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Background Eribulin is a chemotherapeutic drug that prolongs overall survival (OS) in patients with HER2-negative metastatic breast cancer (MBC), mainly in third-line or later chemotherapy (ChT) [1]. However, health-related quality of life (HRQOL) and efficacy in patients who receive eribulin as first- or second-line therapy is not well known. In contrast, S-1, an oral 5-fluorouracil derivative, shows similar OS to taxanes as first-line ChT and better HRQOL, based on a large phase III trial conducted in Japan [2]. Here, we compared the effect on HRQOL and efficacy of eribulin and S-1 in MBC patients in a first- or second-line ChT setting. Methods We planned an open-label, multicenter, randomized controlled phase III study at 50 hospitals in Japan. We enrolled patients with HER2-negative MBC who had no or one previous ChT for MBC regardless of prior administration of anthracyclines and taxanes. Patients were randomly assigned (1:1) to either eribulin (1.4 mg/m² administered on days 1 and 8 of a 21-day) or S-1 (40–60 mg twice daily for 14 consecutive days, followed by a 7-day break). Randomization was stratified by institution, age, treatment line, hormone receptor status, and time from surgery to recurrence. HRQOL assessment was conducted using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 questions (QLQ-C30) every six weeks until week 24, and then every nine weeks until week 42 after baseline assessment. The primary outcome measure was the global health status (GHS) score of EORTC QLQ-C30, with a prespecified non-inferiority margin of 10% for a difference in the proportion of patients experiencing deterioration at one year. Clinically meaningful deterioration was defined as a ≥ 10-point decrease from baseline GHS score or death. Secondary outcomes were OS, progression-free survival (PFS), and adverse events. We estimated that the study needed 330 patients to obtain 80% power for non-inferiority. This trial was registered with the University Hospital Medical Information Network, Japan (protocol ID 000021398). Results Between June 2016 and October 2019, 302 patients were enrolled, with 152 assigned to eribulin and 148 to S-1. The full analysis set for HRQOL assessment included 134 and 136 patients, while that for efficacy consisted of 141 and 144 patients, respectively. Overall compliance with the questionnaire was 85.6 %. Among the full analysis set for efficacy, 28 (19.9%) and 31 (21.5%) cases were triple negative, respectively. Eribulin and S-1 were administered as first-line ChT in 99 (70.2%) and 101 (70.1%) patients, respectively. Risk difference of GHS deterioration through one year for the eribulin versus S1 group was -0.66% (95% CI -12.47 to 11.16; P non-inferiority =0.077). Median time to first deterioration in GHS score was 5.64 months (95% CI 3.51–8.00) and 5.28 months (95% CI 3.28-7.80) (HR 1.07 [95% CI 0.79–1.45]; P =0.667); median OS was 35.0 months (95% CI 27.2-41.0) and 27.8 months (95% CI 24.6-33.5) (HR 0.69 [95% CI 0.50-0.95]; P=0.023); and median PFS was 6.07 months (95% CI 5.48-7.80) and 6.66 months (95% CI 5.48-7.77), respectively (HR 0.90 [95% CI 0.68-1.18]; P=0.427). No previously unrecognized adverse events were observed. Conclusions We found a marginal non-inferiority in HRQOL for eribulin, albeit that the difference was not statistically significant owing to the smaller than planned sample size. Time to first clinically meaningful deterioration was almost identical between the two arms, whereas OS was significantly extended with eribulin. These findings indicate that eribulin in first- or second-line ChT is acceptable as a standard regimen in this patient population. [1] Lancet 2011; 377: 914–23 [2] Lancet Oncol 2016; 17: 90–98 Citation Format: Yuichiro Kikawa, Kosuke Kashiwabara, Naruto Taira, Tsuguo Iwatani, Kojiro Shimozuma, Shoichiro Ohtani, Tetsuhiro Yoshinami, Junichiro Watanabe, Masahiro Kashiwaba, Ken-ichi Watanabe, Masahiro Kitada, Koichi Sakaguchi, Yuko Tanabe, Tomohiko Aihara, Hirofumi Mukai, Masato Takahashi. Eribulin versus S-1 as first- or second- line chemotherapy to assess Health-related Quality of Life and overall survival in HER2-negative metastatic breast cancer (RESQ study): a non-inferiority, randomized controlled trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-03-01.

