Neoadjuvant Breast Cancer Flashcards
Why would we consider neoadjuvant therapy?
1) Survival outcomes are equal
Neoadjuvant = adjuvant
2) Improved tumor down-staging
- Converts inoperable to operable (LABC)
- Mastectomy to breast conserving (Primary operable Breast CA/Subset LABC)
3) Provides opportunity to assess surrogate biological end-points
4) May expedite new drug development
5) Provides in Vivo assessment of anti-tumor effects
6) Early initiation of systemic therapy
What is the evidence showing neoadjuvant = adjuvant ?
1) NSABP B18 Using AC pre- vs post-op - 16yOS: 55% vs 55% - 16y DFS 42% vs 39% - pCR 13% - BCS 68% vs 60%
2) NSABP B27: AC–> S vs AC–> T–>S vs AC–>S–>T
- 8yOS 74% vs 75%
- 8yDFS 59% vs62%
- pCR 14% vs 26% (without or with Taxanes)
3) Meta-analyses
- Mauri JNCI
- Mielog Cochrane
What is considered pCR?
- ypT0 ypN0
- ypT0/is ypN0
- ypT0
What are the strongest association between pCR and long-term clinical outcome?
1) ER-/Her2+
2) Triple negative
3) High grade ER+/Her2-
What does pCR assess?
pCR assess treatment given pre-operatively and not post-operatively
Who are the candidates for BCS after neo-adjuvant chemotherapy?
1) Unifocal disease
2) No skin changes
3) Imaging abnormalities resectable with lumpectomy
4) Candidate for radiotherapy
5) Accepting of increased local recurrence rate
6) No metastatic disease
What are the factors resulting in poorer outcome after neoadjuvant therapy?
1) Advanced disease before treatment
2) Poor clinical response to chemotherapy
3) Axillary nodal status after chemotherapy.
- must achieve both ypT0N0
Tell me about the mechanisms of action for Trastuzumab
Acts extracellularly
on the sub domain IV of HER2
Does not inhibit HER2 dimerisation, thus blocking HER2:HER3
Prevents HER2 receptor shedding
Blocks HER2 signaling and elicits ADCC
What is the MoA for Pertuzumab?
Works extra-cellularly
Works on the dimerisation domain of HER2
Inhibits HER2 forming of dimmer pairs
Activates ADCC
Does not prevent HER2 receptor shedding
What is the MoA of Lapatinib?
Works on the intracellular kinase domain of HER2
Induces HER2 accumulation at Cell surface, stabilizing inactive HER2 homodimers and heterodimers
Accumulation of HER2 enhances Trastuzumab-dependent cytotoxicity
What is the evidence that Herceptin is necessary to achieve better pCR in Her2+ patients in the neoadjuvant setting?
(A) MD Anderson Study
(B) NOAH study
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(A) MD Anderson Study
Buzdar Clin Cancer Res 2007
Breast cancer patients n=40
HER2+
M0, T1-3, N0-1
2arms:
1) 4# Paclitaxel Q3w –> 4#FEC
2) 4# Paclitaxel Q3w + 12#Herceptin –> 4#FEC + 12#Herceptin
RESULTS:
1) pCR with inclusion of Trastuzumab is almost 3x that without.
66% vs 26%
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(B) NOAH Study
Gianni Lancet 2010
N=300
Divided into Her2+ LABC and Her2- LABC
3 arms:
(1) HER2+ = 3#(H+AT)q3w –> 4#(H+T)q3w –> 4#Hq3w + 3#CMF q4w –> Surgery–>RT–>Hq3w until week 52
(2) HER2+ = 3#AT q3w –> 4#T q3w –> 3#CMF q4w –> Sx–>RT
(3) HER2- = 3#AT q3w –> 4#T q3w –> 3#CMF q4w –> Sx–> RT
RESULTS:
1) pCR rates with Herceptin : Without Herceptin = 40% : 20%
2) EFS HR 0.60 in favor of Herceptin
What are the Anti-Her2 Neoadjuvant trials?
1) NeoSphere (n=400) 4arms: (A) Trastuzumab + Docetaxel (B) Pertuzumab + Docetaxel (C) Pertuzumab + Trastuzumab + Docetaxel (D) Pertuzumab + Trastuzumab
2) Neo-ALTTO (n=450)
3 arms:
(A) Trastuzumab –> Trastuzumab+Paclitaxel
(B) Lapatinib –> Lapatinib+Paclitaxel
(C) Trastuzumab/Lapatinib –> Trastuzumab/Lapatnib + Paclitaxel
3) GeparQuinto (n=600)
2arms:
(A) Epirubicin + Cyclophosphamide + Trastuzumab –> Docetaxel +Trastuzumab + GCSF
(B) Epirubicin + Cyclophosphamide + Lapatinib –> Docetaxel + Lapatinib + GCSF
Tell me about the NeoSphere study
Gianni SABCS 2010
N=400
Operable/LABC/inflammatory Her2+ breast cancer
Chemo-naive, primary tumor >2cm
4 arms:
1) Docetaxel/Trastuzumab –> op –> FEC/Trastuzumab
2) Docetaxel/Trastuzumab/Pertuzumab –> op –> FEC/Trastuzumab
3) Trastuzumab/Pertuzumab – op –> Docetaxel–>FEC/Trastuzumab
4) Docetaxel/Pertuzumab –> op –> FEC/Trastuzumab
RESULTS: 1) pCR: = THP> TH> TP> HP - TH = 30% - THP = 45% - HP = 15% - TP = 25%
Tell me about the Neo-ALTTO trial
Jose Baselga 2010
Invasive operable Her2+ Breast Cancer
T>2cm, excluded inflammatory breast cancer
EF>50%
N=450
3arms:
1) 6w Lapatinib–>12w Lapatinib+Paclitaxel–>op–>3#FEC–>Lap
2) 6w Trastuzumab–>12w Trastuzumab+Pac–>op–>3#FEC–>Trast
3) 6w Lap/Trast –>12w Lap/Trast/Pac –>op–>3#FEC–>Lap/Trast
RESULTS: 1) pCR by Hormonal receptor status (A) HR + - Lap: 15% - Trast: 20% - Lap+Trast: 40% (B) HR - - Lap: 35% - Trast: 35% - Lap+Trast: 60%
Tell me about GeparSixto
Minckwitz Lancet Oncol 2014
N=300
TNBC
2 arms:
1) 18# Weekly Pac/Doxo + 6# Bev Q3w –> Surgery
2) 18# Weekly Pac/Doxo/Carboplatin + 6#Bev Q3w –> Surgery
RESULTS:
- pCR Rates PMCb>PM = 50+% vs 30+%
