Download Neoadjuvant therapy decisions

Neoadjuvant therapy decisions
in non-Her2 breast cancer
10/4/16
Objectives
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Rationale for neoadjuvant chemo
Patient selection
Chemo regimens
Surgical considerations- breast and axilla
Special populations- triple neg, her-2 pos, inflammatory
Neoadjuvant endocrine Rx considerations
Ongoing trials
WHY and WHO?
• Why neoadjuvant chemotherapy needs to
be given?
• Who are ideal candidates?
Rationale
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Tumor shrinkage
Down stage axilla
Efficacy of chemo (response adjusted approach)
Prognosticate- pCR
Research- tumor samples while on chemo to identify tumor
and patient specific biomarkers correlating with response
• Allows time for genetic testing and plan reconstruction
Patient selection
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Locally advanced/inflammatory
High tumor to breast ratio
Tumor subtypes
Contraindication to upfront surgery such as pregnancy
Inappropriate pts- diffuse disease, extensive in-situ carcinoma,
tumors not readily palpable
• DO NOT give neoadjuvant chemo to patients that you are
unsure about giving chemo adjuvantly
Patient-1
• 42 y/o female with HTN presents with new Rt breast mass, no
other symptoms reported. Imaging confirms 4.2 cm mass in
the Rt breast, normal axillary contents on US. Biopsy showed
IDC, grade III, ER 100%. PR 20%, Her2 neg. She desires breast
conservation if possible so she is referred to you for
neoadjuvant chemo. What are the next steps? What would
you give her?
Pre-treatment evaluation
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Tumor biopsy and clipping
Nodal eval- bx of abnormal nodes
? Pre-op SLNBx (radiotherapy decisions may be helped)
FNR of post-chemo SLNBx
Routine imaging to assess systemic disease – symptomatic pts
or bulky disease
Chemotherapy
• NCCN: Regimens recommended in adjuvant setting may be
considered in the pre-operative setting.
• Preferred regimens: ddAC  ddPac,
ddAC  weekly Pac
TC
• Other regimens: AC, EC, CMF, ACDoc/Pac, TAC, FEC or FAC
followed by taxane
NSABP B-18 and NSABP B-27
• B18: N = 1523 pts with operable cancer randomized to preoperative AC x4 vs post-operative AC x4
• B27: N = 2411 pts with operable cancer randomized to:
pre-op AC x4  Sx
pre-op ACx4  pre-op Doc x4  Sx
pre-op ACx4 Sx  post-op Doc x4
Fischer et al. J Clin Oncol 1997
Bear et al. J Clin Oncol 2006
OS, DFS and RFI for Protocol B-18 and B-27
Rastogi et al. JCO 2008;26:778-785
Patients with pCR in group 2 (pre-op AC  Doc) versus groups 1 and 3
Harry D. Bear et al. JCO 2006;24:2019-2027
Survival by pCR in NSABP-B18 and NSABP-B27
Priya Rastogi et al. JCO 2008;26:778-785
Refining Taxane therapy: E1199
• Phase III adjuvant trial with N-4950, node positive or high risk
node negative patients
• Treatment arms: AC x4 every 3 weeks followed by Pac x4
every 3 weeks (std arm)
• Comparison arms: weekly Pac x 12,
weekly Doc x 12
Doc every 3 weeks x4
Sparano et al. N Engl J Med 2008
E1199: DFS curves
Sparano JA et al. N Engl J Med 2008;358:1663-1671
Sparano et al. N Engl J Med 2008
E1199: OS curves
Sparano JA et al. N Engl J Med 2008;358:1663-1671
Sparano et al. N Engl J Med 2008
TE1199: Toxicity profile
Effects of Paclitaxel and Docetaxel.
Sparano JA et al. N Engl J Med 2008;358:1663-1671
Sparano et al. N Engl J Med 2008
E1199: Conclusions
• Weekly paclitaxel after AC improves disease-free and overall
survival in women with breast cancer
• It comes at a price of increased neurotoxicity (grades 2,3 and
4- 27% vs 20%)
Sparano et al. N Engl J Med 2008
Patient-2
• 74 y/o female with seasonal allergies present with a large
mass in the left axilla. She is relatively active and does yoga
and pilates four times a week. Imaging showed 2.5 cm mass in
the left breast with several abnormal axillary nodes. Biopsy
showed invasive carcinoma, grade II, ER 80%, PR neg, her-2
neg with mets to axilla. She underwent PET scan which was
neg for systemic disease. She is referred for neoadjuvant
chemotherapy.
