original reports

Incidence of Late Relapses in Patients With

HER2-Positive Breast Cancer Receiving Adjuvant
Trastuzumab: Combined Analysis of NCCTG
N9831 (Alliance) and NRG Oncology/NSABP B-31
Saranya Chumsri, MD1; Zhuo Li, MS1; Daniel J. Serie, MS1; Afshin Mashadi-Hossein, MS2; Gerardo Colon-Otero, MD1; Nan Song, PhD3;
Katherine L. Pogue-Geile, PhD3; Patrick G. Gavin3; Soonmyung Paik, MD3,4; Alvaro Moreno-Aspitia, MD1; Edith A. Perez, MD1; and
E. Aubrey Thompson, PhD1
abstract

PURPOSE Recent trials have shown potential benefit of extended adjuvant endocrine therapy and relatively high
risk of recurrence (RoR) after 5 years in hormone receptor-positive (HR+) human epidermal growth factor
receptor 2–negative (HER22) breast cancer. Although risk of late relapse in HR+ HER22 breast cancer is fairly
well defined, the risk in HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab-based
chemotherapy remains largely unknown.
METHODS We included 3,177 patients with HER2+ breast cancer treated with adjuvant chemotherapy alone or
with trastuzumab from the North Central Cancer Treatment Group N9831 (ClinicalTrials.gov identifier:
ASSOCIATED
NCT00005970) and National Surgical Adjuvant Breast and Bowel Project B-31 (ClinicalTrials.gov identifier:
CONTENT
NCT00004067) trials.
Appendix
Data Supplement RESULTS Overall, HR+ breast cancer was significantly associated with improved recurrence-free survival (RFS)
Author affiliations during the first 5 years (hazard ratio, 0.65; 95% CI, 0.56 to 0.77; P , .001). Among patients treated with
and support trastuzumab, cumulative hazard for RFS was lower in patients with HR+ HER2+ breast cancer during the first
information (if 5 years (10.96% v 17.48%; hazard ratio, 0.60; 95% CI, 0.45 to 0.79; P , .001). However, there was no
applicable) appear
significant difference in RFS based on HR status during years 5 to 10 (hazard ratio, 1.32; 95% CI, 0.93 to 1.88;
at the end of this
article. P = .12). A comparable degree of trastuzumab benefit was observed in HR+ and HR2 breast cancers ( P for
Accepted on interaction = .87). Furthermore, we observed low RoR in years 5 to 10 among patients with HR+ HER2+ breast
September 13, 2019 cancer: 3.23% in patients without lymph node involvement (N0) and 6.39% in patients with involvement of one
and published at to three lymph nodes (N1).
jco.org on October 17,
2019: DOI https://doi. CONCLUSION The benefit of adjuvant trastuzumab persists for a long time. A distinct pattern of recurrence was
org/10.1200/JCO.19. observed between HR+ and HR2 HER2+ disease but with similar degree of benefit from adjuvant trastuzumab.
00443 RoR in years 5 to 10 in HR+ HER2+ breast cancer is low, particularly in patients with N0 or N1 disease.
The content is solely
J Clin Oncol 37. © 2019 by American Society of Clinical Oncology
the responsibility of
the authors and does
not necessarily INTRODUCTION growth factor receptor 2 (HER2)–negative (HER22)
represent the official
Several studies have demonstrated a difference in the breast cancer. The pattern of relapse in HR+ versus
views of the National HR2 among HER2-positive (HER2+) breast cancer
Institutes of Health. pattern of disease recurrence between patients with
hormone receptor (HR)–positive (HR+) and HR- and the incidence of late relapse among patients with
The Pennsylvania
Department of negative (HR2) breast cancer, and it is generally HR+ HER2+ breast cancer are largely unknown.
Health specifically recognized that patients with HR+ breast cancer With the advent of anti-HER2 therapies, the outcome
disclaims
responsibility for any
continue to be at risk for recurrence many years after of patients with HER2+ breast cancer has improved in
analysis, the initial diagnosis.1,2 In HR+ HER22 breast cancer, the past several years. Unlike HR+ HER22 breast
interpretations, or multiple studies have shown relatively high risk of late cancer, the risk of late relapses in patients with HR+
conclusions. relapse, with more than 50% of recurrences occurring HER2+ disease remains unknown. Currently, there are
Clinical Trial after 5 years.3,4 In contrast, patients with HR2 breast limited data available regarding the risk of late re-
Information:
cancer have higher risk of recurrence (RoR) in the currence in patients with HER+ breast cancer treated
NCT00005970
(NCCTG N9831) and
first few years, but RoR considerably declines after with adjuvant trastuzumab-based chemotherapy. We
NCT00004067 5 years.5 To date, most published data are from studies aimed to determine the pattern of recurrence in HR+
(NSABP B-31) that focused on patients with HR+ human epidermal versus HR2 in patients with HER2+ breast cancer and

