Systemic Therapy for Breast Cancer

Adjuvant or Neoadjuvant
AGUSTIN A GARCIA, MD, MMM
PROFESSOR OF MEDICINE AND SECTION CHIEF HEMATOLOGY ONCOLOGY
CHARLES W MCMULLIN III AND RICHARD PAUL GRACE CHAIR IN CANCER RESEARCH
LOUISIANA STATE UNIVERSITY
NEW ORLEANS, LA
 Disclosure

I have the following relationship(s) with commercial interests.

NAME OF COMPANY: Celldex, Seattle Genetics, Iovance

RELATIONSHIP Investigator
RECEIVED Grants

A commercial interest is any entity producing, marketing, re-

selling, or distributing health care goods or services consumed
by, or used on, patients.
Breast CancerMortality by Race
 The 20 Century: th
From radical to more breast-conserving surgery

Removal of whole
Inoperability criteria No difference in survival
breast, including
established for locally with radical mastectomy
pectoral muscles and
advanced breast cancer or lumpectomy
axillary lymph nodes

1880
1880 1900
1900 1920
1920 1940
1940 1960
1960 1980
1980 2000
2000

Modified radical
Radical mastectomy Sentinel lymph
mastectomy and node mapping
supraclavicular
dissection

Winchester DP, et al. Surg Oncol Clin N Am. 2005;14:479.

Advances in the Adjuvant Treatment of Breast Cancer
CALGB 9741 NSABP B31
NSABP B14 Dose dense AC→P AC→P vs NeoSphere
Tamoxifen vs Standard dose AC→P
AC→P + Chemo +
placebo
Trastuzumab
NSABP B15 trastuzumab
(T) vs
Istituto AC vs CMF
CALGB 9344 Chemo + T +
Nazionale pertuzumab
AC vs ACP
Tumori
NCIC MA-5 BCIRG 001
(Milan) NCCTG N9831 ExteNET
CEF vs CMF TAC vs FAC
CMF vs AC→P vs AC→P + Chemo + T vs
placebo FASG 05 trastuzumab vs Chemo + T
FEC100 vs NSABP B28 AC→P→trastuzumab →Neratinib
FEC50 AC vs ACP

BIG 1-98
1970 1980 1990 2000 Letrozole vs
2006 2018
tamoxifen BIG 01-01 HERA CREATE-X
NSABP B27
Local therapy ± TNBC
T→ AC vs
trastuzumab Neoadjuvnant
NSABP B05, B07 TAC
Melphalan vs placebo Chemo Post
EBCTCG BCIRG 006 Capecitabine
PACS-01 (meta-analysis)
AC→T ±
FEC vs Anthracycline-
trastuzumab vs
NSABP B08-B10 FEC + T based regimen vs
TCb + trastuzumab
Melphalan ± 5-FU CMF
 Adjuvant Chemotherapy:
Effects on RFS, long term follow up.

N=386 node-positive patients.

• 35% decrease in risk of recurrence.

• 24% decrease in risk of death
• P<0.04 Bonadonna et al. N Engl J Med. 1995;332:901-906.
Adjuvant Chemotherapy
Effects on RFS

EBCTCG 2000, Lancet 2005

Adjuvant Chemotherapy
Effects on OS
Multidisciplinary Management of Breast Cancer
• Surgical Management
↓
• Systemic Therapy
↓ Endocrine Therapy
• Radiation
HER2 Targeted Tx
Mastectomy
Chemotherapy

Breast
Conservation
Radiation
5
 Neoadjuvant Chemotherapy for Breast Cancer
Historical Perspective

Anhracyclines for
Locally Advanced Locally Advanced Neoadjuvant
Inoperable Breast Inoperable Breast Neoadjuvant
Chemotherapy in all
Cancer (Haagensen) Cancer Chemotherapy Trials for
Stages to Allow Breast
all Stage III Disease
Palliative Care Response Rate 72% Conserving Surgery
Mastectomy: 44%

Hortobagyi Hortoba
GN, Cancer
Jacqui
gyi GN,
1983 Cancer llat C,
1988 Cance
r 1990
 Neoadjuvant or PreOperative Chemotherapy
• Goals
A) Reduce Distant Metastasis
B) Select Individualized Therapy for Non Responders
C) Improve surgical care
– Down stage Tumor
– Allow less extensive surgery
– Facilitate breast conserving surgery
– Improve cosmetic outcome
 Neoadjuvant or PreOperative Chemotherapy
• Goals
A) Reduce Distant Metastasis
Long-term outcomes for neoadjuvant versus adjuvant
chemotherapy in early breast cancer: meta-analysis

