1. 10. BrustkrebsKongress Köln 21.01.2017 Neues aus San Antonio: Adjuvanz
W. Malter

2. Axillachirurgie

3. Sentinel node detection after neoadjuvant chemotherapy (GANEA 2 trial): Follow-up of a prospective multi-institutional cohort Classe J-M et al. General Session 2 Abstract No. S2-07
Axillary
sonography
+/- fine needle
Breast cancer
T1–T3
N0–N1
From: To
From
15 institutions
NAC
pN+
pN-
Group 1:
SLN
+ Axillary lymphadenectomy
Group 2:
+/- Axillary lymphadenectomy
Mod. Classe J-M et al. SABCS 2016, General Session 2, Abstract No. S2-07

4. Gruppe 1: N+  NAC  SNL + Axilla
Axillary
assessment
pN+
pN-
307 Patients
244 SLN successful mapping
Identification rate
79.8%
SENTINA: Detektionsrate bei 80,1 %
103 SLN not involved
19 ALDN
involved FNR 12%
PCR 27%
(n=84)
Mod. Classe J-M et al. SABCS 2016, General Session 2, Abstract No. S2-07

5. ACOSOG und Sentina
Mod. Classe J-M et al. SABCS 2016, General Session 2, Abstract No. S2-07

6. Schlussfolgerung N+ NACH NAC
Das Risiko einer Falsch-negativ-Rate ist mit > 20% unkontrollierbar
Klinisches Risiko eines FN-Falls bleibt unklar
SNL alleine nach NAC – NEIN
Nur in Studien

7. 574 SLN successful mapping
N0 vor NACT – Gruppe2
Axillary
assessment
pN+
pN-
590 Patients
574 SLN successful mapping
SLN involved
24%
(n=139)
SLN alone
(n=418)
SLN not involved
75%
(n=432)
Identification rate 97%
ALND
not mandatory
(n=14)
120 ALND

8. Follow-up organization: Clinical visit / 6 months:
Gruppe 2 OS und DFS
Follow-up organization:
Clinical visit / 6 months:
Clinical breast and axillary assessment
+/- axillary sonography if necessary
AND Mammography/year
3 years survival
N=418 (SLN alone)
Overall survival
97.8 [94.9–99.1]
Diesease free survival
94.8% [91.0–97.1]
Relapse
N=10
Metastasis 3
Breast relapse
3 homo L
3 contra L
Axillary relapse
1 (0.2%)

9. Schlussfolgerung N0
SNL nach NAC scheint sicher zu sein (kürzeres Follow up von 3 Jahren beachten)

10. ACOSOG Z Jahres Daten

12. pN+: TAD - Targeted Axillary Dissection

13. TAD - Targeted Axillary Dissection
histologisch gesichert nodal positive Patientinnen (n=208) LK-Metastase Clip-markiert (Seed : Iodine-125) Neoadjuvante Chemotherapie 191 ALND: davon 120 (63%) Resttumor identifiziert  bei 115 Patientinnen enthielt der Clip markierte LK Metastasen = FNR von 4,3%

14. TAD - Targeted Axillary Dissection
118 Patientinnen (von 191) erhielten SLND und ALND FNR 10,1% In 23% war der Clip markierte LK nicht der SNB Wenn der Clip markierte LK zusätzlich zum SNB entfernt wurde sank die FNR auf 1,4% = (TAD) 85 Patientinnen erhielten TAD und ALND mit einer FNR von 2%

15. Radiatio nach Rekonstruktion

17. Rationale
PMRT ist für ausgewählte Patientinnen etabliert (EBCTCG- Metaanalyse) Der Nutzen einer Rekonstruktion steht ausser Frage Allerdings ist die Kombination von Bestrahlung und Rekonstruktion „weit gefürchtet aber nur schlecht verstanden“

22. Zusammenfassung
Eine autologe Rekonstruktion ist für Patientinnen mit geplanter PMRT besser Allerdings ist zu beachten, dass sich nicht jede Patientin für eine autologe Rekonstruktion eignet oder diese wünscht Unklar ist das Timing geblieben: Sofortrekonstruktion, Vor oder nach der RT

23. Gensignaturen

32. Kopfhautkühlung

37. Tumorinfiltrierende Lymphozyten TILs

38. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy – a metaanalysis of 3771 patients Denkert C et al. General Session 1, Abstract No. S1-09

