This document summarizes new adjuvant treatment strategies for early-stage HER2-positive breast cancer. It discusses trials showing improved disease-free survival when adding trastuzumab to chemotherapy as adjuvant therapy. More recent trials show additional benefits from combining trastuzumab with pertuzumab or using neratinib after initial trastuzumab therapy. The APHINITY trial found that adding pertuzumab to trastuzumab and chemotherapy significantly reduced the risk of invasive disease recurrence compared to placebo, trastuzumab and chemotherapy in the interim analysis. Benefits were greater in patients with node-positive disease or hormone receptor-negative breast cancer.

1. New Adjuvant Treatment Strategies for
Early-Stage HER2-Positive Breast Cancer
DR. R. RAJKUMAR M.D. , D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL SPECIALITY HOSPITAL

2. Background

6. Breast Cancer Remains a Significant Health
Burden Even After Improvements in Adjuvant Tx
 Improvements in outcomes achieved in HER2+ patients, but
higher relapse rate remains in the early yrs after diagnosis
Between Mid-2004 and 2008
Yrs Since Diagnosis
HRofRelapse
Between 1986 and 1992
Cossetti RJ, et al. J Clin Oncol. 2015;33:65-73.
0.25
0.20
0.15
0.10
0.05
0
1 2 3 4 5 6 7 8
HER2+ ER+
HER2+ ER-
HER2- ER+
HER2- ER-
Yrs Since Diagnosis
HRofRelapse
0.25
0.20
0.15
0.10
0.05
0
1 2 3 4 5 6 7 8
HER2+ ER+
HER2+ ER-
HER2- ER+
HER2- ER-
HR of Relapse in Patients With Biopsy-Proven Stage I-III BC Diagnosed

7. Joensuu H. et al. Clin. Cancer Res. 2003;9:923-930
83

8. Systemic Therapy Decision Points in the Patient
Journey: HER2+ EBC
Choice of
neoadjuvant
therapy
Choice of
adjuvant
therapy
Choice of
extended
adjuvant
therapy

9. Who Should Receive Adjuvant Chemotherapy for
HER2+ EBC?
 Patients with clinical stage I, IIA, IIB or T3N1M0
– Patients with HR- HER2+ disease should receive chemo + HER2-
targeted therapy (except possibly those with T1a disease)
– Patients with HR+ HER2+ disease should receive chemo + HER2-
targeted therapy (except possibly those with T1a disease) and all
should receive endocrine therapy
 Decision for adjuvant treatment should be based on various
factors including the predicted sensitivity to treatment, potential
benefit, risk of relapse, and patient preferences and comorbidities
Henry NL, et al. J Clin Oncol. 2016;34:2303-2311. Denduluri N, et al. J Clin Oncol.
2016;34:2416-2427. Burstein HJ, et al. J Clin Oncol. 2016;34:1689-1701.

12. Phase III HERA (BIG 1-01) Trial: Trastuzumab +
Chemo Significantly Reduces Rate of Relapse
 Trastuzumab for 1 yr significantly reduced risk of DFS events (HR: 0.76) and death (HR: 0.74)
vs observation in pts with HER2+ EBC
HR+ HER2+ Disease HR- HER2+ Disease
Some patients will develop recurrence despite adjuvant trastuzumab-based therapy
Yrs Since Randomization
CumulativeIncidence
ofDisease(%)
Cameron D, et al. Lancet. 2017;389:1195-1205.
45
40
35
30
25
20
15
10
5
0
100 1 2 3 4 5 6 7 8 9
Observation; BC event Trastuzumab 1 yr; BC event Trastuzumab 2 yr; BC event
Observation; non–BC DFS event Trastuzumab 1 yr; non–BC DFS event Trastuzumab 2 yr; non–BC DFS event
Yrs Since Randomization
45
40
35
30
25
20
15
10
5
0
100 1 2 3 4 5 6 7 8 9
CumulativeIncidence
ofDisease(%)