EBCTCG Lancet Oncol 2018

 Neoadjuvant or PreOperative Chemotherapy
• Goals
A) Reduce Distant Metastasis
B) Select Individualized Therapy for Non Responders
C) Improve surgical care
– Down stage Tumor
– Allow less extensive surgery
– Facilitate breast conserving surgery
– Improve cosmetic outcome
 Pathological complete response and long-
term clinical benefit in breast cancer: the
CTNeoBC pooled analysis.
• Cortazar P, et al Lancet. 2014 Jul 12;384(9938):164-72
Associations between pathological complete response and
event-free survival and overall survival
Association between pCR and event-free survival, by
breast cancer subtype
 Benefits of Monitoring Efficacy to Neoadjuvant
Chemotherapy:
GeparTrio Trial

TAC X 4

Early Responder

TAC X 6
T2 or LN + Breast Neoadjuvant
cancer
TAC X 2
N= 2012
TAC X 4
Early Non
Responder
NX X 4
TAC= Docetaxel, Adriamycin, Cyclophosphamide
NX= Vinorelbine, Capecitabine
Von Minckwits G, et al. J Clin Oncol 2013
GeparTrio Results
Patients with Triple Negative Breast Cancer who do not
achieve a pCR have a poor prognosis
Post Operative Chemotherapy in Patients with Residual
Disease after Neoadjuvant Therapy:
CREATE-X Trial

Capecitabine

Stage I-III
HER2 neg Neoadjuvant Surgery No pCR
Chemotherapy
N=910
Observation

Masuda N, et al. N Engl J Med 2017

CREATE-X: Results
 CALGB 40603: Addition of Carboplatin to
Neoadjuvnat Chemotherapy in Triple Negative Breast
Cancer
Weekly Taxol x 12 ddAC x 4

Weekly Taxol x 12
Stage II-III Bevacizumab ddAC x 4
Triple
Negative Weekly Taxol x 12
dd AC x 4
Breast Cancer Carboplatin
Weekly Taxol x 12
Carboplatin ddAC x 4
Bevacizumab
CALGB 40603: Results
 What we know about the results of
Neoadjuvant Chemotherapy
• Achieving a pCR is associated with excellent survival
• Patients without a pCR or poor clinical response have a
poor prognosis
• Switching chemotherapy in poor responders leds to
improve outcome
• The addition of carboplatin improves pCR
Proposed Approach to Neoadjvuant Chemotherapy in
Triple Negative Breast Cancer

Standard A,
Good Response  weekly taxol or
Standard surgery
Triple Negative Evaluate
AC (or TC)
Breast Cancer   Response
x4 Weekly Taxol or
Poor Response  A
+ Carboplatin
 HER2 positive breast cancer

• Approx 15% of all breast cancers.

• More common in younger women.
• Tend to be larger, more likely to involve LN and be high
grade
• Poor prognosis

Killelea BK, et al. Am J Surg 2017

 Summary of Trastuzumab Trials
NSABP B-31 HERA
52 wks 1 Yr 2 Yr
4 cycles
Pax HD q 3 wk
4 cycles No therapy
Trastuzumab
Dox/Cyc Standard
4 cycles Trastuzumab
ChemoRx
Pax HD q 3 wk Trastuzumab

NCCTG 9831 BCIRG 006

12 wks 52 wks 64 wks Docetaxel
4 cycles
Trastuzumab
Pax LD/wk Dox/Cyc
Trastuzumab Docetaxel
4 cycles
Dox/Cyc Docetaxel
Pax LD/wk Trastuzumab
Carboplatin
Pax LD/wk Trastuzumab
Accepted Principles of Neoadjuvant Therapy
• Affords outcomes identical to adjuvant therapy
• Improves operability of inoperable, locally advanced breast
cancer
• Improves breast conservation rates
• Improves outcome in Inflammatory Breast Cancer:
Standard of Care
10 year results of adjuvant Chemotherapy +
Trastuzumab

37% improvement
in Survival

Perez E, et al J Clin Oncol 2014

Neoadjuvant Chemotherapy for HER2 positive Breast
Cancer: NOAH Study

Chemotherapy Alone Surgery

Locally Advanced
HER2 Positive Breast
Cancer
N=235 pts
Chemotherapy +
Surgery
Trastuzumab

