Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: a propensity score-adjusted analysis of a prospective cohort study

Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: a propensity score-adjusted analysis of a prospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: a propensity score-adjusted analysis of a prospective cohort study Masataka Sawaki, Naruto Taira, Yukari Uemura, Tsuyoshi Saito, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1112686/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Dec, 2022 Read the published version in The Breast → Version 1 posted You are reading this latest preprint version Abstract Purpose To gauge the effects of treatment practices on prognosis for all older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This report accompanies the RESPECT study, a randomized-controlled trial (RCT) comparing trastuzumab monotherapy with trastuzumab-plus-chemotherapy. Patients and methods Patients who declined the RCT were treated based on the physician’s discretion. We studied the (1) trastuzumab-plus-chemotherapy group, (2) trastuzumab-monotherapy group, and (3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were also assessed. Results We enrolled 123 eligible patients, aged over 70 years, with HER2-positive invasive breast cancer in this cohort study. The median age was 74.5 years. Among cohort study treatment categories were as follows: (1) trastuzumab-plus-chemotherapy group (n = 36, 30%), (2) trastuzumab-monotherapy group (n = 52, 43%), and (3) non-trastuzumab group (n = 32, 27%). A total of 73% of patients received trastuzumab-containing regimens, with or without chemotherapy. The 3-year DFS was 92.3% in the trastuzumab-plus-chemotherapy group, 89.2% in the trastuzumab-monotherapy group, and 82.5% in the non-trastuzumab group. DFS in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR: 3.29; 95% CI: 1.15–9.39; P = 0.026). The RFS in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P < 0.0001). There were no significant intergroup differences in the proportions of patients showing QoL deterioration ( P = 0.717) and improvement ( P = 0.652) at 36 months. Conclusions Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Thus, trastuzumab monotherapy can be considered for patients who reject chemotherapy. Trial registration number The protocol was registered on the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN 000028476). Breast cancer older HER2 trastuzumab without chemotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction This study accompanied the RESPECT study [ 1 ], which is a randomized controlled trial (RCT) designed to compare the value of trastuzumab monotherapy with the standard combination treatment with the value of chemotherapy in patients over 70 years, with human epidermal growth factor receptor type 2 (HER2)-positive invasive breast cancer, who received curative surgery. This study aimed to determine the overall prognosis of older patients with HER2-positive breast cancer who did not agree to participate in the RCT despite meeting the eligibility criteria. Particularly, we aimed to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. Before starting this RCT, we questioned whether acquiring consent to participate in this RCT might be difficult in older patients, because of the possibility of emphasizing treatment in accordance with the patient’s wishes, considering the potential adverse events (AEs) of chemotherapy. It is currently unknown whether adjuvant trastuzumab therapy alone can offer a benefit over no adjuvant therapy. Although we sought to directly compare trastuzumab monotherapy with no treatment in older patients, we were concerned that such a study would not be feasible because some patients might refuse to participate in an arm without trastuzumab, despite having HER2-positive disease. In addition, only healthy patients can participate in the RCT. Thus, we designed a non-interventional cohort study to gauge the effects of treatment practices on prognosis for all older patients with HER2-positive breast cancer. Patients The trial protocol is described within the full text of this article. We recruited patients, aged 70–80 years old, with HER2-positive invasive breast cancer who underwent curative surgery. The patient-inclusion criteria were as follows: patients with invasive breast cancer histologically diagnosed as HER2-positive breast cancer, who underwent curative surgery for stage I (pathological tumor size > 0.5 cm), IIA, IIB, or IIIA disease. HER2-positivity was defined by the ASCO/CAP guidelines [2], which lay down the following criteria: immunohistochemical staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells) and a fluorescence- in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signal: chromosome 17 signal) of more than 2.2. Other key eligibility criteria were as follows: a baseline left ventricular-ejection fraction of ≥55% (measured by echocardiography) within 4 weeks of registration, an Eastern Cooperative Oncology Group performance status (PS) score of 0 or 1, and sufficient organ function that meets the prescribed criteria in laboratory tests performed within four weeks of registration. The key exclusion criteria were as follows: the presence of active multiple primary cancer (synchronous multiple primary cancer and invasive cancer of other organs); ≥4 histological axillary lymph node metastases; no histological evaluation of axillary lymph nodes; a histologically confirmed positive margin found during breast-conservation surgery; a history of drug-related allergy that could hinder planned treatment; any history of or complication following cardiac disorders; a history of congestive heart failure; cardiac infarction; complications requiring treatment, such as ischemic cardiac disorder, arrhythmia, valvular-heart disease, poorly-controlled hypertension, and poorly controlled diabetes; difficulty in regularly attending a medical institution due to a deterioration in the ability to perform the activities of daily living; difficulty participating in the trial because of a psychiatric disorder or psychiatric symptoms; or ineligibility for enrollment according to the decision of an investigator based on contacts and locations. Trial design and oversight Patients who were eligible for but declined participation in the RESPECT trial [1] were recruited to this cohort study. Written informed consent was obtained for each participant. Patients who consented to participate in the RCT were randomly assigned at a 1:1 ratio to the trastuzumab monotherapy group or trastuzumab-plus-chemotherapy group [1]. In this cohort study, treatment was chosen based on the discretion of the treating physician and the patients’ wishes without intervention, and patients were prospectively reviewed based on routine medical records. The cohort study included three categories: 1) the trastuzumab-plus-chemotherapy group, 2) the trastuzumab-monotherapy group, and 3) a group that received no therapy at all or received any anticancer therapy without trastuzumab (the non-trastuzumab group). The purpose of this prospective cohort study was to assess the overall effect of adjuvant therapy on HER2-positive primary breast cancer in older patients (≥ 70 years) and to investigate the efficacy and safety of trastuzumab-plus-chemotherapy, trastuzumab monotherapy, and non-trastuzumab treatment. This study was reviewed and approved by independent ethics committees and institutional review boards. The study conformed with the Declaration of Helsinki and the “Ethical Guidelines for Clinical Research” guidelines of the Ministry of Health, Labor and Welfare. Written informed consent was obtained from all patients. End points The primary endpoint of the cohort study was disease-free survival (DFS), and the secondary endpoints were overall survival (OS), relapse-free survival (RFS), AEs, and health-related quality of life (HRQoL). DFS was defined by the occurrence of any of the following: a diagnosis of recurrence after breast-conservation therapy, local (ipsilateral chest wall) recurrence, regional lymph node recurrence or distant organ metastasis; a diagnosis of metachronous breast cancer or secondary cancer (not including cutaneous basal cell carcinoma, squamous cell cancer, or endometrial intraepithelial carcinoma); and all deaths (regardless of cause). RFS was defined by the occurrence of any of the following: any local recurrence (including local recurrence after breast-conservation therapy), regional lymph node recurrence or distant organ metastasis (not including metachronous breast cancer or secondary cancer), and death (regardless of cause). HRQoL was assessed using the Functional Assessment of Cancer Therapy-general (FACT-G) scale [3]. Assessment In the cohort study, medical records were reviewed by attending physicians to detect DFS, OS, RFS, AEs, and HRQoL events without interventions, such as prospective treatment and testing. The attending physician periodically checked the vital status of the patient. Types and grades of AEs were determined according to Common Terminology Criteria for Adverse Events v3.0. If a recurrence was observed, the date of recurrence, the type of recurrence, and the information on which the judgement was investigated. In the case of death, the date of death and the reason was investigated. The survival data and AEs were reviewed every year, beginning from the time of first enrollment to the end of the study. HRQoL of all participants in this cohort study was assessed at registration, and after 36 months. Statistical analysis The DFS was set as the primary endpoint. The DFS and other endpoints among trastuzumab-plus-chemotherapy, trastuzumab-monotherapy, and non-trastuzumab groups were compared using propensity score-based covariate adjustments by the Cox regression model. The propensity score was estimated for each participant using a multinomial regression model, based on the age (70–75 versus 76–80 years), hormone receptor status (positive versus negative), pathologic nodal status (positive versus negative), and PS (0 or 1) in the model. Group comparisons of FACT-G total and subdomain scores were performed using an Analysis of Co-Variance (ANCOVA). This model used scores at 36 months as an outcome, and the adjusted covariates were scored at baseline in addition to the same factors in the survival analysis (i.e., age, hormone receptor status, pathologic nodal status, and PS). The estimated score difference at 36 months from trastuzumab-plus-chemotherapy (as a reference) in the trastuzumab-monotherapy group and the non-trastuzumab group, 95% confidence interval (CI), and p -value were calculated. In addition, responder analysis for FACT-G was performed, with a decrease/ increase of at least 5 points, which is reported as the minimally important difference (MID), from the baseline FACT-G total score defined as QoL deterioration/ improvement [4]. The number and proportion of patients showing QoL deterioration/ improvement are presented for each group at 36 months and compared between groups using Mantel-Haenszel test, which was stratified by the same factors in the ANCOVA. All collected data were analyzed using SAS ® version 9.4 (SAS Institute, Inc). A p -value of < 0.05 was considered to reflect a statistically significant difference. The end points, assessments, and statistical analyses are described in detail in the protocol. Results Patients We enrolled 123 eligible patients, aged over 70 years, with HER2-positive invasive breast cancer, from 114 institutions, between October 2009 and October 2014 in the cohort study. The CONSORT diagram is presented in Figure 1. In the cohort study, three patients (2.4%) were excluded because all efficacy data was missing, leaving 120 patients for a full-set analysis; the treatment categories were as follows: 1) the trastuzumab-plus-chemotherapy group (n = 36, 30%), 2) the trastuzumab-monotherapy group (n = 52, 43%), and 3) the non-trastuzumab group (n = 32, 27%). A total of 73% of patients received trastuzumab-containing regimens, with or without chemotherapy. The mean age of the patients in the cohort study at entry was 74.6. The characteristics of the patients in the cohort study are shown in Table 1, according to the treatment options (n = 120). P values were assessed by chi squared test. Among the three subgroups in the cohort study, estrogen receptor (ER) and/or progesterone receptor (PgR) positivity were higher in the non-trastuzumab group (81.3% versus 48.1% in the trastuzumab group, 47.2% in the trastuzumab-plus-chemotherapy group; P = 0.005). No differences existed among the groups in terms of the age category, stage, surgical procedure, lymph node metastasis, or co-morbidities. Irradiation of the breast after partial mastectomy was performed for all patients (n = 14/14) in the trastuzumab-plus-chemotherapy group, whereas for only 40.0% (n = 6/15) in the trastuzumab-monotherapy group and 44.4% (n = 4/9) in the non-trastuzumab group. DFS, RFS, and OS The data cut-off date was October 31, 2017. The median follow-up time was 3.2 years (range: 0.9–7.0 years) in this cohort study. The details of DFS events are listed in Table 2. The DFS at 3 years was 96.7% in the trastuzumab-plus-chemotherapy group, 89.2% in the trastuzumab-monotherapy group, and 82.5% in the non-trastuzumab group (Figure 2). In the non-trastuzumab group, 26 of 32 patients (81.3%) were ER-positive; hormone therapy was initiated for 25 patients (96.2%). The DFS of patients in the non-trastuzumab group was lower than that of patients in the trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 3.29; 95% CI: 1.15–9.39, P = 0.026). DFS of the non-trastuzumab group also showed a worse prognosis than that of the trastuzumab-monotherapy group (propensity-adjusted HR: 2.15; 95% CI: 1.20–3.93, P = 0.012). It appeared that more local recurrences were occurred in non-trastuzumab group; three patients recurred, one was ipsilateral breast recurrence without irradiation, two cases were regional lymph nodes recurrence after sentinel lymph node biopsy and axillary dissection, respectively, whereas there was neither local recurrences in the trastuzumab-plus-chemotherapy group nor in the trastuzumab-monotherapy group. The RFS of patients in the non-trastuzumab group was lower than that of patients in the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, P < 0.0001) (Figure 3). In the non-trastuzumab group the OS of patients trended lower than that of patients in the trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR = 3.44; 95% CI: 0.75–15.67, P = 0.11) (Appendix Figure A1). Safety Patients who registered for the cohort group (n = 120) were included in the safety analysis. Common AEs are listed in Table A1. They are fatigue (18.3%), alopecia (18.3%), anorexia (17.5%), nail changes (15.8%) and hypertension (15.0%). The incidences of grade 3 or 4 non-hematological AEs were higher in the RCT group than in the cohort group (18.5% versus 10.8%, P = 0.05). All serious AEs resolved. HRQoL The complete response rates of FACT-G questionnaire at registration and 36 months were 81% and 56% in the non-trastuzumab group, 78% and 50% in the trastuzumab-plus-chemotherapy group, and 69% and 50% in trastuzumab-monotherapy group, respectively. Mean scores and 95% CI for the FACT-G total and sub-domain at each survey point are presented in Appendix Table A2 and Figure 4. ANCOVA showed that there were no significant differences in FACT-G total score after 36 months between the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups, and the trastuzumab-plus-chemotherapy and non-trastuzumab groups (Appendix Table A3). The only difference between the groups was that the social and family well-being (SFWB) score at 36 months between the trastuzumab-plus-chemotherapy group and the trastuzumab monotherapy group (estimated value = -5.5, P = 0.036), and SFWB score of trastuzumab-plus-chemotherapy group at 36 months was better than that of trastuzumab monotherapy group. Responder analysis for FACT-G showed that there were no significant intergroup differences in the proportions of patients showing QoL deterioration ( P = 0.717) and improvement ( P = 0.652) at 36 months (Appendix Table A4). Discussion The RESPECT study is the first randomized adjuvant trial comparing trastuzumab monotherapy with trastuzumab-plus-chemotherapy for patients with HER2-positive breast cancer [ 1 ]. The RESPECT study was accompanied by a cohort study for patients who refused to participate in the RCT. In the cohort study, we could evaluate the overall efficacy of adjuvant therapy for HER2-positive breast cancer patients over 70 years of age in detail, which enabled us to determine the prognoses of patients who did not receive trastuzumab prospectively, despite meeting the criteria for the RCT. We found that the DFS of the non-trastuzumab group was significantly lower than that of the trastuzumab-plus-chemotherapy and the trastuzumab-monotherapy groups. Trastuzumab with chemotherapy has been approved as a standard adjuvant therapy for HER2-positive primary breast cancer based on previous studies that compared chemotherapy with trastuzumab-plus-chemotherapy [ 5 – 8 ]. Since 2005, no data have been generated through clinical trials regarding (i) trastuzumab without chemotherapy, and (ii) no trastuzumab treatment, because all patients receive trastuzumab. Here, for the first time, we added an implication to this issue as prospective data with propensity-adjustment analysis in a non-interventional cohort study group. In a previous study, trastuzumab-plus-pertuzumab was tested in a neoadjuvant setting as a treatment regimen without chemotherapy [ 9 ], but chemotherapy was administered after surgery, and the study lacked a no-treatment arm without anti-HER2 therapy. Recent retrospective data obtained using the National Cancer Database revealed no significant difference in survival by administering HER2 targeted therapy to patients who did not receive chemotherapy [ 10 ]. Data from a large observational study suggested that trastuzumab-plus-chemotherapy should remain the preferred option for all patients indicated for adjuvant treatment, and that a low proportion of patients need an alternative treatment approach, either because of contraindications or the patient’s preference. Trastuzumab monotherapy might be a reasonable option [ 11 ], but to our knowledge, no prospective data exist to suggest that prospective adjuvant trastuzumab alone can offer a benefit over no adjuvant therapy. A trial comparing no adjuvant treatment to trastuzumab alone would not be feasible and unethical. In this cohort study, in the non-trastuzumab group, ER-positivity was 81.3%, and majority of the patients only received hormonal therapy. Subsequently, it was associated with a worse prognosis compared to the chemotherapy-plus-trastuzumab, and the trastuzumab-monotherapy groups. Even in patients with ER-positive tumors trastuzumab would be important, which was compatible to the results of RCT irrespective of hormone receptor status [ 6 , 7 ]. In this study there would be a caution that more local recurrences might be occurred due to undertreatment, especially in the non-trastuzumab group. Older patients are at an increased risk for severe chemotherapy-induced toxicity [ 12 – 14 ]. Regarding the safety of trastuzumab in older patients, the results of a large observational study indicated that the risk of cardiac function toxicity was 5.7% [ 15 ] and that it was associated with age [ 15 , 16 ], although it remained manageable [ 15 ], and the risks associated with trastuzumab were outweighed by the benefits [ 15 , 17 ]. A phase II study of trastuzumab monotherapy in older women showed that DFS at 5-year was 86.4% (95% CI: 73.6 to 93.3) with cardiac safety [ 18 ]. In terms of the balance between benefit and harm, we recommend trastuzumab monotherapy if the patients do not receive chemotherapy, based on our current findings. The ATOP trial (ClinicalTrials.gov identifier: NCT03587740), is an ongoing single-arm study of T-DM1 in patients over 60 years of age that seeks a more definitive insight to anti-HER2 therapy in older patients, the result of which are much anticipated. Besides the incidence of AEs, HRQoL is also important, because chemotherapy causes significant deterioration of HRQoL in older patients [ 19 , 20 ]. The large clinical trial in older patients showed that one-third had a clinically meaningful decline of physical function at 12 months, although half recovered [ 21 ]. We observed a clinically significant HRQoL rate of deterioration between 2 months and 1 year into the RCT, which recovered after 3 years [ 1 , 22 ]. As a result of the QoL evaluation in this cohort study, chemotherapy with trastuzumab or trastuzumab monotherapy as postoperative adjuvant therapy did not affect global QoL at 36 months. We also observed the impact of chemotherapy on cognitive functioning in the RCT [ 23 ], the information would be important to share decision making between clinicians and patients. This study has a few limitations. Although 120 patients in the cohort study were treated and assessed, no definitive conclusions regarding trastuzumab without chemotherapy can be made, because of non-randomized, small study and there were fewer events than expected as >80% of the patients enrolled had stage I or stage IIA breast cancer. Even in the non-trastuzumab arm of the cohort group, the 3-year DFS was over 80%. Although more patients were needed for a higher number of events, it was difficult to complete enrollment, because of the low number of older HER2-positive patients and disease heterogeneity [ 24 ]. We could have extended the follow-up period to detect more events, but it was assumed that non-breast cancer deaths as well as recurrences would accumulate, because eight years passed after the first patient was enrolled. However, a longer follow-up period is needed to shed light on patient prognosis. In older patients the geriatric assessment screening tools can be useful for predicting severe AEs for chemotherapy [ 25 ], and it is important to intensify supportive care and develop modified treatment regimens in vulnerable patients who may subsequently experience greater toxicity [ 26 ]. Chronological age by itself is not a stand-alone biomarker, in this study the scope of assessment included activities of daily living, instrumental activities of daily living, depression, cognitive function, and subjective well-being. After analyzing them we hope to create predictive tools for AEs or prognosis. In conclusion, we found that patients who received any trastuzumab-containing regimen, even trastuzumab monotherapy, had a better prognosis than those who were not treated with trastuzumab, without deterioration of QoL. Although trastuzumab-plus-chemotherapy remains a standard of care, trastuzumab monotherapy could be considered for selected older patients, even if the patients are not willing to receive chemotherapy. Declarations Ethical approval The trial protocol was approved by the institutional review boards of all participating institutions. Informed consent All patients provided written informed consent. Acknowledgments We acknowledge Toru Watanabe and Yasuo Ohashi for valuable advice on the research plan. We thank the patients who participated in this trial and their families and caregivers, all investigators involved in this study, and all members of the independent data-monitoring committee for their contributions to the study. Author contributions Study concept and design: MS, NT, YU, HB, TN, MK, TM, YY, HI and HM. Provision of study material or patients: TS, SB, KK, HK, HM, MT, NS, MT, MY, TT, KT and TT. Data and statistical analysis: YU and TK. Manuscript preparation: MS, NT, YU, and TK. Manuscript editing: MS and NT. Manuscript review: All authors. Data availability The datasets analyzed during the current study are available from the corresponding author on reasonable request. Code availability The codes used to analyze the datasets during the current study are available from the corresponding author on reasonable request. Conflict of interest YU reports honoraria for consulting from Chugai pharmaceutical Co., Ltd. TT reports honoraria for lectures from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K., AstraZeneca K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Daiichi Sankyo Co., Ltd. TN reports fees for Non-CME services and honoraria for lectures from Chugai pharmaceutical Co., Ltd., AstraZeneca K.K., Novartis Pharma K.K., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, and Eisai Co., Ltd. TM reports fees for non-CME services and honoraria for lectures from AstraZeneca K.K., Chugai pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., Nippon Kayaku Co., Ltd., and Pfizer Japan Inc. HI reports honoraria for lectures from Chugai pharmaceutical Co., Ltd. HM reports honoraria from AstraZeneca K.K., Pfizer Japan Inc, Takeda Pharmaceutical Company Limited, Daiichi Sankyo Co., Ltd and Taiho Pharmaceutical Co., Ltd; and research grants from the Japanese government, Daiichi Sankyo Co., Ltd, Eisai Co., Ltd, Nippon Kayaku Co., Ltd and Pfizer Japan Inc, outside the submitted work. Funding information This study was funded by the Comprehensive Support Project for Oncology Research (CSPOR) of the Public Health Research Foundation, Japan. All decisions concerning the planning, implementation, and publication of this study were made by the executive committee of this study. 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Breast Cancer Res Treat 187:815-830. doi: 10.1007/s10549-021-06115-9 Dall P, Koch T, Gohler T, Selbach J, Ammon A, Eggert J, Gazawi N, Rezek D, Wischnik A, Hielscher C, Schleif N, Cirrincione U, Hinke A, Feisel-Schwickardi G (2018) Trastuzumab without chemotherapy in the adjuvant treatment of breast cancer: subgroup results from a large observational study. BMC Cancer 18:51. doi: 10.1186/s12885-017-3857-5 Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH (2007) Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 25:3808-3815. doi: 10.1200/JCO.2006.10.4976 Patt DA, Duan Z, Fang S, Hortobagyi GN, Giordano SH (2007) Acute Myeloid Leukemia After Adjuvant Breast Cancer Therapy in Older Women: Understanding Risk. J Clin Oncol 25:3871-3876. doi: 10.1200/jco.2007.12.0832 Du XL, Xia R, Liu CC, Cormier JN, Xing Y, Hardy D, Chan W, Burau K (2009) Cardiac toxicity associated with anthracycline-containing chemotherapy in older women with breast cancer. Cancer 115:5296-5308. doi: 10.1002/cncr.24621 [doi] Dall P, Lenzen G, Gohler T, Lerchenmuller C, Feisel-Schwickardi G, Koch T, Eggert J, Heilmann V, Schindler C, Wilke J, Tesch H, Selbach J, Wohlfarth T, Eustermann H, Hinke A (2015) Trastuzumab in the treatment of elderly patients with early breast cancer: Results from an observational study in Germany. J Geriatr Oncol 6:462-469. doi: 10.1016/j.jgo.2015.06.003 Vaz-Luis I, Keating NL, Lin NU, Lii H, Winer EP, Freedman RA (2014) Duration and toxicity of adjuvant trastuzumab in older patients with early-stage breast cancer: a population-based study. J Clin Oncol 32:927-934. doi: 10.1200/JCO.2013.51.1261 Brollo J, Curigliano G, Disalvatore D, Marrone BF, Criscitiello C, Bagnardi V, Kneubil MC, Fumagalli L, Locatelli M, Manunta S, Goldhirsch A (2013) Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: a systematic review of randomized controlled trials. Cancer Treat Rev 39:44-50. doi: 10.1016/j.ctrv.2012.03.009 Owusu C, Margevicius SP, Klepin HD, Vogel CL, Alahmadi A, Vuyyala S, Brufsky A (2020) Safety and efficacy of single-agent adjuvant trastuzumab in older women with early-stage breast cancer. J Clin Oncol 38:528-528. doi: 10.1200/JCO.2020.38.15_suppl.528 Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP (2009) Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360:2055-2065. doi: 10.1056/NEJMoa0810266 Kornblith AB, Lan L, Archer L, Partridge A, Kimmick G, Hudis C, Winer E, Casey R, Bennett S, Cohen HJ, Muss HB (2011) Quality of Life of Older Patients With Early-Stage Breast Cancer Receiving Adjuvant Chemotherapy: A Companion Study to Cancer and Leukemia Group B 49907. J Clin Oncol 29:1022-1028. doi: 10.1200/jco.2010.29.9859 Hurria A, Soto-Perez-de-Celis E, Allred JB, Cohen HJ, Arsenyan A, Ballman K, Le-Rademacher J, Jatoi A, Filo J, Mandelblatt J, Lafky JM, Kimmick G, Klepin HD, Freedman RA, Burstein H, Gralow J, Wolff AC, Magrinat G, Barginear M, Muss H (2019) Functional Decline and Resilience in Older Women Receiving Adjuvant Chemotherapy for Breast Cancer. J Am Geriatr Soc 67:920-927. doi: 10.1111/jgs.15493 Taira N, Sawaki M, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Ohashi Y, Mukai H, Kawahara T (2021) Health-related quality of life with trastuzumab monotherapy versus trastuzumab plus standard chemotherapy as adjuvant therapy in older patients with HER2-positive breast cancer. J Clin Oncol 20.02751, in press. Hagiwara Y, Sawaki M, Uemura Y, Kawahara T, Shimozuma K, Ohashi Y, Takahashi M, Saito T, Baba S, Kobayashi K, Mukai H, Taira N (2021) Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial. Breast Cancer Res Treat 188:675-683. doi: 10.1007/s10549-021-06253-0 Leonard R, Ballinger R, Cameron D, Ellis P, Fallowfield L, Gosney M, Johnson L, Kilburn LS, Makris A, Mansi J, Reed M, Ring A, Robinson A, Simmonds P, Thomas G, Bliss JM (2011) Adjuvant chemotherapy in older women (ACTION) study - what did we learn from the pilot phase? Br J Cancer 105:1260-1266. doi: 10.1038/bjc.2011.377 Hurria A, Mohile S, Gajra A, Klepin H, Muss H, Chapman A, Feng T, Smith D, Sun CL, De Glas N, Cohen HJ, Katheria V, Doan C, Zavala L, Levi A, Akiba C, Tew WP (2016) Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer. J Clin Oncol 34:2366-2371. doi: 10.1200/JCO.2015.65.4327 Magnuson A, Sedrak MS, Gross CP, Tew WP, Klepin HD, Wildes TM, Muss HB, Dotan E, Freedman RA, O'Connor T, Dale W, Cohen HJ, Katheria V, Arsenyan A, Levi A, Kim H, Mohile S, Hurria A, Sun CL (2021) Development and Validation of a Risk Tool for Predicting Severe Toxicity in Older Adults Receiving Chemotherapy for Early-Stage Breast Cancer. J Clin Oncol 39:608-618. doi: 10.1200/jco.20.02063 Tables Table 1 and 2 are available in the Supplementary Files section. Supplementary Files FigA1.png Appendix Fig A1. Kaplan–Meier estimates of overall survival (OS). The OS of patients in the non-trastuzumab group was marginally lower than that of patients in the trastuzumab-plus-chemotherapy, and trastuzumab monotherapy groups (propensity-adjusted HR = 3.44; 95% CI: 0.75–15.67, P = 0.11). Tick marks indicate censored data. Table1.jpg Table2.jpg Appendix.docx Cite Share Download PDF Status: Published Journal Publication published 01 Dec, 2022 Read the published version in The Breast → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1112686","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":133935762,"identity":"da8fda65-cabc-413e-abf2-27f3333ca3e4","order_by":0,"name":"Masataka 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School: Nagoya Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Toyama","suffix":""},{"id":133935781,"identity":"84474ffb-f487-4b7b-87de-47b903eb1e50","order_by":19,"name":"Koichiro Tsugawa","email":"","orcid":"","institution":"St Marianna University School of Medicine: Sei Marianna Ika Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Koichiro","middleName":"","lastName":"Tsugawa","suffix":""},{"id":133935782,"identity":"b40da2f3-1ee1-4176-bfc2-ffe33f24dd94","order_by":20,"name":"Takuya Kawahara","email":"","orcid":"","institution":"The University of Tokyo Hospital: Tokyo Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Kawahara","suffix":""},{"id":133935783,"identity":"e836c0fd-6faf-4437-baf4-a71f623a4f24","order_by":21,"name":"Hirofumi Mukai","email":"","orcid":"","institution":"National Cancer Center-Hospital East: Kokuritsu Gan Center Higashi Byoin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hirofumi","middleName":"","lastName":"Mukai","suffix":""}],"badges":[],"createdAt":"2021-11-25 03:57:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1112686/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1112686/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1016/j.breast.2022.10.017","type":"published","date":"2022-12-01T15:15:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":26187173,"identity":"9ba39e31-4406-42f3-a11e-f0c3c084c4d6","added_by":"auto","created_at":"2022-09-07 16:36:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":147969,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram. Patients who met the eligibility criteria but did not agree to participate in the randomized controlled trial were included in the cohort study with written informed consent. The treatment was selected for each patient based on the discretion of the treating physician and the patient’s wishes, without intervention.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/c15be5cfe106cbc2562d7e09.png"},{"id":26187176,"identity":"0739e6d4-2c18-48f3-84b8-124deb0742c3","added_by":"auto","created_at":"2022-09-07 16:36:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":349247,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of disease-free survival (DFS). The DFS at 3 years was 96.7% in the trastuzumab-plus-chemotherapy group, 89.2% in the trastuzumab-monotherapy group, and 82.5% in the non-trastuzumab group. The DFS period of the non-trastuzumab group was lower than that of the trastuzumab-plus-chemotherapy and the trastuzumab monotherapy groups (propensity-adjusted HR: 3.29; 95% CI: 1.15–9.39; \u003cem\u003eP\u003c/em\u003e = 0.026). The DFS in the non-trastuzumab group also showed a worse prognosis compared with the trastuzumab monotherapy group (propensity-adjusted HR: 2.15; 95% CI: 1.20–3.93; \u003cem\u003eP\u003c/em\u003e = 0.012). Tick marks indicate censored data.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/40a4d62db6c37a79537402ee.png"},{"id":26187105,"identity":"98c3073c-1405-424b-89ed-8e67674d3128","added_by":"auto","created_at":"2022-09-07 16:31:05","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":346101,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of relapse-free survival (RFS). The RFS of patients in the non-trastuzumab group was lower than that of patients in the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001). Tick marks indicate censored data.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/87c30a319006ec60ef47b73f.png"},{"id":26187106,"identity":"2f17a3e5-989e-4e93-9fe2-5b530fae292f","added_by":"auto","created_at":"2022-09-07 16:31:05","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":559858,"visible":true,"origin":"","legend":"\u003cp\u003eMeans and 95%CI of FACT-G scores at each survey point. Mean value and 95% confidential interval (95%CI) of A) Functional Assessment of Cancer Therapy-general (FACT-G) total, B) physical well-being (PWB), C) social and family well-being (SFWB), D) emotional well-being (EWB) and E) functional well-being (FWB) scores at baseline, and after 36 months in each group.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/9a8dbbc0598a758397faf5dc.png"},{"id":55941108,"identity":"137cc071-e332-4397-b8b9-174858ccdda8","added_by":"auto","created_at":"2024-05-06 15:15:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":845401,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/ee7c2be1-3f90-4e28-8b01-78970d4b2f45.pdf"},{"id":26187102,"identity":"a97f0026-3f60-4c75-8f2b-ffc87d60f477","added_by":"auto","created_at":"2022-09-07 16:31:05","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":307459,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAppendix Fig A1.\u003c/strong\u003e Kaplan–Meier estimates of overall survival (OS). The OS of patients in the non-trastuzumab group was marginally lower than that of patients in the trastuzumab-plus-chemotherapy, and trastuzumab monotherapy groups (propensity-adjusted HR = 3.44; 95% CI: 0.75–15.67, \u003cem\u003eP\u003c/em\u003e = 0.11). Tick marks indicate censored data.\u003c/p\u003e","description":"","filename":"FigA1.png","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/1b2516c2cdf8729889fac875.png"},{"id":26187673,"identity":"8f11c9d6-ce68-48fd-8cb2-c7d9c1e8e259","added_by":"auto","created_at":"2022-09-07 16:46:05","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":169385,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/3d42aca7b4b936a04ed5c774.jpg"},{"id":26187108,"identity":"cb77787d-ffa1-479f-b96c-a95998589067","added_by":"auto","created_at":"2022-09-07 16:31:06","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":92804,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/accc9dc52ca1fa7c9996c4d3.jpg"},{"id":26187464,"identity":"7bc3f2a1-0c57-43f7-9b19-c90b63e904f2","added_by":"auto","created_at":"2022-09-07 16:41:05","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":60691,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-1112686/v1/7c154a8e3baf1eb92811a9d0.docx"}],"financialInterests":"","formattedTitle":"Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: a propensity score-adjusted analysis of a prospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThis study accompanied the RESPECT study [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], which is a randomized controlled trial (RCT) designed to compare the value of trastuzumab monotherapy with the standard combination treatment with the value of chemotherapy in patients over 70 years, with human epidermal growth factor receptor type 2 (HER2)-positive invasive breast cancer, who received curative surgery. This study aimed to determine the overall prognosis of older patients with HER2-positive breast cancer who did not agree to participate in the RCT despite meeting the eligibility criteria. Particularly, we aimed to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. Before starting this RCT, we questioned whether acquiring consent to participate in this RCT might be difficult in older patients, because of the possibility of emphasizing treatment in accordance with the patient\u0026rsquo;s wishes, considering the potential adverse events (AEs) of chemotherapy. It is currently unknown whether adjuvant trastuzumab therapy alone can offer a benefit over no adjuvant therapy. Although we sought to directly compare trastuzumab monotherapy with no treatment in older patients, we were concerned that such a study would not be feasible because some patients might refuse to participate in an arm without trastuzumab, despite having HER2-positive disease. In addition, only healthy patients can participate in the RCT. Thus, we designed a non-interventional cohort study to gauge the effects of treatment practices on prognosis for all older patients with HER2-positive breast cancer.\u003c/p\u003e"},{"header":"Patients","content":"\u003cp\u003eThe trial protocol is described within the full text of this article. We recruited patients, aged 70\u0026ndash;80 years old, with HER2-positive invasive breast cancer who underwent curative surgery. The patient-inclusion criteria were as follows: patients with invasive breast cancer histologically diagnosed as HER2-positive breast cancer, who underwent curative surgery for stage I (pathological tumor size \u0026gt; 0.5 cm), IIA, IIB, or IIIA disease. HER2-positivity was defined by the ASCO/CAP guidelines [2], which lay down the following criteria: immunohistochemical staining of 3+ (uniform, intense membrane staining of \u0026gt; 30% of invasive tumor cells) and a fluorescence-\u003cem\u003ein situ\u003c/em\u003e hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signal: chromosome 17 signal) of more than 2.2. Other key eligibility criteria were as follows: a baseline left ventricular-ejection fraction of \u0026ge;55% (measured by echocardiography) within 4 weeks of registration, an Eastern Cooperative Oncology Group performance status (PS) score of 0 or 1, and sufficient organ function\u0026nbsp;that meets the prescribed criteria in laboratory tests performed within four weeks of registration. The key exclusion criteria were as follows: the presence of active multiple primary cancer (synchronous multiple primary cancer and invasive cancer of other organs); \u0026ge;4 histological axillary lymph node metastases; no histological evaluation of axillary lymph nodes; a histologically confirmed positive margin found during breast-conservation surgery; a history of drug-related allergy that could hinder planned treatment; any history of or complication following cardiac disorders; a history of congestive heart failure; cardiac infarction; complications requiring treatment, such as ischemic cardiac disorder, arrhythmia, valvular-heart disease, poorly-controlled hypertension, and poorly controlled diabetes; difficulty in regularly attending a medical institution due to a deterioration in the ability to perform the activities of daily living; difficulty participating in the trial because of a psychiatric disorder or psychiatric symptoms; or ineligibility for enrollment according to the decision of an investigator based on contacts and locations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design and oversight\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who were eligible for but declined participation in the RESPECT trial [1] were recruited to this cohort study. Written informed consent was obtained for each participant. Patients who consented to participate in the RCT were randomly assigned at a 1:1 ratio to the trastuzumab monotherapy group or trastuzumab-plus-chemotherapy group [1]. In this cohort study, treatment was chosen based on the discretion of the treating physician and the patients\u0026rsquo; wishes without intervention, and patients were prospectively reviewed based on routine medical records. The cohort study included three categories: 1) the trastuzumab-plus-chemotherapy group, 2) the trastuzumab-monotherapy group, and 3) a group that received no therapy at all or received any anticancer therapy without trastuzumab (the non-trastuzumab group). The purpose of this prospective cohort study was to assess the overall effect of adjuvant therapy on HER2-positive primary breast cancer in older patients (\u0026ge; 70 years) and to investigate the efficacy and safety of trastuzumab-plus-chemotherapy, trastuzumab monotherapy, and non-trastuzumab treatment.\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by independent ethics committees and institutional review boards. The study conformed with the Declaration of Helsinki and the\u0026nbsp;\u0026ldquo;Ethical Guidelines for Clinical Research\u0026rdquo;\u0026nbsp;guidelines of the Ministry of Health, Labor and Welfare. Written informed consent was obtained from all patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEnd points\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of the cohort study was disease-free survival (DFS), and the secondary endpoints were overall survival (OS), relapse-free survival (RFS), AEs, and health-related quality of life (HRQoL). DFS was defined by the occurrence of any of the following: a diagnosis of recurrence after breast-conservation therapy, local (ipsilateral chest wall) recurrence, regional lymph node recurrence or distant organ metastasis; a diagnosis of metachronous breast cancer or secondary cancer (not including cutaneous basal cell carcinoma, squamous cell cancer, or endometrial intraepithelial carcinoma); and all deaths (regardless of cause). RFS was defined by the occurrence of any of the following: any local recurrence (including local recurrence after breast-conservation therapy), regional lymph node recurrence or distant organ metastasis (not including metachronous breast cancer or secondary cancer), and death (regardless of cause). HRQoL was assessed using the Functional Assessment of Cancer Therapy-general (FACT-G) scale [3].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the cohort study,\u0026nbsp;medical records were reviewed by attending physicians to detect DFS, OS, RFS, AEs, and HRQoL events\u0026nbsp;without interventions, such as prospective treatment and testing.\u0026nbsp;The attending physician periodically checked the vital status of the patient.\u0026nbsp;Types and grades of AEs were determined according to Common Terminology Criteria for Adverse Events v3.0.\u0026nbsp;If a recurrence was observed, the date of recurrence, the type of recurrence, and the information on which the judgement was investigated. In the case of death, the date of death and the reason was investigated.\u0026nbsp;The survival data and AEs were reviewed every year, beginning from the time of first enrollment to the end of the study.\u0026nbsp;HRQoL of\u0026nbsp;all participants in this cohort study\u0026nbsp;was assessed at registration, and after 36 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe DFS was set as the primary endpoint. The DFS and other endpoints among\u0026nbsp;trastuzumab-plus-chemotherapy, trastuzumab-monotherapy, and\u0026nbsp;non-trastuzumab\u0026nbsp;groups were compared using propensity score-based\u0026nbsp;covariate adjustments by the Cox regression model.\u0026nbsp;The propensity score\u0026nbsp;was estimated for each participant using a\u0026nbsp;multinomial regression model, based on the\u0026nbsp;age (70\u0026ndash;75 versus 76\u0026ndash;80 years), hormone receptor status (positive versus negative), pathologic nodal status (positive versus negative), and PS (0 or 1) in the model.\u0026nbsp;Group comparisons of FACT-G total and subdomain scores were performed using an Analysis of Co-Variance (ANCOVA). This model used scores at 36 months as an outcome, and the adjusted covariates were scored at baseline in addition to the same factors in the survival analysis (i.e., age, hormone receptor status, pathologic nodal status, and PS). The estimated score difference at 36 months from trastuzumab-plus-chemotherapy (as a reference) in the trastuzumab-monotherapy group and the non-trastuzumab group, 95% confidence interval (CI), and \u003cem\u003ep\u003c/em\u003e-value were calculated. In addition, responder analysis for FACT-G was performed, with a decrease/ increase of at least 5 points, which is reported as the minimally important difference (MID), from the baseline FACT-G total score defined as QoL deterioration/ improvement [4]. The number and proportion of patients showing QoL deterioration/ improvement are presented for each group at 36 months and compared between groups using Mantel-Haenszel test, which was stratified by the same factors in the ANCOVA.\u003c/p\u003e\n\u003cp\u003eAll collected data were analyzed using SAS\u003csup\u003e\u0026reg;\u003c/sup\u003e version 9.4 (SAS Institute, Inc). A \u003cem\u003ep\u003c/em\u003e-value of \u0026lt; 0.05 was considered to reflect a statistically significant difference. The end points, assessments, and statistical analyses are described in detail in the protocol.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe enrolled 123 eligible patients, aged over 70 years, with HER2-positive invasive breast cancer, from 114 institutions, between October 2009 and October 2014 in the cohort study.\u0026nbsp;The CONSORT diagram is presented in Figure 1. In the cohort study, three patients (2.4%) were excluded because all efficacy data was missing, leaving 120 patients for a full-set analysis; the treatment categories were as follows:\u0026nbsp;1) the trastuzumab-plus-chemotherapy group (n = 36, 30%), 2) the trastuzumab-monotherapy group (n = 52, 43%), and 3) the\u0026nbsp;non-trastuzumab group (n = 32, 27%).\u0026nbsp;A total of 73% of patients received trastuzumab-containing regimens, with or without chemotherapy. The mean age of the patients in the cohort study at entry was 74.6. \u0026nbsp;The characteristics of the patients in the cohort study are shown in Table 1, according to the treatment options (n = 120). P values were assessed by chi squared test. Among the three subgroups in the cohort study, estrogen receptor (ER) and/or progesterone receptor (PgR) positivity were higher in the non-trastuzumab group (81.3% versus 48.1% in the trastuzumab group, 47.2% in the trastuzumab-plus-chemotherapy group; \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.005). No differences existed among the groups in terms of the age category, stage, surgical procedure, lymph node metastasis, or co-morbidities. Irradiation of the breast after partial mastectomy was performed for all patients (n = 14/14) in\u0026nbsp;the trastuzumab-plus-chemotherapy group, whereas for only 40.0% (n =\u0026nbsp;6/15) in the trastuzumab-monotherapy group and 44.4% (n = 4/9)\u0026nbsp;in the\u0026nbsp;non-trastuzumab group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDFS, RFS, and OS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data cut-off date was October 31, 2017. The median follow-up time was 3.2 years (range: 0.9\u0026ndash;7.0 years) in this cohort study. The details of DFS events are listed in Table 2. The DFS at 3 years was 96.7% in the\u0026nbsp;trastuzumab-plus-chemotherapy group, 89.2% in the\u0026nbsp;trastuzumab-monotherapy group,\u0026nbsp;and 82.5% in the non-trastuzumab group (Figure 2). In the non-trastuzumab group, 26 of 32 patients (81.3%) were ER-positive; hormone therapy was initiated for 25 patients (96.2%). The DFS of patients in the non-trastuzumab group was lower than that of patients in the\u0026nbsp;trastuzumab-plus-chemotherapy\u0026nbsp;and\u0026nbsp;trastuzumab-monotherapy\u0026nbsp;groups (propensity-adjusted HR = 3.29; 95% CI: 1.15\u0026ndash;9.39, \u003cem\u003eP\u003c/em\u003e = 0.026). DFS of the non-trastuzumab group\u0026nbsp;also\u0026nbsp;showed a worse prognosis than that of\u0026nbsp;the trastuzumab-monotherapy\u0026nbsp;group (propensity-adjusted HR: 2.15; 95% CI: 1.20\u0026ndash;3.93, \u003cem\u003eP\u003c/em\u003e = 0.012). It appeared that more local recurrences were occurred in non-trastuzumab group; three patients recurred, one was ipsilateral breast recurrence without irradiation, two cases were regional lymph nodes recurrence after sentinel lymph node biopsy and axillary dissection, respectively, whereas there was neither local recurrences in the trastuzumab-plus-chemotherapy group nor in the trastuzumab-monotherapy group. The RFS of patients in the non-trastuzumab group was lower than that of patients in the\u0026nbsp;trastuzumab-plus-chemotherapy\u0026nbsp;and\u0026nbsp;trastuzumab monotherapy\u0026nbsp;groups (propensity-adjusted HR = 7.80; 95% CI: 2.32\u0026ndash;26.2, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001) (Figure 3). In the non-trastuzumab group the OS of patients trended lower than that of patients in the\u0026nbsp;trastuzumab-plus-chemotherapy\u0026nbsp;and\u0026nbsp;trastuzumab-monotherapy\u0026nbsp;groups (propensity-adjusted HR = 3.44; 95% CI: 0.75\u0026ndash;15.67, \u003cem\u003eP\u003c/em\u003e = 0.11) (Appendix Figure A1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who registered for the cohort group (n = 120) were included in the safety analysis. Common AEs are listed in Table A1. They are fatigue (18.3%), alopecia (18.3%), anorexia (17.5%), nail changes (15.8%) and hypertension (15.0%). The incidences of grade 3 or 4 non-hematological AEs were higher in the RCT group than in the cohort group (18.5% versus 10.8%, \u003cem\u003eP\u003c/em\u003e = 0.05). All serious AEs resolved.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHRQoL\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe complete response rates of FACT-G questionnaire at registration and 36 months were 81% and 56% in the non-trastuzumab group, 78% and 50% in the trastuzumab-plus-chemotherapy group, and 69% and 50% in trastuzumab-monotherapy group, respectively. Mean scores and 95% CI for the FACT-G total and sub-domain at each survey point are presented in Appendix Table A2 and Figure 4. ANCOVA showed that there were no significant differences in FACT-G total score after 36 months between the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups, and the trastuzumab-plus-chemotherapy and non-trastuzumab groups (Appendix Table A3). The only difference between the groups was that the social and family well-being (SFWB) score at 36 months between the trastuzumab-plus-chemotherapy group and the trastuzumab monotherapy group (estimated value = -5.5, \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.036), and SFWB score of trastuzumab-plus-chemotherapy group at 36 months was better than that of trastuzumab monotherapy group. Responder analysis for FACT-G showed that there were no significant intergroup differences in the proportions of patients showing QoL deterioration (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.717) and improvement (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.652) at 36 months (Appendix Table A4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe RESPECT study is the first randomized adjuvant trial comparing trastuzumab monotherapy with trastuzumab-plus-chemotherapy for patients with HER2-positive breast cancer [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The RESPECT study was accompanied by a cohort study for patients who refused to participate in the RCT. In the cohort study, we could evaluate the overall efficacy of adjuvant therapy for HER2-positive breast cancer patients over 70 years of age in detail, which enabled us to determine the prognoses of patients who did not receive trastuzumab prospectively, despite meeting the criteria for the RCT. We found that the DFS of the non-trastuzumab group was significantly lower than that of the trastuzumab-plus-chemotherapy and the trastuzumab-monotherapy groups. Trastuzumab with chemotherapy has been approved as a standard adjuvant therapy for HER2-positive primary breast cancer based on previous studies that compared chemotherapy with trastuzumab-plus-chemotherapy [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Since 2005, no data have been generated through clinical trials regarding (i) trastuzumab without chemotherapy, and (ii) no trastuzumab treatment, because all patients receive trastuzumab.\u003c/p\u003e \u003cp\u003eHere, for the first time, we added an implication to this issue as prospective data with propensity-adjustment analysis in a non-interventional cohort study group. In a previous study, trastuzumab-plus-pertuzumab was tested in a neoadjuvant setting as a treatment regimen without chemotherapy [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], but chemotherapy was administered after surgery, and the study lacked a no-treatment arm without anti-HER2 therapy. Recent retrospective data obtained using the National Cancer Database revealed no significant difference in survival by administering HER2 targeted therapy to patients who did not receive chemotherapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Data from a large observational study suggested that trastuzumab-plus-chemotherapy should remain the preferred option for all patients indicated for adjuvant treatment, and that a low proportion of patients need an alternative treatment approach, either because of contraindications or the patient\u0026rsquo;s preference. Trastuzumab monotherapy might be a reasonable option [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], but to our knowledge, no prospective data exist to suggest that prospective adjuvant trastuzumab alone can offer a benefit over no adjuvant therapy. A trial comparing no adjuvant treatment to trastuzumab alone would not be feasible and unethical. In this cohort study, in the non-trastuzumab group, ER-positivity was 81.3%, and majority of the patients only received hormonal therapy. Subsequently, it was associated with a worse prognosis compared to the chemotherapy-plus-trastuzumab, and the trastuzumab-monotherapy groups. Even in patients with ER-positive tumors trastuzumab would be important, which was compatible to the results of RCT irrespective of hormone receptor status [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In this study there would be a caution that more local recurrences might be occurred due to undertreatment, especially in the non-trastuzumab group.\u003c/p\u003e \u003cp\u003eOlder patients are at an increased risk for severe chemotherapy-induced toxicity [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Regarding the safety of trastuzumab in older patients, the results of a large observational study indicated that the risk of cardiac function toxicity was 5.7% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and that it was associated with age [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], although it remained manageable [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and the risks associated with trastuzumab were outweighed by the benefits [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A phase II study of trastuzumab monotherapy in older women showed that DFS at 5-year was 86.4% (95% CI: 73.6 to 93.3) with cardiac safety [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In terms of the balance between benefit and harm, we recommend trastuzumab monotherapy if the patients do not receive chemotherapy, based on our current findings. The ATOP trial (ClinicalTrials.gov identifier: NCT03587740), is an ongoing single-arm study of T-DM1 in patients over 60 years of age that seeks a more definitive insight to anti-HER2 therapy in older patients, the result of which are much anticipated.\u003c/p\u003e \u003cp\u003eBesides the incidence of AEs, HRQoL is also important, because chemotherapy causes significant deterioration of HRQoL in older patients [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The large clinical trial in older patients showed that one-third had a clinically meaningful decline of physical function at 12 months, although half recovered [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. We observed a clinically significant HRQoL rate of deterioration between 2 months and 1 year into the RCT, which recovered after 3 years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. As a result of the QoL evaluation in this cohort study, chemotherapy with trastuzumab or trastuzumab monotherapy as postoperative adjuvant therapy did not affect global QoL at 36 months. We also observed the impact of chemotherapy on cognitive functioning in the RCT [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], the information would be important to share decision making between clinicians and patients.\u003c/p\u003e \u003cp\u003eThis study has a few limitations. Although 120 patients in the cohort study were treated and assessed, no definitive conclusions regarding trastuzumab without chemotherapy can be made, because of non-randomized, small study and there were fewer events than expected as \u0026gt;80% of the patients enrolled had stage I or stage IIA breast cancer. Even in the non-trastuzumab arm of the cohort group, the 3-year DFS was over 80%. Although more patients were needed for a higher number of events, it was difficult to complete enrollment, because of the low number of older HER2-positive patients and disease heterogeneity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. We could have extended the follow-up period to detect more events, but it was assumed that non-breast cancer deaths as well as recurrences would accumulate, because eight years passed after the first patient was enrolled. However, a longer follow-up period is needed to shed light on patient prognosis. In older patients the geriatric assessment screening tools can be useful for predicting severe AEs for chemotherapy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and it is important to intensify supportive care and develop modified treatment regimens in vulnerable patients who may subsequently experience greater toxicity [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Chronological age by itself is not a stand-alone biomarker, in this study the scope of assessment included activities of daily living, instrumental activities of daily living, depression, cognitive function, and subjective well-being. After analyzing them we hope to create predictive tools for AEs or prognosis.\u003c/p\u003e \u003cp\u003eIn conclusion, we found that patients who received any trastuzumab-containing regimen, even trastuzumab monotherapy, had a better prognosis than those who were not treated with trastuzumab, without deterioration of QoL. Although trastuzumab-plus-chemotherapy remains a standard of care, trastuzumab monotherapy could be considered for selected older patients, even if the patients are not willing to receive chemotherapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u0026nbsp;\u003c/strong\u003eThe trial protocol was approved by the institutional review boards of all participating institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u0026nbsp;\u003c/strong\u003eAll patients provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge Toru Watanabe and Yasuo Ohashi for valuable\u0026nbsp;advice on the research plan. We thank the patients who participated in this trial and their families and caregivers, all investigators involved in this study, and all members of the independent data-monitoring committee for their contributions to the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eStudy concept and design: MS, NT, YU, HB, TN, MK, TM, YY, HI and HM. Provision of study material or patients: TS, SB, KK, HK, HM, MT, NS, MT, MY, TT, KT and TT. Data and statistical analysis: YU and TK. Manuscript preparation: MS, NT, YU, and TK. Manuscript editing: MS and NT. Manuscript review: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e The datasets analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e The codes used to analyze the datasets during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003eYU reports honoraria for consulting from Chugai pharmaceutical Co., Ltd. TT reports honoraria for lectures from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., Pfizer Japan Inc., Novartis Pharma K.K., AstraZeneca K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Daiichi Sankyo Co., Ltd. TN reports fees for Non-CME services and honoraria for lectures from Chugai pharmaceutical Co., Ltd., AstraZeneca K.K., Novartis Pharma K.K., Eli Lilly Japan K.K., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, and Eisai Co., Ltd. TM reports fees for non-CME services and honoraria for lectures from AstraZeneca K.K., Chugai pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., Nippon Kayaku Co., Ltd., and Pfizer Japan Inc. HI reports honoraria for lectures from Chugai pharmaceutical Co., Ltd. HM reports honoraria from AstraZeneca K.K., Pfizer Japan Inc, Takeda Pharmaceutical Company Limited, Daiichi Sankyo Co., Ltd and Taiho Pharmaceutical Co., Ltd; and research grants from the Japanese government, Daiichi Sankyo Co., Ltd, Eisai Co., Ltd, Nippon Kayaku Co., Ltd and Pfizer Japan Inc, outside the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Comprehensive Support Project for Oncology Research (CSPOR) of the Public Health Research Foundation, Japan. All decisions concerning the planning, implementation, and publication of this study were made by the executive committee of this study. The corporate and individual sponsors of this study are listed on the CSPOR website (http://www.csp.or.jp/cspor/kyousan_e.html).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSawaki M, Taira N, Uemura Y, Saito T, Baba S, Kobayashi K, Kawashima H, Tsuneizumi M, Sagawa N, Bando H, Takahashi M, Yamaguchi M, Takashima T, Nakayama T, Kashiwaba M, Mizuno T, Yamamoto Y, Iwata H, Kawahara T, Ohashi Y, Mukai H (2020) Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. 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The Lancet 369:29-36. doi: 10.1016/s0140-6736(07)60028-2\u003c/li\u003e\n\u003cli\u003eSlamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273-1283. doi: 10.1056/NEJMoa0910383\u003c/li\u003e\n\u003cli\u003eGianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. 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J Clin Oncol 38:528-528. doi: 10.1200/JCO.2020.38.15_suppl.528\u003c/li\u003e\n\u003cli\u003eMuss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP (2009) Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360:2055-2065. doi: 10.1056/NEJMoa0810266\u003c/li\u003e\n\u003cli\u003eKornblith AB, Lan L, Archer L, Partridge A, Kimmick G, Hudis C, Winer E, Casey R, Bennett S, Cohen HJ, Muss HB (2011) Quality of Life of Older Patients With Early-Stage Breast Cancer Receiving Adjuvant Chemotherapy: A Companion Study to Cancer and Leukemia Group B 49907. 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J Clin Oncol 39:608-618. doi: 10.1200/jco.20.02063\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Breast cancer, older, HER2, trastuzumab, without chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-1112686/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1112686/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose \u003c/strong\u003eTo gauge the effects of treatment practices on prognosis for all older patients with HER2-positive early breast cancer, particularly to determine whether adjuvant trastuzumab alone can offer benefit over no adjuvant therapy. This report accompanies the RESPECT study, a randomized-controlled trial (RCT) comparing trastuzumab monotherapy with trastuzumab-plus-chemotherapy.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePatients and methods \u003c/strong\u003ePatients who declined the RCT were treated based on the physician’s discretion. We studied the (1) trastuzumab-plus-chemotherapy group, (2) trastuzumab-monotherapy group, and (3) non-trastuzumab group (no therapy or anticancer therapy without trastuzumab). The primary endpoint was disease-free survival (DFS), which was compared using the propensity-score method. Relapse-free survival (RFS) and health-related quality of life (HRQoL) were also assessed.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eWe enrolled 123 eligible patients, aged over 70 years, with HER2-positive invasive breast cancer in this cohort study. The median age was 74.5 years. Among cohort study treatment categories were as follows: (1) trastuzumab-plus-chemotherapy group (n = 36, 30%), (2) trastuzumab-monotherapy group (n = 52, 43%), and (3) non-trastuzumab group (n = 32, 27%). A total of 73% of patients received trastuzumab-containing regimens, with or without chemotherapy. The 3-year DFS was 92.3% in the trastuzumab-plus-chemotherapy group, 89.2% in the trastuzumab-monotherapy group, and 82.5% in the non-trastuzumab group. DFS in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab-monotherapy groups (propensity-adjusted HR: 3.29; 95% CI: 1.15–9.39; \u003cem\u003eP\u003c/em\u003e = 0.026). The RFS in the non-trastuzumab group was lower than in the trastuzumab-plus-chemotherapy and trastuzumab monotherapy groups (propensity-adjusted HR = 7.80; 95% CI: 2.32–26.2, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.0001). There were no significant intergroup differences in the proportions of patients showing QoL deterioration (\u003cem\u003eP \u003c/em\u003e= 0.717) and improvement (\u003cem\u003eP \u003c/em\u003e= 0.652) at 36 months.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e Trastuzumab-treated patients had better prognoses than patients not treated with trastuzumab without deterioration of HRQoL. Thus, trastuzumab monotherapy can be considered for patients who reject chemotherapy.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration number \u003c/strong\u003eThe protocol was registered on the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID: UMIN 000028476).\u003c/p\u003e","manuscriptTitle":"Adjuvant trastuzumab without chemotherapy for treating early HER2-positive breast cancer in older patients: a propensity score-adjusted analysis of a prospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-09-07 16:31:03","doi":"10.21203/rs.3.rs-1112686/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec4a093b-bdc1-4ff3-8663-2e3414119b74","owner":[],"postedDate":"September 7th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-06T15:15:07+00:00","versionOfRecord":{"articleIdentity":"rs-1112686","link":"https://doi.org/10.1016/j.breast.2022.10.017","journal":{"identity":"the-breast","isVorOnly":true,"title":"The Breast"},"publishedOn":"2022-12-01 15:15:07","publishedOnDateReadable":"December 1st, 2022"},"versionCreatedAt":"2022-09-07 16:31:03","video":"","vorDoi":"10.1016/j.breast.2022.10.017","vorDoiUrl":"https://doi.org/10.1016/j.breast.2022.10.017","workflowStages":[]},"version":"v1","identity":"rs-1112686","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1112686","identity":"rs-1112686","version":["v1"]},"buildId":"omnImTCwR2MFx8CMYfrG7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}