13. Adjuvant Trastuzumab in EBC
IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation
1. Gianni L, et al. Lancet Oncol 2011; 12:236244; 2. Slamon D, et al. N Engl J Med 2011; 365:12731283; 3. Perez EA, et al.
J Clin Oncol 2011; 29:33663373.
Docetaxel
NCCTG N9831 (USA)3
BCIRG 006 (global)2
NSABP B-31 (USA)3
IHC/FISH
N = 1944
FISH
N = 3222
IHC/FISH
N = 2101
Docetaxel +
carboplatin
Doxorubicin +
cyclophosphamide
Trastuzumab Paclitaxel
HERA (ex-USA)1
IHC/FISH
N = 5102
Observation
1 year
Chemotherapy
+/- radiotherapy
2 years
1 year
1 year
1 year
1 year
1 year

14. DFS and OS Benefits Demonstrated With
Addition of Trastuzumab
DFS OS
Study Follow-up (yrs) N HR p value HR p value
1 3387 0.54 < 0.0001 0.76 0.26
2 3401 0.64 < 0.0001 0.66 0.0115
HERA1–4
4 3401 0.76 < 0.0001 0.85 0.1087
8 3399 0.76 < 0.0001 0.76 0.0005
11 3399 0.76 < 0.0001 0.74 < 0.0001
2 3351 0.48 < 0.0001 – –
NCCTG N9831/ 4 4045 0.52 < 0.001 0.61 <0.001
NSABP B-315–7
ACTax+TT vs. ACTax 8.4 4046 0.60 < 0.0001 0.63 <0.0001
10 4046 0.60 < 0.001 0.63 <0.001
BCIRG 0068
ACTax + T vs. ACTax 0.64 < 0.001 0.63 <0.001
5.4 3222
Tax+CbT vs. ACTax 0.75 0.04 0.77 0.04
ACTax + T vs. ACTax 10.3 3222 0.72 < 0.001 0.63 <0.001
Tax+CbT vs. ACTax 0.77 0.0011 0.76 0.0075
CT±RTT vs. CT±RT
AC, doxorubicin and cyclophosphamide; Cb, carboplatin; CT, chemotherapy; DFS, disease-free survival;
HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, trastuzumab; Tax, taxane.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Trastuzumab Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;
353:1659-1672.
Smith I, Procter M, Gelber RD, et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:29-36.
Gianni L, Dafni U, Gelber RD, et al; Trastuzumab Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-
year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236-244.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013;
382:1021–1028.
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673-1684.
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data
from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:3366-3373.
Romond EH, Suman VJ, Jeong J-H, et al. Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer: Final Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831.
Cancer Res 2012; 72 (Suppl 3): Abstract S5-5 (and associated oral presentation).
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:1273-1283.

15. DFS Outcomes in Trastuzumab HER2+
EBC Trials
AC, doxorubicin + cyclophosphamide; chemo, chemotherapy; EBC, early breast cancer; H, Herceptin;
HER2, human epidermal growth factor receptor 2; iDFS, invasive disease-free-survival; N, NERLYNX; PH, Perjeta + Herceptin; TCH, docetaxel
+ carboplatin + Herceptin; TH, Taxol + Herceptin.
1. Romond EH, et al. N Engl J Med. 2005;353(16):1673-1684. 2. Perez E, et al. J Clin Oncol. 2014;32(33):3744-3752. 3. Untch M, et al. Ann Oncol.
2008;19(6):1090-1096. 4. Cameron D, et al. Lancet. 2017;389(10075):1195-1205. 5. Slamon D, et al. N Engl J Med. 2011;365(14):1273-1283.
6. Slamon D, et al. SABCS. 2015 Abstract S5-04. 7. von Minckwitz G, et al. Oral Presentation at ASCO 2017. LBA 500. 8. Martin M, et al. Oral
Prestation at ESMO 2017. 1490.
(i)DFS(%)
3 yr
10 yr
94.1% 94.3*
87.1% 87.0% 88.0%
80.6% 90.2%†
75.4%
74% 73% 75%
69%
62%
Joint Analysis
chemo
HERA
H + chemo
Joint Analysis
AC→TH
BCIRG 006
TCH
BCIRG 006
AC→TH
APHINITY
PH + chemo
ExteNET Extended
Adjuvant NERLYNX
monotherapy

18. Building on Trastuzumab: Additional HER2-
Targeted Therapy
 Combination of trastuzumab + pertuzumab
– FDA pertuzumab approval: for use in combination with
trastuzumab and chemotherapy as adjuvant treatment of patients
with HER2-positive EBC at high risk of recurrence[1]
– High-risk patients included those with HR-negative or node-positive
breast cancer[2]
 Use of neratinib after trastuzumab-based chemotherapy
– FDA neratinib approval: for extended adjuvant treatment of
patients with HER2-positive EBC, to follow adjuvant trastuzumab-
based therapy[3]
1. Pertuzumab [package insert]. 2017. 2. von Minckwitz G, et al.
N Engl J Med. 2017;377:122-131. 3. Neratinib [package insert]. 2017.