Locally Advanced
Triple Negative Breast
Cancer Chemotherapy Surgeryt
N= 99 pts
Gianni L et al. Lancet 2010
NOAH Trial: Results

Rates of pCR
40

35

30

25

20

15

10

HER2 Pos Chemo alone

HER2 Pos Chemo + T
Triple Negative
NEOSPHERE RESULTS
ExteNET Results

33% Reduction
in Recurrence
 What we know about the results of
Neoadjuvant Chemotherapy in HER2 Pos
Breast Cancer
• Achieving a pCR is associated with excellent survival
• Patients without a pCR or poor clinical response have a poor
prognosis
• The addition of pertuzumab significantly improves pCR
• The addition of neratinib after trastuzumab significantly improves
DFS
Proposed Approach to Neoadjvuant Chemotherapy in
HER2 postivie Breast Cancer

Standard Treatment
pCR +

No neratinib
Standard
HER2 positive
Surgery
breast cancer  Chemotherapy +  Standard Treatment
T+P
+
No pCR 
Neratinib after
Trastuzumab
 Neoadjuvant or PreOperative Chemotherapy
• Goals
A) Reduce Distant Metastasis
B) Select Individualized Therapy for Non Responders
C) Improve surgical care
– Down stage Tumor
– Allow less extensive surgery
– Facilitate breast conserving surgery
– Improve cosmetic outcome
 Effects of Neoadjuvant Chemotherapy on
BCT

Trial Rate of BCT (%)

Surgery First Chemotherapy First
Royal Marsden 78 89
Institut Curie 77 82
NSABP-B18 60 67
EORTC 21 37
Challenges with Neoadjuvant Therapy
Effects of surgery in Risk of Local Recurrence after Neoadjvuant
Chemoterapy
 Considerations for Lumpectomy after Neoadjuvnat
Chemotherapy

• Remove any suspicious clinical or radiologic findings

• Generous sample of “normal” breast tissue
• It is not necessary to remove the entire volume of tissue initially occupied by
tumor
– If viable tumor is present throughout the specimen, even if it does not extend
to the margin, a further re-excision should be considered
( American College of Radiology, American College of Surgeons, College of
American Pathology, Society of Surgical Oncology)
Management of the Axilla After Neoadjuvant
Chemotherapy (NAC)
• NAC downstages axilla in up to 40% of patients
• Consider SLNB after NAC and avoid ALND?
• Influence of pretreatment clinical node stage
 SLN Biopsy after Neoadjuvant Chemotherapy
cN1converted to CN0
ACOSOG Z1071 SENTINA SN FNAC
Number of patients 649 592 153
Mapping Dual Recommended Technetium required Technetium required,
IHC
Pre-op biopsy Yes Not required Yes
Nodal pCR (%) 41 52 35
IR (%) 92.7 80.1 87.6
False Negative Rate (%) 12.6 14.2 8.4
1 SLN 31.5 24.3 18.2
2 SLN 21.1 18.5 4.9
> 3 SLN 9.1 7.3 NS
 SLNB after Neoadjuvant Chemotherapy:
Considerations
• Use Dual agent mapping
• Normal Physical Exam and axillary US after chemotherapy
• Remove > 2 nodes
• Place a clip at time of LN biopsy
• Include IHC + and micromets as node positive
• Intraoperative Frozen Section of all nodes
• ALND required for
– Failed Mapping
– < 3 nodes
– Any positive LN
 Post NAC Trials of Axillary Management <br />cN1 to cN0

Can axillary RT replace ALND

Can Response to NAC be used to select Radiation
Is there a role for neoadjuvant endocrine
therapy?
21-Gene Recurrence Score
Genomic Profiling to Identify Patients who do not
require adjuvant chemotherapy
Should patients with HR+, HER2 neg breast
cancer receive neoadjuvant chemotherapy?

