The current treatment landscape
for early breast cancer: Advances
in cytotoxic and endocrine
treatment Ahmad Awada, MD, PhD
Head of Medical Oncology Clinic
Institut Jules Bordet
Université Libre de Bruxelles (U.L.B.)
Brussels, Belgium
October 2015 HQ/ONC/14/0007
Systemic treatment of early breast cancer
- plan of the talk -
1. Why chemotherapy is still an important therapeutic
component
2. Which patients? Which tumors? Chemotherapy and
endocrine therapy settings?
3. Role of dose-dense regimens
4. Latest advances in the neoadjuvant setting (TNBC;
HER2+)
5. Perspectives (Tumor sequencing, TILs)
CLINICAL CASE
• ER 7/8 PR 3/8 – grade 2 – Ki67 is 20% and
HER2 is negative (Luminal B disease)
• LVEF is 60%
A 61-year-old postmenopausal woman seeks your opinion 2 weeks after surgery for a 3cm invasive
ductal cancer of the left breast. Two positive axillary
lymph nodes.
CLINICAL CASE
Your recommendation as adjuvant endocrine therapy is:
1. An aromatase inhibitor upfront (5 y)
2. Tamoxifen alone (5 y)
3. Tamoxifen alone (10 y)
4. Sequential therapy: tamoxifen AI (5 y)
5. Five years of tamoxifen followed by an extended AI
6. Other
CLINICAL CASE
In addition to endocrine therapy, should we
prescribe zoledronic acid as an adjuvant
antitumoral approach (pts with estrogen
deprivation)?
CLINICAL CASE
Of note: each chemotherapy option is followed by endocrine therapy.
Your adjuvant chemotherapy recommendation is
1. CMF x 6 cycles or AC x4
2. TC x 4
3. Anthracycline-based chemotherapy x6 (eg, FEC x 6)
4. Anthracycline plus taxane-based chemotherapy (eg, FEC
taxane or TAC x 6)
5. Dose-dense ECx4 taxane (docetaxel x 4 or paclitaxel wx12)
6. Anthracycline + taxane/carboplatin – based
7. Chemotherapy + bevacizumab
8. Other
1. Why chemotherapy is still an important therapeutic component in early BC
The Basis of Systemic Therapy = Chemotherapy
except for luminal A diseases !
Luminal B tumors
(ER+/HER2-)
Anders CK. San Antonio Breast Cancer Symposium 2013: Abstract ES03-2.
TUMOR
BURDEN
T size
N status
Metastases
? Circulating tumor DNA or cells
TUMOR
BIOLOGY
ER
PR
HER2
Ki67
PIK3CA mutations?
Gene profiling?
TILs?
HRD?
Here resides the decision to
“escalate”/“de-escalate” the chemotherapy
Here are the targets!
Targeted therapies (endocrine and HER2 therapies)
Patients
Characteristics
• Age
• Comorbidities (organs dysfunction)
TREATMENT
BURDEN
Host tolerance to
chemotherapy
2. Adjuvant therapy of breast cancer:
which patients? Which tumors? Which biology?
Prognostic and/or predictive marker:
PiK3CA mutations
• 30% of BC (mainly HR+)
• Good outcome (HR+)
• Sensitivity to everolimus
(HER2+/BOLERO 1 & 3)
• Lower pCR in the neoadjuvant
PIK3CA mutations
Solid rationale to include PiK3CA mutation as
a biological marker
Challenge: which technic?
(ASCO 2015,Abs 516, 511, 512)
Predictive markers: Homologous
recombination deficiency scoring (HRD)
• More and more studied in
TNBC/basal-like (and high risk HR+)
• The magnitude of sensitivity
prediction to platinum or
PARPi is unclear
Homologous recombination
deficiency scoring (HRD)
The application of HRD scoring needs validation
(ASCO 2015, Abs 521, 1018, 1004)
≈10% 50%-60%
30%-40%
TAILORx and MINDACT
Bringing molecular prognostic signatures
to daily clinical practice in a selected group of pts?!
•High-risk 21-gene R.S.
•High-risk 70-gene signature + High-risk adjuvant online
OR •Medium-risk 21-gene R.S.