Background: Trastuzumab Deruxtecan (T-DXd) is a novel antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) with a DNA topoisomerase I inhibitor payload and has demonstrated antitumor activity in clinical trials. Based on the results of a global Phase II clinical trial (DESTINY-Breast01, NCT03248492), T-DXd was conditionally approved for the treatment of patients with HER2+ unresectable or metastatic breast cancer who had received ≥2 prior anti-HER2 based therapies (US, EU, UK, etc) or after prior chemotherapy (Japan). With regards to the safety profile, the incidence of cumulative toxicities such as peripheral neuropathy and edema was lower with T-DXd as compared to what has been observed with taxanes. However, chemotherapy-induced nausea and vomiting (CINV), fatigue, and neutrophil count decrease were observed as treatment emergent adverse events (TEAE). Interstitial lung disease (ILD)/pneumonitis was especially observed in 15.2% of patients treated with T-DXd, leading to death in 2.7% of patients. These adverse events need appropriate monitoring and management in daily clinical practice. We hypothesized that electronic patient-reported outcomes (ePROs) monitoring would allow early detection of adverse events due to T-DXd and thus improve patient safety and quality of life (QoL). Study design: This is an open-label, multicenter, randomized controlled study comparing ePRO monitoring with routine follow-up of patients with HER2+ advanced or metastatic breast cancer who receive T-DXd in routine clinical practice. Patients randomized to the ePRO group are monitored through weekly PRO-CTCAE assessment as well as daily temperature and SpO2 measurement using the ePRO application on the patient's mobile device. Changes in symptoms are monitored by the attending physician using an electronic chart. In addition, an e-mail alert is sent to the site medical staff if any symptoms exceed a predetermined threshold. The primary endpoint of the study is the change from baseline in the EORTC QLQ-C30 (Global QoL) score at 24 weeks. Secondary endpoints include time to deterioration of Global QoL, EORTC FA12 score change, overall survival, progression-free survival, and adherence to the ePRO monitoring as assessed by the proportion of patients completing the questionnaires. Analysis of primary endpoint will be done using mixed effects models for repeated measures (MMRM) and sample size will be estimated based on the Wald test for differences between groups in mean parameters at 24 weeks. To detect 10-points score difference between the groups with a standard deviation of 24, with a two-sided alpha level of 10%, and a power of 87%, 55 patients would be required in each group. Enrollment started in March 2021. Clinical trial identification: jRCTs031200387 Citation Format: Takafumi Sangai, Yuichiro Kikawa, Mitsuchika Hosoda, Yohei Hamanaka, Yuko Tanabe, Tatsuya Yoshida, Kaori Tane, Daisuke Takabatake, Tetsuhiko Taira, Kazuhiro Araki, Takayuki Iwamoto, Mamoru Takada, Kazutaka Narui, Takeshi Yamaguchi, Akimitsu Yamada, Tomoko Miura, Yukari Uemura, Tomohiko Aihara, Hirofumi Mukai, Naruto Taira. Randomized study comparing electronic patient reported outcomes (ePROs) monitoring with routine follow up during trastuzumab deruxtecan treatment in patients with inoperable or metastatic breast cancer (PRO-DUCE study) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-08.