1
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
 Chumsri et al
the risk of late relapse in patients with HR+ HER2+ breast
cancer treated with adjuvant trastuzumab-based chemo-
therapy in the North Central Cancer Treatment Group
(NCCTG) and the National Surgical Adjuvant Breast and
Bowel Project (NSABP, now NRG Oncology) B-31, trials.
NCCTG is now a part of the Alliance for Clinical Trials in
Oncology.
METHODS
Patient Population
NCCTG N9831 (ClinicalTrials.gov identifier: NCT00005970),
a randomized, multicenter, phase III trial, enrolled women
with primary, operable node-positive or high-risk node-
negative HER2+ breast cancer. Patients were randomly
assigned to one of three arms: Arm A received only stan-
dard adjuvant chemotherapy with doxorubicin and cyclo-
phosphamide, followed by weekly paclitaxel (AC-T); arm B
received AC-T followed by trastuzumab after completion of
chemotherapy; and arm C received AC-T concurrently with
trastuzumab. NSABP B-31 (ClinicalTrials.gov identifier:
NCT00004067), a two-arm, randomized, phase III trial,
enrolled patients with operable, node-positive HER2+ breast
cancer. Eligible patients were randomly assigned to AC-T,
with paclitaxel either every 3 weeks or weekly, or to AC-T
concurrently with trastuzumab. To match the trastuzumab-
treated arm in the NSABP B-31 trial, only patients in arm C of
the NCCTG N9831 trial were included in this analysis.
Analysis was performed according to T and N stage,6 with
T1 referring to a tumor 2 cm or smaller; T2, a tumor be-
tween 2 cm and 5 cm; N0, no node involvement; N1,
involvement of one to three nodes; N2, involvement of four
to nine nodes; and N3, involvement of 10 or more nodes.
Each participant signed an institutional review board–approved,
protocol-specific informed consent document in accor-
dance with federal and institutional guidelines. The primary
results of these two trials were published in 2005,7 2011,8,9
and 2014.10
Intrinsic Subtype Classification
Using NanoString platform (NanoString Technologies,
Seattle, WA), the mRNA abundance was measured to
evaluate PAM50 subtype signature in the NCCTG N9831
and NSABP B-31 trials. Gene expression data for the
NSABP B-31 trial was acquired from the database of
Genotypes and Phenotypes (https://www.ncbi.nlm.nih.gov/
gap/); one of the PAM50 genes, CCNE1, was not included
in the data set, but this exclusion of this gene had little
impact on subtype assignment.11 NanoString data for
PAM50 genes plus housekeeping genes were analyzed
using the Prosigna algorithm (NanoString Technologies) to
defined intrinsic subtype, as previously described.12
Statistical Analysis
For outcome analysis, recurrence-free survival (RFS) was
defined as the time from randomization to breast cancer
2 © 2019 by American Society of Clinical Oncology
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recurrence, which included local, regional, or distant re-
currence of breast cancer or breast cancer–related death.
Patients without disease recurrence at the time of last
follow-up or death were censored at the date of last follow-
up or death. Observed follow-up time was calculated as
years between randomization and recurrence or death, or
the last contact, if no event occurred. Continuous variables
were compared between the two studies, using Wilcoxon
rank-sum test; categorical variables were compared using
the x2 test. Log-rank P values were used to assess RFS
differences among groups. The Kaplan-Meier method was
used to estimate RFS rates, and Cox proportional hazard
models were used to generate point estimates of hazard
ratios and corresponding 95% CIs.
Cox proportional hazards regression models were used to
identify univariable and multivariable predictors for relapse
between years 0 to 5 and years 5 to 10. When analyzing
relapse between 5 to 10 years, only patients without relapse
or death at 5 years were included, so the calculation of
cumulative hazard started at year 5 and patients who had
survived without relapse at 10 years were censored at
10 years. Annual hazard of recurrence was defined as the
fraction of patients whose disease recurred during a 1-year
interval. Hazard rates in time periods were calculated
using the maximum likelihood estimates from a piece-wise
exponential Cox regression model, and comparisons be-
tween subgroups within time intervals were made using log-
rank tests restricted just to follow-up contributions from the
specified time interval.13 All tests were two-sided, with a
level set at 0.05 for statistical significance. All analyses
were based on the study database frozen on January 8,
2018, for NCCTG N9831 and December 21, 2017, for
NSABP B-31.
RESULTS
Patient Characteristics
A total of 3,177 patients were included in this combined
analysis—1,762 patients from the NCCTG N9831 trial and
1,415 patients from the NSABP B-31 trial (Appendix Fig
A1, online only). The baseline characteristics of patients in
each trial are listed in Table 1. The mean age (6 standard
deviation) of patients was similar in both trials (49.4 6
10.3 years in NCCTG N9831 and 49.6 6 9.9 years in
NSABP B-31), with a mean of 49.5 6 10.2 years in the
combined cohort. The median time to recurrence or death
was 2.5 (range, 0.0 to 13.8) years in all patients; median
follow-up time for patients without an event was 8.0 (0.0 to
15.3) years in the combined cohort (10.4 years in NCCTG
N9831 and 7.0 years in NSABP B-31). In both trials, 54.5%
of patients had HR+ disease (57.0% in NCCTG N9831 and
51.4% in NSABP B-31), and 48.0% (50% in NSABP B-31
and 46% in NCCTG N9831) of patients in the overall
population were treated with adjuvant trastuzumab-based
chemotherapy.
 Late Relapse in HER2-Positive Breast Cancer with Trastuzumab

TABLE 1. Patient Characteristics in the NCCTG N9831 and NSABP B-31 Trials
NSABP B-31 NCCTG N9831 Total
Characteristic (n = 1,415) (n = 1,762) (N = 3,177) P
Age, years .525
Mean (SD) 49.6 (9.9) 49.4 (10.3) 49.5 (10.2)
Median 49.0 49.0 49.0
Range 26.0-77.0 23.0-80.0 23.0-80.0
Q1, Q3 42.0, 56.0 42.0, 56.0 42.0, 56.0
Follow-up period, years , .001
Mean (SD) 6.3 (2.6) 8.7 (4.5) 7.7 (4.0)
Median (range) 7.0 (0.0-10.0) 10.4 (0.1-15.3) 8.0 (0.0-15.3)
Complete follow-up rate,
% (95% CI), years
5 81.37 (79.51 to 83.28) 83.16 (81.10 to 85.28) 82.19 (80.80 to 83.60)
8 70.11 (67.83 to 72.45) 29.40 (26.73 to 32.35) 52.99 (51.07 to 54.99)
10 58.40 (55.90 to 61.01) 0.10 (0.01 to 0.74) 33.93 (32.08 to 35.88)
Nodal status, No. (%) .431
1 787 (55.6) 978 (55.5) 1,765 (55.6)
2 433 (30.6) 515 (29.2) 948 (29.8)
3 195 (13.8) 269 (15.3) 464 (14.6)
HR status, No. (%) .002
Negative 688 (48.6) 758 (43.0) 1446 (45.5)
Positive 727 (51.4) 1004 (57.0) 1731 (54.5)
Treatment, No. (%) .036
Chemotherapy alone 706 (49.9) 945 (53.6) 1,651 (52.0)
Trastuzumab-based chemotherapy 709 (50.1) 817 (46.4) 1,526 (48.0)
Intrinsic subtype, No. (%) , .001
Missing 0 982 982
Basal-like 57 (4.0) 48 (6.2) 105 (4.8)
HER2-enriched 1145 (80.9) 555 (71.2) 1,700 (77.4)
Luminal A 89 (6.3) 79 (10.1) 168 (7.7)
Luminal B 124 (8.8) 98 (12.6) 222 (10.1)

Abbreviations: HER2, human epidermal growth factor receptor 2; HR, hormone receptor; HR2, hormone receptor–negative; HR+, hormone
receptor–positive; NCCTG, North Central Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project; Q1, first
interquartile range; Q3, third interquartile range; SD, standard deviation.

Baseline Characteristics in HR+ and HR2 HER2+
Breast Cancer
Comparing baseline characteristics between HR+ and
HR2 HER2+ breast cancer (Table 2), there was no dif-
ference in age (P = .5254) and nodal status (P = .4309).
HR2 HER2+ breast tumors are more likely to be catego-
rized as HER2-enriched, on the basis of the Prosigna al-
gorithm: 88.4% compared with 67.9% in HR+ HER2+
breast cancer. As might be expected, HR+ HER2+ breast
cancers are more likely to be classified as luminal subtypes:
12.4% of HR+ were classified as luminal A compared with
2.2% in HR2 HER2+ tumors. A similar trend was observed
in the luminal B subtype, with 18.4% in HR+ versus 0.6%
in HR2 HER2+ tumors.
Outcome of HR+ Versus HR2 HER2+ Breast Cancer
Overall, patients with HR+ breast cancer had significantly
better RFS at 10 years (73.84%; 95% CI, 71.51% to
76.25%) compared with the HR2 group (69.22%; 95% CI,
66.59% to 71.96%; P , .001). Patients with HR2 HER2+
breast cancer had a significantly shorter median time to
relapse or death (1.9 years) compared with patients with
HR+ HER2+ breast cancer (2.9 years; P , .001). However,
a similar benefit of adjuvant trastuzumab was observed in
both HR+ (hazard ratio, 0.46; 95% CI, 0.37 to 0.57;
P , .001) and HR2 (hazard ratio, 0.47; 95% CI, 0.38 to
0.58; P , .001) HER2+ breast cancer (Fig 1). For HR+
HER2+ breast cancer, 10-year RFS was 81.39% (95% CI,
78.54% to 84.34%) in patients who were treated with

