rapid communications

Randomized Controlled Trial of Trastuzumab With

or Without Chemotherapy for HER2-Positive Early
Breast Cancer in Older Patients
Masataka Sawaki, MD, PhD1; Naruto Taira, MD, PhD2; Yukari Uemura, PhD3; Tsuyoshi Saito, MD, PhD4; Shinichi Baba, MD5;
Kokoro Kobayashi, MD6; Hiroaki Kawashima, MD, PhD7; Michiko Tsuneizumi, MD, PhD8; Noriko Sagawa, MD, PhD9;
Hiroko Bando, MD, PhD10; Masato Takahashi, MD, PhD11; Miki Yamaguchi, MD, PhD12; Tsutomu Takashima, MD, PhD13;
Takahiro Nakayama, MD, PhD14; Masahiro Kashiwaba, MD, PhD5; Toshiro Mizuno, MD, PhD15; Yutaka Yamamoto, MD, PhD16;
Hiroji Iwata, MD, PhD1; Takuya Kawahara, PhD17; Yasuo Ohashi, PhD18; and Hirofumi Mukai, MD, PhD19, for the RESPECT study group

PURPOSE Adjuvant trastuzumab monotherapy has not been compared with trastuzumab 1 chemotherapy. We
abstract

investigated the relative value of trastuzumab monotherapy for older patients with breast cancer.
METHODS This study was an open-label, randomized controlled study with a treatment selection design in which
a noninferiority criterion was predefined. Patients aged 70-80 years with surgically treated human epidermal
growth factor receptor 2–positive invasive breast cancer received trastuzumab monotherapy or trastuzumab 1
chemotherapy. The primary end point was disease-free survival (DFS) with assessment of prespecified hazard
ratio (HR), relapse-free survival (RFS), adverse events (AEs), health-related quality of life (HRQoL), and re-
stricted mean survival time (RMST).
ASSOCIATED
CONTENT
RESULTS The study involved 275 patients (mean age, 73.5 years) who were followed up for a mean of 4.1 years
Appendix
(range, 0.3-8.0 years). The percentages of patients by cancer stage were as follows: I (pT . 0.5 cm), 43.6%; IIA,
Data Supplement
41.7%; IIB, 13.5%; and IIIA, 1.1%. Three-year DFS was 89.5% with trastuzumab monotherapy versus
Protocol 93.8% with trastuzumab 1 chemotherapy (HR, 1.36; 95% CI, 0.72 to 2.58; P 5 .51). At 3 years, RMST differed
Author affiliations by 20.39 months between arms (95% CI, 21.71 to 0.93; P 5 .56). Three-year RFS was 92.4% with tras-
and support tuzumab monotherapy versus 95.3% with trastuzumab 1 chemotherapy (HR, 1.33; 95% CI, 0.63 to 2.79; P 5
information (if .53). Common AEs were anorexia (7.4% v 44.3%; P , .0001) and alopecia (2.2% v 71.7%; P , .0001), and
applicable) appear
grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% (P 5 .0003) for trastuzumab monotherapy
at the end of this
article.
versus trastuzumab 1 chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed
Accepted on July 22,
significant differences at 2 months (31% for trastuzumab monotherapy v 48% for trastuzumab 1 chemo-
2020 and published at therapy; P 5 .016) and at 1 year (19% v 38%; P 5 .009).
ascopubs.org/journal/
CONCLUSION The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the
jco on September 16,
2020: DOI https://doi.
observed loss of survival without chemotherapy was , 1 month at 3 years. Therefore, and in light of the lower
org/10.1200/JCO.20. toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy
00184 option for selected older patients.
All decisions
J Clin Oncol 16. © 2020 by American Society of Clinical Oncology
concerning the
planning,
implementation and
publication of this
INTRODUCTION induced toxicity,7-9 but it is not used in clinical practice,
study were made by
because its benefit has not been investigated.10 Be-
the executive Trastuzumab with chemotherapy is a standard adju-
committee of this cause even the Early Breast Cancer Trialists’ Collab-
vant systemic therapy for human epidermal growth
study. The corporate orative Group overview does not arrive at a clear
factor receptor 2 (HER2)–positive primary breast
and individual conclusion on the usability of chemotherapy in pa-
sponsors of this study cancer.1-4 Overexpression of HER2 is also associated
tients . 70 years of age, due to limited data,11 no
are listed on the with potentially more aggressive tumors5,6; conse-
standard treatment exists for these patients.
Comprehensive quently, trastuzumab is a key drug for the treatment of
Support Project for HER2-positive primary cancer. Trastuzumab mono- Women in Japan have the highest life expectancy in
Oncology Research
therapy used as an adjuvant treatment without che- the world, at 86.8 years.12 Breast cancer is the most
website (http://
www.csp.or.jp/cspor/ motherapy avoids toxicity, especially in older patients prevalent cancer in women; 95,257 women were di-
kyousan_e.html). who are at increased risk of severe chemotherapy- agnosed in 2016, of whom 26.3% were older than

1
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 Sawaki et al

CONTEXT
Key Objective
To compare trastuzumab with or without chemotherapy in older patients, we carried out a randomized, prospective adjuvant
trial comparing trastuzumab monotherapy with trastuzumab 1 chemotherapy for human epidermal growth factor
receptor 2–positive breast cancer, specifically in patients older than 70 years.
Knowledge Generated
The primary objective of noninferiority for trastuzumab monotherapy was not met. However, restricted mean survival time
revealed that the observed loss of survival without chemotherapy was , 1 month at 3 years, and health-related quality of
life (HRQoL) was better with lower rates of common adverse events.
Relevance
Trastuzumab 1 chemotherapy remains a standard of care. In patients . 70 years of age who need to avoid chemotherapy
because of contraindications or patient preference, especially patients aged . 75 years with performance status 1
disease and estrogen-receptor positivity, we found relatively small influences on chemotherapy effects. With lower toxicity
and better HRQoL profile, trastuzumab monotherapy can be a reasonable option for selected older patients with favorable
outcomes.

