Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of Japanese patients with breast cancer

Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of Japanese patients with breast cancer | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of Japanese patients with breast cancer Akane Higami, Masahiro Takada, Nobuko Kawaguchi-Sakita, Masahiro Kawashima, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3878376/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Aug, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background The prognostic value of the risk-of-recurrence (ROR) score calculated using PAM50 has been validated using clinical trials and patient cohorts. This study aimed to investigate the prognostic value of the PAM50 ROR score in Japanese patients with early breast cancer using long-term follow-up data. Methods We enrolled postmenopausal patients with ER -positive, HER2 -negative, stage I–II breast cancer who had undergone surgery at the Kyoto University Hospital between 2014 and 2018. The intrinsic subtype and ROR score were calculated using PAM50 . The primary endpoint was invasive disease-free survival (IDFS). Results We enrolled 147 patients, of whom 48 (33%) patients had node-positive disease, and 37 (25%) had received neoadjuvant or adjuvant chemotherapy. The proportions of intrinsic subtypes for luminal A, luminal B, HER2 -enriched, and basal-like subtypes were 67%, 27%, 3%, and 2%, respectively. The median follow-up duration was 8.4 (range: 6.3–10.0) years, and 21 IDFS events were observed. Based on the ROR score, 37%, 33%, and 30% of the patients were classified as low-, intermediate-, and high-risk, respectively. Patients in the high-risk group had a significantly worse 8-year IDFS rate than those in the low-to-intermediate-risk groups (75.7% vs. 91.6%, p = 0.04). The same trend was observed in patients with and without neoadjuvant or adjuvant chemotherapy. Conclusions Using long-term follow-up data, this study showed that the ROR score can predict the prognosis of ER -positive, HER2 -negative early breast cancer in Japanese postmenopausal patients. Further investigations are required to confirm the prognostic value of the ROR score in Asian populations. Breast cancer PAM50 genomic subtyping Japanese patients postmenopausal Figures Figure 1 Figure 2 Figure 3 Introduction Advances in systemic therapy have improved the prognosis of breast cancer. Adjuvant systemic therapy should be based on the individual risk of recurrence (ROR). Traditionally, the estimation of ROR has relied on clinical and pathological factors, such as age, tumor size, lymph node involvement, histological grade, ER status, HER2 status, and proliferative markers. Recent studies and guidelines recommend the incorporation of gene expression profiling to enhance the accuracy of predicting the ROR. The PAM50 expression panel was developed to classify breast cancer into intrinsic subtypes [1, 2]. PAM50 also yields an ROR score by combining gene expression profiles with clinical information, including histological grade, tumor size, and lymph node metastasis status. The features of the ROR score lie in its amalgamation of gene expression profiles with clinical risk factors. The clinical utility of the ROR score was evaluated using tumor samples from 1,478 patients who had participated in the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) trial of adjuvant endocrine therapy for postmenopausal patients with ER -positive disease. The ROR score added a significant prognostic value to the clinical risk model. The ROR-based risk groups separated patient prognosis, with the low-risk group demonstrating a favorable outcome (10-year distant recurrence-free survival rates: 96.7%, 91.3%, and 79.9% in the low-, intermediate-, and high-risk groups) [3]. Patients with luminal A-type tumors showed a significantly better prognosis than those with luminal B-type tumors (10-year distant recurrence-free survival rate: 93.9% vs. 82.2%, p < 0.0001). Another study utilizing the Danish Breast Cancer Cooperative Group database involved 2,558 postmenopausal patients who had received 5 years of endocrine therapy [4]. Among the lymph node-positive cases, the 10-year distant metastasis recurrence rate differed significantly between the low- and high-risk groups (3.5% vs. 22.1%). Similarly, even in lymph node-negative cases, the 10-year distant metastasis recurrence rate differed significantly between the low- and high-risk groups (5.0% vs. 17.8%). A similar analysis was conducted in patients who had participated in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial of anastrozole and tamoxifen for postmenopausal patients with ER -positive disease. It revealed that the ROR provided more prognostic information than the Oncotype DX Recurrence Score. Continuous ROR scores correlated with the predicted 10-year risk of distant recurrence [5]. Nevertheless, the prognostic significance of the ROR score has not been extensively examined in Asians with early breast cancer. Therefore, this study aimed to investigate the prognostic significance of the ROR score using single-center long-term follow-up cohort data of postmenopausal patients with early breast cancer in Japan. Patients and methods This was a retrospective cohort study involving postmenopausal patients with stage I–II (cT1cN0 or higher), ER -positive, HER2 -negative breast cancer who had undergone surgery at the Kyoto University Hospital between January 2008 and December 2014. The study protocol was approved by the Institutional Review Board of the Kyoto University Hospital. A genetic analysis of PAM50 was performed using tumor tissues from surgical specimens of the target population to evaluate the intrinsic subtype and ROR score at Medbis Co., Kyoto, Japan. Clinical information, such as tumor stage, pathological diagnosis, treatment, and outcome, was extracted from medical records. The primary endpoint was invasive disease-free survival (IDFS) rates stratified by ROR-based risk groups and intrinsic subtypes (luminal A vs. B). Secondary endpoints included distant disease-free survival (DDFS) and overall survival. In patients without lymph node metastasis, ROR scores of 0–40, 41–60, and 61–100 were classified as low-, intermediate-, and high-risk groups, respectively. In patients with lymph node metastasis, ROR scores of 0–40 and 41–100 were classified as low- and high-risk groups, respectively. Survival curves were estimated using the Kaplan–Meier method, stratified by ROR score-based risk groups and intrinsic subtypes. Survival rates 8 years postoperatively, along with 95% confidence intervals, were calculated. Statistical analyses were performed using JMP Pro version 16.1.0 (SAS Institute, Cary, NC, USA). Statistical significance was defined as a two-sided p -value < 0.05. Results We enrolled 150 patients, 147 of whom had tissue samples available for genetic analyses and were included in the analysis. Table 1 summarizes the patient characteristics and treatment histories. The median patient age was 67 (range: 46–89) years. pT1 and pT2 disease were found in 57.7% and 40.8% of the patients, respectively. Lymph node metastasis was observed in 33% of the patients. Adjuvant endocrine therapy was administered to 138 (93.9%) patients, and neoadjuvant or adjuvant chemotherapy was administered to 37 (25%) patients. The distribution of intrinsic subtypes was as follows: luminal A, 99 (67.3%) cases; luminal B, 40 (27.2%) cases; HER2 -enriched, five (3.4%) cases; and basal-like, three (2.0%) cases. The median ROR score was 41 (range: 0–89), with 54 (36.7%),48 (32.7%), and 45 (30.6%) cases classified as low-, intermediate-, and high-risk, respectively. Table 1 Patient characteristics Factors n (%) Age, median (range) 67 (46–89) years Tumor stage Tis 1 (0.7) T1a/b 10 (6.8) T1c 74 (50.3) T2 60 (40.8) T3 2 (1.4) Nodal stage N0 99 (67.3) N1 47 (20.4) N2 1 (0.7) Histological grade 1 47 (32.0) 2 79 (53.7) 3 20 (13.6) Not applicable 1 (0.7) Surgery Lumpectomy 99 (67.3) Mastectomy 48 (32.7) Radiotherapy Yes 87 (59.2) No 60 (40.8) Systemic therapy Neoadjuvant/adjuvant chemotherapy 37 (25.2) Endocrine therapy 138 (93.9) The median follow-up duration was 8.4 (range: 6.3–10.0 years), and 21 IDFS events were observed, including eight (5.4%) cases of local recurrence, ten (6.8%) cases of distant recurrence, and nine (6.1%) cases of death. Among the deceased patients, four (2.7%) were considered breast cancer-specific deaths. Four cases of recurrence occurred ≥ 5 years postoperatively. The 8-year IDFS rate was 86.5% (95% confidence interval [CI]: 79.6–91.4%; Fig. 1). The 8-year IDFS rate based on the ROR score were 91.9% (95% CI: 80.4–96.9%) for low-risk, 91.0% (95% CI: 78.1–96.6%) for intermediate-risk, and 75.7% (95% CI: 60.3–86.5%) for high-risk (Fig. 2A). The combined 8-year IDFS rate of low- and intermediate-risk groups differed significantly from that of the high-risk group (low-to-intermediate-risk group: 91.6%, 95% CI: 84.0–95.7%; high-risk group: 75.7%, 95% CI: 60.3–86.5%, p = 0.044; Fig. 2B). In patients who had received neoadjuvant/adjuvant chemotherapy, the 8-year IDFS rate was 95.8% (95% CI: 75.6–99.4%) for the low-to-intermediate-risk group and 64.1% (95% CI: 32.8–86.7%) for the high-risk group (Figure S1 A). In patients who did not receive neoadjuvant/adjuvant chemotherapy, the 8-year IDFS rate was 90.2% (95% CI: 80.7–95.3%) for low-to-intermediate-risk group and 79.0% (95% CI: 60.5–90.3%) for the high-risk group (Figure S1 B). Patients with luminal A disease had a numerically higher 8-year IDFS rate compared to those with luminal B disease, although without statistical significance (87.6%, 95% CI: 78.8–93.0% vs. 83.6%, 95% CI: 68.0–92.5%; Fig. 3). Owing to the small number of cases and events, IDFS was not estimated for HER2 -enriched and basal-like subtypes. The 8-year DDFS rate was 90.0% (95% CI: 83.1–94.3%; Figure S2 A) overall, 95.7% (95% CI: 84.5–98.9%) for the low-risk group, 92.9% (95% CI: 80.2–97.7%) for the intermediate-risk group, and 80.1% (95% CI: 63.5–90.3%) for the high-risk group (Figure S2 B). The combined 8-year DDFS rate of low- and intermediate-risk groups differed significantly from that of the high-risk group (low-to-intermediate-risk group: 94.4%, 95% CI: 87.2–97.6%; high-risk group: 80.1%, 95% CI: 63.5–90.3%; p = 0.041; Figure S2 C). The 8-year DDFS rates were 90.8% (95% CI: 81.8–95.6%) for luminal A and 88.7% (95% CI: 73.5–95.7%) for luminal B (Figure S2 D). Eight cases were classified as HER2 -enriched or basal-like subtypes based on PAM50 (Table 2 ). All three patients with the basal-like disease showed relatively low ER expressions. Of the five patients with the HER2 -enriched disease, only one showed HER2 expression. None of the eight patients were classified into the low-risk group. Table 2 Characteristics of patients with subtypes other than the luminal type Case Subtype ROR Risk group ER (%) PgR (%) HER2 score Ki67 (%) 1 Basal-like 46 Intermediate 30 0 1+ 40 2 Basal-like 36 Intermediate 5 < 5 0 30 3 Basal-like 49 Intermediate 5 0 0 27 4 HER2 -enriched 73 High Allred score 3 Allred score 3 2+ 40 5 HER2 -enriched 53 Intermediate 100 < 1 1+ 20 6 HER2 -enriched 89 High 100 0 0 40 7 HER2 -enriched 81 High 100 0 0 40 8 HER2 -enriched 68 High 60 0 0 10 ROR, rate of recurrence Discussion We evaluated the prognostic value of the PAM50 ROR score using long-term follow-up data from Japanese postmenopausal patients with ER -positive and HER2 -negative early breast cancer. Patients classified into the high-risk group showed significantly worse IDFS than those classified into the low- or intermediate-risk groups. Most patients were classified as luminal A/B subtype, and eight (5.4%) patients were classified as HER2 -enriched or basal-like subtypes. The distribution of intrinsic subtypes in our cohort of patients with ER -positive and HER2 -negative early breast cancer was almost consistent with that reported in previous studies. In a report by Parker et al. examining the intrinsic subtypes in patients with ER -positive breast cancer who did not receive systemic therapy, 73%, 11%, and 5% of whom were classified as luminal, HER2 -enriched, and basal-like subtypes, respectively [2]. In the ABCSG8 trial, the intrinsic subtypes of ER -positive patients undergoing hormone therapy were investigated. In this trial, 67.9%, 28.3%, 3.3%, and 0.5% of the patients were classified as having luminal A, luminal B, HER2 -enriched, and basal-like types, respectively. In the Trans-ATAC trial, 4.0% of patients had HER2 -enriched disease, and 0.9% had basal-like disease. In the Danish cohort, including patients with ER -positive and HER2 -negative status who received hormone therapy, 57.6%, 37.0%, 4.0%, and 1.0% had luminal A, luminal B, HER2 -enriched, and basal-like disease. These results indicate the absence of ethnic differences in the distribution of intrinsic subtypes among patients with ER -positive, HER2 -negative early breast cancer. Our results of the relationship between prognosis and risk groups by ROR are consistent with those of previous reports. In the ABCSG-8 trial, the luminal A type showed a significantly better prognosis compared to the luminal B type (10-year DDFS: 93.9% vs. 82.2%, p < 0.0001), and the low-risk group showed a favorable 10-year DDFS compared to the high-risk group (10-year DDFS rate: low-risk group, 96.7%; intermediate-risk group, 91.3%; high-risk group, 79.9%) [3]. In the Danish cohort, the 10-year DDFS rate differed among risk groups. Among patients with node-negative disease, the DDFS rates were 5.0% for low-risk, 7.3% for intermediate-risk, and 17.8% for high-risk patients. Among patients with node-positive disease, the DDFS rates were 3.5% for low-risk, 11.0% for intermediate-risk, and 22.0% for high-risk patients. The incidence of distant recurrence was significantly lower in patients with luminal A disease than in those with luminal B disease (7.6% vs. 18.4%) [4]. In the present study, the high-risk group had significantly worse IDFS compared to the other groups. These results indicate that the ROR score could also provide prognostic information for Japanese postmenopausal patients with ER -positive, HER2 -negative early breast cancer. In terms of the relationship between the prognosis and the intrinsic subtype, patients with luminal A- and B-type tumors showed no significant difference. Both the ABCSG8 trial and Danish cohort included patients treated with endocrine therapy alone as adjuvant treatment. In contrast, our study involved patients who received adjuvant chemotherapy in addition to adjuvant endocrine therapy based on the physician’s treatment choice. A higher proportion of patients with luminal B disease received adjuvant chemotherapy than those with luminal A disease (27.5% vs. 14.1%), which may partly explain the lack of a significant prognostic difference between luminal A and B disease. A combined analysis of the ABCSG 8 and TransATAC trial showed that ROR scores were also useful for predicting late distant recurrence after 5 years of endocrine therapy. In the lymph node-negative/HER2-negative subgroup, ROR scores were significantly prognostic at 5 to 10 years. The risk of distant recurrence at 5 to 10 years was 16.6% (95%CI:13.1%-20.9%) for the high-risk group, 8.3% (95%CI, 6.1–11.2%) for the intermediate-risk group, and 2.4% (95% CI: 1.6%-3.5%) for the low-risk group, respectively. In our study, we were unable to examine the ability of the ROR to predict late recurrence due to the limited number of events [6]. In the present study, eight cases were classified as basal-like or HER2 -enriched. These cases tended to have a higher ROR score and were classified as intermediate- or high-risk. Of these eight cases, one experienced distant recurrence and breast cancer-related death. In the present study, the basal-like type exhibited a lower rate of ER positivity. Ohara et al. reported that among patients (n = 16) with low ER (1–9%), 93.7% were identified as HER2 -enriched or basal-like types, while only 6.3% were classified as the luminal type [7]. In another study, of all patients with ER -deficient tumors, 8% had luminal B tumors, and 48% had basal-like tumors [8]. The optimal treatment for ER -deficient tumors remains controversial and requires further investigations [9]. This study had several limitations. This was a retrospective study involving a limited number of patients; therefore, the number of IDFS events was limited because we included patients with early breast cancer, which limited the statistical evaluation using the multivariate analysis. However, a strength of this study was the availability of long-term follow-up data from an academic institution, with a median follow-up duration of 8.4 years. To our knowledge, this was the first study to investigate the prognostic value of the PAM50 expression in Japanese patients with breast cancer. The present study suggests the clinical utility of PAM50 ROR scores for predicting the prognosis in Japanese postmenopausal patients with ER -positive, HER2 -negative early breast cancer, based on long-term follow-up data. The results of this study support the possibility of extrapolating previous results demonstrating the clinical utility of PAM50 . Further investigations are required to confirm the prognostic value of PAM50 . Declarations Acknowledgments We thank all the participants who were involved in this study. We would like to thank Editage (www.editage.jp) for English language editing. Conflict of interest Masahiro Takada received institutional grants from AstraZeneca (Osaka, Japan), Daiichi Sankyo (Tokyo, Japan), Eisai (Tokyo, Japan), Yakult (Tokyo, Japan), Medbis (Kyoto, Japan), Taiho (Tokyo, Japan), the Japan Breast Cancer Research Group Association (JBCRG), the Kyoto Breast Cancer Research Network (KBCRN), ABCSG, and IQVIA Japan; and personal fees from Chugai (Tokyo, Japan), AstraZeneca, Daiichi Sankyo, Taiho, Pfizer (Tokyo, Japan), Eli Lilly (Kobe, Japan), Eisai, and MSD (Tokyo, Japan).Nobuko Kawaguchi-Sakita：Dr. Kawaguchi-Sakita reports personal fees from Chugai, personal fees from Daiichi-Sankyo, grants from Fuji Chemical Industrial, personal fees from Fujitsu, personal fees from Kyowa Kirin, personal fees from Meiji Seika Pharma, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Yakult, personal fees from NTT, personal fees from PRiME-R, personal fees from CANNON Medical, personal fees from HUG, personal fees from NTT-DATA, personal fees from IHC, grants from Kansai Medical Net, personal fees from Taiho, personal fees from Eisai, personal fees from Astra Zeneca, personal fees from Zene, outside the submitted work.Masakazu Toi：Dr. Toi has funding from Chugai, Takeda, Pfizer, Taiho, JBCRG assoc., KBCRN assoc., Eisai, Eli-Lilly and companies, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technology, Luxonus, Shionogi, GL Science and Sanwa Shurui as a research grant. He has funding from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly and companies, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon Kayaku、Devicore Medical Japan and Sysmex as compensation for Lecture honoraria or lecture chairs. He has funding from Daiichi-Sankyo, Eli Lilly and companies, BMS, Athenex Oncology, Bertis, Terumo, Kansai Medical Net for Advisory board. He has funding from British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women’s Cancer, Asian Journal of Surgery, and Asian Journal of Breast Surgery for Associate editor. Author contributions Date analysis was performed by Akane Higami and Masahiro Takada. Akane Higami and Masahiro Takada wrote first draft. all the other authors critically revised previous versions of the manuscript. All the authors read and approved the final manuscript. References Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS et al : Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001, 98(19):10869-10874. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z et al : Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009, 27(8):1160-1167. Gnant M, Filipits M, Greil R, Stoeger H, Rudas M, Bago-Horvath Z, Mlineritsch B, Kwasny W, Knauer M, Singer C et al : Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol 2014, 25(2):339-345. Laenkholm AV, Jensen MB, Eriksen JO, Rasmussen BB, Knoop AS, Buckingham W, Ferree S, Schaper C, Nielsen TO, Haffner T et al : PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer. J Clin Oncol 2018, 36(8):735-740. Dowsett M, Sestak I, Lopez-Knowles E, Sidhu K, Dunbier AK, Cowens JW, Ferree S, Storhoff J, Schaper C, Cuzick J: Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 2013, 31(22):2783-2790. Sestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, Cowens JW, Ferree S, Schaper C, Fesl C et al : Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol 2015, 33(8):916-922. Ohara AM, Naoi Y, Shimazu K, Kagara N, Shimoda M, Tanei T, Miyake T, Kim SJ, Noguchi S: PAM50 for prediction of response to neoadjuvant chemotherapy for ER-positive breast cancer. Breast Cancer Res Treat 2019, 173(3):533-543. Iwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ, Ueno NT, Zhang J, Shi W, Qi Y et al : Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry. J Clin Oncol 2012, 30(7):729-734. 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Supplementary Files FigS1A.IDFSby2riskbychemo.pdf FigS1B.IDFSby2riskbychemo.pdf FigS2A.DDFSAll.pdf FIgS2B.DDFSby3risk.pdf FigS2C.DDFSby2risk.pdf FigS2D.DDFSbyLumsubtype.pdf Cite Share Download PDF Status: Published Journal Publication published 23 Aug, 2024 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 02 Apr, 2024 Reviewers agreed at journal 12 Feb, 2024 Reviewers invited by journal 08 Feb, 2024 First submitted to journal 21 Jan, 2024 Editor assigned by journal 18 Jan, 2024 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. 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Byoin","correspondingAuthor":false,"prefix":"","firstName":"Kosuke","middleName":"","lastName":"Kawaguchi","suffix":""},{"id":272099143,"identity":"b0e30880-daac-4681-9151-16a3b1c8ea7c","order_by":5,"name":"Ayane Yamaguchi","email":"","orcid":"","institution":"Kyoto University Hospital: Kyoto Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Ayane","middleName":"","lastName":"Yamaguchi","suffix":""},{"id":272099144,"identity":"a4c93c77-b619-4b4c-b660-7b3fe38da03c","order_by":6,"name":"Yasuhide Takeuchi","email":"","orcid":"","institution":"Kyoto University Hospital: Kyoto Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yasuhide","middleName":"","lastName":"Takeuchi","suffix":""},{"id":272099145,"identity":"659e2aed-542a-4db2-ab81-8372b481e895","order_by":7,"name":"Yosuke Yamada","email":"","orcid":"","institution":"Kyoto University Hospital: Kyoto Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Yamada","suffix":""},{"id":272099146,"identity":"569130ce-ce20-46ef-9be3-e7769143c93e","order_by":8,"name":"Masakazu Kawaguchi Toi","email":"","orcid":"","institution":"Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital: Tokyo Toritsu Komagome Byoin","correspondingAuthor":false,"prefix":"","firstName":"Masakazu","middleName":"Kawaguchi","lastName":"Toi","suffix":""}],"badges":[],"createdAt":"2024-01-19 10:05:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3878376/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3878376/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-024-02604-1","type":"published","date":"2024-08-23T15:57:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51080955,"identity":"65b50636-0583-46a0-aa24-3c63c875f9e0","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":119664,"visible":true,"origin":"","legend":"\u003cp\u003eInvasive disease-free survival in an ITT population of Japanese postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive breast cancer\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/ad9b62d967c5111071cbeddd.jpg"},{"id":51082144,"identity":"72deaf94-b846-4afd-8641-3f5f9baf8909","added_by":"auto","created_at":"2024-02-13 19:22:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":483251,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Relationship between the risk of recurrence score calculated using \u003cem\u003ePAM50 \u003c/em\u003eand invasive disease-free survival (IDFS) in Japanese postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive breast cancer, divided into low-, intermediate-, and high-risk groups. (B) IDFS with separate comparisons for low-to-intermediate- and high-risk groups.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/9f860539bfd7e6d6b9913c7c.jpg"},{"id":51080958,"identity":"f17fe364-e6b0-460c-a0f3-58dd8baedb46","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":145788,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between luminal A and B subtypes by \u003cem\u003ePAM50\u003c/em\u003e and invasive disease-free survival in Japanese postmenopausal patients\u003cem\u003e \u003c/em\u003ewith\u003cem\u003e ER\u003c/em\u003e-positive breast cancer\u003c/p\u003e","description":"","filename":"FIg3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/cc170ded743e5c76a17f00f1.jpg"},{"id":63300035,"identity":"d3c52a02-2402-4986-aae2-7dccf75a04b3","added_by":"auto","created_at":"2024-08-26 16:10:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1198824,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/343accde-818f-4ddc-9f96-0d88158d73d4.pdf"},{"id":51080961,"identity":"a0f37e15-af60-468c-861d-4381a91f1926","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":26932,"visible":true,"origin":"","legend":"","description":"","filename":"FigS1A.IDFSby2riskbychemo.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/e91aac8b9c9eea25c09c6cdc.pdf"},{"id":51080956,"identity":"40b957db-6450-4f55-a81f-19decd565663","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":27623,"visible":true,"origin":"","legend":"","description":"","filename":"FigS1B.IDFSby2riskbychemo.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/e029cf804dfb8e39364b495a.pdf"},{"id":51080964,"identity":"8f155838-8b03-4b6a-8368-35089d0bfcbb","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":17071,"visible":true,"origin":"","legend":"","description":"","filename":"FigS2A.DDFSAll.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/33d8dd2dc4941ca3b298f18c.pdf"},{"id":51080963,"identity":"0f3bcb39-af40-480d-9933-4542f092bb8f","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":27749,"visible":true,"origin":"","legend":"","description":"","filename":"FIgS2B.DDFSby3risk.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/2c0e393b4be29a0c10ca53aa.pdf"},{"id":51080962,"identity":"bb663610-71bd-4caa-b0cd-022df3cd2806","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":27760,"visible":true,"origin":"","legend":"","description":"","filename":"FigS2C.DDFSby2risk.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/1bf7c6c45f8f937ccf60316e.pdf"},{"id":51080960,"identity":"3aac4acc-7c12-4efa-a4ac-7335faddadec","added_by":"auto","created_at":"2024-02-13 19:14:07","extension":"pdf","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":25374,"visible":true,"origin":"","legend":"","description":"","filename":"FigS2D.DDFSbyLumsubtype.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878376/v1/9f0a9e3715c72a084d22cb12.pdf"}],"financialInterests":"","formattedTitle":"Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of Japanese patients with breast cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdvances in systemic therapy have improved the prognosis of breast cancer. Adjuvant systemic therapy should be based on the individual risk of recurrence (ROR). Traditionally, the estimation of ROR has relied on clinical and pathological factors, such as age, tumor size, lymph node involvement, histological grade, \u003cem\u003eER\u003c/em\u003e status, \u003cem\u003eHER2\u003c/em\u003e status, and proliferative markers. Recent studies and guidelines recommend the incorporation of gene expression profiling to enhance the accuracy of predicting the ROR.\u003c/p\u003e \u003cp\u003eThe \u003cem\u003ePAM50\u003c/em\u003e expression panel was developed to classify breast cancer into intrinsic subtypes [1, 2]. \u003cem\u003ePAM50\u003c/em\u003e also yields an ROR score by combining gene expression profiles with clinical information, including histological grade, tumor size, and lymph node metastasis status. The features of the ROR score lie in its amalgamation of gene expression profiles with clinical risk factors.\u003c/p\u003e \u003cp\u003eThe clinical utility of the ROR score was evaluated using tumor samples from 1,478 patients who had participated in the Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG-8) trial of adjuvant endocrine therapy for postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive disease. The ROR score added a significant prognostic value to the clinical risk model. The ROR-based risk groups separated patient prognosis, with the low-risk group demonstrating a favorable outcome (10-year distant recurrence-free survival rates: 96.7%, 91.3%, and 79.9% in the low-, intermediate-, and high-risk groups) [3]. Patients with luminal A-type tumors showed a significantly better prognosis than those with luminal B-type tumors (10-year distant recurrence-free survival rate: 93.9% vs. 82.2%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Another study utilizing the Danish Breast Cancer Cooperative Group database involved 2,558 postmenopausal patients who had received 5 years of endocrine therapy [4]. Among the lymph node-positive cases, the 10-year distant metastasis recurrence rate differed significantly between the low- and high-risk groups (3.5% vs. 22.1%). Similarly, even in lymph node-negative cases, the 10-year distant metastasis recurrence rate differed significantly between the low- and high-risk groups (5.0% vs. 17.8%). A similar analysis was conducted in patients who had participated in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial of anastrozole and tamoxifen for postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive disease. It revealed that the ROR provided more prognostic information than the Oncotype DX Recurrence Score. Continuous ROR scores correlated with the predicted 10-year risk of distant recurrence [5]. Nevertheless, the prognostic significance of the ROR score has not been extensively examined in Asians with early breast cancer. Therefore, this study aimed to investigate the prognostic significance of the ROR score using single-center long-term follow-up cohort data of postmenopausal patients with early breast cancer in Japan.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003eThis was a retrospective cohort study involving postmenopausal patients with stage I\u0026ndash;II (cT1cN0 or higher), \u003cem\u003eER\u003c/em\u003e-positive, \u003cem\u003eHER2\u003c/em\u003e-negative breast cancer who had undergone surgery at the Kyoto University Hospital between January 2008 and December 2014. The study protocol was approved by the Institutional Review Board of the Kyoto University Hospital.\u003c/p\u003e \u003cp\u003eA genetic analysis of \u003cem\u003ePAM50\u003c/em\u003e was performed using tumor tissues from surgical specimens of the target population to evaluate the intrinsic subtype and ROR score at Medbis Co., Kyoto, Japan. Clinical information, such as tumor stage, pathological diagnosis, treatment, and outcome, was extracted from medical records.\u003c/p\u003e \u003cp\u003eThe primary endpoint was invasive disease-free survival (IDFS) rates stratified by ROR-based risk groups and intrinsic subtypes (luminal A vs. B). Secondary endpoints included distant disease-free survival (DDFS) and overall survival. In patients without lymph node metastasis, ROR scores of 0\u0026ndash;40, 41\u0026ndash;60, and 61\u0026ndash;100 were classified as low-, intermediate-, and high-risk groups, respectively. In patients with lymph node metastasis, ROR scores of 0\u0026ndash;40 and 41\u0026ndash;100 were classified as low- and high-risk groups, respectively. Survival curves were estimated using the Kaplan\u0026ndash;Meier method, stratified by ROR score-based risk groups and intrinsic subtypes. Survival rates 8 years postoperatively, along with 95% confidence intervals, were calculated. Statistical analyses were performed using JMP Pro version 16.1.0 (SAS Institute, Cary, NC, USA). Statistical significance was defined as a two-sided \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe enrolled 150 patients, 147 of whom had tissue samples available for genetic analyses and were included in the analysis. Table\u0026nbsp;1 summarizes the patient characteristics and treatment histories. The median patient age was 67 (range: 46\u0026ndash;89) years. pT1 and pT2 disease were found in 57.7% and 40.8% of the patients, respectively. Lymph node metastasis was observed in 33% of the patients. Adjuvant endocrine therapy was administered to 138 (93.9%) patients, and neoadjuvant or adjuvant chemotherapy was administered to 37 (25%) patients. The distribution of intrinsic subtypes was as follows: luminal A, 99 (67.3%) cases; luminal B, 40 (27.2%) cases; \u003cem\u003eHER2\u003c/em\u003e-enriched, five (3.4%) cases; and basal-like, three (2.0%) cases. The median ROR score was 41 (range: 0\u0026ndash;89), with 54 (36.7%),48 (32.7%), and 45 (30.6%) cases classified as low-, intermediate-, and high-risk, respectively.\u003c/p\u003e\n\u003ctable border=\"1\" width=\"412\"\u003e\u003ccaption\u003e\n\u003cp\u003eTable 1\u003c/p\u003e\n\u003cp\u003ePatient characteristics\u003c/p\u003e\n\u003c/caption\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003e\u003cstrong\u003eFactors\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e\u003cstrong\u003en (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eAge, median (range)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e67 (46\u0026ndash;89) years\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eTumor stage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eTis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e1 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eT1a/b\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e10 (6.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eT1c\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e74 (50.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eT2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e60 (40.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eT3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e2 (1.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eNodal stage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eN0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e99 (67.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eN1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e47 (20.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eN2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e1 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eHistological grade\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e47 (32.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e79 (53.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e20 (13.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e1 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eSurgery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eLumpectomy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e99 (67.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eMastectomy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e48 (32.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eRadiotherapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eYes\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e87 (59.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e60 (40.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eSystemic therapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eNeoadjuvant/adjuvant chemotherapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e37 (25.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"237\"\u003e\n\u003cp\u003eEndocrine therapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"175\"\u003e\n\u003cp\u003e138 (93.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe median follow-up duration was 8.4 (range: 6.3\u0026ndash;10.0 years), and 21 IDFS events were observed, including eight (5.4%) cases of local recurrence, ten (6.8%) cases of distant recurrence, and nine (6.1%) cases of death. Among the deceased patients, four (2.7%) were considered breast cancer-specific deaths. Four cases of recurrence occurred\u0026thinsp;\u0026ge;\u0026thinsp;5 years postoperatively. The 8-year IDFS rate was 86.5% (95% confidence interval [CI]: 79.6\u0026ndash;91.4%; Fig.\u0026nbsp;1). The 8-year IDFS rate based on the ROR score were 91.9% (95% CI: 80.4\u0026ndash;96.9%) for low-risk, 91.0% (95% CI: 78.1\u0026ndash;96.6%) for intermediate-risk, and 75.7% (95% CI: 60.3\u0026ndash;86.5%) for high-risk (Fig.\u0026nbsp;2A). The combined 8-year IDFS rate of low- and intermediate-risk groups differed significantly from that of the high-risk group (low-to-intermediate-risk group: 91.6%, 95% CI: 84.0\u0026ndash;95.7%; high-risk group: 75.7%, 95% CI: 60.3\u0026ndash;86.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044; Fig.\u0026nbsp;2B). In patients who had received neoadjuvant/adjuvant chemotherapy, the 8-year IDFS rate was 95.8% (95% CI: 75.6\u0026ndash;99.4%) for the low-to-intermediate-risk group and 64.1% (95% CI: 32.8\u0026ndash;86.7%) for the high-risk group (Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003eA). In patients who did not receive neoadjuvant/adjuvant chemotherapy, the 8-year IDFS rate was 90.2% (95% CI: 80.7\u0026ndash;95.3%) for low-to-intermediate-risk group and 79.0% (95% CI: 60.5\u0026ndash;90.3%) for the high-risk group (Figure \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003eB).\u003c/p\u003e\n\u003cp\u003ePatients with luminal A disease had a numerically higher 8-year IDFS rate compared to those with luminal B disease, although without statistical significance (87.6%, 95% CI: 78.8\u0026ndash;93.0% vs. 83.6%, 95% CI: 68.0\u0026ndash;92.5%; Fig.\u0026nbsp;3). Owing to the small number of cases and events, IDFS was not estimated for \u003cem\u003eHER2\u003c/em\u003e-enriched and basal-like subtypes.\u003c/p\u003e\n\u003cp\u003eThe 8-year DDFS rate was 90.0% (95% CI: 83.1\u0026ndash;94.3%; Figure \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003eA) overall, 95.7% (95% CI: 84.5\u0026ndash;98.9%) for the low-risk group, 92.9% (95% CI: 80.2\u0026ndash;97.7%) for the intermediate-risk group, and 80.1% (95% CI: 63.5\u0026ndash;90.3%) for the high-risk group (Figure \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003eB). The combined 8-year DDFS rate of low- and intermediate-risk groups differed significantly from that of the high-risk group (low-to-intermediate-risk group: 94.4%, 95% CI: 87.2\u0026ndash;97.6%; high-risk group: 80.1%, 95% CI: 63.5\u0026ndash;90.3%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041; Figure \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003eC). The 8-year DDFS rates were 90.8% (95% CI: 81.8\u0026ndash;95.6%) for luminal A and 88.7% (95% CI: 73.5\u0026ndash;95.7%) for luminal B (Figure \u003cspan class=\"InternalRef\"\u003eS2\u003c/span\u003eD).\u003c/p\u003e\n\u003cp\u003eEight cases were classified as \u003cem\u003eHER2\u003c/em\u003e-enriched or basal-like subtypes based on \u003cem\u003ePAM50\u003c/em\u003e (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). All three patients with the basal-like disease showed relatively low \u003cem\u003eER\u003c/em\u003e expressions. Of the five patients with the \u003cem\u003eHER2\u003c/em\u003e-enriched disease, only one showed \u003cem\u003eHER2\u003c/em\u003e expression. None of the eight patients were classified into the low-risk group.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of patients with subtypes other than the luminal type\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCase\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSubtype\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eROR\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRisk group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eER\u003c/em\u003e (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ePgR\u003c/em\u003e (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e score\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eKi67\u003c/em\u003e (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBasal-like\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntermediate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBasal-like\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e36\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntermediate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBasal-like\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntermediate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e27\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e-enriched\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e73\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAllred score 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAllred score 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e-enriched\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e53\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntermediate\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e-enriched\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e89\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e-enriched\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e81\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e40\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e-enriched\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHigh\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eROR, rate of recurrence\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe evaluated the prognostic value of the \u003cem\u003ePAM50\u003c/em\u003e ROR score using long-term follow-up data from Japanese postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive and \u003cem\u003eHER2\u003c/em\u003e-negative early breast cancer. Patients classified into the high-risk group showed significantly worse IDFS than those classified into the low- or intermediate-risk groups. Most patients were classified as luminal A/B subtype, and eight (5.4%) patients were classified as \u003cem\u003eHER2\u003c/em\u003e-enriched or basal-like subtypes.\u003c/p\u003e \u003cp\u003eThe distribution of intrinsic subtypes in our cohort of patients with \u003cem\u003eER\u003c/em\u003e-positive and \u003cem\u003eHER2\u003c/em\u003e-negative early breast cancer was almost consistent with that reported in previous studies. In a report by Parker et al. examining the intrinsic subtypes in patients with \u003cem\u003eER\u003c/em\u003e-positive breast cancer who did not receive systemic therapy, 73%, 11%, and 5% of whom were classified as luminal, \u003cem\u003eHER2\u003c/em\u003e-enriched, and basal-like subtypes, respectively [2]. In the ABCSG8 trial, the intrinsic subtypes of \u003cem\u003eER\u003c/em\u003e-positive patients undergoing hormone therapy were investigated. In this trial, 67.9%, 28.3%, 3.3%, and 0.5% of the patients were classified as having luminal A, luminal B, \u003cem\u003eHER2\u003c/em\u003e-enriched, and basal-like types, respectively. In the Trans-ATAC trial, 4.0% of patients had \u003cem\u003eHER2\u003c/em\u003e-enriched disease, and 0.9% had basal-like disease. In the Danish cohort, including patients with \u003cem\u003eER\u003c/em\u003e-positive and \u003cem\u003eHER2\u003c/em\u003e-negative status who received hormone therapy, 57.6%, 37.0%, 4.0%, and 1.0% had luminal A, luminal B, \u003cem\u003eHER2\u003c/em\u003e-enriched, and basal-like disease. These results indicate the absence of ethnic differences in the distribution of intrinsic subtypes among patients with \u003cem\u003eER\u003c/em\u003e-positive, \u003cem\u003eHER2\u003c/em\u003e-negative early breast cancer.\u003c/p\u003e \u003cp\u003eOur results of the relationship between prognosis and risk groups by ROR are consistent with those of previous reports. In the ABCSG-8 trial, the luminal A type showed a significantly better prognosis compared to the luminal B type (10-year DDFS: 93.9% vs. 82.2%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and the low-risk group showed a favorable 10-year DDFS compared to the high-risk group (10-year DDFS rate: low-risk group, 96.7%; intermediate-risk group, 91.3%; high-risk group, 79.9%) [3]. In the Danish cohort, the 10-year DDFS rate differed among risk groups. Among patients with node-negative disease, the DDFS rates were 5.0% for low-risk, 7.3% for intermediate-risk, and 17.8% for high-risk patients. Among patients with node-positive disease, the DDFS rates were 3.5% for low-risk, 11.0% for intermediate-risk, and 22.0% for high-risk patients. The incidence of distant recurrence was significantly lower in patients with luminal A disease than in those with luminal B disease (7.6% vs. 18.4%) [4]. In the present study, the high-risk group had significantly worse IDFS compared to the other groups. These results indicate that the ROR score could also provide prognostic information for Japanese postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive, \u003cem\u003eHER2\u003c/em\u003e-negative early breast cancer. In terms of the relationship between the prognosis and the intrinsic subtype, patients with luminal A- and B-type tumors showed no significant difference. Both the ABCSG8 trial and Danish cohort included patients treated with endocrine therapy alone as adjuvant treatment. In contrast, our study involved patients who received adjuvant chemotherapy in addition to adjuvant endocrine therapy based on the physician\u0026rsquo;s treatment choice. A higher proportion of patients with luminal B disease received adjuvant chemotherapy than those with luminal A disease (27.5% vs. 14.1%), which may partly explain the lack of a significant prognostic difference between luminal A and B disease.\u003c/p\u003e \u003cp\u003eA combined analysis of the ABCSG 8 and TransATAC trial showed that ROR scores were also useful for predicting late distant recurrence after 5 years of endocrine therapy. In the lymph node-negative/HER2-negative subgroup, ROR scores were significantly prognostic at 5 to 10 years. The risk of distant recurrence at 5 to 10 years was 16.6% (95%CI:13.1%-20.9%) for the high-risk group, 8.3% (95%CI, 6.1\u0026ndash;11.2%) for the intermediate-risk group, and 2.4% (95% CI: 1.6%-3.5%) for the low-risk group, respectively. In our study, we were unable to examine the ability of the ROR to predict late recurrence due to the limited number of events [6].\u003c/p\u003e \u003cp\u003eIn the present study, eight cases were classified as basal-like or \u003cem\u003eHER2\u003c/em\u003e-enriched. These cases tended to have a higher ROR score and were classified as intermediate- or high-risk. Of these eight cases, one experienced distant recurrence and breast cancer-related death. In the present study, the basal-like type exhibited a lower rate of \u003cem\u003eER\u003c/em\u003e positivity. Ohara et al. reported that among patients (n\u0026thinsp;=\u0026thinsp;16) with low ER (1\u0026ndash;9%), 93.7% were identified as \u003cem\u003eHER2\u003c/em\u003e-enriched or basal-like types, while only 6.3% were classified as the luminal type [7]. In another study, of all patients with \u003cem\u003eER\u003c/em\u003e-deficient tumors, 8% had luminal B tumors, and 48% had basal-like tumors [8]. The optimal treatment for \u003cem\u003eER\u003c/em\u003e-deficient tumors remains controversial and requires further investigations [9].\u003c/p\u003e \u003cp\u003eThis study had several limitations. This was a retrospective study involving a limited number of patients; therefore, the number of IDFS events was limited because we included patients with early breast cancer, which limited the statistical evaluation using the multivariate analysis. However, a strength of this study was the availability of long-term follow-up data from an academic institution, with a median follow-up duration of 8.4 years. To our knowledge, this was the first study to investigate the prognostic value of the \u003cem\u003ePAM50\u003c/em\u003e expression in Japanese patients with breast cancer.\u003c/p\u003e \u003cp\u003eThe present study suggests the clinical utility of \u003cem\u003ePAM50\u003c/em\u003e ROR scores for predicting the prognosis in Japanese postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive, \u003cem\u003eHER2\u003c/em\u003e-negative early breast cancer, based on long-term follow-up data. The results of this study support the possibility of extrapolating previous results demonstrating the clinical utility of \u003cem\u003ePAM50\u003c/em\u003e. Further investigations are required to confirm the prognostic value of \u003cem\u003ePAM50\u003c/em\u003e.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the participants who were involved in this study.\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMasahiro Takada received institutional grants from AstraZeneca (Osaka, Japan), Daiichi Sankyo (Tokyo, Japan), Eisai (Tokyo, Japan), Yakult (Tokyo, Japan), Medbis (Kyoto, Japan), Taiho (Tokyo, Japan), the Japan Breast Cancer Research Group Association (JBCRG), the Kyoto Breast Cancer Research Network (KBCRN), ABCSG, and IQVIA Japan; and personal fees from Chugai (Tokyo, Japan), AstraZeneca, Daiichi Sankyo, Taiho, Pfizer (Tokyo, Japan), Eli Lilly (Kobe, Japan), Eisai, and MSD (Tokyo, Japan).Nobuko Kawaguchi-Sakita：Dr. Kawaguchi-Sakita reports personal fees from Chugai, personal fees from Daiichi-Sankyo, grants from Fuji Chemical Industrial, personal fees from Fujitsu, personal fees from Kyowa Kirin, personal fees from Meiji Seika Pharma, personal fees from Nippon Kayaku, personal fees from Pfizer, personal fees from Yakult, personal fees from NTT, personal fees from PRiME-R, personal fees from CANNON Medical, personal fees from HUG, personal fees from NTT-DATA, personal fees from IHC, grants from Kansai Medical Net, personal fees from Taiho, personal fees from Eisai, personal fees from Astra Zeneca, personal