•Discordant risk group
OR
•Low-risk 21-gene R.S.
•Low-risk 70-gene signature + Low-risk adjuvant on line
OR
CHEMOTHERAPY • RANDOMIZE
CHEMO YES or NO (TailorX)
• RANDOMIZE FOR the decision-
making tool (Mindact)
ENDOCRINE
THERAPY
TAILORx trial: Clinical Trials.gov #NCT00310180
MINDACT study: Clinical Trials.gov # NCT00433589
Tumor-Infiltrating Lymphocytes In Breast Cancer (TILs)
Lymphocyte predominant breast cancer (LP) (≥ 60% Str-TIL): 10% of pts Non-Lymphocyte predominant breast cancer (Non-LP) (< 60% Str-TIL): 90% of pts
Arm A: Chemotherapy Arm C: Chemotherapy + Trastuzumab
Lymphocyte predominant breast cancer and treatment outcome: Provocative results
Increasing Str-TILS (≥ 60%) associated with increased RFS in pts treated with chemotherapy alone
Patients with non-LPBC had better RFS when treated with chemotherapy plus trastuzumab
RFS: Recurrent-Free Survival
CMF
AC
AC->Pac(3w)
ddA/EC->Pac(2w)
AC->Pac(qw) or Doc(3w)
Doc-C
CAF/FAC DocAC
CEF/FEC FEC->Doc
<
=
<
<
<
<
<
<
<
=
Addition of capecitabine,
gemcitabine, bevacizumab not beneficial
6 cycles
4 cycles
8 cycles
= =
Overview of the most important adjuvant chemotherapy studies in
early breast cancer
Wildiers H, …, Awada A, Belg J Med Oncol. 2014
Author
(n) N status Control arm Dose dense (+CSF) Outcome
Citron
(n = 1992) 100% N+ 4xAC->4xPac(3w)
4xAC->4xPac(2w)
DFS ↗
OS ↗
Venturini
(n = 1214) 66% N0 6xFE60C(3w) 6xFE60C(2w)
DFS =
OS =
Cameron
(n = 4391) 47%N0
4xE100(3w)-
>4xCMF/X 4xE100(2w)->4xCMF/X
DFS =
OS =
Cognetti
(n = 2091) 100% N+
4x(F)E90C-
>4xPac(3w) 4x(F)E90C->4xPac(2w)
DFS ↗
OS ↗
5-FU no
benefit
3. “Pure” adjuvant dose-dense chemotherapy (+G-CSF)
studies in early breast cancer
Wildiers H, …, Awada A, Belg J Med Oncol. 2014
EBCTCG meta-analyses (2011) of studies using
polychemotherapy: Five main findings (1)
1. Polychemotherapy regimens with significantly
lower dose per cycle appeared less effective
(role of G-CSF)
2. Standard ACx4 = standard CMFx6
3. Regimens with substantially more
chemotherapy than 4AC (eg, CAF, CEF, A+T)
were somewhat more effective
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2012;379(9814):432-44.
EBCTCG meta-analyses (2011) of studies using
polychemotherapy: Five main findings (2)
4. In all chemotherapy comparisons (A+T, higher-
cumulative-dosage anthracycline-based), 10-
year overall mortality was reduced by one-third
5. In all meta-analyses involving taxane-based or
anthracycline-based regimens, proportional risk
reductions were little affected by age, nodal
status, tumor diameter or differentiation, ER
status, or tamoxifen use
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2012;379(9814):432-44.
SELECTION OF ADJUVANT ENDOCRINE THERAPY
FOR POSTMENOPAUSAL PATIENTS ACCORDING TO ENDOCRINE
RESPONSIVENESS AND TUMOR RISK
Hormone receptors
expression
Absent Intermediate High
AI
Upfront
TAM alone
Switch
AI TAM
AI upfront
ADD CHEMOTHERAPY
FOR HIGH-RISK PATIENTS
C
H
E
M
O
T
H
E
R
A
P
Y
High
Low
T
U
M
O
R
R
I
S
K
AI switch TAM
Premenopausal patients: Tamoxifen ± GnRH analogs or AI + GnRH analogs according to the tumor risk and side effects.