70 years. In the SEER program of the National Cancer was registered at the University Hospital Medical Information
Institute, 268,600 women were diagnosed with breast Network, Japan (protocol ID: UMIN000002349), on Sep-
cancer in 2019, of whom 44.1% were . 65 years old. Older tember 1, 2009, and with ClinicalTrials.gov (identifier:
adults suffer the majority of cancer diagnoses and deaths, NCT01104935) on November 6, 2009.
and also make up the majority of cancer survivors; however,
the evidence base for treating this population is sparse.
Trial Design and Oversight
ASCO has proposed developing recommendations to im-
prove the evidence base for treating older adults with This was an open-label, randomized, parallel group,
cancer in response to a critical need.13 comparative study with a treatment selection design in
which a determining criterion was defined in advance and
To address this, we designed a randomized controlled trial used to demonstrate clinical benefit between two groups in
to investigate the benefit of trastuzumab monotherapy terms of efficacy. Patients were randomly assigned in a 1:1
compared with trastuzumab in combination with chemo- ratio to receive either trastuzumab monotherapy or tras-
therapy on the efficacy, incidence of adverse events (AEs), tuzumab 1 chemotherapy. Randomization was performed
and quality of life in terms of the noninferiority criterion. at the data center after confirming patient eligibility with
assignment adjustment factors, as follows: age (70-75 v
PATIENTS AND METHODS 76-80 years), performance status (0 v 1), hormone receptor
Patients status (positive [$ 10%] v negative), pathologic nodal
status (positive v negative), and participating institution.
The trial protocol is provided in the Data Supplement. We
recruited patients aged 70-80 years with HER2-positive We hypothesized that (1) trastuzumab monotherapy is not
breast cancer who had undergone surgery with curative markedly inferior to trastuzumab 1 chemotherapy in terms
intent. Inclusion criteria comprised the following: invasive of disease-free survival (DFS), and (2) trastuzumab mon-
breast cancer histologically diagnosed as HER2 positive otherapy is superior in terms of safety and health-related
according to the ASCO and College of American Patholo- quality of life (HRQoL).
gists guidelines14; stage I (pathologic tumor size . 0.5 cm), Trastuzumab 1 chemotherapy treatment comprised a
IIA, IIB, or IIIA cancer; and left ventricular ejection fraction loading dose of trastuzumab at 8 mg/kg and a maintenance
(LVEF) $ 55%. Other eligibility criteria and exclusion cri- dose of 6 mg/kg every 3 weeks for 1 year. Chemotherapy
teria are listed in the Data Supplement. was selected from the following regimens prespecified in
This study was reviewed and approved by the appropriate the protocol, based on a joint decision by physician and
independent ethics committees and institutional review patient:
boards. This study conformed with the Declaration of 1. Paclitaxel 80 mg/m2 for 12 weeks.
Helsinki and the Ethical Guidelines for Clinical Research of 2. Docetaxel 75 mg/m2 for 4 cycles.
Japan’s Ministry of Health, Labor, and Welfare. Written in- 3. Doxorubicin 60 mg/m 2 and cyclophosphamide
formed consent was obtained from all patients. The protocol 600 mg/m2 for 4 cycles.

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 Trastuzumab Without Chemotherapy in HER2-Positive Older Patients

4. Epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 hazards model, not exceeding 1.69, would demonstrate the
for 4 cycles. marked noninferiority of trastuzumab monotherapy, mak-
5. Cyclophosphamide 75-100 mg orally, methotrexate ing this a possible treatment option.
40 mg/m2, and 5-fluorouracil 500-600 mg/m2 (CMF) In this study, RMST was calculated as a supplementary
intravenously for 6 cycles. analysis because blinded annual monitoring on September
6. Docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 1, 2015, showed that the number of events was far fewer
(TC) for 4 cycles. than expected, and the statistical power of the noninferiority
7. Docetaxel 60-75 mg/m2, carboplatin area under the test based on HR was not assured. The conventional
curve 5-6 mg/ml/min trastuzumab loading dose procedure for evaluating long-term treatment effects on
4 mg/kg, 2 mg/kg (TCbH) for 6 cycles. survival is the log-rank test and HR. However, if the number
Patients treated with trastuzumab monotherapy re- of events is too small in a noninferior study to give sufficient
ceived the same dose of trastuzumab. Details, including information regarding the two treatment arms, RMST can
dose modifications, are provided in the protocol (Data be an option to qualify survival benefit in a comparative
Supplement). oncology clinical study.17-19 All collected data were ana-
lyzed using SAS, version 9.4 (SAS Institute, Cary, NC).
End Points
Details of the end points, assessment, and the statistical
The primary end point was DFS, comparing treatment arms analysis are provided in the Data Supplement.
by hazard ratio (HR), and calculating restricted mean
survival time (RMST) for each arm as a supplementary
RESULTS
analysis. Secondary end points were overall survival (OS),
relapse-free survival (RFS), adverse events (AEs), HRQoL, Patients
and comprehensive geriatric assessment (CGA). The CONSORT diagram is shown in Figure 1. From October
Assessment 2009 through November 2014, a total of 275 patients aged
70-80 years with HER2-positive invasive breast cancer
The protocol required assessment of LVEF at registration, were enrolled from 99 institutions. Nine patients (3.3%)
every 3 months during trastuzumab administration, and were excluded, leaving 266 for full-set analysis (trastuzu-
every 6 months after completion of trastuzumab treatment. mab monotherapy [n 5 135] and trastuzumab 1 che-
The HRQoL of the study population was assessed using the motherapy [n 5 131]). Characteristics of the patients at
Functional Assessment of Cancer Therapy-general (FACT-G) baseline are listed in Table 1. The median age of patients
scale at baseline, 2 months, 1 year, and 3 years. FACT-G is was 73.5 years (range, 70-80 years) and the median follow-
a validated, brief yet sensitive, 28-item general cancer up time was 4.1 years (range, 0.3-8.0 years). Most patients
HRQoL measure.15 The analysis of HRQoL was FACT-G (43.6%) had stage I disease, 41.7% had stage IIA,
total score, and a $ 5-point change from baseline score 13.5% had IIB, and 1.1% had IIIA. Chemotherapy regi-
was considered meaningful.16 After completion of the mens were paclitaxel (35.1%), anthracycline (22.9%),
protocol treatment, clinical examinations were required CMF (19.8%), docetaxel (14.5%), or TC (3.1%). The rel-
at each hospital visit. ative dose intensity (RDI) values are shown in Appendix
Statistical Analysis Table A1 (online only). The RDI of trastuzumab was
84.4% with trastuzumab monotherapy and 81.8% with
The primary end point required 120 events in total, given
trastuzumab 1 chemotherapy. Concurrent infusion of
a power of 80% and a threshold HR of 1.69. Given that the
trastuzumab was allowed when combined with paclitaxel,
probability of 3 years’ DFS in the study population was
docetaxel, or CMF, as received by 93.5%, 94.7%, and
68%-72%, and assuming that the survival time follows an
46.2% of patients, respectively. Selective estrogen receptor
exponential distribution, a total of 260 patients registered
(ER) modulators were administered to 14.2% of patients
over 4 years and followed-up for 3 years was necessary to
and aromatase inhibitors were administered to 69.3%.
assess 120 events.
Partial mastectomy was performed in 80 patients (30.0%),
To evaluate the clinical position of each treatment, the of whom 9 received irradiation of the breast.
estimated HR was compared with a threshold HR of 1.69.
This threshold for “addition of chemotherapy is determined DFS, RFS, and OS
to be a definite advantage” was based on the results of The data cutoff date was October 31, 2017. The planned
a questionnaire in advance answered by physicians of this analysis showed that 3-year DFS was 89.5% (95% CI,
medical field (Data Supplement). The threshold was used 82.9 to 93.6) with trastuzumab monotherapy versus
to determine whether trastuzumab treatment was definitely 93.8% (95% CI, 87.9 to 96.8) with trastuzumab 1 che-
equivalent (not inferior) to trastuzumab 1 chemotherapy motherapy (HR, 1.36; 95% CI, 0.72 to 2.58; P 5 .51;
with regard to DFS. An upper limit of the 95% CI of the HR Fig 2). The cumulative total number of events in DFS was
for trastuzumab monotherapy relative to trastuzumab 1 18 with trastuzumab monotherapy and 15 with trastuzu-
chemotherapy, calculated by applying the proportional mab 1 chemotherapy. Details are listed in Appendix Table A2.

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 Sawaki et al

Assessed for eligibility

(N = 403)

Excluded (n = 128)
Declined to participate (n = 123)
Did not meet inclusion criteria (n = 5)

Patients randomly assigned

(n = 275)

Assigned to trastuzumab Assigned to trastuzumab

monotherapy + chemotherapy
(n = 137) (n = 138)

Excluded because of Excluded because of withdrawal (n = 6)

withdrawal Excluded because of difficulty of
(n = 2) attending the hospital (n = 1)

Included in intention-to-treat Included in intention-to-treat

analysis analysis
(n = 135) (n = 131)

FIG 1. CONSORT diagram for the RESPECT study. Patients were randomly assigned to receive adjuvant treatment
either with trastuzumab monotherapy or with trastuzumab 1 chemotherapy ( investigator’s selection from regimens
specified on the protocol: paclitaxel, docetaxel, doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2; epi-
rubicin 90 mg/m2 and cyclophosphamide 600 mg/m2; fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cy-
clophosphamide 500 mg/m2; cyclophosphamide 75-100 mg orally, methotrexate 40 mg/m2, and 5-fluorouracil
500-600 mg/m2; docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2; or docetaxel 60-75 mg/m2, carboplatin
area under the curve 5-6 mg/ml/min, trastuzumab loading dose 4 mg/kg, 2 mg/kg for 6 cycles).