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 Chumsri et al

TABLE 2. Patient Characteristics by Hormone Receptor Status in the NCCTG N9831 and NSABP B-31 Trials
HR2 HR+ Total
Characteristic (n = 1,446) (n = 1,731) (N = 3,177) P
Age, years .5254
Mean (SD) 50.4 (10.6) 48.7 (9.7) 49.5 (10.2)
Median (range) 50.0 (24.0-80.0) 48.0 (23.0-79.0) 49.0 (23.0-80.0)
Q1, Q3 43.0, 58.0 42.0, 55.0 42.0, 56.0
Follow-up period, years , .001
Mean (SD) 7.4 (4.0) 7.9 (4.0) 7.7 (4.0)
Median (range) 7.7 (0.0-15.0) 8.2 (0.1-15.3) 8.0 (0.0-15.3)
Nodal status, No. (%) .4309
1 795 (55.0) 970 (56.0) 1,765 (55.6)
2 437 (30.2) 511 (29.5) 948 (29.8)
3 214 (14.8) 250 (14.4) 464 (14.6)
Intrinsic subtype, No. (%) , .001
Missing 424 558 982
Basal-like 91 (8.9) 14 (1.2) 105 (4.8)
HER2enriched 903 (88.4) 797 (67.9) 1,700 (77.4)
Luminal A 22 (2.2) 146 (12.4) 168 (7.7)
Luminal B 6 (0.6) 216 (18.4) 222 (10.1)

Abbreviations: HER, human epidermal growth factor receptor 2; HR, hormone receptor; HR2, hormone receptor–negative; HR+, hormone
receptor–positive; NCCTG, North Central Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project; Q1, first
interquartile range; Q3, third interquartile range; RFS, relapse-free survival; SD, standard deviation.

adjuvant trastuzumab-based chemotherapy, compared with in HR2 HER2+ breast cancer, with 10-year RFS of 77.78%
65.17% (95% CI, 61.52% to 69.03%) in patients who (95% CI, 74.46% to 81.25%) in patients who received
received chemotherapy alone (hazard ratio, 0.46; 95% CI, adjuvant trastuzumab-based chemotherapy, compared
0.37 to 0.57; P , .001). Comparable benefit was observed with 59.27% (95% CI, 55.27% to 63.56%) in patients who

100

90

80
Relapse-Free Survival (%)

70

60

50
FIG 1. Kaplan-Meier curves
40 of relapse-free survival by
hormone receptor (HR)
30 status and treatment arm
in the North Central Can-
20 Chemotherapy alone, HR+
Chemotherapy alone, HR– cer Treatment Group N9831
10 Trastuzumab-based chemotherapy, HR+ and National Surgical Ad-
Trastuzumab-based chemotherapy, HR– juvant Breast and Bowel
Project B-31 trials.
0 1 2 3 4 5 6 7 8 9 10
Follow-Up (years)
No. at risk:
Chemotherapy alone, HR+ 905 744 650 564 521 475 434 380 300 236 195
Chemotherapy alone, HR– 746 570 459 404 371 348 319 269 218 167 138
Trastuzumab-based chemotherapy, HR+ 826 811 785 747 728 691 613 535 428 338 269
Trastuzumab-based chemotherapy, HR– 700 668 617 585 563 534 473 380 291 217 171

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 Late Relapse in HER2-Positive Breast Cancer with Trastuzumab

received chemotherapy alone (hazard ratio, 0.47; 95% CI, years 5 to 10 (hazard ratio, 1.32; 95% CI, 0.93 to 1.88;
0.38 to 0.58; P , .001). Furthermore, the benefit of ad- P = .12). Similar findings were also observed with the
juvant trastuzumab-based chemotherapy was seen in both mixed-effects Cox model analysis (Appendix Table A2
trials in years 0 to 5 (hazard ratio, 0.42; 95% CI, 0.35 to (online only). The peak of recurrence for HR2 HER2+
0.49; P , .001) and years 5 to 10 (hazard ratio, 0.69; 95% disease was at the 2-year time point, with an annualized
CI, 0.49 to 97; P = .03). hazard rate of recurrence of 10.42% (95% CI, 8.70% to
Similar to what has been previously reported in HR+ 12.38%). In contrast, the peak of recurrence in HR+
HER22 breast cancer,13 RoR was higher in patients with HER2+ disease occurred at the 3-year time point, with an
HR2 HER2+ breast cancer during the first 5 years (Fig 2A; annualized hazard rate of recurrence of 6.62% (95% CI,
Appendix Table A1 (online only). In the multivariable 5.36% to 8.09%). Similar trends were observed in patients
analysis of both treatment groups, HR+ was significantly who were treated with chemotherapy alone (Fig 2B; Ap-
associated with improved RFS during the first 5 years pendix Table A3 (online only) and those treated with
(hazard ratio, 0.65; 95% CI, 0.56 to 0.77; P , .001). adjuvant trastuzumab-based chemotherapy (Fig 2C; Ap-
However, there was no significant difference during pendix Table A4 (online only).

A
Hazard Rates for Relapse or Death

0.15 Hormone receptor

Negative
Positive

0.10

0.05

0.00

1 2 3 4 5 6 7 8 9 10
Follow-Up (years)
No. at risk:
HR– 1,446 1,238 1,076 989 934 882 792 649 509 384
HR+ 1,731 1,555 1,435 1,311 1,249 1,166 1,047 915 728 574

B C
Hazard Rates for Relapse or Death

Hazard Rates for Relapse or Death

0.20 Hormone receptor 0.20 Hormone receptor

Negative Negative
Positive Positive

0.15 0.15

0.10 0.10

0.05 0.05

0.00 0.00

1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10
Follow-Up (years) Follow-Up (years)
No. at risk: No. at risk:
HR– 746 570 459 404 371 348 319 269 218 167 HR– 700 668 617 585 563 534 473 380 291 217
HR+ 905 744 650 564 521 475 434 380 300 236 HR+ 826 811 785 747 728 691 613 535 428 338

FIG 2. Annualized hazard rates for relapse or death by hormone receptor (HR) status. (A) Rates in the North Central Cancer Treatment Group (NCCTG)
N9831 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trials. (B) Rates in the NCCTG N9831 and NSABP B-31 trials in patients
treated with chemotherapy alone. (C) Rates in the NCCTG N9831 and NSABP B-31 trials in patients treated with trastuzumab-based chemotherapy.

