PE = 1.87 C Davies, Lancet 2013

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46 Terapia adiuvante con agenti anti-her2

47 Linea Guida 2015 QUALE TERAPIA MEDICA ADIUVANTE?

48 Disease-free Survival Overall survival The Cochrane Library 2012, Issue 4

49 Trials exploring different duration of trastuzumab administration Trial Sponsor Trastuzumab CT months schedule regimen HERA BIG 12 v 24 All S Center s choice PHARE INCA 6 v 12 S or C Center s choice Hellenic Oncology PERSEPHONE SHORTHER University of Heraklion University of Warwick University of Modena sample size status 3,387 completed & reported 3,400 completed & reported 6 v 12 All C ddfec/d 478 completed 12/ v 12 All S Center s choice 2 v12 All C A+T vs. T+FEC 4,000 ongoing 1,250 Completed 10/2013 SOLD Finnish BCG 2 v 12 All C T+FEC 3,000 ongoing S= sequential trastuzumab C= concomitant trastuzumab

50 Terapia neo-adiuvante

51 PDTA tumore della mammella- R.O.V.

52 Primary systemic therapy (PST) for breast cancer: historical background PST represents the use of systemic therapy as the first modality of treatment for a primary malignant tumor Firstly introduced into clinical practice in 70s for inoperable LABC and IBC Main aim: to achieve operability for large, bulky tumors, often accompanied by matted involved axillary nodes Courtesy of Guarneri V.

53 Courtesy of Guarneri V. The Cochrane Library, Issue 3, 2008

54 Cortazar P, ASCO 2012

55 Cortazar P, ASCO 2012

56 Is the pcr associated with long term outcomes (EFS and OS)? Cortazar P, ASCO 2012

57 Which pcr definition is best associated with long term outcome? Cortazar P, ASCO 2012

58 Cortazar P, ASCO 2012

59 In which BC subtypes does pcr associate with long term outcome? Cortazar P, ASCO 2012

60 pcr rates (breast/axilla) in HER2+ BC CT + T CT + T + P CT + T + L CT + T + Afatinib 0 MDACC 1 NOAH 2 Z NeoALTTO 4 Cher LOB 5 Gepar6 6 NSABP CALGB TRIO US 9 NeoSphere 10 Tryphaena 11 Gepar7 12 DAFNE 13 B Buzdar AU, CCR 2007; 2. Gianni L, Lancet Buzdar AU, Lancet Oncol Baselga J. Lancet 2012; 5. Guarneri V. J Clin Oncol 2012; 6. von Minckwitz. Lancet Oncol 2014; 7. Robidoux A. Lancet Oncol 2013; 8. Carey L.ASCO 2013; 9. Hurvitz S SABCS Gianni L. Lancet Oncol 2012; 11. Schneeweiss A. Ann Oncol 2013 ; 12 Untch M. SABCS 2014; 13. Hanusch C. Clin Cancer Res 2015 Courtesy of Guarneri V.

61 pcr rates (breast/axilla) in TNBC TAC Gepar3 1 EC-P (+/-gem) NeoTango 2 EC-D EC-D+Bev PM PM+carbo Gepar5 3 (+ Bev) Gepar6 4 P-AC P+carbo- AC (+/- Bev) CALGB P+carbo+bev nabp-carbo Ca.Pa.Be 6 ADAPT 7 nabp-ec Gepar Huober J, BCRT 2010; 2. Earl HM, Lancet Oncol 2014; 3. von Minckwitz, NEJM 2012; 4. von Minckwitz, Lancet Oncol 2014; 5. Sikov, J Clin Oncol 2015; 6. Guarneri V, Ann Surg Oncol 2015; 7. Gluz O, ASCO 2015; 8. Untch M, SABCS 2014 Courtesy of Guarneri V.

62 PST Selection of the patients All patients known to be candidates for adjuvant therapy are candidates for neoadjuvant therapy If indication for systemic therapy is uncertain, surgical removal is preferable PST should be tailored on the molecular subtype of the tumor In HER2+ disease, dual anti her2 blockade + chemotherapy produces higher pcr rates HR+/HER2 patients can be candidate to trials of endocrine therapy + STI (with molecular response as end point) Encouraging data with platinum salts in TNBC Courtesy of Guarneri V.

63 THANK YOU! CANCER CARE CENTER Sacro Cuore -Don Calabria Negrar-VERONA