Distant metastasis occurred in nine patients who re- Subgroup analysis of DFS is shown in Table 2. On the basis
ceived trastuzumab monotherapy and eight patients who of the Cox model prespecified subgroup analyses for
received trastuzumab 1 chemotherapy. The posterior background or prognostic factors conducted to estimate
probability that the HR was , 1.69 was estimated at HR with 95% CI, age . 75 years, performance status 1
74.5%. The difference in RMST for DFS between the study (PS1), and ER positivity had relatively small effects on the
arms at 3 years was 20.39 months (95% CI, 21.71 to 0.93; outcome of chemotherapy, which were not significant.
P 5 .56). The 3-year RFS was 92.4% (95% CI, 86.3 to
95.8; n 5 17 events with seven deaths) with trastuzumab Safety
monotherapy versus 95.3% (95% CI, 89.7 to 97.8; n 5 12 All patients who underwent the protocol treatment were
events with six deaths) with trastuzumab 1 chemotherapy included in the safety analysis. Common AEs are listed in
(HR, 1.33; 95% CI, 0.63 to 2.79; Fig 3). The difference in Table 3. Common AEs were neutropenia (9.6% with
RMST for RFS between arms at 3 years was 20.41 months trastuzumab monotherapy v 42.0% with trastuzumab 1
(95% CI, 21.51 to 0.68; P 5 .53). Three-year OS was chemotherapy; P , .0001), anorexia (7.4% v 44.3%; P ,
97.2% (95% CI, 91.2 to 99.1) with trastuzumab mono- .0001), and alopecia (2.2% v 71.7%; P , .0001). No grade
therapy versus 96.6% (95% CI, 89.5 to 98.9) with tras- 4 hematologic AEs occurred with trastuzumab mono-
tuzumab 1 chemotherapy (HR, 1.07; 95% CI, 0.36 to therapy but were reported with trastuzumab 1 chemo-
3.19; Fig 4). Distant DFS at 3 years was 93.1% with therapy (0% v 13.7%; P , .0001). Similarly, some grade 3
trastuzumab monotherapy versus 96.8% with trastuzumab 1 or 4 nonhematological AEs occurred with trastuzumab
chemotherapy (HR, 1.42; 95% CI, 0.64 to 3.17; P 5 .39; monotherapy but the rate more than doubled with trastu-
Appendix Fig A1, online only). Breast cancer–specific zumab 1 chemotherapy (11.9% v 29.8%; P 5 .0003). In
survival at 3 years was 99.2% with trastuzumab mono- patients who received the most-used regimen, paclitaxel 1
therapy versus 99.2% with trastuzumab 1 chemotherapy trastuzumab, neuropathy-sensory AEs of any grade occurred
(HR, 0.20; 95% CI, 0.02 to 1.67; P 5 .14; Appendix in 65.2% of patients. No patients discontinued trastuzumab
Fig A2). treatment because of toxicity. All serious AEs resolved.

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 Trastuzumab Without Chemotherapy in HER2-Positive Older Patients

TABLE 1. Baseline Characteristics of the Full Analysis Set (N 5 266) All patients recovered after appropriate medication con-
Trastuzumab taining a diuretic agent. Hypertension of grade 3/4 oc-
Monotherapy Trastuzumab 1 Chemotherapy curred in five patients (3.7%) who received trastuzumab
Characteristic (n 5 135) (n 5 131) P
monotherapy and nine patients (6.9%) who received
Mean age, years (SD) 73.9 (2.8) 73.9 (3.0) .79 trastuzumab 1 chemotherapy (P 5 .043). No congestive
Performance status .76 heart failure (CHF) occurred in either group.
0 126 (93.3) 121 (92.4) HRQoL
1 9 (6.7) 10 (7.6)
Among study patients, 116 who received trastuzumab
Pathologic tumor size .57 monotherapy and 115 who received trastuzumab 1 che-
T1b 10 (7.4) 11 (8.4) motherapy who achieved the baseline response were an-
T1c 55 (40.7) 54 (41.2) alyzed. We detected a significant difference between
T2 64 (47.4) 64 (48.9) treatment groups in clinically meaningful HRQoL de-
terioration rate using the FACT-G at 2 months (31% for
T3 6 (4.4) 2 (1.5)
trastuzumab monotherapy v 48% for trastuzumab 1
Lymph node metastasis .39 chemotherapy; P 5 .016), and at 1 year (19% v 38%; P 5
Negative 111 (82.2) 103 (78.6) .009), and in clinically meaningful HRQoL improvement
Positive 23 (17.0) 24 (18.4) rate at 2 months (38% for trastuzumab monotherapy v
Unknown 1 (0.7) 4 (3.1) 15% for trastuzumab 1 chemotherapy; P , .01), and at
1 year (43% v 25%; P 5 .021). There was no significant
Stage .8
difference between the two arms at 3 years.
I 58 (43.0) 58 (44.3)
IIA 56 (41.5) 55 (42.0) DISCUSSION
IIB 20 (14.8) 16 (12.2)
To our knowledge, this is the first randomized prospective
IIIA 1 (0.7) 2 (1.5) adjuvant trial to compare trastuzumab monotherapy with
Surgery .2 trastuzumab 1 chemotherapy for HER2-positive breast
Mastectomy 97 (71.9) 87 (66.4) cancer. The primary end point was not met on HR, although
Partial mastectomy 36 (26.7) 44 (33.6) prespecified analysis was performed supplementary to in-
vestigation of RMST. To our knowledge, it is also the first
Others 2 (1.5) 0 (0.0)
study to specifically enroll patients older than 70 years. DFS
Hormone receptor status .55 at 3 years was 93.8% in the trastuzumab 1 chemotherapy
ER1 and/or PgR1 62 (45.9) 65 (49.6) group but 89.5% with less toxicity and a better HRQoL profile
ER2 and PgR2 73 (54.1) 66 (50.4) in the trastuzumab monotherapy group.
Major comorbidity Trastuzumab without chemotherapy has not been
Hypertension .83 assessed in the adjuvant setting, as far as we are aware. In
Absent 76 (56.3) 72 (55.0) the metastatic setting, trastuzumab monotherapy has ef-
ficacy with low toxicity,20,21 although combination chemo-
Present 59 (43.7) 59 (45.0)
therapy with trastuzumab is generally preferred.22 In the
Diabetes .52 neoadjuvant setting, trastuzumab 1 pertuzumab without
Absent 119 (88.1) 112 (85.5) chemotherapy was tested, but chemotherapy was ad-
Present 16 (11.9) 19 (14.5) ministered after surgery.23
Osteoporosis .13 With regard to trastuzumab AEs, cardiac dysfunction and
Absent 117 (86.7) 121 (92.4) CHF have been reported.24-26 A long-term assessment
Present 18 (13.3) 10 (7.6) found that the incidence of decreased LVEF was 3.6%,
whereas that of severe CHF was 0.8%.27 The cardiac event
Hyperlipidemia .67
rate was highest in patients who received anthracycline
Absent 101 (74.8) 95 (72.5)
(1.9%-3.8%)28 and lowest in patients who received a TCbH
Present 34 (25.2) 36 (27.5) regimen (0.4%).4 Independent predictors of cardiac events
were age . 50 years and a low LVEF.29 Among older
NOTE. Data presented as No. (%).
Abbreviations: ER, estrogen receptor; PgR, progesterone receptor; SD, standard
patients, a systematic review indicated that cardiac events
deviation. occurred in 5% of patients.30 A large observational study
indicated that the risk of cardiac function toxicity was 5.7%31
LVEF decreases occurred in 11 patients (8.1%) in the and that this risk was associated with age,31,32 although
trastuzumab monotherapy group and in nine patients it remained manageable31 and the risks associated with
(6.8%) in the trastuzumab 1 chemotherapy group (P 5 .647). trastuzumab were outweighed by the benefits.30,31 In our

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 Sawaki et al

1.0

FIG 2. Kaplan-Meier estimates

0.8 of disease-free survival (DFS).