Background: NET is one of option in postmenopausal PBC with ER+ and molecular signature is useful tool to determine with/without CT after surgery. We presented a relationship between molecular signature and response of NET in this study cohort (BCRT; 2018). Here we report the primary analysis of NEOS trial, a Phase III study that evaluated long-term prognosis with/without CT in ER+ PBC who received NET. Methods: Postmenopausal BC pts with ER +/HER2 negative, T1c-2, clinically node negative, under 76 years old were enrolled at primary registration. Pts were treated by letrozole (LET) in weeks 24-28 after primary enrollment. Pts experienced progression disease (PD) during neoadjuvant phase or with more than 4 positive lymph nodes in pathological findings after surgery were excluded at randomization and received any systemic therapy driven by investigators before or after surgery. Pts who met eligibility criteria were randomized 1:1 to LET for 4.5-5 years after CT or LET alone for 4.5-5 years without CT after surgery. Primary endpoint is disease-free survival (DFS) with/without adjuvant CT. Secondary endpoints include distant DFS (DDFS), overall survival (OS), DFS/DDFS/OS according clinical response of NET and QoL. Statistical analysis plan is as follow. The Hazard ratio (HR) will be compared with the threshold HRs obtained in a pre-study questionnaire survey to reach a conclusion about the choice between LET plus chemotherapy or LET alone. Based on these survey results, the HR thresholds used to choose between the two treatments were set at 0.9 and 0.6. After amendment, the selection probability was finally set as 80-85%. About 170 events were required for both arms. Results: Between May 2008 and June 2013, 904 patients were enrolled at primary registration from 100 institutions in Japan and 21 pts were withdrawn before neoadjuvant phase. 42pts were excluded by PD during NET. 172pts were not randomized because of non-eligible for second enrolled criteria after surgery and patient’s preference. 669pts were randomized (1:1) to adjuvant CT + ET (333pts) or ET alone (336pts). Patients’ characteristics (age, tumor size, progesterone receptor(PgR) status, nuclear grade (NG), clinical and pathological response of NET and a number of Ax LN metastasis) were well balance among two arms. Median follow up is 7.8 years. Primary endpoint (DFS) was not able to evaluated for necessity of chemotherapy because DFS events (CT+ET:46, ET alone:61) was lower compared with planned numbers (HR:0.74 (95%CI; 0.51, 1.09), P=0.13). DDFS was also not able to evaluated similar with DFS (HR:0.79 (95%CI; 0.46, 1.35) P=0.39). DFS/DDFS rate at 8Y were 85.6%/93.1% and 82.7%/91.7% in CT+ ET and ET alone, respectively. OS was not difference between two arms (HR 0.46 (95%CI; 0.20, 1.07) P=0.072). Both DDFS and locoregional events were lower in CT+ET than ET alone arm. A number of any secondary cancers was higher than DDFS events among both arms. DFS was statistically significant better in CT+ET arm than ET alone arm among any subgroups who < 60 years (HR:0.30, p=0.003, clinical T2 (HR:0.56, p=0.012) and ki67 >20% cases (HR:0.49, P=0.026) at baseline characteristics. No statistically significant difference of DFS between two arms according to response of NET (HR:0.76, P=0.35 in CR and PR group, HR:0.70, p=0.19 in SD group). PgR status, NG, a number of Ax LN metastasis were also not predictive factors about the difference of DFS between CT+ET and ET alone. Conclusion: The decision to use adjuvant chemotherapy could not be based solely on clinical response of NET. Adjuvant chemotherapy should be selected by any clinical factors and genomic tool regardless of response by NET for ER+ PBC. UMIN000001090 Citation Format: Hiroji Iwata, Tatsuya Toyama, Naruto Taira, Norikazu Masuda, Yutaka Yamamoto, Tomomi Fujisawa, Shoichiro Ohtani, Masahiro Kashiwaba, Takehiko Sakai, Yoshie Hasegawa, Rikiya Nakamura, Hiromitsu Akabane, Yukiko Shibahara, Hironobu Sasano, Takuhiro Yamaguchi. Primary analysis from NEOS trial: A randomized phase III study that assessed the long-term prognosis of estrogen receptor positive (ER+) primary breast cancer (PBC) pts who received neoadjuvant endocrine therapy (NET) with/without adjuvant chemotherapy (CT) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-09.