• Would you offer neoadjuvant chemo and if so what chemo
regimen would you pick for her?
Dose density: CALGB- 9741 Treatment schema
Citron et al. J Clin Oncol. 2003
(A) Disease-free survival by dose density; (B) overall survival by dose density
DFS was significantly prolonged for the
dose-dense regimens compared with
the every-3-weeks regimens (risk ratio
[RR] = 0.74; P = .010).
OS was significantly prolonged in the
dose-dense regimens (RR = 0.69; P =
.013)
This dose-density effect remained
significant even after adjusting for
number of positive nodes, tumor size,
menopausal status, and ER status.
Citron et al. J Clin Oncol. 2003
Patient-3
• 58 y/o female with 2.8 cm breast mass and positive nodes,
triple neg disease is receiving neoadjuvant chemotherapy. She
has completed dose dense AC and has tolerated it fairly. She
has had some tumor shrinkage so far clinically. She is starting
weekly Taxol today but as soon as she is started, she starts c/o
chest tightness, difficulty breathing and feeling lightheaded.
Her HR is 122 and she is hypoxic at 87% on RA, BP is normal.
She is given additional hydrocortisone and benadryl. After 30
minutes, she is feeling better and her vitals return to normal.
• What would you do?
GBG 69 – GeparSepto: Pac Vs Nab-Pac
Untch et al. Lancet 2016
GBG 69 - GeparSepto
ypT0N0
275 TNBC:
• 48% vs 26% (p<0.001)
• HR 2.69 (1.62-4.46)
Neuropathy worse with nab-P
• Gr 3+ 14% vs 3%
• D/c rate 17% vs 6%
Untch et al. Lancet 2016
ETNA: Evaluating Treatment with Neoadjuvant Nab
Paclitaxel
• 695 patients with centrally confirmed HER2 negative
breast cancer
• Randomized to paclitaxel (90 mg/m2) or nab-paclitaxel (125 mg/m2)
• Given weekly: 3 weeks on, one week off x 4 cycles
• Followed by 4 cycles of anthracycline regimen of choice, then surgery
• Primary endpoint: pCR (absence of invasive disease
in breast and nodes)
• pCR was similar between the two arms
Gianni et al, J Clin Oncol 34, 2016 (suppl; abstr 502)
ETNA Trial and Implications
• Why is this different?
• 16 week exposure rather than 12
• Dose per week lower: 125 mg/m2 vs 93.75 mg/m2
• Clinical Implications
• Await DFS data from GeparSepto
• Caution about neuropathy which is clearly increased
• No need for steroids may be an advantage with immunotherapy
Patient-4
• 40 y/o female was found to have a 3.5 cm mass in Rt breast
upon her first routine mammogram. US showed one abnormal
node which showed enhancement on MRI, biopsy confirmed
positive node. Biopsy showed IDC, high grade, triple negative.
Her sister was diagnosed with breast cancer at age 44 and is
doing well.
• What are your recommendations?
• Patients who became BCS candidates with neoadjuvant
therapy 55% versus 41% , p= NS
Role of Neoadjuvant Platinum in TNBC: Randomized Trials
Primary end-point: pCR rates
Study
No
Backbone Regimen
No Carbo
Carboplatin
GeparSixto*
315
Weekly paclitaxel + liposomal dox + bev
38%
59%
P< 0.05
C40603**
433
Sequential weekly paclitaxel – AC +/- bev
41%
54%
P=0.0029
Tamura et al
75
Sequential weekly pacl+/- Carb AUC5 - CEF
26%
62%
Alba et al
94
EC – Doc +/- Carbo AUC6
30%
30%
*3-yr DFS from Gepar-Sixto 86% vs 76% favoring carboplatin reported at SABCS 2015
**Patients who became BCS candidates with neoadjuvant therapy 55% versus 41% , p= NS
Von Minckwitz et al. Lancet Oncol 2014; Sikov et al. JCO 2015;
Alba et al. BRCT 2012; Tamura et al. ASCO 2014, Abstract 1107
ISPY-2: Adaptive randomization of Veliparib-carboplatin
• Adaptive trial design:
- minimize the exposure of patients to inactive agents
- detect more active regimens sooner
Adding veliparib and carboplatin to standard therapy
improved outcome in triple-negative breast cancer.
Rugo et al. N Engl J Med. 2016
Trial Design
Rugo HS et al. N Engl J Med 2016;375:23-34
Rugo et al. N Engl J Med. 2016
Estimated Rate of pCR with Veliparib–Carboplatin versus the Concurrent HER2-Negative Control.