DFS (probability)
DFS at 3 years was 89.5%
0.6 (95% CI, 82.9 to 93.6) in the
trastuzumab monotherapy
0.4 group versus 93.8% (95% CI,
87.9 to 96.8) in the trastuzu-
Trastuzumab + chemotherapy mab 1 chemotherapy group
0.2
Trastuzumab monotherapy (HR, 1.36; 95% CI, 0.72 to
2.58; P 5 .51). The difference
in restricted mean survival time
0 1 2 3 4 5 6 7
for DFS between the study
Time Since Random Assignment (years) arms at 3 years was 20.39
No. at risk:
months (95% CI, 21.71 to
Trastuzumab + chemotherapy 131 126 121 112 64 38 19 6
Trastuzumab monotherapy 135 132 125 112 71 40 17 9
0.93; P 5 .56). Tick marks
indicate censored data.

trial, cardiac events occurred in 7.5% of patients, but they do differ in terms of willingness to trade survival for
because this was a prospective study, LVEF was routinely current QoL.35 Consequently, HRQoL deterioration, even if
evaluated and, as a result, decreases in LVEF were de- temporary, is important when deciding whether to receive
tected, and no CHF occurred. Our results thus provide chemotherapy. In our trial, the upper threshold of HR of
safety data on trastuzumab with or without chemotherapy 1.69, an inferior margin defined in advance, was set based
for older patients. on a questionnaire among physicians, because older pa-
tients may not accept a small absolute benefit if treatment
In older patients, HRQoL is important in addition to the
carries a high risk of AEs, loss of independence, and
incidence of AEs, because chemotherapy causes signifi-
cognitive impairment.
cant deterioration of HRQoL.33 The European Society for
Medical Oncology proposed a Clinical Benefit Scale in- For a more definitive answer to anti-HER2 therapy without
corporating toxicity and HRQoL as outcomes of living better chemotherapy, biomarkers will be important in selecting
with adjuvant therapy,34 although there is no definitive a suitable population to optimize benefit. Meanwhile, we
consensus on how to assess and interpret risks and ben- await the results from other studies of de-escalation. In the
efits. The findings of our study on short-term toxicity and the ATEMPT trial comparing paclitaxel 1 trastuzumab with
impact on HRQoL are useful for treatment selection in older trastuzumab emtansine (T-DM1), the latter was associated
patients. Older adults do not differ from their younger with a low rate of recurrence, although it did not meet the
counterparts regarding chemotherapy acceptance, but preplanned relative reduction in toxicity.36 The ATOP trial

1.0
FIG 3. Kaplan-Meier estimates
of relapse-free survival (RFS).
0.8 RFS at 3 years was 92.4%
RFS (probability)

(95% CI, 86.3 to 95.8, 17

0.6 events with seven deaths) in
the trastuzumab monotherapy
0.4 group versus 95.3% (95% CI,
89.7 to 97.8, 12 events with six
0.2 Trastuzumab + chemotherapy deaths) in the trastuzumab 1
Trastuzumab monotherapy chemotherapy group (HR 5
1.33; 95% CI, 0.63 to 2.79). The
difference in restricted mean
0 1 2 3 4 5 6 7
survival time for RFS between
Time Since Random Assignment (years) the study arms at 3 years was
No. at risk:
-0.41 months (95% CI, -1.51 to
Trastuzumab + chemotherapy 131 126 121 112 64 38 19 6
Trastuzumab monotherapy 135 132 125 112 71 40 18 9 0.68; P 5 0.53). Tick marks
indicate censored data.

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 Trastuzumab Without Chemotherapy in HER2-Positive Older Patients

1.0

0.8

OS (probability)
0.6 FIG 4. Kaplan-Meier estimates
of overall survival (OS). OS at
0.4 3 years was 97.2% (95% CI,
91.2 to 99.1) in the trastuzu-
0.2 Trastuzumab + chemotherapy mab monotherapy group ver-
Trastuzumab monotherapy sus 96.6% (95% CI, 89.53 to
98.9) in the trastuzumab 1
0 1 2 3 4 5 6 7
chemotherapy group (HR, 1.07;
95% CI, 0.36 to 3.19). Tick
Time Since Random Assignment (years)
marks indicate censored data.
No. at risk:
Trastuzumab + chemotherapy 131 129 127 118 71 43 20 6
Trastuzumab monotherapy 135 135 133 120 76 45 23 9

(ClinicalTrials.gov identifier: NCT03587740) is a single-arm the timing of DFS events and patterns, providing prognostic
study of T-DM1 in patients . 60 years of age. Short du- information.38
ration of trastuzumab combined with chemotherapy was
Limitations of this study include, first, that although 266
associated with worse outcome despite a favorable car- patients were treated according to the protocol, the primary
diotoxicity.37 In our subgroup analysis, we found age . 75 end point was not met on HR, because of the low numbers
years, PS1, and ER positivity had relatively small influ- of events consequent to an underpowered analysis. As
ences on the effects of chemotherapy. There might be a result, no definitive conclusions regarding trastuzumab
a difference in the impact of chemotherapy between pure- without chemotherapy in this setting can be made. The
HER2 and luminal-HER2 type,23 and ER positivity affected prognosis of patients in both arms was better than expected

TABLE 2. Subgroup Analysis of Disease-Free Survival

95% CI
Hazard
Subgroup Treatment No. of Patients No. of Events (%) Ratio Upper Lower P
Age group, years
70-75 Trastuzumab monotherapy 96 14 (14.6) 1.85 0.75 4.58 .31
Trastuzumab 1 chemotherapy 89 7 (7.9)
76-80 Trastuzumab monotherapy 39 9 (23.1) 1.04 0.41 2.61 .94
Trastuzumab 1 chemotherapy 42 9 (21.4)
Performance status
0 Trastuzumab monotherapy 126 22 (17.5) 1.62 0.81 3.21 .17
Trastuzumab 1 chemotherapy 121 13 (10.7)
1 Trastuzumab monotherapy 9 1 (11.1) 0.32 0.03 3.09 .32
Trastuzumab 1 chemotherapy 10 3 (30.0)
Lymph node metastasis
Negative Trastuzumab monotherapy 106 18 (17.0) 1.62 0.75 3.52 .22
Trastuzumab 1 chemotherapy 97 10 (10.3)
Positive Trastuzumab monotherapy 29 5 (17.2) 0.91 0.28 2.99 .87
Trastuzumab 1 chemotherapy 34 6 (17.6)
Hormone receptor
Positive Trastuzumab monotherapy 62 9 (14.5) 1.19 0.44 3.19 .74
Trastuzumab 1 chemotherapy 65 7 (10.8)
Negative Trastuzumab monotherapy 73 14 (19.2) 1.48 0.64 3.43 .36
Trastuzumab 1 chemotherapy 66 9 (13.6)

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 Sawaki et al

TABLE 3. Common Adverse Events in All Patients (N 5 266)

Trastuzumab Monotherapy Trastuzumab 1 Chemotherapy
AE Grade AE Grade
(n 5 135) (n 5 131)

1 2 3 4 3 or 4 1 2 3 4 3 or 4

Adverse Event No. of Patients % No. of Patients % P

Hematologic
Neutrophils 6 7 0 0 0.0 7 25 9 14 17.6 , .0001
Leukocytes 15 10 0 0 0.0 21 29 12 8 15.3 , .0001
Platelets 20 0 0 0 0.0 30 1 0 1 0.8 .026
Hemoglobin 37 7 0 0 0.0 46 25 8 3 8.4 , .0001
Nonhematologic
Left ventricular systolic dysfunction: LVEF 8 3 0 0 0.0 7 2 0 0 0.0 .647
Hypertension 9 19 5 0 3.7 10 27 9 0 6.9 .043
Diarrhea 4 0 1 0 0.7 17 3 1 0 0.8 .004
Fatigue 18 7 0 1 0.7 43 19 8 1 6.9 , .0001
Anorexia 8 2 0 0 0.0 33 17 8 0 6.1 , .0001
Alopecia 3 0 NA NA NA 35 59 NA NA NA , .0001
Oral cavity mucositis (clinical examination) 6 1 0 0 0.0 29 9 1 0 0.8 , .0001
Taste alteration (dysgeusia) 5 0 NA NA NA 39 8 NA NA NA , .0001
Vomiting 0 1 0 0 0.0 9 4 0 0 0.0 .0037
Nausea 9 1 0 0 0.0 26 7 4 0 3.1 , .0001
Edema: limb 10 1 0 0 0.0 18 4 0 0 0.0 .026
Neuropathy: motor 1 1 2 0 1.5 2 2 1 0 0.8 .966
Neuropathy: sensory 8 1 0 0 0 30 12 4 0 3.1 , .0001

Abbreviations: AE, adverse event; LVEF, left ventricular ejection fraction, NA, not applicable.

because . 80% of patients enrolled had stage I or stage IIA deemed suitable may be offered standard treatment. To
disease. In view of patients’ baseline risk, it is not always distinguish between fit or vulnerable older persons, CGA
possible to apply results to all HER2-positive older patients. may be useful.41 In this study, we selected as many patients
It was assumed that enlarging the sample size to increase as possible who could be treated at least with trastuzumab
the number of events would have rendered the study as monotherapy, with optional chemotherapy regimens at
unfeasible because of the relatively smaller proportion of the physician’s discretion. We did not exclude less-fit older
HER2-positive older patients and their heterogeneity.39 We patients but included both fit and vulnerable patients. After
could have extended the follow-up period to detect more analyzing CGA data, we hope to create predictive tools for
events, but it was assumed that non–breast cancer deaths, AEs or prognosis. In the field of geriatric oncology, the
as well as recurrences, would accumulate in both arms over inclusion of functional end points is needed, which can aid
the 8 years that had passed since the first patient was in shared decision-making by physicians and patients.42 In
enrolled. However, a longer follow-up period is needed older patients considered fit for chemotherapy, standard
to shed light on patient prognosis. Second, patients aged treatment can be offered, but such decisions could be
70-80 years still had only a modest number of comorbidities, individualized by weighing competing risks.
with LVEF $ 55%; in other words, they were healthy pa- In conclusion, the primary objective of noninferiority for
tients with good performance. In fact, the majority of these trastuzumab monotherapy was not met. However, the
patients received . 80% of the RDI. These healthy patients observed loss of survival without chemotherapy was , 1
were able to tolerate standard chemotherapy with trastu- month at 3 years. Therefore, and in light of the lower
zumab, which results in the best prognosis, as supported by toxicity and more favorable HRQoL profile, trastuzumab
the results of the APT trial.40 Chronological age by itself is monotherapy can be considered an adjuvant therapy op-
not a stand-alone biomarker; thus, fit older patients who are tion for selected older patients.

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 Trastuzumab Without Chemotherapy in HER2-Positive Older Patients

AFFILIATIONS SUPPORT
1
Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Funded by the Comprehensive Support Project for Oncology Research of
Japan the Public Health Research Foundation, Japan (M.S.).
2
Department of Breast and Endocrine Surgery, Okayama University
Hospital, Okayama, Japan
3
CLINICAL TRIAL INFORMATION
Biostatistics Section, Department of Data Science, Center for Clinical
NCT01104935
Sciences, National Center for Global Health and Medicine, Tokyo, Japan
4
Department of Surgery, Japanese Red Cross Saitama Hospital, Saitama,
Japan DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND
5
Department of Surgery, Sagara Hospital, Kagoshima, Japan DATA AVAILABILITY STATEMENT
6
Department of Medical Oncology, the Cancer Institute Hospital of the Disclosures provided by the authors and data availability statement (if
Japanese Foundation for Cancer Research, Tokyo, Japan applicable) are available with this article at DOI https://doi.org/10.1200/
7
Department of Surgery, Aomori City Hospital, Aomori, Japan JCO.20.00184.
8
Department of Breast Surgery, Shizuoka General Hospital, Shizuoka,
Japan
9
Department of Breast Surgery, Kameda Medical Center, Kamogawa,
AUTHOR CONTRIBUTIONS
Japan Conception and design: Masataka Sawaki, Naruto Taira, Hiroko Bando,
10
Department of Breast and Endocrine Surgery, Faculty of Medicine, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Yutaka
University of Tsukuba, Tsukuba, Japan Yamamoto, Hiroji Iwata, Yasuo Ohashi
11
Department of Breast Surgery, National Hospital Organization Administrative support: Naruto Taira, Hirofumi Mukai
Hokkaido Cancer Center, Sapporo, Japan Provision of study material or patients: Masataka Sawaki, Naruto Taira,
12
Department of Breast Surgery, JCHO Kurume General Hospital, Shinichi Baba, Masato Takahashi, Miki Yamaguchi, Yutaka Yamamoto,
Kurume, Japan Yasuo Ohashi, Hirofumi Mukai
13
Department of Breast and Endocrine Surgery, Osaka City University Collection and assembly of data: Masataka Sawaki, Naruto Taira, Tsuyoshi
Graduate School of Medicine, Osaka, Japan Saito, Shinichi Baba, Kokoro Kobayashi, Hiroaki Kawashima, Noriko
14
Department of Breast and Endocrine Surgery, Osaka International Sagawa, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima,
Cancer Institute, Osaka Japan Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka
15
Department of Medical Oncology, Mie University Hospital, Tsu, Japan Yamamoto, Hiroji Iwata, Hirofumi Mukai
16
Department of Breast and Endocrine Surgery, Graduate School of Data analysis and interpretation: Masataka Sawaki, Yukari Uemura,
Medical Sciences, Kumamoto University, Kumamoto, Japan Shinichi Baba, Michiko Tsuneizumi, Hiroko Bando, Masato Takahashi,
17
Biostatistics Division, Clinical Research Support Center, The University Takahiro Nakayama, Yutaka Yamamoto, Hiroji Iwata, Takuya Kawahara,
of Tokyo Hospital, Tokyo, Japan Yasuo Ohashi, Hirofumi Mukai
18
Department of Integrated Science and Engineering for Sustainable Manuscript writing: All authors
Society, Chuo University, Tokyo, Japan Final approval of manuscript: All authors
19
Department of Breast and Medical Oncology, National Cancer Center Accountable for all aspects of the work: All authors
Hospital East, Kashiwa, Japan
ACKNOWLEDGMENT
CORRESPONDING AUTHOR We thank the patients who participated in this trial and their families and
Masataka Sawaki, MD, PhD, Department of Breast Oncology, Aichi caregivers, and all investigators involved in this study and all members of
Cancer Center Hospital. 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, the independent data monitoring committee for their contributions to
Japan; e-mail: [email protected]. the study.

PRIOR PRESENTATION
Presented in part at the ASCO Annual Meeting, Chicago, IL, June 1-
5, 2018.

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n n n

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 Trastuzumab Without Chemotherapy in HER2-Positive Older Patients

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients
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 5 Immediate Family Member, Inst 5 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/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Yukari Uemura Toshiro Mizuno

Honoraria: Chugai Pharma, Teijin Pharma Honoraria: Chugai Pharma, Nippon Kayaku, Daiichi Sankyo, Ono
Consulting or Advisory Role: Pfizer (I), Ono Pharmaceutical (I), Zeria Pharmaceutical, AstraZeneca, Pfizer, Eli Lilly Japan, Kyowa Hakko Kirin,
Pharmaceutical (I), Daiichi Sankyo (I) Genomic Health
Speakers’ Bureau: Pfizer
Yutaka Yamamoto
Travel, Accommodations, Expenses: Pfizer, Chugai Pharma
Honoraria: Chugai, AstraZeneca, Novartis, Kyowa Hakko Kirin, Eisai, Eli Lilly
Hiroko Bando Japan, Pfizer, Takeda, Nippon Kayaku
Honoraria: Chugai Pharmaceutical, Kyowa Hakko Kirin, Eisai, AstraZeneca, Consulting or Advisory Role: AstraZeneca, Novartis, Chugai Pharma, Eli Lilly,
Novartis Pharma, Eli Lilly Japan, Nippon Kayaku, Pfizer Japan Pfizer, Daiichi Sankyo, Nippon Kayaku
Research Funding: Eli Lilly, MSD Oncology, Daiichi Sankyo, Chugai Pharma,
Masato Takahashi
Nippon Kayaku, Taiho Pharmaceutical, Maruho
Honoraria: AstraZeneca, Eisai, Pfizer, Eli Lilly, Chugai, Nippon Kayaku
Research Funding: Taiho Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst), Eisai Hiroji Iwata
(Inst), Nippon Kayaku (Inst) Honoraria: Chugai Pharma, AstraZeneca, Eisai, Pfizer, Daiichi Sankyo, Eli Lilly
Japan, Novartis, Kyowa Hakko Kirin
Recipient: Your Institution
Consulting or Advisory Role: Chugai Pharma, Daiichi Sankyo, Pfizer,
Miki Yamaguchi AstraZeneca, Eli Lilly Japan, Kyowa Hakko Kirin, Novartis
Speakers’ Bureau: Chugai Pharma, Pfizer Research Funding: MSD (Inst), AstraZeneca (Inst), Eisai (Inst), Kyowa Hakko
Kirin (Inst), GlaxoSmithKline (Inst), Daiichi Sankyo (Inst), Chugai Pharma (Inst),
Tsutomu Takashima
Nihonkayaku (Inst), Eli Lilly Japan (Inst), Novartis (Inst), Bayer (Inst), Pfizer (Inst)
Honoraria: Eisai, Taiho Pharmaceutical, Chugai Pharmaceutical, Kyowa Hakko
Kirin, Pfizer Japan, Novartis Pharma, AstraZeneca, Daiichi Sankyo Yasuo Ohashi
Leadership: Statcom
Takahiro Nakayama
Stock and Other Ownership Interests: Statcom
Honoraria: Chugai Pharma, Novartis, Eli Lilly, AstraZeneca, Takeda, Taiho
Honoraria: Chugai Pharma, Daiichi Sankyo, Sanofi, Eisai, Shionogi
Pharmaceutical, Pfizer
Research Funding: Medical Member System
Masahiro Kashiwaba
Hirofumi Mukai
Speakers’ Bureau: Chugai Pharma, Kyowa Hakko Kirin, Novartis, Pfizer,
Honoraria: Pfizer, Daiichi Sankyo, Taiho Pharmaceutical, Takeda
AstraZeneca, Eisai, Asahi Kasei, Daiichi Sankyo, Taiho Pharmaceutical,
Research Funding: Daiichi Sankyo (Inst)
Shionogi, Eli Lilly Japan
No other potential conflicts of interest were reported.

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Copyright © 2020 American Society of Clinical Oncology. All rights reserved.
 Sawaki et al

APPENDIX

1.0

0.8

DDFS (probability)
0.6

0.4

0.2 Trastuzumab + chemotherapy

Trastuzumab monotherapy

0 1 2 3 4 5 6 7
Time Since Random Assignment (years)
No. at risk:
Trastuzumab + chemotherapy 131 126 121 112 64 38 19 6
Trastuzumab monotherapy 135 132 125 112 71 40 17 9

FIG A1. Kaplan-Meier estimates of distant disease–free survival (DDFS). DDFS at 3 years was 93.1% in the
trastuzumab monotherapy group versus 96.8% in the trastuzumab 1 chemotherapy group (HR, 1.42; 95% CI,
0.64 to 3.17; P 5 .39). Tick marks indicate censored data.

1.0

0.8
BCSS (probability)

0.6

0.4

0.2 Trastuzumab + chemotherapy

Trastuzumab monotherapy

0 1 2 3 4 5 6 7
Time Since Random Assignment (years)
No. at risk:
Trastuzumab + chemotherapy 131 129 127 118 71 43 20 6
Trastuzumab monotherapy 135 135 133 120 76 45 23 9

FIG A2. Kaplan-Meier estimates of breast cancer–specific survival (BCSS). BCSS at 3 years was 99.2% in the
trastuzumab monotherapy group versus 99.2% in the trastuzumab 1 chemotherapy group (HR, 0.20;
95% CI, 0.02 to 1.67; P 5 .14). Tick marks indicate censored data.

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 Trastuzumab Without Chemotherapy in HER2-Positive Older Patients

TABLE A1. Chemotherapy Regimen Received and Relative Dose

Intensity in the Trastuzumab Plus Chemotherapy Group (n 5 131)
Chemotherapy No. (%) Relative Dose
Regimen (n 5 131) Intensity (%)
Paclitaxel 46 (35.1) 79
Docetaxel 19 (14.5) 87
AC/EC 28 (21.4) 84/97
FEC75 2 (1.5) 62
TC 4 (3.1) 78
CMF 26 (19.8) 84
TCbH 0 —
Unknown 6 (4.6)

Abbreviations: —, Regimens specified on the protocol, Initial dose;

AC, doxorubicin 60 mg/m2 1 cyclophosphamide 600 mg/m2; CMF,
cyclophosphamide 75-100 mg orally, methotrexate 40 mg/m2, and
fluorouracil 500-600 mg/m 2 ; EC, epirubicin 90 mg/m 2 1
cyclophosphamide 600 mg/m2; FEC75, fluorouracil 500 mg/m2,
epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2; TC,
docetaxel 75 mg/m 2 1 cyclophosphamide 600 mg/m 2 ; TCbH,
docetaxel 60-75 mg/m2, carboplatin area under the curve 5-6 mg/ml/min,
trastuzumab loading dose 4 mg/kg, 2 mg/kg for 6 cycles.

TABLE A2. Events in Disease-Free Survival

Trastuzumab, Trastuzumab 1 Chemotherapy,
No. of Events No. of Events
Variable (n 5 135) (n 5 131)
Recurrence 18 15
Ipsilateral breast 1 1
Regional lymph node 4 3
Distant 9 8
Second malignancy 9 4
Death 7 6
Breast cancer specific 1 5
Others 6 1

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