39. Stromal TILs – predefined subgroups
Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kümmel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy – A metaanalysis of 3771 patients. SABCS 2016, General Session 1, Abstract No. S1-09
all tumors stored by increased TILs
Mod. Denkert C et al. SABCS 2016, General Session 1, Abstract No. S1-09

40. Distribution of TILs in different breast cancer subtypes
low (0–10%)
intermed. (11–59%)
high (≥60%)
Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kümmel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy – A metaanalysis of 3771 patients. SABCS 2016, General Session 1, Abstract No. S1-09
% of tumors
Mod. Denkert C et al. SABCS 2016, General Session 1, Abstract No. S1-09

41. TILs are linked to increased pCR rates in all subtypes
low (0–10%)
intermed. (11–59%)
high (≥60%)
Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kümmel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy – A metaanalysis of 3771 patients. SABCS 2016, General Session 1, Abstract No. S1-09 n=
1667
1369
725
759
435
172
605
512
262
260
373
273
all patiens
lum/HER2-
HER2+
TNBC
pCR: ypT0ypN0
Mod. Denkert C et al. SABCS 2016, General Session 1, Abstract No. S1-09

42. TILs in TNBC vs. luminal BC – main prognostic difference in non-pCR group
no pCR+low TILs:
poor prognosis in TNBC (n.s.)
pCR rate
37%
TILs low
good prognosis of pCR pts.:
regardless of TILs
similar in TNBC and lum/HER2-
p=ns
p=ns
TNBC, no pCR, n= TNBC, pCR, n=333
TILs low
no CR+low TILs:
good prognosis in lum BC
highly significant
pCR rate
Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kümmel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy – A metaanalysis of 3771 patients. SABCS 2016, General Session 1, Abstract No. S1-09
10%
p<0.0005
p=ns
lum/HER2-, no pCR, n= lum/HER2-, pCR, n=142
overall survival (months)
overall survival (months)
Mod. Denkert C et al. SABCS 2016, General Session 1, Abstract No. S1-09

44. Antrazyklinhaltige Chemotherapie

45. DBCG 07-READ: A randomized phase III trial comparing six cycles of Docetaxel and Cyclophosphamide (DC) to three cycles of Epirubicin and Cyclophosphamide followed by three cycles of Docetaxel (EC-D) in patients with early breast cancer Mod. Ejlertsen B et al. General Session 6 Abstract No. S6-03

46. Anthracycline Anthracyclines are topoisomerase II inhibitors
The mode of action is identical for Doxorubicin and Epirubicin
In early breast cancer Anthracycline-based chemotherapy provides an absolute 3% benefit in survival at 10 year compared to CMF
Average benefits observed in randomized trials or meta-analyses may be explained by a small number of patients having a much larger benefit
HER2 amplification, TOP2A alteration, CEP17 duplication and TIMP1 immunoreactivity have retrospectively been associated with benefit either alone or in combination
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

47. Joint analysis of the ABC trials
The ABC (Anthracyclines in early breast cancer) phase III trials included only HER2 negative patients
USOR (N=1870)
NSABP B-46I/USOR (N=1077)
NSABP-B49 NCT (N=1295)
Primary endpoint was invasive disease-free survival (DFS)
Blum and colleagues reported that the 4-year DFS was 88.2% in the DC arm and 90.7% in the AC followed by Paclitaxel arm
 A hazard ratio (HR) of 1.20 was demonstrated and exceeded the predefined limit for futility (>1.18)
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

48. DBCG 07-READ trial design
6 x DC
75/600 mg/m²
3 x Docetaxel
100 mg/m²
3 x EC
90/600 mg/m²
Selection Criteria
Invasive breast cancer
Comorbidity index <3
High risk
Node positive
High risk node neg.
Young age
ER negative
HER2+
T size
High grade
Altered TOP2A
TOP2A/Cen17 ratio <0.8 or ≥2.0
Normal TOP2A
TOP2A/Cen17 ratio 0.8–1.9
3 x EC
90/600 mg/m²
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

49. Trial Profile
2012 patients R
1001 assigned to EC-D
1011 assigned to DC
1 TOP2A altered
1 TOP2A altered
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
5 self-selected DC
2 withdrew consent
5 self-selected EC-D
994 received allocated treatment
1006 received allocated treatment
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