fees from Zene, outside the submitted work.Masakazu Toi：Dr. Toi has funding from Chugai, Takeda, Pfizer, Taiho, JBCRG assoc., KBCRN assoc., Eisai, Eli-Lilly and companies, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI technology, Luxonus, Shionogi, GL Science and Sanwa Shurui as a research grant. He has funding from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly and companies, MSD, Exact Science, Novartis, Shimadzu, Yakult, Nippon Kayaku、Devicore Medical Japan and Sysmex as compensation for Lecture honoraria or lecture chairs. He has funding from Daiichi-Sankyo, Eli Lilly and companies, BMS, Athenex Oncology, Bertis, Terumo, Kansai Medical Net for Advisory board. He has funding from British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women\u0026rsquo;s Cancer, Asian Journal of Surgery, and Asian Journal of Breast Surgery for Associate editor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDate analysis was performed by Akane Higami and Masahiro Takada. Akane Higami and Masahiro Takada wrote first draft. all the other authors critically revised previous versions of the manuscript. All the authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS\u003cem\u003e et al\u003c/em\u003e: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. \u003cem\u003eProc Natl Acad Sci U S A \u003c/em\u003e2001, 98(19):10869-10874.\u003c/li\u003e\n\u003cli\u003eParker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z\u003cem\u003e et al\u003c/em\u003e: Supervised risk predictor of breast cancer based on intrinsic subtypes. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2009, 27(8):1160-1167.\u003c/li\u003e\n\u003cli\u003eGnant M, Filipits M, Greil R, Stoeger H, Rudas M, Bago-Horvath Z, Mlineritsch B, Kwasny W, Knauer M, Singer C\u003cem\u003e et al\u003c/em\u003e: Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. \u003cem\u003eAnn Oncol \u003c/em\u003e2014, 25(2):339-345.\u003c/li\u003e\n\u003cli\u003eLaenkholm AV, Jensen MB, Eriksen JO, Rasmussen BB, Knoop AS, Buckingham W, Ferree S, Schaper C, Nielsen TO, Haffner T\u003cem\u003e et al\u003c/em\u003e: PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2018, 36(8):735-740.\u003c/li\u003e\n\u003cli\u003eDowsett M, Sestak I, Lopez-Knowles E, Sidhu K, Dunbier AK, Cowens JW, Ferree S, Storhoff J, Schaper C, Cuzick J: Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2013, 31(22):2783-2790.\u003c/li\u003e\n\u003cli\u003eSestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, Cowens JW, Ferree S, Schaper C, Fesl C\u003cem\u003e et al\u003c/em\u003e: Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2015, 33(8):916-922.\u003c/li\u003e\n\u003cli\u003eOhara AM, Naoi Y, Shimazu K, Kagara N, Shimoda M, Tanei T, Miyake T, Kim SJ, Noguchi S: PAM50 for prediction of response to neoadjuvant chemotherapy for ER-positive breast cancer. \u003cem\u003eBreast Cancer Res Treat \u003c/em\u003e2019, 173(3):533-543.\u003c/li\u003e\n\u003cli\u003eIwamoto T, Booser D, Valero V, Murray JL, Koenig K, Esteva FJ, Ueno NT, Zhang J, Shi W, Qi Y\u003cem\u003e et al\u003c/em\u003e: Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2012, 30(7):729-734.\u003c/li\u003e\n\u003cli\u003ePrat A, Chaudhury A, Solovieff N, Pare L, Martinez D, Chic N, Martinez-Saez O, Braso-Maristany F, Lteif A, Taran T\u003cem\u003e et al\u003c/em\u003e: Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies. \u003cem\u003eJ Clin Oncol \u003c/em\u003e2021, 39(13):1458-1467.\u003c/li\u003e\n\u003c/ol\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Breast cancer, PAM50, genomic subtyping, Japanese patients, postmenopausal","lastPublishedDoi":"10.21203/rs.3.rs-3878376/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3878376/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe prognostic value of the risk-of-recurrence (ROR) score calculated using \u003cem\u003ePAM50\u003c/em\u003e has been validated using clinical trials and patient cohorts. This study aimed to investigate the prognostic value of the \u003cem\u003ePAM50\u003c/em\u003e ROR score in Japanese patients with early breast cancer using long-term follow-up data.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe enrolled postmenopausal patients with \u003cem\u003eER\u003c/em\u003e-positive, \u003cem\u003eHER2\u003c/em\u003e-negative, stage I\u0026ndash;II breast cancer who had undergone surgery at the Kyoto University Hospital between 2014 and 2018. The intrinsic subtype and ROR score were calculated using \u003cem\u003ePAM50\u003c/em\u003e. The primary endpoint was invasive disease-free survival (IDFS).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe enrolled 147 patients, of whom 48 (33%) patients had node-positive disease, and 37 (25%) had received neoadjuvant or adjuvant chemotherapy. The proportions of intrinsic subtypes for luminal A, luminal B, \u003cem\u003eHER2\u003c/em\u003e-enriched, and basal-like subtypes were 67%, 27%, 3%, and 2%, respectively. The median follow-up duration was 8.4 (range: 6.3\u0026ndash;10.0) years, and 21 IDFS events were observed. Based on the ROR score, 37%, 33%, and 30% of the patients were classified as low-, intermediate-, and high-risk, respectively. Patients in the high-risk group had a significantly worse 8-year IDFS rate than those in the low-to-intermediate-risk groups (75.7% vs. 91.6%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04). The same trend was observed in patients with and without neoadjuvant or adjuvant chemotherapy.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eUsing long-term follow-up data, this study showed that the ROR score can predict the prognosis of \u003cem\u003eER\u003c/em\u003e-positive, \u003cem\u003eHER2\u003c/em\u003e-negative early breast cancer in Japanese postmenopausal patients. Further investigations are required to confirm the prognostic value of the ROR score in Asian populations.\u003c/p\u003e","manuscriptTitle":"Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of Japanese patients with breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-13 19:14:02","doi":"10.21203/rs.3.rs-3878376/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2024-04-02T17:14:07+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-02-12T22:31:19+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-02-09T02:59:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2024-01-22T04:52:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-18T13:53:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"304e887f-87bb-4577-b55e-fe6fcff2c1b9","owner":[],"postedDate":"February 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-26T15:59:24+00:00","versionOfRecord":{"articleIdentity":"rs-3878376","link":"https://doi.org/10.1007/s10147-024-02604-1","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2024-08-23 15:57:02","publishedOnDateReadable":"August 23rd, 2024"},"versionCreatedAt":"2024-02-13 19:14:02","video":"","vorDoi":"10.1007/s10147-024-02604-1","vorDoiUrl":"https://doi.org/10.1007/s10147-024-02604-1","workflowStages":[]},"version":"v1","identity":"rs-3878376","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3878376","identity":"rs-3878376","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}