19. APHINITY: Study Design
 International, randomized, double-blind, placebo-controlled phase III trial[1]
 Primary endpoint: IDFS per modified STEEP definition[2] (excludes second primary non-BC
as event)
 Secondary endpoints: IDFS per STEEP definition,[2] OS, distant recurrence-free survival,
DFS, recurrence-free interval, safety, cardiac safety, health-related QoL
1. von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.
2. Hudis CA, et al. J Clin Oncol. 2007;25:2127-2132.
Patients with HER2+ EBC, no
prior invasive BC or anticancer
tx or RT, N+ any tumor size
(no T0) or N0 tumor size
> 1 cm,* BL LVEF ≥ 55%
(N = 4805)
Pertuzumab + Trastuzumab + CT†
(n = 2400)
Placebo + Trastuzumab + CT†
(n = 2405)
10-yr follow-upSurgery
Wk 52
*Or node negative with tumors > 0.5 to ≤ 1 cm + at least 1 of following: histologic/nuclear grade 3; ER negative and PgR negative;
aged < 35 yrs. Node-negative enrollment capped after first 3655 patients randomized. †Tx initiated ≤ 8 wks post surgery. Permitted CT:
standard anthracycline or nonanthracycline regimens. Endocrine and/or radiotherapy could be started at end of adjuvant CT.

20. APHINITY: Interim Analysis of IDFS (ITT)
 Data cutoff after 381 IDFS events (median f/u: 45.4 mos)
von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.
IDFS(%)
Mos
Pertuzumab
Placebo
Stratified HR: 0.81 (95% CI: 0.66-1.00; P = .045)
Patients at Risk, n
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48
98.6% 96.4% 94.1% 92.3%
98.8% 95.7% 93.2% 90.6%
Pertuzumab
Placebo
2400
2404
2309
2335
2275
2312
2236
2274
2199
2215
2153
2168
2101
2108
1687
1674
879
866
(Expected: 89.2%)

21. APHINITY: IDFS by Patient Subgroups
von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.
Nodal Status Hormone Receptor Status
Node
Positive
Node
Negative
IDFS(%)
Hormone
Receptor
Positive
Hormone
Receptor
Negative
Pertuzumab (n = 1503), 139 events
Placebo (n = 1502), 181 events
Unstratified HR: 0.77 (95% CI: 0.62-0.96;
P = .02)
Mos
100
80
60
40
20
0
480 6 12 18 24 30 36 42
98.1
98.2
94.9 92.0
93.7 90.2 86.7
89.9
IDFS(%)
Pertuzumab (n = 897), 32 events
Placebo (n = 902), 29 events
Unstratified HR: 1.13 (95% CI: 0.68-1.86;
P = .064)
100
80
60
40
20
0
480 6 12 18 24 30 36 42
99.7
99.5
99.1 98.4
99.0 97.5 96.2
96.7
IDFS(%)
Pertuzumab (n = 1536), 100 events
Placebo (n = 1546), 119 events
Unstratified HR: 0.86 (95% CI: 0.66-1.13;
P = .277)
Mos
100
80
60
40
20
0
480 6 12 18 24 30 36 42
98.9
99.3
96.5 94.8
96.8 94.4 91.6
93.0
IDFS(%)
Pertuzumab (n = 864), 71 events
Placebo (n = 858), 91 events
Unstratified HR: 0.76 (95% CI: 0.56-1.04;
P = .085)
100
80
60
40
20
0
480 6 12 18 24 30 36 42
98.1
97.9
96.2 92.8
93.7 91.2 88.7
91.0