50. Disease Free Survival (%)
Results: DFS and OS
EC-D DC
Disease Free Survival (%)
Years
HR= %Cl (0.78; 1.28), p=1.00
Overall Survival (%)
Years
HR= %Cl (0.83; 1.59), p=0.41
EC-D DC
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
PT.s at risk
1001
1011
949
957
818
820
357
361
PT.s at risk
1001
1011
980
993
905
902
435
437
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

51. Results: subgroup analysis
Disease-free survival
Favors DC
0.5
1.0
2.0
4.0
Favors EC-D
Factor n HR
95% CI p
Tumor Size (mm)
0–20
1197
0.97
(0.68–1.39)
0.80
21+
815
1.03
(0.76–1.39)
Estrogen Receptor Status (%)
0–9
572
1.01
(0.71–1.44)
0.98
10+
1440
1.00
(0.72–1.40)
Malignancy Grade I
335
1.89
(0.90–4.00)
0.02 II
912
1.40
(0.96–2.05)
III
639
0.70
(0.49–0.99)
KI67 (%)
0–14
632
1.20
(0.77–1.89)
0.38
>14
1156
0.96
(0.72–1.28)
Menopausal Status
Pre
1052
0.77
(0.54–1.11)
0.04
Post
960
1.29
(0.91–1.82)
All
2012
(0.79–1.29)
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
Hazard Ratio
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

52. Results: subgroup analysis
Overall survival
Favors DC
0.5
1.0
2.0
4.0
Favors EC-D
Factor n HR
95% CI p
Tumor Size (mm)
0–20
1197
1.29
(0.79–2.10)
0.64
21+
815
1.12
(0.77–1.65)
Estrogen Receptor Status (%)
0–9
572
1.11
(0.72–1.71)
0.67
10+
1440
1.27
(0.79–2.03)
Malignancy Grade I
335
1.82
(0.56–5.93)
0.03 II
912
1.94
(1.13–3.30)
III
639
0.79
(0.51–1.24)
KI67 (%)
0–14
632
1.54
(0.82–2.88)
0.39
>14
1156
1.15
(0.78–1.67)
Menopausal Status
Pre
1052
0.85
(0.53–1.37)
0.07
Post
960
1.57
(1.00–2.47)
All
2012
1.18
(0.85–1.63)
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
Hazard Ratio
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

53. Patient Reported Adverse Events
EC-D (N=988)
DC (N=1004)
Grade 1–4
Grade 3–4
Mucositis*
848 (86)
25 (3)
800 (80)
11 (1)
Myalgia/arthralgia*
942 (96)
427 (43)
956 (95)
331 (33)
Peripheral neuropathy‡
722 (73)
121 (12)
683 (68)
85 (8)
Rash/skin disorders
630 (64)
625 (62)
14 (1)
Nails changes
716 (73) -
722 (72)
Vomiting*
390 (40)
59 (6)
221 (22)
7 (1)
Nausea*
883 (90)
78 (8)
749 (75)
15 (1)
Fatigue*
975 (99)
297 (30)
971 (97)
245 (24)
Peripheral edema*
599 (61)
670 (67)
26 (3)
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
*p<.0001; ‡p=0.002
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

54. Conclusion
EC followed by Docetaxel did not demonstrate any overall significantly superior efficacy compared to DC in patients with early and TOP2A normal breast cancer. A possible greater benefit from EC-D was demonstrated in patients with Grade 1–2 tumors and from DC in patients with Grade 3 tumors. A possible greater benefit from EC-D was demonstrated in postmenopausal patients and from DC in premenopausal patients. Patients more often reported adverse events following EC-D as compared to DC.
Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen M-B, Knoop AS, Hoejris I, Ewertz M, Balslev E, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. DBCG 07-READ: A randomized phase III trial comparing six cycles of docetaxel and cyclophosphamide (DC) to three cycles of epirubicin and cyclophosphamide followed by three cycles of docetaxel (EC-D) in patients with early breast cancer. SABCS 2016, General Session 6, Abstract No. S6-03
Mod. Ejlertsen B et al. SABCS 2016, General Session 6, Abstract No. S6-03

56. Vielen Dank!