Rugo HS et al. N Engl J
Med 2016;375:23-34
Rugo et al. N Engl J Med. 2016
Final Predictive Probabilities.
Rugo HS et al. N Engl J Med 2016;375:23-34
Rugo
et al. N Engl J Med. 2016
Selected Adverse Events and Toxic Effects.
Rugo et al. N Engl J Med. 2016
2016;375:23-34
Chemotherapy conclusions
• Pre-op AC is equivalent to pos-op AC
• Addition of pre-op Doc to pre-op AC improves pCR which
translates in to improved survival
• Pac given every week is better than every 3 weeks in terms of
DFS and OS but is associated with slightly increase neurotoxicity
• Dose density improves DFS and OS in breast cancer at no added
toxicity
Chemotherapy conclusions
• TC regimen is strictly studied in adjuvant setting and need to
use caution before using it pre-operatively
• Substitution of Pac with Abraxane is still premature till DFS
and OS data is available
• Addition of carboplatin may be considered in TNBC,
particularly those with inadequate response to AC
• Other agents tested for NACT- gemcitabine and capecitabine,
no improvement in pCR or breast conservation
Assessment of tumor response
• Clinical exam through chemo every 2-4 weeks (neoadjuvant
endocrine therapy every 4-8 weeks)
• US/MRI during treatment only is progression suspected
• Mammogram and MRI after chemo
• Discordance between clinical exam, imaging and path findings
can be seen due to variable patterns of tumor response
Post-chemo nodal evaluation
Clinically negative nodes before NACT:
SLNbx after
NACT
Neg
No further axillary surgery
Pos
If 1-2 LN then ALND or nodal XRT
If >=3 LN then ALND
Clinically positive nodes before NACT:
Pos
ALND
Clinical response
to NACT
Neg
Neg
No more
axillary Sx
Pos
ALND
SLNbx
Patient- 5 and 6
• 42 y/o female with 4 cm mass and one palpable node with biopsy
prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your
next step?
• 76 y/o female with 4 cm mass and one palpable node with biopsy
prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your
next step?
• How would you approach these patients? Are your
recommendations same for both?
• Would you give neoadjuvant therapy or send them to surgery first?
Patient- 5 and 6
• 42 y/o female with 4 cm mass and one palpable node with biopsy
prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your
next step?
• 76 y/o female with 4 cm mass and one palpable node with biopsy
prove metastasis, ER 100%, PR 100%, Her-2 neg tumor. What is your
next step?
• How would you approach these patients? Are your
recommendations same for both?
• Would you give neoadjuvant therapy or send them to surgery first?
• What if the surgeon ordered an oncotype and it was 10?
Neoadjuvant endocrine therapy
Study
No
Backbone Regimen
RR
Note
Russian trial
239
AT x4 Vs Anastrozole/Exemestane
64% both
BCS rates:
33% vs 24%
P= 0.058
GIECAM
95
EC x4Doc x4 Vs Exemestane for
24 weeks
66% vs 48%
P= 0.075
favor CT
Low Ki-67
63% vs 58%
P= 0.74
GEICAM
premenopausal
51
CT-24 and HT-27
75% vs 44%
P= 0.027
Exploratory
unplanned
analysis
Semiglazov et al. Cancer 2007
Alba et al. Ann Oncol. 2012
Neoadjuvant endocrine therapy
• Neoadjuvant endocrine therapy currently restricted to postmenopausal
patients
• Neoadjuvant endocrine therapy approach should be considered
investigational for premenopausal women.
• pCR uncommonly seen with either chemo or endocrine therapy, usual
duration is 4-6 months so is pCR a good end-point for HR + breast
cancer?
• PEPI takes into account tumor and nodal stage, level of ER expression,
and Ki67 following neoadjuvant endocrine therapy; and measurement
of Ki67 before and during treatment
• AI better than Tam in terms of RR and rates of breast conserving
surgery, all AIs have similar clinical response rates
Inflammatory breast cancer
• Dx: rapid onset or erythema/peau d’orange, duration < 6
months, erythema occupying at least third of the breast &
path confirmation of cancer
• Staging/evaluation similar to locally advanced, third present
with distant mets
• NACT usually with ACT based on data in locally advanced
tumors, add Traz/Per for her-2 pos tumors
• XRT is given to all patients regardless of the surgery or
response to NACT
Operable
NACT
Inoperable
Mastectomy
+ ALND
Change chemo
Pre-op XRT if
inadequate
response
Future directions
• Additional chemotherapy adjuvantly if inadequate response to
NACT
• Neoadjuvant endocrine therapy trials
• Neoadjuvant CDK4/6 inhibitors
• Platinum adjuvantly for inadequate response to NACT in TNBC
• PARP inhibitors in TNBC and BRCAm breast cancerneoadjuvant and adjuvant settings
• Neoadjuvant oncotype to guide therapy decisions
CREATE-X: A Phase III Trial of Adjuvant Capecitabine in HER2-Negative BC
with Pathologic Residual Invasive Disease After NACT
Capecitabine
Control
HR (p-value)
2-year DFS rate
87.3%
80.5%
0.688 (0.001)
2-year OS rate
96.2%
93.9%
0.658 (0.086)
Lee S-J et al. San Antonio Breast Cancer Symposium 2015;Abstract S107.
ALTERNATE: Phase III trial of Fulvestrant and/or Anastrozole in
postmenopausal women with stage II-III breast cancer undergoing surgery
Estimated enrollment: 2820 patients
Anastrozole
Eligibility: T2-T4, any N, M0
pts with invasive breast
cancer having PS 0-2
R
Fulvestrant
Anastrozole+
Fulvestrant
Primary endpoints: Rates of endocrine resistance,
recurrence free survival and pCR
Secondary endpoint: post-treatment PEPI scores an its correlation
with RFS and pCR if patient gets off study and gets chemo
neoMONARCH: A Phase II Neoadjuvant Trial of Abemaciclib or
Anastrozole Alone or the Combination
Trial Identifier: NCT02441946
Enrollment: 148 (Closed)
Abemaciclib
Eligibility
• Postmenopausal
• HR+/HER2-negative breast
adenocarcinoma
• Clinical Stage I (≥1 cm),
Stage II, Stage IIIA or IIIB
R
Anastrozole
After day 14
all pts get the
combination
for 14 weeks
Abemaciclib +
anastrozole
Primary endpoint: Change in Ki-67 levels between baseline and after 2
weeks of therapy
www.clinicaltrials.gov, September 2016.
EA1131 Trial Design
Pre-Registration
Stage II/III
TNBC§
Primary Endpoint:
- DFS in patients with basal-like TNBC
Neoadjuvant
Chemotherapy*
Secondary Endpoints:
- OS
- RFS
Stratification factors:
1) Disease stage at diagnosis (II or III)
2) Residual cancer burden after NAC (1~3 cm or >3 cm)
3) Platinum agent choice (cisplatin or carboplatin)
4) Anthracycline exposure (yes or no)
Definitive surgery
Residual cancer
≥1 cm
Within
48 days
Cisplatin 75 mg/m2
Registration
Basal-like
Randomization
Tissue collection
PAM50 analysis
OR
Carboplatin AUC 6
Q3W x 4 doses
(1:1)
Within 84 days
Radiotherapy (when applicable)
should be completed prior to
protocol platinum therapy
§TNBC:
ER/PR classified locally as negative, or Allred score ≤ 2, or < 5% weakly positive staining
*Taxane +/- Anthracycline based; platinum agents not allowed
(physician’s choice)
Observation
Brightness trial
Eligibility: N = 624
Neoadjuvant
chemotherapy for
Early stage TNBC
Veliparib + Carboplatin +
Paclitaxel  AC
R
Placebo + Carboplatin +
Paclitaxel  AC
Placebo + Placebo+
Paclitaxel  AC
www.clinicaltrials.gov, September 2016
OlympiA: OLaparib in Adjuvant BRCAm breast
cancer
Germline mutation carriers
Olaparib
300 mg bd
12 months duration
IDFS
R
1:1
Double blind
N = 1,320
Post adjuvant gBRCA
TNBC
T2 or N+
Placebo
12 month duration
Distant DFS; OS
Post neoadjuvant gBRCA
TNBC,
Non-PathCR pts
Neoadjuvant HT or CT based on Oncotype scores
Trial Identifier: NCT01293032 – Pilot study
Enrollment: 64 (Closed)
Eligibility
• Pre and postmenopausal
• HR+/HER2-negative invasive
breast cancer
• Primary tumor > 2cm, stages
II and III
O
N
C
O
T
Y
P
E
RS < 11
Hormone therapy
RS 11-25
RS> 25
Chemotherapy
www.clinicaltrials.gov, September 2016.
CT
R
HT
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