Bear HD, et al. J Surg Oncol 2017

 Chart Title
100
90
80
70
60
50
40
30
20
10
0
Group A, RS < 11, NHT Goup B RS 11-18 NHT Group C RS 11-25, NCT Group D, RS > 25, NCT

Response pCR Succesful BCS

NHT= Neoadjuvant Endocrine Therapy

NCT+ Neoadjuvant Chemotherapy
 Neoadjuvant Chemotherapy:
Summary and Future
• 40-60% of patients with triple negative or HER2 positive breast
cancer achieve a pCR with neoadjuvant chemotherapy
• Patients with pCR have an excellent prognosis independent of
clinical stage or tumor characteristics
• Do patients with pCR benefit from local therapy (surgery and/or
radiation)?
• Can these patients be identified preoperatively?
 Neoadjuvant Chemotherapy:
Summary and Future
• 40-60% of patients with triple negative or HER2 positive breast
cancer achieve a pCR with neoadjuvant chemotherapy
• Patients with pCR have an excellent prognosis independent of
clinical stage or tumor characteristics
• Do patients with pCR benefit from local therapy (surgery and/or
radiation)?
• Can we avoid surgery in patients with a pCR? Can these
patients be identified preoperatively?
 Neoadjuvant Chemotherapy
What is next?
• Why avoid surgery
– Morbidity
• Breast Deformity
• Acute and Chronic Pain
• Hematoma, fat necrosis, seeroma
• Anesthesia risk
– Cost and rationale use of resources
• Outpatient surgery= $12,000 per patient
– Patient’s preference
Can we avoid surgery in patients who achieve a pCR?
Can we avoid surgery in patients who achieve a pCR?
Problem: pCR identified after surgery
Can we avoid surgery in patients who achieve a pCR
Problem pCR identified after surgery
 Imaging studies in identifying pCR
Study Mammography Ultrasound MRI
NPV (%) FNR (%) NPV (%) FNR (%) NPV (%) FNR (%)
Schottt 91 9 91 9 94 6
Peintinger NPV 93 FNR 7 NR NR
Chen NR NR NR NR 74 26
Bhattacharyya NR NR NR NR 96 NR
Keune 86 NR 85 NR NR NR
Croshaw 30 70 33 67 44 56
De Los Santos NR NR NR NR 47 NR
Schaefgen 52 13 51 24 60 4

Van la Parra R, et al. Breast Cancer Rest 2016

 A Clinical Feasibility Trial for Identification of Exceptional
Responders in Whom Breast Cancer Surgery Can Be
Eliminated Following Neoadjuvant Systemic Therapy.
Kuerer H et al. Annals of Surgery. 267(5):946-951, May 2017

Mammogram + US + MRI + Biopsy

Accuracy = 98%
FNR= 5%
NPV= 95%
 NRG BR005
A Phase II Trial Assessing the Accuracy of Tumor Bed
Biopsies in Predicting Pathologic Response in Patients with
Clinical/Radiologic Complete Response after Neoadjuvant
Chemotherapy in Order to Explore the Feasibility of Breast
Conserving Treatment without Surgery
 Eligibility:
Stage I-III
Neoadjuvant Chemotherapy
Clinical CR

Image-
Trimodality
Guided Core Lumpectomy
Imaging
Biopsy
 Primary Objective
• To assess the accuracy of post-neoadjuvant systemic
therapy image-directed tumor bed biopsy for pCR in cases
of clinical and radiologic complete response with
trimodality imaging.
 Aim
• To develop a multidisciplinary approach combining clinical
exam, imaging and pathology (biopsy) to
– Predict pCR > 90%
 Indications for Neoadjuvant Therapy
• Inflammatory Breast Cancer
• Localized Advanced Breast Cancer
• Facilitate BCT

• Consider for all patients candidates for systemic

chemotherapy: Triple negative or HER 2 + > 2 cms
• Don’t forget the role of neoadjuvant endocrine therapy
 Evolution of Local Management of Breast Cancer

Removal of whole
Inoperability criteria No difference in survival
breast, including
established for locally with radical mastectomy
pectoral muscles and
advanced breast cancer or lumpectomy
axillary lymph nodes

1880
1880 1900
1900 1920
1920 1940
1940 1960
1960 1980
1980 2000
2000

Modified radical
Radical mastectomy Sentinel lymph
mastectomy and node mapping
supraclavicular
dissection

Winchester DP, et al. Surg Oncol Clin N Am. 2005;14:479.

 Evolution of Local Management of Breast Cancer

Removal of whole
Inoperability criteria No difference in survival
breast, including
established for locally with radical mastectomy
pectoral muscles and No Surgery?
advanced breast cancer or lumpectomy
axillary lymph nodes

1880
1880 1900
1900 1920
1920 1940
1940 1960
1960 1980
1980 2000
2000 2020
2020

Modified radical
Radical Sentinel lymph
mastectomy
mastectomy and node mapping
supraclavicular
dissection

Winchester DP, et al. Surg Oncol Clin N Am. 2005;14:479.

We’ve come a long way
Thank You
Questions?