*Luminal A disease
SELECTION OF ADJUVANT CHEMOTHERAPY
REGIMENS : ACCORDING TO ENDOCRINE-
RESPONSIVENESS AND TUMOR RISK
Hormone receptors
expression
Absent Intermediate High
Low
Intermediate
High
A+T TC
A+T
Endocrine
therapy
Anthracyclines (A)
+
taxane (T)
Tumor
risk
ADD Endocrine therapy
A+T: sequencially or in combination (including dose-dense)
A(C) CMF (contraindication to taxane)
TC: of great interest in pts at risk of cardiac failure
Trastuzumab
(T) use Study Control arm Trastuzumab arm
Concurrent
BCIRG 006 4xAC->4xDoc 4xAC->4xDoc+T
6xDocCarboT (TCH)*
NSABP B-31 4xAC->4xPac(3w) or
12xPac(qw)
4xAC->4xPac(3w) or 12xPac(qw)
+T
Sequential HERA Chemotherapy
Chemo->T1y
Chemo->T2y
PACS-04 6xFEC or 6xEDoc 6xFEC or 6xEDoc->T1y
Concurrent
versus
sequential
NCCTG
N9831 4xAC->12xPac(qw)
4xAC->12xPac(qw)+T1y
4xAC->12xPac(qw)->T1y
Chemotherapy regimens used in pivotal studies for HER2+ breast cancer:
significant positive outcome mainly when trastuzumab combined with taxane
T = trastuzumab; y = years; Carbo = carboplatin Wildiers H, … Awada A, Belg J Med Oncol. 2014
*of great interest in pts at risk of cardiac failure
ALTTO trial (+ lapatinib): negative study
Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: Primary analysis at 2 years of a phase 3 randomized, placebo-controlled trial (ExteNET))
Study Design
Primary Endpoint: Invasive DFS (ITT)
2,3 %
Extenet Summary
ExteNET: Summary
• Absolute difference in invasive disease-free survival at 2 years is 2.3 % in favor of neratinib
4. Neoadjuvant setting: An attractive approach for clinical practice and for translational research
Standard preoperative
therapy Surgery Biopsy
Standard preoperative
therapy
+ new agent
• “Real-time” evaluation of primary tumor response
• Postoperative therapy adapted based on the induction efficacy (investigational)
• Caveat: Difference in biology of micrometastasis versus primary tumor?!
Molecular
Markers; PET/CT
Ki67
Gene profiling
Tumor sequencing
PET/CT
Author (n) Control arm Experimental arm Outcome
NSABP-B27
(n = 2411) 4xAC->S
4xAC->S->4xDoc
4xAC->4xDoc->S
pCR ↗ with Doc
DFS =
OS =
Aberdeen
(n = 162)
PR/CR after 4xCVAP:
4xCVAP
PR/CR after 4xCVAP:
4xDoc
pCR ↗
DFS ↗
OS ↗
ACCOG
(n = 363) 6xAC 4xADoc
pCR =
DFS =
OS =
Dieras
(n = 200) 4xAC-> 4xAPac
pCR ↗
DFS ↗
OS ↗
Meta-
analysis
(n = 2455);
7 trials
Anthracycline based Anthracycline based +
taxane
pCR ↗ with sequential,
but not concomitant
taxane
DFS =
S = surgery; pCR = pathological complete response rate (in breast and axilla); PR = partial response; CR = complete response
Selection of important neoadjuvant randomized trials incorporating taxanes
Wildiers H, … Awada A, Belg J Med Oncol. 2014
Cortazar, et al. Cancer Res. 2012;72(24)suppl 3:Abstract S1-11.
Weekly non-pegylated liposomal doxorubicin + paclitaxel ±
carboplatin as primary therapy for TNBC or HER+ tumors (1)
von Minckwitz G, et al. ASCO 2013:abstract 1004; von Minckwitz G, et al. Lancet Oncol. 2014;15(7):747-56.
Weekly non-pegylated liposomal doxorubicin + paclitaxel ±
carboplatin as primary therapy for TNBC or HER+ tumors (2)
von Minckwitz G, et al. ASCO 2013:abstract 1004; von
Minckwitz G, et al. Lancet Oncol. 2014;15(7):747-56.