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 Chumsri et al
Outcome of HR+ HER2+ Breast Cancer Treated With
Adjuvant Trastuzumab-Based Chemotherapy Between
Years 0 to 5 and 5 to 10
Among 2,048 patients who survived 5 years without re-
currence, more than 90% of patients survived without
additional recurrence, regardless of their HR status or
treatment arm. In the combined analysis in patients with
lymph node involvement treated with adjuvant trastuzumab-
based chemotherapy, patients with HR+ HER2+ disease
had significantly lower RoR during the first 0 to 5 years
(hazard ratio, 0.60; 95% CI, 0.45 to 79; P , .001; Table 3).
The cumulative hazard for relapse in HR+ HER2+ disease
was 10.96% (95% CI, 8.78% to 13.08%) compared with
17.48% (95% CI, 14.59% to 20.27%) in HR2 HER2+
disease in the first 5 years. For years 5 to 10, the cumulative
hazard of relapse or death in HR+ HER2+ patients treated
with adjuvant trastuzumab-based chemotherapy was 8.6%
(95% CI, 6.16% to 10.97%), which was slightly higher than
in patients with HR2 HER2+ disease (5.75%).
Using the univariate Cox regression analysis, there ap-
peared to be no significant difference in the outcome
between HR+ HER2+ and HR2 HER2+ subgroups be-
tween years 5 to 10 (hazard ratio, 1.62; 95% CI, 0.97 to
2.71; P = .065). However, when adjusted for lymph node
status, age, and trial using multivariate Cox regression
analysis, the adjusted hazard ratio was 1.7 (95% CI, 1.01 to
2.85; P , .05). During years 5 to 10, patients with HR+
HER2+ breast cancer with N3 disease appeared to have
higher RoR compared with patients with HR2 HER2+
breast cancer (adjusted hazard ratio, 4.39; 95% CI, 0.94 to
20.50; P = .06). However, the adjusted hazard ratio of
patients with N1 and N2 disease was 1.42 (95% CI, 0.81 to
2.48; P = .221).
Given that NCCTG N9831 was the only trial in this analysis
to include patients with no lymph node involvement, we
additionally analyzed the RoR among those patients alone
(Table 4). Only 3.23% (95% CI, 0% to 9.25%) of patients
with HR+ HER2+ disease with N0 disease and 6.39%
(95% CI, 3.09% to 9.59%) with N1 disease developed
recurrence in years 5 to 10, compared with the recently
reported 11% and 19% RoR after 5 years in HR+ HER22
disease with N0 and N1 disease, respectively.4
Intrinsic Subtypes and Outcome
In the NCCTG N9831 trial, intrinsic subtype classification
information is only available for 982 patients (55.7%). As
we described previously,12 there was no statistically sig-
nificant difference between the cohort with intrinsic sub-
type classification and overall cohort. Using the Prosigna
algorithm to determine the intrinsic subtype, 77.4% of
patients had HER2-enriched subtype, 10.1% had luminal
B subtype, 7.7% had luminal A subtype, and 4.8% had
basal-like subtype. Regardless of the treatment patients
received, those with luminal A subtype had the best out-
come, with 10-year RFS of 77.32% (95% CI, 70.45% to
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84.87%), followed by the luminal B subtype (73.17%; 95%
CI, 66.36% to 80.68%), HER2-enriched subtype (68.67%;
95% CI, 66.12% to 71.32%), and basal-like subtype
(64.0%; 95% CI, 54.59% to 75.04%; P , .001; Appendix
Table A5 (online only).
Among patients who received adjuvant trastuzumab-based
chemotherapy, patients with luminal A subtype also had
the best outcome, with 10-year RFS of 89.84% (95% CI,
82.31% to 98.05%), followed by luminal B subtype
(82.27%; 95% CI, 74.57% to 90.77%), HER2-enriched
subtype (76.78%; 95% CI, 73.48% to 80.22%), and basal-
like subtype (74.19.0%; 95% CI, 62.12% to 88.59%;
P = 0.014; Appendix Table A6 (online only). Of note, pa-
tients without lymph node involvement who had HER2-
enriched subtype also had an excellent 10-year RFS of
89.01% (95% CI, 80.32% to 98.64%). The cumulative
hazard and hazard ratio of relapse or death according to
intrinsic subtypes and hormone receptor status are also
reported in Appendix Table A7 (online only).
DISCUSSION
With the advent of anti-HER2 therapy, the outcome of
patients with HER2+ breast cancer has dramatically
improved. Although the outcome of patients with HER2+
breast cancer is generally perceived as favorable with
the use of adjuvant trastuzumab-based chemotherapy,
little is known about the effects of anti-HER2 therapies
on the patterns of late relapses in this group of patients.
To our knowledge, this analysis is the first to address
the risk of late relapses in subsets of patients with
HER2+ breast cancer who were treated with adjuvant
trastuzumab.
Overall, our analysis demonstrated persistent benefit of
adjuvant trastuzumab in the long term. Furthermore,
similar degree of benefit from adjuvant trastuzumab was
observed among patients with HR+ and HR2 HER2+
breast cancer. In HR+ HER22 breast cancer, several
studies have demonstrated substantial risk of late relapse
beyond 5 years after the initial diagnosis. Saphner et al13
demonstrated that although patients with HR2 HER22
disease had higher initial RoR, their annual hazard rate of
relapse declined over time. In contrast, patients with HR+
HER22 breast cancer had relatively constant RoR over
time that surpassed that of patients with HR2 HER22
breast cancer after 5 years.13 This observation was con-
firmed in several subsequent studies.1,2,14 Similar to this
observation, our analysis also demonstrated a distinct
pattern of recurrence in patients with HER2+ breast cancer
in the first 5 years among HR+ and HR2 HER2+ disease.
Patients with HR2 HER2+ breast cancer had a significantly
higher annualized hazard rate of relapse in the first 5 years
compared with patients with HR+ HER2+ disease. How-
ever, after 5 years, patients with HR+ HER2+ breast cancer
who received adjuvant trastuzumab-based chemotherapy
had no significant difference in the annualized hazard rate
 Journal of Clinical Oncology
TABLE 3. Cumulative Hazard and Hazard Ratio with Univariate Cox Regression Analysis of Relapse or Death Among Patients With Lymph Node Involvement Who Received Adjuvant Trastuzumab-Based
Chemotherapy in the NCCTG N9831 and NSABP B-31 Trials, by Hormone Receptor Status
Years 0-5 Years 5-10*

HR+ HR2 Hazard Ratio HR+ HR2 Hazard Ratio

No. of Cumulative Hazard No. of Cumulative Hazard No. of Cumulative Hazard No. of Cumulative Hazard
Trial Patients Rate, % (95% CI) Patients Rate, % (95% CI) (95% CI) P Patients Rate, % (95% CI) Patients Rate, % (95% CI) (95% CI) P
All 826 10.96 (8.78 to 13.08) 700 17.48 (14.59 to 20.27) 0.59 (0.45 to 0.78) , .001 691 8.60 (6.16 to 10.97) 534 5.75 (3.18 to 8.24) 1.62 (0.97 to 2.71) .065
N9831 472 9.10 (6.44 to 11.69) 345 18.11 (13.89 to 22.12) 0.47 (0.31 to 0.69) , .001 405 7.03 (4.38 to 9.60) 262 4.49 (1.72 to 7.19) 1.65 (0.80 to 3.42) .178
B-31 354 13.42 (9.77 to 16.92) 355 16.86 (12.85 to 20.70) 0.77 (0.52 to 1.12) .172 286 NA 272 NA NA

Abbreviations: HR+, hormone receptor–positive; HR2, hormone receptor–negative; NA, not available; NCCTG, North Central Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and
Bowel Project.
*Estimated on the basis of patients who survived 5 years without disease relapse.
Late Relapse in HER2-Positive Breast Cancer with Trastuzumab

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7
 8 © 2019 by American Society of Clinical Oncology
TABLE 4. Cumulative Hazard and Hazard Ratio with Univariate Cox Regression Analysis of Relapse or Death Among Patients With or Without Lymph Node Involvement Who Received Adjuvant
Trastuzumab-Based Chemotherapy in the NCCTG N9831 Trial, by Hormone Receptor Status
Years 0-5 Years 5-10*

HR+ HR2 Hazard Ratio HR+ HR2 Hazard Ratio

Nodal No. of Cumulative Hazard No. of Cumulative Hazard No. of Cumulative Hazard No. of Cumulative Hazard
Status Patients Rate, % (95% CI) Patients Rate, % (95% CI) (95% CI) P Patients rate, % (95% CI) Patients Rate, % (95% CI) (95% CI) P
0 43 7.71 (0.00 to 15.74) 89 16.05 (7.98 to 23.42) 0.47 (0.13 to 1.62) .231 32 3.23 (0.00 to 9.25) 70 8.86 (1.05 to 16.04) 0.46 (0.05 to 3.96) .482
1 278 6.70 (3.66 to 9.64) 186 10.63 (5.99 to 15.04) 0.61 (0.32 to 1.15) .127 241 6.39 (3.09 to 9.59) 152 5.57 (1.46 to 9.51) 1.26 (0.50 to 3.12) .618
2 125 13.68 (7.42 to 19.52) 110 20.99 (12.98 to 28.26) 0.60 (0.32 to 1.13) .115 105 5.10 (0.64 to 9.35) 85 1.22 (0.00 to 3.57) 3.81 (0.45 to 32.68) .222
Chumsri et al

3 69 10.25 (2.76 to 17.17) 49 39.76 (24.11 to 52.18) 0.22 (0.09 to 0.51) .001 59 13.19 (3.54 to 21.88) 25 8.52 (0.00 to 19.16) 1.45 (0.30 to 6.98) .644

Abbreviations: HR+, hormone receptor–positive; HR2, hormone receptor–negative; NCCTG, North Central Cancer Treatment Group.
*Estimated on the basis of patients who survived 5 years without disease relapse.