OBJECTIVE: Nab-paclitaxel (nab-PTX) has superior efficacy compared to conventional paclitaxel in metastatic breast cancer (MBC), but chemotherapy-induced peripheral neuropathy (CIPN) is more frequent with nab-PTX. In a single arm phase 2 trial (CA002-0LD), low dose nab-PTX (175 mg/m2) every 3 weeks (q3w) resulted in a good objective response rate (39.5%) without CIPN of grade 3 or higher. Therefore, we conducted a randomized controlled study to evaluate the optimal dose of nab-PTX by comparing a low dose (LD) and a medium dose (MD) to the standard dose (SD). Here, we evaluate the patients-reported outcomes (PROs) and health-related quality of life (HRQoL) in the ABROAD study. PATIENTS AND METHODS: Three different doses of q3w nab-PTX (SD: 260 mg/m2 vs. MD: 220 mg/m2 vs. LD: 180 mg/m2) were administered in patients with HER2-negative metastatic breast cancer. The primary endpoint was progression-free survival (PFS). Grade 3/4 neuropathy rates with the three doses were estimated by logistic regression. The optimal dose was selected by 2-step selection. First, if the hazard ratio (HR) for PFS was 1.33, the inferior dose was dropped. Then, a dose with an estimated incidence of grade 3/4 neurotoxicity >10% was also dropped. PROs and HRQoL were assessed as secondary endpoints at baseline, and during the 2nd, 4th and 6th courses of protocol treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Patient Neurotoxicity Questionnaire (PNQ), Cancer Fatigue Scale (CFS) and EuroQol 5 Dimension (EQ-5D). The primary outcome for PROs and HRQoL was the FACT-Taxane trial outcome index (TOI), and inter-group comparison was performed using a mixed effect model for repeated measures (MMRM). This trial was registered with the University Hospital Medical Information Network (UMIN), Japan (protocol ID C000012429). RESULTS: A total of 141 patients were randomly assigned to SD (n=47), MD (n=46) or LD (n=48) nab-PTX. PFS analysis showed that LD nab-PTX at 180 mg/m2/3 weeks was the optimal dose with good clinical efficacy and tolerability for patients with MBC (reported by Hara at ASCO2019). Longitudinal analysis (MMRM) showed that the difference from the baseline FACT-Taxane TOI score at MD and LD were significantly better than that at SD (MD vs. SD p CONCLUSION: Our results show that low dose nab-PTX at 180 mg/m2/3 weeks could be an optimal dose for PFS and from the perspectives of PROs and HRQoL. Citation Format: Hiroaki Kato, Fumikata Hara, Masahiro Kitada, Masato Takahashi, Yuichiro Kikawa Yuichiro Kikawa, Eiko Sakata, Yoichi Naito, Yoshie Hasegawa, Tsuyoshi Saito, Tsutomu Iwasa, Junji Tsurutani, Naruto Taira, Tsutomu Takashima, Kosuke Kashiwabara, Tomohiko Aihara Tomohiko Aihara, Hirofumi Mukai. Patient-reported outcomes in a randomized, optimal dose finding, phase II study of triweekly nab-paclitaxel in patients with metastatic breast cancer (the ABROAD study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-04.

Background In hormone receptor (HR)-positive / human epidermal growth factor receptor 2 (HER2)-negative breast cancers, high Ki-67 predicts poor prognosis. Recently, it has been reported that among breast cancers with high Ki-67, low Ki-67 after short-term preoperative hormone therapy (post Ki-67) might predict favorable prognosis compared to high post Ki-67 (SABCS 2017). However, the differences in gene expression profiling of breast cancers between high and low post Ki-67 among high Ki-67 before treatment are unclear. Therefore, this study aimed to clarify genetic differences in two groups and to explore novel therapeutic targets for the poor prognostic group after the treatment. Methods Seventy-seven patients with primary HR-positive / HER2-negative breast cancer who received an aromatase inhibitor for 2 weeks [NCBI Gene Expression Omnibus repository GSE80077:19 cases, GSE20181:58 cases] were enrolled in this study. Forty-five patients with high pre Ki-67 among them were stratified into two groups, high (H→H) and low (H→L) post Ki-67 after short-term preoperative hormone therapy. We compared gene expression profiling in two groups about the followings. 1) 3 genes (ESR1, PGR and ERBB2) related to classical clinical treatment strategy of breast cancer, immune- and inflammatory-related genes 2) 178 pathways (gene set analysis) 3) 41 genes that are targeted by FDA-approved drugs or have been investigated with clinical trials as molecular target agents for various malignant tumors including breast cancer Results 1) TNF that is inflammatory-related gene were significantly overexpressed in H→L group (P=0.021). However, 3 genes related to clinical treatment of breast cancer and immune-related genes expression had no significant difference between two groups. 2) 5 gene sets (Tryptophan metabolism, Propanoate metabolism, beta-Alanine metabolism, SNARE interactions in vesicular transport and Nucleotide excision repair) were significantly upregulated in H→L group. (P ≤ 0.005) 3) 5 targeted genes (PARP, BRCA2, FLT4, CDK6 and PDCD1LG2) were significantly overexpressed in H→H group (P ≤ 0.05). Conclusions There were different gene expression and biological processes in two groups stratified by post-Ki67. In the future, it is necessary to seek new therapeutic strategies for poor prognostic group with high post-Ki67 in considerations of these differences. Citation Format: Yukiko Kajiwara, Takayuki Iwamoto, Yusuke Otani, Miwa Fujihara, Yoko Suzuki, Minami Hatono, Takahiro Tsukioki, Kengo Kawada, Mariko Kochi, Hirokuni Ikeda, Tadahiko Shien, Naruto Taira, Hiroyoshi Doihara. Gene expression profiling of breast cancers between high and low Ki-67 after short-term preoperative hormone therapy among hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancers with high Ki-67 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-13-04.