22. APHINITY: Safety
Outcome, n (%)
Pertuzumab
(n = 2364)
Placebo
(n = 2405)
Treatment Difference
(95% CI)
Primary cardiac endpoint
 Heart failure NYHA III/IV + LVEF drop*
 Cardiac death†
 Recovered according to LVEF
17 (0.7)
15 (0.6)
2 (0.1)
7 (0.3)
8 (0.3)
6 (0.2)
2 (0.1)
4 (0.2)
0.4% (0% to 0.8%)
Asymptomatic or mildly symptomatic LVEF drop‡ 64 (2.7) 67 (2.8) -0.1% (-1.0% to 0.9%)
Grade ≥ 3 AEs
 Neutropenia
 Febrile neutropenia
 Decreased neutrophil count
 Diarrhea
• Anthracycline CT, n/N (%)
• Nonanthracycline CT, n/N (%)
 Anemia
16.3
12.1
9.6
9.8
7.5
18.0
6.9
15.7
11.1
9.6
3.7
3.1
6.1
4.7
Fatal AE 18 (0.8) 20 (0.8)
*LVEF drop defined as ejection fraction decrease ≥ 10% from BL to below 50%. †Determined by Cardiac Advisory Board per prospective definition.
‡Secondary cardiac endpoint.
von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.

23. APHINITY: Conclusions
 Adjuvant pertuzumab + trastuzumab + CT significantly reduced risk of recurrence
events vs placebo + trastuzumab + CT in patients with HER2+ EBC
– HR: 0.81 (95% CI: 0.66-1.00; P = .045)
– Patients with node-positive or hormone receptor–negative disease had greatest
IDFS benefit
– Most recurrences to distant sites (pertuzumab: 4.7%; placebo: 5.8%)
 Investigators concluded:
– No new safety signals identified with addition of pertuzumab to trastuzumab + CT
– Low incidence of cardiac events
– No difference in fatal AE rates between arms (0.8% for both)
– Increased diarrhea incidence with pertuzumab (any grade: 71.2% vs 45.2% with placebo)
– Ongoing follow-up important to determine long-term IDFS, safety, and OS
von Minckwitz G, et al. N Engl J Med. 2017;377:122-131.

24. ExteNET 5-Yr Update: Neratinib vs PBO After
Adjuvant Trastuzumab in HER2+ EBC
 Primary endpoint: IDFS at 2 yrs
 Primary analysis of 2-yr IDFS rate: neratinib, 93.9%; placebo,
91.6% (HR: 0.67; 95% CI: 0.50-0.91; P = .0091)
Chan A, et al. Lancet Oncol. 2016;17:367-377. Martin M, et al. Lancet Oncol. 2017;18:1688-1700.
Patients with HER2+ EBC (stage I-III);
adjuvant trastuzumab completed ≤ 2 yrs
before randomization*; N+/- disease or
residual disease after neoadjuvant
therapy; known ER and PgR status
(N = 2840)
Neratinib 240 mg/day PO
(n = 1420)
Placebo
(n = 1420)
1 yr
*Amendment in Feb 2010
restricted enrollment to
patients with N+ disease
who completed trastuzumab
≤ 1 yr before randomization.
Stratified by hormone receptor status (ER+ and/or PgR+
vs ER- and PgR-), nodal status (0 vs 1-3 vs ≥ 4), adjuvant
trastuzumab regimen (sequential vs concurrent with CT)
Endocrine therapy given according to
local practice

25. ExteNET: 5-Yr IDFS Analysis
Martin M, et al. Lancet Oncol. 2017;18:1688-1700.
Mos After Randomization
IDFS(%)
Patients at Risk, n
Neratinib
Placebo
HR: 0.73 (95% CI: 0.57-0.92; P = .0083)
1420
1420
1316
1354
1272
1298
1225
1248
1106
1142
978
1029
965
1011
949
991
938
978
920
958
885
927
100
90
70
60
80
50
40
30
20
10
0
Neratinib
Placebo
600 6 18 2412 30 36 42 48 54
97.9%
95.5%
94.3%
91.7%
92.2%
90.2%
91.2%
89.1% 87.7%
90.2%

26. ExteNET: 5-Yr IDFS Analysis by Hormone
Receptor Status
Martin M, et al. Lancet Oncol. 2017;18:1688-1700.
Mos After Randomization
IDFS(%)
Patients at Risk, n
Hormone Receptor Positive Hormone Receptor Negative
HR: 0.95 (95% CI: 0.66-1.35)HR: 0.60 (95% CI: 0.43-0.83)
Neratinib
Placebo
816
815
757
779
731
750
705
719
642
647
571
581
565
567
558
556
554
551
544
542
532
525
600 6 12 18 24 30 36 42 48 54
100
90
80
70
60
50
40
30
20
10
0
Neratinib
Placebo
98.1%
96.1%
95.4%
91.7%
93.6%
89.8% 88.5%
92.6% 91.2%
86.8%
Mos After Randomization
IDFS(%)
Patients at Risk, n
Neratinib
Placebo
604
605
559
575
541
548
520
529
464
495
407
448
400
444
391
435
384
427
376
416
362
402
600 6 12 18 24 30 36 42 48 54
100
90
80
70
60
50
40
30
20
10
0
Neratinib
Placebo
97.5%
94.7%
92.8%
91.8%
90.8%
90.4% 89.3%
89.9%
88.9%
88.8%

27. ExteNET: Safety and HRQoL at 5 Yrs
 Diarrhea was main AE reported[1]
– Grade 3 diarrhea occurred in 40% of patients receiving neratinib with
median duration of 5 days (range: 2-9)
– Most resolved in < 30 days; 1.4% patients required hospitalization
 No indications of long-term toxicity (symptomatic cardiotoxicity, second
primary malignancies) with neratinib vs placebo after discontinuation[2]
– No late-term effects from neratinib-associated diarrhea
 Patient-reported outcomes indicated a transient reduction in HRQoL
during the first month of neratinib treatment followed by a steady
recovery toward baseline[3]
1. Chan A, et al. Lancet Oncol. 2016;17:367-377. 2. Martin M, et al. Lancet Oncol.
2017;18:1688-1700. 3. Delaloge S, et al. ESMO 2017. Abstract 177P.

28. Phase II CONTROL Trial: Antidiarrheal
Prophylaxis for Neratinib-Associated Diarrhea
 An international, sequential-cohort, open-label phase II study in
patients who completed adjuvant trastuzumab-based tx in ≤ 1 yr
LPM + colestipol
LPM + budesonide
Loperamide (LPM)
All cohorts Neratinib 240 mg/day (13 cycles)
0 1 2 3 4 5 6 7 8 9 10 11 12 13
LPM 4 mg TID D1-14,
then BID D15-56
LPM 4 mg TID D1-14,
then BID D15-56
Budesonide 9 mg QD
LPM 4 mg TID D1-14,
then BID D15-28
Colestipol 2 mg BID
Hurvitz S, et al. SABCS 2017. Abstract P3-14-01. Slide credit: clinicaloptions.com
Patients
Worst Grade of Tx-Emergent Diarrhea
5% 20% 14%
33%23%
25%
25%
30%33%
24% 34%
26%40% 31% 27%
11%
0%
20%
40%
60%
80%
100%
ExteNet
(n = 1408)
LPM Alone
(n = 137)
LPM +
Budesonide
(n = 64)
LPM +
Colestipol
(n = 120)
No diarrhea Grade 1 Grade 2 Grade 3

29. ExteNET: Conclusions
 The 5-yr analysis of the ExteNET trial confirms sustained benefit
with extended adjuvant neratinib:
– 2.5% absolute benefit in ITT population (HR: 0.73; P = .008)
– 4.4% absolute benefit in hormone receptor–positive cohort
(HR: 0.60; P = .002)
 No evidence of long-term toxicity (ie, no increased symptomatic
cardiac toxicity or second primary malignancies) with neratinib vs
placebo or late-term consequences from neratinib-associated
diarrhea
 OS data expected to mature in 2019
Martin M, et al. Lancet Oncol. 2017;18:1688-1700. Martin M, et al. ESMO 2017. Abstract 149O.

30.  A randomized (3:1), open-label phase II study
 Coprimary endpoints: 3-yr DFS in T-DM1; comparison of incidence of clinically relevant toxicities
with T-DM1 vs TH, including: grade ≥ 3 non-hematologic AEs, grade ≥ 2 neurotoxicity, grade ≥ 4
hematologic AEs, febrile neutropenia, and any AE requiring dose delay or discontinuation of
protocol therapy
Phase II ATEMPT: Study Design
Women with stage 1 HER2+ BC
with N0 or N1mic disease;
LVEF ≥ 50%; no prior invasive
BC surgery; ≤ 90 days
from last surgery
(N = 497)
Follow-up for
5 yrs after
final dose of
T-DM1 or TH
T-DM1
3.6 mg/kg IV Q3W x 17
(n = 383)
Paclitaxel 80 mg/m2 IV +
Trastuzumab 2 mg/kg IV Q1W x 12
(n = 114)
Tolaney. SABCS 2019. Abstr GS1-05.
Stratified by age (<55, ≥ 55), planned radiation therapy (Y/N), planned hormonal therapy (Y/N)
Study not powered to assess efficacy of TH or to compare efficacy of T-DM1 to TH
Trastuzumab
6 mg/kg Q3W x 13

31. Phase II ATEMPT: T-DM1 DFS in ITT and by
Hormone Receptor Status and Tumor Size
Tolaney. SABCS 2019. Abstr GS1-05.
Cohort N Events, n 3-Yr DFS, % 95% CI P Value
T-DM1 383 10 97.7 96.2-99.3 < .0001
Mos
ProbabilityofDFS
HR Status
Events,
n
3-Yr DFS,
% (95% CI)
HR+ (n = 289) 8 97.5 (95.6-99.3)
HR- (n = 94) 2 98.5 (95.6-100)
Tumor Size, cm
Events,
n
3-Yr DFS,
% (95% CI)
< 1 (n = 163) 2 98.5 (96.5-100)
≥ 1 (n = 22) 8 97.1 (94.9-99.4)
12 18
0.25
0 6
0.00
1.00
0.50
0.75
24
367 227383 375 373 325381 140
No. at Risk
30 36 42 48 54 60 66
85 18 146

32. De-Escalated Approach for
Lower Risk Tumors
• Chemotherapy (APT Trial – weekly Taxol)
• Shorter Duration of Trastuzumab (9 weeks or 6 months –
PERSOPHONE)
• Biosimilars (Lowered Cost)

33. Clinical Trial Data on Shorter Duration of
HER2-Targeted Therapy
Trial Arms DFS, % Subset Analysis
PHARE[1]
(N = 3384)
6 mos vs 12 mos
of trastuzumab
2 yrs:
91.1 vs 93.8
(P = .29)
Short-Her[2]
(N = 1253)
9 wks vs 1 yr
of trastuzumab
5 yrs:
85.4 vs 87.5
1 yr favored in high-risk: multiple positive nodes, stage III
9 wks may have similar benefit in lower-risk pts: stage I/II,
limited nodal burden
FinHer[3]
(N = 1010)
No trastuzumab vs
9 wks of trastuzumab
3 yrs:
77.6 vs 89.3
(P = .01)
Persephone[4]
(N = 4000)
6 mos vs 12 mos
of trastuzumab
4 yrs:
89.4 vs 89.8
(P = .01)
12 mos favored in higher-risk, ER–, taxane chemotherapy
without anthracycline, and neoadjuvant chemotherapy
1 yr of trastuzumab remains standard of care,
but shorter duration is better than nothing

34. Evolving Standard of HER2 Treatment
More or Less
De-escalation of Treatment
• T1a/T1b/T1c
• Node Negative
• ? Patients achieving pCR
• ? Immunomodulatory host factors
Escalation (incorporation of newer tx)
• Node positive
• LABC/Inflammatory
• ? no pCR
• ? Resistant Phenotype/Signatures

35. The Risk Spectrum Treatment Approach in 2017
Node Negative
T1a
(generally noif
ER+ve)
May consider
Pac + Tras
Node Negative
T1b
(especially if
ER-ve)
Pac + Tras
Node Negative
T1c
Pac+Tras
Node Negative
(T2 or greater)
Docetaxel +
Carbo + Trasor
AC – Tax+Tras
Node Positive
AC-Tax+Trasor
Docetaxel +
Carbo + Tras
(esp if cardiac
concerns)

36. The Risk Spectrum Treatment Approach in 2018
Node NegativeT1a
Pac + Tras
? Shorterduration
of Trastuzumab
Node NegativeT1b
Pac + Tras
? Shorterduration
of Trastuzumab
Node NegativeT1c
Pac+Tras
? Shorterduration
of Trastuzumab
NodeNegative
(T2 orgreater)
Docetaxel + Carbo + Trasor
AC – Tax+Tras
? Extended Neratinib forHR
+ve patients
? Addition of Pertuzumab
Node Positive
AC-Tax+Trasor
Docetaxel + Carbo
+ Tras
ExtendedNeratinib
for HR +ve patients
Addition of
Pertuzumab

37. Who Should Be Considered for Preoperative
Systemic Therapy for EBC?
Systemic neoadjuvant treatment should be considered for:
 High tumor volume-to-breast ratio
 Lymph node-positive disease
 High-risk features (high grade, HR-, HER2+, or TNBC)
 Younger age at diagnosis
Patients with HER2+ EBC who have a tumor ≥ 2 cm (T2) in
diameter or who have node-positive disease should receive
neoadjuvant chemotherapy with trastuzumab/pertuzumab

38. n = 364
n = 471
50‡
31‡
p = not reported
n = 385
n = 701
CTNeoBC
meta-analysis5
30‡
18‡
Chemotherapy+H
Chemotherapy
(hormone receptor-positive)
Chemotherapy+H
Chemotherapy
(hormone receptor-negative)
p = not reported
Impact on pCR rates from the addition of trastuzumab to
neoadjuvant chemotherapy in patients with
HER2-positive EBC
* No evidence of residual invasive cancer, in breast or axilla
† No evidence of residual disease in breast tissue
‡ Absence of invasive cancer in the breast and axillary nodes; absence of DCIS/
absence of invasive cancer in the breast and axillary nodes;
DCIS allowed/absence of invasive cancer in the breast and DCIS allowed;
regardless of nodal involvement
DCIS, ductal carcinoma in situ; FEC, 5-fluorouracil+epirubicin+cyclophosphamide;
EC, epirubicin+cyclophosphamide; X, capecitabine.
1. Buzdar AU, et al. Clin Cancer Res 2007;
13:228233; 2. Gianni L, et al. Lancet 2010;
375:377384;
3. Untch M, et al. J Clin Oncol 2010; 28:20242031;
4. Loibl S, et al. SABCS 2011 (Abstract S5-4; oral presentation);
5. Cortazar P, et al. SABCS 2012 (Abstract S1-11; oral presentation.
n = 662
n = 665
n = 118
n = 19
n = 445
n = 117
n = 45
n = 1050 16*
32*
GeparQuattro3
NOAH2
MD Anderson1
pCR (%)
German trials
meta-analysis4
H+(TFEC) 60*
TFEC 26*
H+(ACTCMF) 43†
ACTCMF 22†
H+(ECT([X])
ECTX
(HER2-negative)
27*
18*
Chemotherapy+H
Chemotherapy
p < 0.0007
p = not reported
0 20 40 60
p = not reported
p = not reported

39. FDA CT NeoBC Meta-Analysis
There was no correlation between
magnitude of pCR difference and EFS/OS
It can not be considered a surrogate endpoint
Cortazar P,Zhang L, et al. Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC).
Cancer Res December 15, 2012; 72 (24 Supplement):S1-11.

40. FDA CT NeoBC Meta-analysis
There was no correlation between
magnitude of pCR difference and EFS/OS
• Heterogenous population
• Trastuzumab was used in only three trials
(GeparQuattro,12 NOAH,and TECHNO)
• NOAH suggesting a trial-level correlation
between frequency of pathological complete
response and long-term outcome could be
identified in future trials with more
homogeneous populations and incorporation of
targeted therapies
Cortazar P,Zhang L, et al. Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC).
Cancer Res December 15, 2012; 72 (24 Supplement):S1-11.

41. Slide 32

42. pCR (%)
Chemo (Includes Anthra and Taxane)
70
60
50
40
30
20
10
0
Chemo Chemo + H Chemo + L Chemo+ H Chemo +
+ L H+P
H+P
Neoadjuvant Anti-Her2 Studies
H + L
+ AI (ER+ve)

43. Designs based on response to therapy
Target
Population
Neoadjuvant
Therapy
SURGERY
pCR/npCR
No pCR

44. Designs based on response to therapy
Target
Population
Neoadjuvant
Therapy
SURGERY
pCR/npCR
Standard Treatment
De-escalate Treatment

45. Designs based on response to therapy
Target
Population
Neoadjuvant
Therapy
SURGERY
pCR/npCR
No pCR
Standard Treatment
Standard Treatment
De-escalate Treatment
Experimental Treatment

46. KATHERINE: Non-pCR Study
• Primary Endpoint: DFS
• Secondary Endpoints: OS, Safety
• FPI April 2013
HER2-positive
EBC
T-DM1
Residual
invasive tumor
(breast or nodes)
Target
3 year
DFS rate
70%
Preoperative
Taxane +
Herceptin
n=1484
76.5%
14 cycles
S
U
R
G
E
R
Y
HR=0.75
Trastuzumab

47. KATHERINE: Trastuzumab Emtansine vs Trastuzumab
as Adjuvant Therapy for HER2+ EBC
 International, randomized, open-label phase III study
Patients with HER2+ EBC (cT1-4/N0-3/M0) who had
residual invasive disease in breast or axillary nodes
after neoadjuvant chemotherapy plus HER2-targeted
therapy* at surgery
(N = 1486)
T-DM1† 3.6 mg/kg IV Q3W x 14 cycles
(n = 743)
Trastuzumab 6 mg/kg IV Q3W x 14 cycles
(n = 743)
Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].
Randomization occurred within 12 wks of surgery; radiotherapy and/or endocrine therapy given per local standards. *Minimum
of 9 wks taxane and trastuzumab. †Patients who d/c T-DM1 for toxicity allowed switch to trastuzumab to complete 14 cycles.
Stratified by clinical stage, HR status, single vs dual neoadjuvant HER2-targeted therapy,
pathological nodal status after neoadjuvant therapy
 Primary endpoint: IDFS
 Secondary endpoints including: distant recurrence-free survival, OS,
safety

48. KATHERINE: IDFS
Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].
First IDFS
Event, %
T-DM1 T
Any 12.2 22.2
Distant
recurrence
10.5* 15.9†
Locoregional
recurrence
1.1 4.6
Contralateral
breast cancer
0.4 1.3
Death without
prior event
0.3 0.46 12
100
80
60
40
20
0
IDFS(%)
18 24 30 36 4842 54 600
Mos Since Randomization
707
676
681
635
658
594
633
555
561
501
409
342
142
119
255
220
44
38
4
4
743
743
Patients at Risk, n
T-DM1
Trastuzumab
Events, n (%)
3-yr IDFS, %
T-DM1
(n = 743)
91 (12.2)
88.3
Trastuzumab
(n = 743)
165 (22.2)
77.0
HR: 0.50 (95% CI: 0.39-0.64; P < .001)
CNS events: *5.9% vs †4.3%.

49. KATHERINE: Conclusions
 In patients with HER2+ EBC who had residual invasive disease after
neoadjuvant chemotherapy plus HER2-targeted therapy at surgery,
T-DM1 significantly prolonged IDFS compared with trastuzumab
‒ HR: 0.50 (95% CI: 0.39-0.64; P < .001)
‒ Benefit with T-DM1 consistent across examined subgroups
 No unexpected safety signals
 Longer follow-up needed for OS
 Study investigators conclude that T-DM1 will likely represent a new
standard of care in this population
Slide credit: clinicaloptions.comGeyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

50. Systemic Therapy Decision Points in the Patient
Journey: HER2+ EBC
Choice of
neoadjuvant
therapy
Choice of
adjuvant
therapy
Choice of
extended
adjuvant
therapy
Trastuzumab/Pertuzumab
 Patients with high-risk, HER2+, node-positive disease
 Continue pertuzumab/trastuzumab to complete 1 year
of HER2-targeted treatment
 Add pertuzumab to trastuzumab and chemotherapy for patients
who did not receive neoadjuvant treatment (not as common)

51. Choice of
neoadjuvant
therapy
Choice of
adjuvant
therapy
Choice of
extended
adjuvant
therapy
Neratinib
 Patients with node-positive, HER2+ ER+ disease who have
recently completed 1 yr of adjuvant HER2-targeted therapy
 Patients with high-risk, node-positive HER2+ ER– disease,
with residual disease after neoadjuvant treatment, who have
recently completed 1 yr of adjuvant HER2-targeted therapy

52. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. 52

53. Summary
• We have made significant advances in the management of
early stage Her2-positive EBC
• The goal now is to balance gains in survival with reducing
toxicity by individualizing therapy and shared decision making
• The road ahead demands that we are integrating therapies
that provide meaningful benefit to optimize value for our
patients and health care system