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 Late Relapse in HER2-Positive Breast Cancer with Trastuzumab
of relapse compared with patients with HR2 HER+ breast
cancer, particularly in patients with N0, N1, and N2 dis-
ease. Nevertheless, there appeared to be a higher RoR
between years 5 to 10 in patients with HR+ HER2+ breast
cancer with more lymph node involvement, particularly
those with N3 disease.
A recent meta-analysis of 62,923 women with HR+ breast
cancer by the Oxford Overview demonstrated that despite
5 years of adjuvant endocrine therapy, patients still had
substantial risk of distant recurrence.4 By 10 years, pa-
tients without lymph node involvement had an 11% risk of
distant recurrence and risk of distant recurrence was
projected to increase to as high as 22% by year 20. In
patients with N1 and N2 disease, the risk of distant re-
currence was projected to be 31% and 52% by year 20,
respectively. However, only 2% of the patients in that
analysis had HER2+ breast cancer, and trastuzumab was
not administered in any of the included trials.4 In the
Oxford analysis,4 5% of patients with HR+ breast cancer
without lymph node involvement had disease recurrence
between years 5 to 10, compared with 3.23% in our
combined analysis, and 9% compared with 6.39% in
patients with N1 disease, respectively. A more pro-
nounced difference was observed in patients with N2
HR+ HER22, with 14% RoR in the Oxford analysis,4
compared with 5.1% in our combined analysis.
Beyond standard HR and HER2 status, there are several
multigene tests currently used in clinic to assess individual
RoR and benefit of adjuvant chemotherapy. In patients with
HR+ HER22 breast cancer, Prosigna PAM50 RoR, the
Breast Cancer Index (Biotheranostics, San Diego, CA), and
EndoPredict (Myriad Genetic Laboratories, Salt Lake City,
UT) have prognostic value in predicting the risk of late
relapse beyond 5 years after the initial diagnosis.13 The
PAM50 RoR score is based on the 50-gene panel de-
veloped to identify intrinsic subtypes of breast cancer.
However, ROR score also integrates information on tumor
size. In previous studies in the translational arm of the
Anastrozole or Tamoxifen Alone or Combined trial16 and
Austrian Breast and Colorectal Cancer Study Group 8
trial,17 ROR score added significant prognostic information
on risk of late relapse beyond conventional clinical path-
ologic parameters. Interestingly, similar to previous reports
in HR+ HER22 breast cancer, our study demonstrated the
prognostic value of Prosigna PAM50 intrinsic subtype in
predicting risk for late relapse in patients with HR+ HER2+
breast cancer. Albeit rare, patients with luminal A tumors
had excellent long-term outcome, with 89.8% RFS at
10 years compared with luminal B (82.3%), HER2-
enriched (76.8%), and basal-like (74.19%) subtypes.
Our study has several limitations, the first being the lack of
longer follow-up. The Oxford Overview4 provided up to
20 years of follow-up data, whereas we had only up to
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10 years of follow-up data. Furthermore, our combined
analysis had a smaller sample size. After separating pa-
tients with HR+ HER2+ breast cancer treated with tras-
tuzumab according to lymph node involvement, there were
only 43, 278, 125, and 69 patients with N0, N1, N2, and
N3 disease, respectively. Therefore, the results of this study
should be viewed with caution. Moreover, because of po-
tential multiple comparisons, the Bonferroni correction
method may be applied. To avoid overinterpretation, each
P value need to be less than .025 to consider statistically
significant. Late relapse among patients with HR+ HER2+
breast cancer who received adjuvant trastuzumab can be
better assessed in a meta-analysis of additional adjuvant
trastuzumab trials. In addition, it is unclear whether the risk
of late relapse in patients with HR+ HER2+ breast cancer
will be even lower with the use of additional anti-HER2
therapies such as pertuzumab, neratinib, and ado-
trastuzumab emtansine.
Currently, there is no prospective, randomized, controlled
clinical trial specifically addressing the benefit of ex-
tended adjuvant endocrine therapy in HER2+ patients.
Nevertheless, because patients who were treated with
adjuvant trastuzumab and completed 5 years of adjuvant
endocrine therapy without recurrence had low RoR,
particularly patients with N0 and N1 disease, it is unclear
whether the benefit of extended adjuvant endocrine
therapy will outweigh the risks and adverse effects as-
sociated with these extended therapies. For extended
adjuvant endocrine therapy with tamoxifen, the absolute
benefit of tamoxifen in reducing RoR was reported to be
2.8% to 4%, with the relative reduction of approximately
15%, in both ATLAS and aTTom trials.18-20 However, this
benefit may be offset by increased risks of endometrial
cancer (range, 1.6% to 3.1%) and thromboembolism with
relative risk of 1.87 for pulmonary embolism.18 The benefit
of 10 years versus 5 years of adjuvant aromatase inhibi-
tor remains controversial. Recent trials demonstrated
the benefit of extended adjuvant aromatase inhibitors
appeared to be limited to reducing the risk of second breast
cancer, but there was none or only a small benefit for
distant metastasis.21-25
In summary, we demonstrated in this study persistent
long-term benefit of adjuvant trastuzumab in patients with
HER2+ breast cancer. Similar degree of benefit from
adjuvant trastuzumab was observed in both HR+ and
HR2 disease. Given concerning adverse effects and
potentially less benefit of extended adjuvant endocrine
therapy, particularly in patients with N0 or N1 disease,
our findings highlight the need to develop better risk-
prediction models and biomarkers to identify which pa-
tients have sufficient risk for late relapse to warrant the
use of extended endocrine therapy in HER2+ breast
cancer.
9
 Chumsri et al

AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

1
Mayo Clinic, Jacksonville, FL AND DATA AVAILABILITY STATEMENT
2
NanoString, Seattle, WA Disclosures provided by the authors and data availability statement (if
3
NRG Oncology, Pittsburgh, PA applicable) are available with this article at DOI https://doi.org/10.1200/
4
Yonsei University College of Medicine, Seoul, Republic of South Korea JCO.19.00443.

CORRESPONDING AUTHOR AUTHOR CONTRIBUTIONS

Saranya Chumsri, MD, Division of Hematology and Medical Oncology, Conception and design: Saranya Chumsri, Soonmyung Paik, Edith A.
Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: Perez, E. Aubrey Thompson
chumsri.saranya@mayo.edu. Financial support: E. Aubrey Thompson
Provision of study material or patients: Zhuo Li, Katherine L. Pogue-Geile,
Soonmyung Paik, Edith A. Perez, E. Aubrey Thompson
PRIOR PRESENTATION
Collection and assembly of data: Saranya Chumsri, Nan Song, Katherine
Presented at the San Antonio Breast Cancer Symposium Meeting 2018,
Pogue-Geile, Patrick G. Gavin, Soonmyung Paik, Edith A. Perez, E.
December 4-8, 2018, San Antonio, TX.
Aubrey Thompson
Manuscript writing: All authors
SUPPORT Final approval of manuscript: All authors
Supported by the National Cancer Institute of the National Institutes of Accountable for all aspects of the work: All authors
Health under Award Numbers U10CA180821 and U10CA18082 (to the
Alliance for Clinical Trials in Oncology), U24CA196171,
U10CA180868, UG1CA189867, U10CA180822, and U24CA196067;
Genentech; and in part by funds to E.A.T. from the Breast Cancer
Research Foundation (Grant No. BCRF-17-161), Bankhead-Coley
Research Program (Grant No. 6BC05), and the DONNA Foundation.

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JAMA 295:1658-1667, 2006
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10. Perez EA, Romond EH, Suman VJ, et al: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer:
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J Clin Oncol 33:1340-1347, 2015
12. Perez EA, Ballman KV, Mashadi-Hossein A, et al: Intrinsic subtype and therapeutic response among HER2-positive breas tumors from the NCCTG (Alliance)
N9831 trial. J Natl Cancer Inst 109:djw207, 2016
13. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 14:2738-2746, 1996
14. Dukić V, Dignam J: Bayesian hierarchical multiresolution hazard model for the study of time-dependent failure patterns in early stage breast cancer. Bayesian
Anal 2:591-610, 2007
15. Sestak I, Cuzick J: Markers for the identification of late breast cancer recurrence. Breast Cancer Res 17:10, 2015
16. Dowsett M, Sestak I, Lopez-Knowles E, et al: Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence
after endocrine therapy. J Clin Oncol 31:2783-2790, 2013
17. Filipits M, Nielsen TO, Rudas M, et al: The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal
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18. Davies C, Pan H, Godwin J, et al: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-
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19. Gray RG, Rea D, Handley K, et al: aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early
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20. Burstein HJ, Temin S, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical
Oncology clinical practice guideline focused update. J Clin Oncol 32:2255-2269, 2014
21. Goss PE, Ingle JN, Pritchard KI, et al: Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 375:209-219, 2016
22. Tjan-Heijnen VCG, van Hellemond IEG, Peer PGM, et al: Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): A randomised,
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 Late Relapse in HER2-Positive Breast Cancer with Trastuzumab

23. Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg E, et al: Optimal duration of extended adjuvant endocrine therapy for early breast cancer; Results of the IDEAL
trial (BOOG 2006-05). J Natl Cancer Inst 110:40-48, 2018
24. Mamounas E, Bandos H, Lembersky B, et al: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy (tx) with
letrozole (L) in postmenopausal women with hormone-receptor (+) breast cancer (BC) who have completed previous adjuvant tx with an aromatase inhibitor
(AI): Results from NRG Oncology/NSABP B-42. San Antonio Breast Cancer Symposium. San Antonio, TX, December 6-10, 2016
25. van Hellemond IEG, Geurts SME, Tjan-Heijnen VCG: Current status of extended adjuvant endocrine therapy in early stage breast cancer. Curr Treat Options
Oncol 19:26, 2018

n n n

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 Chumsri et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Incidence of Late Relapses in Patients With HER2-Positive Breast Cancer Receiving Adjuvant Trastuzumab: Combined Analysis of NCCTG N9831 (Alliance) and
NRG Oncology/NSABP B-31
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Saranya Chumsri Katherine L. Pogue-Geile

Consulting or Advisory Role: Syndax, Puma Biotechnology, Novartis, Eisai, Research Funding: National Surgical Adjuvant Breast and Bowel Project (Inst)
Immunomedics Patents, Royalties, Other Intellectual Property: US Patent Application Serial
Research Funding: Merck, Array BioPharma No. 14/738,757, entitled “Methods of Subtyping CRC and their Association with
Treatment of Colon Cancer Patients with Oxaliplatin,” published on December
Daniel J. Serie
24, 2015.
Employment: InterVenn Biosciences
Stock and Other Ownership Interests: InterVenn Biosciences Soonmyung Paik
Stock and Other Ownership Interests: ImmunOncia Therapeutics
Afshin Mashadi-Hossein
Consulting or Advisory Role: Medpacto
Employment: NanoString Technologies, Celgene Corporation
Stock and Other Ownership Interests: NanoString Technologies, Celgene Alvaro Moreno-Aspitia
Corporation Stock and Other Ownership Interests: Merrimack
Patents, Royalties, Other Intellectual Property: Royalties from the development
Gerardo Colon-Otero
of a xenograft model. Royalties were assigned to go to my institution, not to me.
Research Funding: Novartis (Inst)
Edith A. Perez
Nan Song
Employment: Genentech
Patents, Royalties, Other Intellectual Property: Patent Application Serial No.
Stock and Other Ownership Interests: Roche
14/738,757 entitled “Methods of Subtyping CRC and their Association with
Consulting or Advisory Role: Seattle Genetics, Puma, Daiichi Sankyo
Treatment of Colon Cancer Patients with Oxaliplatin,” published on December
24, 2015. No other potential conflicts of interest were reported.

© 2019 by American Society of Clinical Oncology

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 Late Relapse in HER2-Positive Breast Cancer with Trastuzumab

APPENDIX

B
NCCTG N9831 NSABP B-31
(N = 1,762) (N = 1,415)
Women 18 years or older with primary, operable, Women 18 years or older with primary, operable,
histologically confirmed node-positive or high-risk histologically confirmed node-positive HER2-positive
node-negative HER2-positive invasive breast cancer invasive breast cancer
Study entry: May 19, 2000 to April 30, 2005 Study entry: February 21, 2000 to April 30, 2005

Group 2
Arm C
Group 1 (n = 709)
(n = 817)
Arm A (n = 706) Doxorubicin 60 mg/m2 and
Doxorubicin 60 mg/m2 and
(n = 945) Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2
cyclophosphamide 600 mg/m2
Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks x 4 followed by
every 3 weeks x 4 followed by
cyclophosphamide 600 mg/m2 every 3 weeks x 4 followed by paclitaxel 175 mg/m2 every 3
paclitaxel 80 mg/m2
every 3 weeks x 4 followed by paclitaxel 175 mg/m2 weeks x 4 or paclitaxel 80 mg/m2
weekly for 12 weeks concurrently
paclitaxel 80 mg/m2 every 3 weeks x 4 or weekly for 12 weeks concurrently
with trastuzumab initial loading
weekly for 12 weeks paclitaxel 80 mg/m2 with trastuzumab initial loading
dose 4 mg/kg then 2 mg/kg
weekly for 12 weeks dose 4 mg/kg then 2 mg/kg
weekly for 52 weeks
weekly for 52 weeks

Arm A Arm C Group 1 Group 2

HR+ (n = 532) HR+ (n = 472) HR+ (n = 373) HR+ (n = 354)
HR– (n = 413) HR– (n = 345) HR– (n = 333) HR– (n = 355)

FIG A1. CONSORT diagram of the North Central Cancer Treatment Group (NCCTG N9831) and National Surgical Adjuvant Breast and Bowel Project
(NSABP) B-31 trials.

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 Chumsri et al

TABLE A1. Annualized Hazard Rate of Relapse or Death by Hormone Receptor Status in the North Central Cancer Treatment Group N9831 and National
Surgical Adjuvant Breast and Bowel Project B-31 Trials
HR2 HR+

No. of Patients at No. of Events No. of Patients at No. of Events

Year Start of Year During the Year Hazard Rate % (95% CI) Start of Year During the Year Hazard Rate % (95% CI) P
1 1,446 70 5.19 (4.00 to 6.41) 1,731 32 1.93 (1.26 to 2.59) , .001
2 1,238 129 11.16 (9.26 to 13.09) 1,555 71 4.76 (3.72 to 5.86) , .001
3 1,076 70 6.80 (5.24 to 8.44) 1,435 96 7.00 (5.63 to 8.43) .829
4 989 38 3.95 (2.79 to 5.28) 1,311 41 3.21 (2.25 to 4.22) .348
5 934 19 2.09 (1.18 to 3.02) 1,249 43 3.55 (2.53 to 4.62) .062
6 882 14 1.67 (0.85 to 2.54) 1,166 31 2.81 (1.86 to 3.81) .105
7 792 20 2.80 (1.65 to 4.03) 1,047 20 2.04 (1.21 to 2.97) .408
8 649 9 1.57 (0.60 to 2.57) 915 22 2.70 (1.59 to 3.83) .160
9 509 2 0.46 (0.01 to 1.08) 728 9 1.38 (0.55 to 2.26) .136
10 384 4 1.15 (0.20 to 2.25) 574 5 0.97 (0.25 to 1.82) .792

Abbreviations: HR+, hormone receptor–positive; HR2, hormone receptor–negative.

TABLE A2. The Mixed-Effects Cox Model Analysis of Relapse or Death Among Patients in the North Central Cancer Treatment Group N9831 and
National Surgical Adjuvant Breast and Bowel Project B-31 Trials
Year 0-5 Year 5-10

Group Hazard Ratio (95% CI) P Hazard Ratio (95% CI) P

Trastuzumab 0.42 (0.35 to 0.49) , .001 0.69 (0.49 to 0.97) .031
HR+ 0.65 (0.56 to 0.76) , .001 1.32 (0.93 to 1.87) .123
Age . 40 years 0.71 (0.59 to 0.85) , .001 0.70 (0.47 to 1.04) .078
N2 1.78 (1.48 to 2.15) , .001 0.78 (0.52 to 1.18) .235
N3 3.53 (2.90 to 4.31) , .001 1.49 (0.93 to 2.38) .1

Abbreviation: HR+, hormone receptor–positive.

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 Late Relapse in HER2-Positive Breast Cancer with Trastuzumab

TABLE A3. Annualized Hazard Rate of Relapse or Death, by Hormone Receptor Status, in Patients Treated with Chemotherapy Alone in North Central Cancer
Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 Trials
HR2 HR+

No. of Patients at No. of Events No. of Patients at No. of Events

Year Start of Year During the Year Hazard Rate % (95% CI) Start of Year During the Year Hazard Rate % (95% CI) P
1 746 47 7.07 (5.10 to 9.12) 905 20 2.39 (1.41 to 3.46) , .001
2 570 81 15.83 (12.44 to 19.29) 744 50 7.21 (5.34 to 9.30) , .001
3 459 42 9.73 (6.88 to 12.73) 650 65 10.75 (8.21 to 13.36) .678
4 404 24 6.22 (3.87 to 8.72) 564 32 5.94 (3.95 to 8.01) .849
5 371 12 3.33 (1.55 to 5.16) 521 27 5.42 (3.50 to 7.49) .634
6 348 9 2.69 (1.12 to 4.48) 475 15 3.28 (1.69 to 4.93) .222
7 319 12 4.12 (1.94 to 6.46) 434 9 2.20 (0.89 to 3.70) .222
8 269 5 2.06 (0.56 to 3.88) 380 10 2.95 (1.29 to 4.80) .516
9 218 1 0.54 (0.00 to 1.61) 300 2 0.75 (0.03 to 1.76) .757
10 167 1 0.66 (0.00 to 2.01) 236 4 1.88 (0.34 to 3.67) .321

Abbreviation: HR+, hormone receptor–positive; HR2, hormone receptor–negative.

TABLE A4. Annualized Hazard Rate of Relapse or Death by hormone receptor status in patients who were treated with adjuvant trastuzumab-based
chemotherapy in the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 Trials
HR2 HR+

No. of Patients at No. of Events No. of Patients at No. of Events

Year Start of Year During the Year Hazard Rate % (95% CI) Start of Year During the Year Hazard Rate % (95% CI) P
1 700 23 3.37 (2.09 to 4.82) 826 12 1.47 (0.69 to 2.30) .016
2 668 48 7.46 (5.38 to 9.59) 811 21 2.62 (1.57 to 3.75) , .001
3 617 28 4.67 (3.04 to 6.43) 785 31 4.03 (2.70 to 5.45) .684
4 585 14 2.43 (1.25 to 3.71) 747 9 1.22 (0.48 to 2.01) .098
5 563 7 1.27 (0.46 to 2.26) 728 16 2.25 (1.21 to 3.39) .201
6 534 5 1.00 (0.25 to 1.89) 691 16 2.47 (1.32 to 3.65) .067
7 473 8 1.88 (0.66 to 3.15) 613 11 1.94 (0.82 to 3.04) .964
8 380 4 1.20 (0.21 to 2.39) 535 12 2.52 (1.20 to 3.91) .181
9 291 1 0.41 (0.00 to 1.24) 428 7 1.82 (0.67 to 3.25) .125
10 217 3 1.55 (0.16 to 3.29) 338 1 0.33 (0.00 to 1.00) .138

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 TABLE A5. Kaplan-Meier Estimates of RFS Rate Based on Demographic and Treatment Groups in the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel
Project B-31 Trials
1-Year RFS, 3-Year RFS, 5-Year RFS, 8-Year RFS, 10-Year RFS,
Group No. of Patients No. of Events % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) P
Treatment

© 2019 by American Society of Clinical Oncology

Chemotherapy alone 1,651 478 95.35 (94.29 to 96.43) 77.27 (75.05 to 79.56) 69.53 (67.07 to 72.09) 63.79 (61.15 to 66.54) 62.53 (59.80 to 65.38) , .001
Trastuzumab 1,526 286 97.69 (96.94 to 98.45) 89.19 (87.64 to 90.77) 86.06 (84.33 to 87.84) 81.33 (79.30 to 83.41) 79.69 (77.50 to 81.93)
HR type
HR2 1,446 383 94.80 (93.63 to 95.99) 79.28 (77.10 to 81.52) 74.65 (72.30 to 77.07) 70.32 (67.78 to 72.95) 69.22 (66.59 to 71.96) , .001
HR+ 1,731 381 97.99 (97.31 to 98.67) 87.18 (85.53 to 88.86) 81.49 (79.56 to 83.47) 75.58 (73.37 to 77.85) 73.84 (71.51 to 76.25)
Age, years
# 40 635 190 96.02 (94.48 to 97.60) 79.66 (76.41 to 83.04) 72.50 (68.88 to 76.31) 66.34 (62.37 to 70.56) 63.88 (59.63 to 68.43) , .001
. 40 2,542 574 96.68 (95.96 to 97.39) 84.59 (83.12 to 86.09) 79.86 (78.21 to 81.53) 74.88 (73.05 to 76.75) 73.63 (71.72 to 75.59)
Nodal status
N1 1,765 316 97.76 (97.05 to 98.48) 89.25 (87.72 to 90.80) 85.51 (83.77 to 87.29) 79.69 (77.61 to 81.82) 78.12 (75.89 to 80.42) , .001
Chumsri et al

N2 948 248 96.59 (95.41 to 97.78) 81.46 (78.90 to 84.10) 75.33 (72.49 to 78.28) 71.54 (68.51 to 74.71) 70.25 (67.11 to 73.54)
N3 464 200 91.92 (89.43 to 94.49) 67.22 (62.89 to 71.83) 58.49 (53.94 to 63.42) 52.66 (47.94 to 57.85) 51.19 (46.35 to 56.53)
Intrinsic subtype
Basal 105 33 90.81 (85.25 to 96.74) 76.42 (68.24 to 85.58) 70.79 (62.06 to 80.75) 64.00 (54.59 to 75.04) 64.00 (54.59 to 75.04) , .001
HER2 1,700 446 95.48 (94.47 to 96.50) 81.01 (79.07 to 82.99) 75.96 (73.84 to 78.14) 70.63 (68.28 to 73.05) 68.67 (66.12 to 71.32)
Luminal A 168 32 99.38 (98.16 to 100.0) 92.02 (87.79 to 96.46) 83.73 (77.97 to 89.91) 77.32 (70.45 to 84.87) 77.32 (70.45 to 84.87)

Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

Luminal B 222 49 98.62 (97.08 to 100.0) 88.17 (83.83 to 92.73) 82.06 (76.91 to 87.55) 75.94 (69.90 to 82.51) 73.17 (66.36 to 80.68)
Unknown 982 204 98.04 (97.15 to 98.94) 86.43 (84.18 to 88.75) 81.74 (79.17 to 84.39) 77.24 (74.41 to 80.17) 76.12 (73.23 to 79.14)

Abbreviations: HER, human epidermal growth factor receptor 2; HR+, hormone receptor–positive; HR2, hormone receptor–negative; RFS, relapse-free survival.

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 Journal of Clinical Oncology
TABLE A6. Kaplan-Meier Estimates of RFS Rate Based on Demographic and Treatment Groups of Patients Treated with Trastuzumab-Based Adjuvant Chemotherapy in the North Central Cancer Treatment
Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 Trials
1-Year RFS, 3-Year RFS, 5-Year RFS, 8-Year RFS, 10-Year RFS,
Group No. of Patients No. of Events % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) P
HR type
HR2 700 145 96.69 (95.36 to 98.03) 85.64 (83.06 to 88.30) 82.52 (79.73 to 85.41) 79.27 (76.20 to 82.46) 77.78 (74.46 to 81.25) .0153
HR+ 826 141 98.54 (97.73 to 99.36) 92.18 (90.36 to 94.04) 89.04 (86.92 to 91.22) 83.14 (80.48 to 85.88) 81.39 (78.54 to 84.34)
Age, years
# 40 282 63 97.15 (95.23 to 99.12) 86.39 (82.46 to 90.51) 83.44 (79.18 to 87.93) 77.64 (72.64 to 82.98) 74.68 (69.16 to 80.64) .0713
. 40 1,244 223 97.82 (97.00 to 98.63) 89.83 (88.15 to 91.53) 86.66 (84.77 to 88.59) 82.17 (79.97 to 84.43) 80.82 (78.48 to 83.24)
Nodal status
N1 860 125 98.71 (97.96 to 99.47) 93.38 (91.72 to 95.07) 90.82 (88.89 to 92.80) 85.35 (82.85 to 87.93) 83.55 (80.78 to 86.41) , .001
N2 456 92 97.36 (95.89 to 98.84) 86.31 (83.20 to 89.54) 82.28 (78.84 to 85.88) 80.11 (76.45 to 83.94) 78.85 (75.00 to 82.90)
N3 210 69 94.27 (91.17 to 97.47) 78.41 (73.01 to 84.20) 74.97 (69.30 to 81.10) 67.74 (61.44 to 74.69) 65.88 (59.32 to 73.18)
Intrinsic subtype
Basal 43 11 95.35 (89.26 to 100.0) 81.40 (70.56 to 93.90) 76.74 (65.10 to 90.47) 74.19 (62.12 to 88.59) 74.19 (62.12 to 88.59) .0137
HER2 847 172 96.91 (95.75 to 98.09) 87.14 (84.90 to 89.43) 84.22 (81.78 to 86.73) 79.30 (76.47 to 82.24) 76.78 (73.48 to 80.22)
Luminal A 73 6 100.0 (100.0 to 100.0) 97.22 (93.50 to 100.0) 97.22 (93.50 to 100.0) 89.84 (82.31 to 98.05) 89.84 (82.31 to 98.05)
Luminal B 100 16 99.00 (97.07 to 100.0) 93.00 (88.13 to 98.14) 89.97 (84.26 to 96.06) 82.27 (74.57 to 90.77) 82.27 (74.57 to 90.77)
Late Relapse in HER2-Positive Breast Cancer with Trastuzumab

Unknown 463 81 98.69 (97.65 to 99.74) 91.61 (89.09 to 94.20) 87.72 (84.72 to 90.81) 84.16 (80.78 to 87.67) 82.70 (79.16 to 86.39)

Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

Abbreviations: HER, human epidermal growth factor receptor 2; HR+, hormone receptor–positive; HR2, hormone receptor–negative; RFS, relapse-free survival.

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 © 2019 by American Society of Clinical Oncology
TABLE A7. Cumulative Hazard and Hazard Ratio with Univariate Cox Regression Analysis of Relapse or Death Among Patients With Lymph Node Involvement Who Received Adjuvant Trastuzumab-Based
Chemotherapy in the North Central Cancer Treatment Group N9831 and National Surgical Adjuvant Breast and Bowel Project B-31 Trials, by HR Status and Intrinsic Subtypes
Year 0-5 Year 5-10*

HR+ HR2 HR+ HR2

Cumulative Hazard Rate, Cumulative Hazard Rate, Cumulative Hazard Rate, Cumulative Hazard Rate,
Subtype No. % (95% CI) No. % (95% CI) Hazard Ratio (95% CI) P No. % (95% CI) No. % (95% CI) Hazard Ratio (95% CI) P
Basal 8 50.00 (0.02 to 75.00) 35 17.14 (3.67 to 28.73) 4.18 (1.17 to 14.89) .027 4 0.00 (0.00 to 0.00) 28 3.70 (0.00 to 10.57) NA NA
HER2 389 13.50 (10.02 to 16.85) 458 17.72 (14.12 to 21.17) 0.72 (0.51 to 1.03) .074 319 10.42 (6.16 to 14.49) 348 7.31 (2.85 to 11.57) 1.73 (0.90 to 3.35) .102
Chumsri et al

Luminal A 64 1.56 (0.00 to 4.55) 9 12.50 (0.00 to 32.66) 0.13 (0.01 to 2.01) .143 60 8.72 (0.07 to 16.62) 7 0.00 (0.00 to 0.00) NA NA
Luminal B 97 9.31 (3.33 to 14.93) 3 33.33 (0.00 to 70.05) 0.20 (0.03 to 1.60) .13 83 6.99 (0.75 to 12.83) NA NA NA NA

Abbreviations: HER, human epidermal growth factor receptor 2; HR+, hormone receptor–positive; HR2, hormone receptor–negative; NA, not applicable; RFS, relapse-free survival.

Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

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