Background: Currently, treatment for older breast cancer patients is largely based on data derived from trials enrolling younger patients; thus, the standard of care for older breast cancer patients remains controversial. Aim: To investigate the clinicopathological characteristics, treatments, and prognosis in older stage II and III breast cancer patients using data from the Japanese Breast Cancer Registry (JBCR). Methods: We reviewed data from the JBCR, a nationwide registry of newly diagnosed and operated primary breast cancer patients in Japan. To clarify those characteristics, we compared clinicopathological characteristics, treatments, and prognosis among three groups: older group, patients aged ≥75 years; young-old group, patients aged 65–74 years; post-menopause group, patients aged 55–64 years. Results: In total, we reviewed 56,093 cases of stage II/III breast cancer diagnosed between 2004 and 2011 (older: n=12,727; young-old: n=17,860; post-menopause: n=25,506). The estrogen receptor (ER) positivity rate was higher (older vs. young-old vs. post-menopause: 73.3% vs. 72.0% vs. 68.0%) and HER2 positivity rate was lower in the older group than in the other two groups (12.9% vs. 16.8% vs. 23.6%) (p The following table shows the rate of administration of adjuvant systemic therapy according to the ER and HER2 status. Age (years)≥7565–7455–64p-valueER+Chemotherapy10.042.562.9 Nearly half of the older patients (48.3%) who received chemotherapy received either cyclophosphamide-methotrexate-fluorouracil or oral fluorouracil. As for hormone therapy, tamoxifen was used more frequently in the older group than in the young-old and post-menopause groups (16.5% vs. 8.6% vs. 7.2%). The following table shows the results of the 5-year overall survival (OS) and breast cancer-specific survival (BCSS) analyses: Conclusions: Chemotherapy was less common in older patients, especially patients with HER2+ or triple negative breast cancer, resulting in worse BCSS. As older patients tend to have several comorbidities, comprehensive geriatric assessment might be helpful in determining systemic therapies for older patients. Age (years)≥7565–7455–64p-valueER+OS/BCSS (%)84.1/94.592.5/96.093.2/94.9 Citation Format: Akimitsu Yamada, Masataka Sawaki, Hiraku Kumamaru, Hiroaki Miyata, Kanako Nakayama, Chikako Shimizu, Mika Miyashita, Naoko Honma, Itaru Endo, Naruto Taira, Shigehira Saji. Systemic therapy for and prognosis of older stage II and III breast cancer patients: Evaluation of data from the Japanese breast cancer registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-06.