BRCAness TNBC benefit most from carboplatin
All TNBC
Sikov W, et al. San Antonio Breast Cancer Symposium 2013: Abstract S5-01.
CALGB 40603 Study: PCR Result
Sikov W, et al. San Antonio Breast Cancer Symposium 2013: Abstract S5-01.
All TNBC
41 %
54 %
, BRCA mutated tumors, TILS, HRD…)
Should carboplatin now be standard in the neoadjuvant setting?
Probably not except for a subgroup of patients (which one?)
Cortazar, et al. Cancer Res. 2012;72(24)suppl 3:Abstract S1-11.
Dual HER2 targeting together
with a taxane
Dual HER2 + taxane in the neoadjuvant setting: doubling pCR
mainly in HR negative tumors
Single HER2 inhibition
+
chemotherapy
Dual HER2
inhibition
+ chemo
Dual HER2 inhibition
No chemotherapy!
Trastuzumab
Docetaxel
Pertuzumab
Docetaxel
Trastuzumab
Pertuzumab
Docetaxel
Trastuzumab
Pertuzumab
ITT 29% 24% 46% 17%
NEO-SPHERE
NEO-ALTTO
Single HER2 inhibition
+ chemotherapy
Dual HER2
inhibition
Trastuzumab
Paclitaxel
Lapatinib
Paclitaxel
Trastuzumab
Lapatinib
Paclitaxel
ITT 29% 25% 51%
Gianni L, et al. Lancet Oncol. 2012 Jan;13(1):25-32.
Baselga J, et al. Lancet. 2012;379(9816):633-40.
HR negative tumors benefit most from dual HER inhibition
DUAL HER-2 THERAPY IN THE NEOADJUVANT
SETTING: CONCLUSIONS (2015)
• Trastuzumab + lapatinib + paclitaxel:
• Standard use not justified in view of the negative
results of ALTTO trial
• Trastuzumab + pertuzumab + docetaxel:
• Of interest in locally « bulky » disease, HR negative
• Standard use await APHINITY trial
• Dual HER-2 therapy alone
• Intensify translational research to help in the selection
of patients candidates for dual HER-2 therapy without
chemotherapy
• Of interest in elderly patients?
Neoadjuvant therapy
• T-DM1 : 40.5%
• T-DM1 + Endocrine treatment: 46%
• Trastuzumab + ET : 7%
pCR
Validation in a phase 3 trial is needed as well as the
correlation with DFS and OS
T-DM1 (12 weeks) ± endocrine therapy (ET) versus ET +
trastuzumab in HER2+/HR+ tumors
Ki-67 (3w vs baseline) not predictive of pCR
(ASCO 2015, Abs 506)
CLINICAL CASE
• ER 7/8 PR 3/8 – grade 2 – Ki67 is 20% and
HER2 is negative (Luminal B disease)
• LVEF is 60%
A 61-year-old postmenopausal woman seeks your opinion 2 weeks after surgery for a 3cm invasive
ductal cancer of the left breast. Two positive axillary
lymph nodes.
CLINICAL CASE
Your recommendation as adjuvant endocrine therapy is:
1. An aromatase inhibitor upfront (5 y)
2. Tamoxifen alone (5 y)
3. Tamoxifen alone (10 y)
4. Sequential therapy: tamoxifen AI (5 y)
5. Five years of tamoxifen followed by an extended AI
6. Other
CLINICAL CASE
In addition to endocrine therapy, should we
prescribe zoledronic acid as an adjuvant
antitumoral approach (pts with estrogen
deprivation)?
CLINICAL CASE
Of note: each chemotherapy option is followed by endocrine therapy.
Your adjuvant chemotherapy recommendation is
1. CMF x 6 cycles or AC x4
2. TC x 4
3. Anthracycline-based chemotherapy x6 (eg, FEC x 6)
4. Anthracycline plus taxane-based chemotherapy (eg, FEC
taxane or TAC x 6)
5. Dose-dense ECx4 taxane (docetaxel x 4 or paclitaxel wx12)
6. Anthracycline + taxane/carboplatin – based
7. Chemotherapy + bevacizumab
8. Other
THANK YOU
