Luminal early breast cancer: (neo-) adjuvant chemotherapy

Transkript

1 CAMPUS GROSSHADERN CAMPUS INNENSTADT KLINIK UND POLIKLINIK FÜR FRAUENHEILKUNDE UND GEBURTSHILFE DIREKTOR: PROF. DR. MED. SVEN MAHNER Luminal early breast cancer: (neo-) adjuvant chemotherapy Nadia Harbeck Breast Center, University of Munich, Germany der Universität München Leitung: Prof. Nadia Harbeck

2 Luminal EBC: (Neo-)adjuvant chemotherapy Treatment concepts in luminal EBC Indication for chemotherapy Standard regimens Additional agents Dose-dense options Standard duration Open questions YOUR Questions

3 Therapy strategies in early breast cancer Harbeck & Gnant, Lancet 2017

4 EC-DOC Trial (1-3 LN): EFS EC-Doc vs. FEC LUMINAL B Nitz et al, SABCS 2009; Huober et al, SABCS 2010

5 Multigene assays in early breast cancer Harbeck & Gnant, Lancet 2017

6 Substantial 34.1% discordance between clinical and molecular luminal subtypes Table 3: Reclassification by BluePrint BluePrint/MammaPrint Clinical subtype Luminal A Luminal B Basal Total luminal A-like luminal B-like Her Total MammaPrint and the corresponding molecular subtype BluePrint strongly impacted clinical therapy decisions (28.4% switch) in EBC with up to 3 involved LN. Table 4: CT decision based on BluePrint/MammaPrint Post test recommendation BluePrint/MammaPrint Luminal A Luminal B Basal Total CT 25 (9.2%) 142 (93.4%) 5 (83.3%) 172 no CT 247 (90.8%) 10 (6.6%) 1 (16.7%) 258 Total Würstlein et al, 2016

7 MINDACT: Primary Endpoint Piccart et al, AACR 2016

8 9-Years Risk of Distant Recurrence (%) TransATAC: For Any Recurrence Score the Rate of Distant Recurrence Increases with the Number of Positive Nodes Mean 95%CI 4+ Positive Nodes 1-3 Positive Nodes Node Negative Recurrence Score Dowsett et al, SABCS 2008, Abstract # 53

9 planb trial: Design HER2-negative breast cancer pt1-4 R0 pn+ pn0 high risk pt>2cm G2-3 upa/pai-1 age <35y HR- HR- HR+ R E C U R R E N C E S C O R E 0-3 LK and RS>11 or > 4 LK 0-3 LK and RS<11 R A N D O M I Z A T I O N T 75 C 600 x 6* E 90 C 600 x4 Doc 100 x4* Endocrine therapy* * endocrine therapy and radiotherapy according to national guidelines

10 PlanB: Grade assesment by local and central pathology lab Overall agreement in HR+ disease 66% WSG GmbH Gluz O, Nitz U, Harbeck N. JCO 2016

11 PlanB: Recurrence Score by (central) Ki-67 Good Correlation: RS and Ki67 (if <10% or if >40%) WSG GmbH Gluz O, Nitz U, Harbeck N. JCO 2016

12 PlanB: Excellent DFS in RS low-risk group with endocrine therapy alone (5-y DFS in pp population, n=2160, no chemotherapy in pn0-1 RS 0-11) 5-Y DFS 94% 5-Y DFS 94% 5-Y DFS 84% N0 5-Y DFS 94% 5-Y DFS 95% 5-Y DFS 88% N1 94% 94% 84% Gluz et al., EBCC 2016; Nitz et al, BCRT 2017

13 WSG PlanB Trial: 5-year DFS in subgroups Luminal, Ki67 < 10% TNBC Luminal, Ki67 > 40% Nitz U, Gluz O, Harbeck N. BCRT 2017

14 Luminal EBC: (Neo-)adjuvant chemotherapy Which are standard regimens?

15 OXFORD OVERVIEW 2011: TAXANE + ANTHRACYCLINE VS. ANTHRACYCLINE (N=44.000) Luminal early breast cancer Prof. Harbeck Survival benefit from adjuvant taxanes in all settings Risk Sparano reduction et al, SABCS independent 2014 of age, T, N, G or HR status

16 Adjuvant chemotherapy standards: weekly paclitaxel and docetaxel q3w Sparano et al, SABCS 2014

17 Particular benefit for weekly paclitaxel in TNBC Sparano et al, SABCS 2014

18 PlanB: Disease-free survival (DFS) by chemotherapy arm (ITT population) HR (TC vs. EC-Doc) = %CI: [ ] 5y DFS 90% 90% Presented by: Nadia Harbeck, MD 18

19 PlanB: Disease-free survival (DFS) according to Recurrence Score (HR+)* RS<25 RS>25 5y DFS TC: 94% EC-Doc 95% 5y DFS TC: 86% EC-Doc 85% *ITT patients with RS measured; after early amendment 19 Presented by: Nadia Harbeck, MD

20 PlanB: DFS in subgroups (ITT population) Presented by: Nadia Harbeck, MD 20

21 High-risk N+: Dose-dense, dose-intensified chemotherapy (ETC) Möbus et al,

22 ROLE OF DOSE DENSE CHEMOTHERAPY Del Mastro et al, Lancet 2015

23 Luminal EBC: (Neo-)adjuvant chemotherapy Is there a role for additional agents?

24 NSABP B-38 TRIAL: NO BENEFIT VS. TAC GAINED BY ADDING GEMCITABINE TO DD-AC-P IN NODE-POSITIVE BREAST CANCER DD AC P G (n = 1630) DD AC P (n = 1634) TAC (n = 1630) 5 year DFS 80.6 % 82.2 % 80.1% 5 year OS 90.8 % 89.1 % 89.6% HR DFS HR 0.89 p= 0.14 HR OS HR 1.01 p= 0.92 Toxicity (significant) More febrile neutropenia and diarrhea More sensory neuropathy. More anemia (increased use of ESA and tranfusions) Deaths AML/MDS Swain et a, LBA #

25

26 ROLE OF 5 FU Del Mastro et al, Lancet 2015

27 NSABP TRIAL: PARTICULAR BENEFIT FROM BEVACIZUMAB IN LUMINAL DISEASE similar pcr with additional drugs (X, G) pcr higher with bevacizumab Additional impact of bevacizumab Bear et al, NEJM 2012; von Minckwitz et al, NEJM 2012

28 NSABP B40 and G5: Inconsistent results regarding benefit from bevacizumab in subgroups Bear et al, NEJM 2012; von Minckwitz et al, NEJM 2012

29 Luminal EBC: (Neo-)adjuvant chemotherapy Chemotherapy before or after surgery?

30 Luminal EBC: Neoadjuvant chemotherapy

31

32 Neoadjuvant chemotherapy: Subtype matters (n=4,193) Luminal A like Luminal B (HER2-) Luminal B (HER2+) Non-luminal HER2+ Triple-negative von Minckwitz et al, 2012

33 Sonography Gepartrio Trial NX NX Vinorelbine Capecitabine Core biopsy: uni/bilateral ct2-4 cn0-3 size 2 cm* NC CR/ PR R R TAC TAC x 6 TAC Docetaxel Adriamycin Cyclophosphamide +G-CSF TAC x 8 von Minckwitz G et al, JNCI 2008 & JNCI 2008

34

35 Luminal EBC: (Neo-)adjuvant chemotherapy Future developments

36 WSG-ADAPT Trial: HR+/HER2- Subprotocol (n~4500) Prognosis Corebiopsy (RS, Ki-67) Endocrine therapy 3 weeks Response Surgery / Corebiopsy (RS, Ki-67) High RS or pn2/3 Intermediate RS/pN0-1 Low RS/pN0-1 poor proliferation response good proliferation response Principal investigators: N. Harbeck (LKP), Munich; U. Nitz, Mönchengladbach chemotherapy endocrine therapy endocrine therapy Presented by: Nadia Harbeck, MD 36

37

38 Luminal early breast cancer: Chemotherapy Adjuvant CT reduces the relative risk of relapse by ~25% In luminal EBC, the main question remains who needs chemotherapy in addition to endocrine therapy (pn0-1) Luminal B or patients with high risk luminal disease If there is a CT indication, neoadj. or adjuvant CT is feasible Standard duration is weeks Standard regimens contain an anthracycline and a taxane, given in combination or sequentially (eg. TAC; EC/ACpaclitaxel weekly; EC/AC-docetaxel q3w) 6 cycles of Doc/Cyclo (TC) are an evidence-based option for patients with intermediate clinical risk (pn0-1) Dose-dense chemotherapy seems warranted in patients at high-risk or with high tumor burden (pn2-3)

39 EVIDENCE-BASED, PATIENT-ORIENTED BREAST CANCER THERAPY The Digital Diary for Every Patient Annually revised, evidence-based recommendations for diagnosis and treatment AGO (DKG, DGGG)