Background: Patient reported outcomes (PROs) have been increasingly important in breast cancer treatment. The questionnaires to evaluate PROs require high response compliance, simplicity, and friendliness. Recently, the communication with Emojis has become friendliness because of the development of social networking services and electronic devices. Therefore, we developed the Emoji scale, a novel indicator to evaluate PROs. Furthermore, two-step validation pilot studies were planned to examine the reliability of the Emoji scale for breast cancer patients at a single center. Pilot 1(Step 1) Aims: To evaluate the content validity (the primary endpoint), concurrent validity and test retest reliability of the Emoji scales (secondary endpoints). Eligibility criteria: (1) Patients with stage 0-III breast cancer. (2) Patients who have been over 1 year since the end of the initial treatment such as surgery, chemotherapy, and radiation therapy or (3) hormone receptor positive patients who have been over 1 year from the start of the endocrine therapy. (4) Patients aged >20 years who understand Japanese. Methods: The participants will complete the PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE) and Emoji scale questionnaires regarding 18 cancer related symptoms twice. First, both questionnaires will be completed in a consulting room while the staff will track the time required for completion of each questionnaire. Thereafter, the patients will be asked if there are any difficult or confused items. Second, both questionnaires will be completed again at home 7 days later. The number of planned participants is 100. Statistical analyses: Content validity will be evaluated by categorizing the comments from participants, and the nature of problems will be determined. The correlation coefficient between the PRO-CTCAE and Emoji scale scores will evaluate the concurrent validity. For the test-retest reliability, the kappa statistic between each scale at different time will be used. We will compare the time required for completion with using the t-test. Pilot 2(Step2) Aims: To evaluate the responsiveness (the primary endpoint), the effect size, the concurrent validity and comparison of the average score between participants with high and low Performance Status. (the secondary endpoints). Eligibility criteria: (1) Patients with stage 0-IV breast cancer who are scheduled to start chemotherapy or endocrine therapy. (2) Patients aged >20 years who understand Japanese. Methods: The participants will complete both the PRO-CTCAE and Emoji scales before they start a new breast cancer treatment (T1). Those will comprise chemotherapy (Cohort A: anthracycline based regimens, Cohort B: docetaxel based regimens, Cohort C: paclitaxel based regimens, Cohort E: eribulin based regimens, and Cohort F: capecitabine/S1 based regimens) or endocrine therapy (Cohort D: tamoxifen/aromatase inhibitor). After several weeks, the participants will complete the same questionnaires again (T2). This time interval will depend on the therapy, and some participants will be complete once again the questionnaires (T3) a few weeks after T2. The number of planned participants is 30 in each cohort. Statistical analyses: Responsiveness will be evaluated by the correlation coefficient between the change from the baseline to second or third score of each scale. The effect size of the Emoji scale will be determined by the difference between the average score of the second or third and that of the baseline divided by the standard deviation of the baseline score. The correlation coefficient for each scale at each time will evaluate the concurrent validity at each time. A comparison of the average scores between PS will be performed using the t-test. Citation Format: Yoko Suzuki, Naruto Taira, Yukiko Kajiwara, Mariko Kochi, Takayuki Iwamoto, Hirokuni Ikeda, Tadahiko Shien, Hiroyoshi Doihara, Yuichiro Kikawa, Yukari Uemura. Validation study of the Emoji scale in evaluating patient reported outcomes for breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-19-01.

Background: The randomized controlled trial (RCT) is accepted as the standard clinical trial to decide a standard therapy, but it remains unclear whether or not elderly patients benefit as much as other patients from participation in an RCT. In the RESPECT study (NCT01104935), the relative value of trastuzumab (H) monotherapy as an adjuvant treatment was compared in an RCT with the standard combination treatment with chemotherapy (H+CT) in patients over 70 years old with HER2-positive invasive breast cancer (BC) who received curative surgery. This cohort study was aimed at comparing prognoses between RCT participants (RCT group) and non-participants (Cohort group). Methods: Patients were divided into RCT participants, and those who did not agree to participate in the RCT despite meeting the eligibility criteria and receiving the explanation given by the investigator. In the RCT group patients were randomized to H or H+CT; in the Cohort group treatment was selected for each patient based on the discretion of the treating physician and the patient's wishes without intervention. Treatment categories were divided into three groups: (1) trastuzumab monotherapy group (cH group), (2) trastuzumab plus chemotherapy group (cH+CT group), and (3) those who received either no therapy at all, or any other anticancer therapies without H (cOther group). The primary endpoint was disease-free survival (DFS). