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+%
What about CALGB 40603 ? The other trial for neoadjuvant TNBC?
CALGB 40603 SABC 2014
Sikov JCO 2014
N=400
2x2 factorial design
1) 12# weekly Pac –> 4# ddAC
2) 12# Weekly Pac/Bev Q2w –> 4#ddAC/BevQ2w
3) 12# weekly Pac/4# CarboQ3w —> 4#ddAC
4) 12# weekly Pac/4#CarboQ3w/BevQ2w–> 4#ddAC/BevQ2w
RESULTS:
1) pCR by No Bev vs Bev = 50% vs 60%
2) pCR by no Carbo vs Carbo = 45% vs 60%
Between Letrozole and Tamoxifen as Neoadjuvant endocrine therapy, which is better?
Letrozole.
P024 trial n=300 Ineligible for BCS 2 arms: - Letrozole vs Tamoxifen - 4 months therapy
RESULTS:
Higher ORR with Letrozole 55% vs 30%
Higher rate of BCS with Letrozole 45% vs 35%
What are the risk factors for breast cancer?
Genetic predisposition Exposure to estrogens (endogenous and exogenous) Ionizing radiation Low parity Hx of atypical hyperplasia Western-style diet Obesity Alcohol
What are the risk factors for breast cancer in males?
How common?
~1% Clinic disorders carrying hormonal imbalances - Gynaecomastia - Cirrhosis Radiation exposure Family Hx Genetic predisposition
When is BCS not possible?
Tumor size (relative to breast size) Tumor multicentricity Inability to achieve negative surgical margins after multiple resections Prior RT to chest wall/breast Other contraindications to RT Patient choice
If a sentinel LN has Micromets (0.2-2m), is further Axillary treatment required?
Based on IBCSG 23-01, no.
Why is post-op RT strongly recommended after BCS?
WBRT alone reduces:
- the 10-year risk of any 1st recurrence by 15%
» including locoregional and distant
- 15y risk of breast cancer-related mortality by 4%
Boost irradiation gives a further 50% RR reduction.
When is boost irradiation indicated?
Unfavorable risk factors for local control. Eg:
- Age
Why is radiation after mastectomy important in N+ patients?
Reduces:
- 10y recurrence risk (anywhere) by 10%
- 20y risk of breast-cancer-related mortality by 8%
Should now consider routine use of PMRT for those with 1-3 LN + as well as the benefits of PMRT are independent from the no. Of involved Axillary LN and chemo.
What is the usual RT schedule ?
45-50Gy in 25-28# of 1.8-2Gy each
Typical boost dose of 10-16Gy in 2Gy single doses
Define ER positivity
1% or more of invasive cancer cells
Name me a breast tumor marker that can suggest tumor invasiveness
uPA-PAI1
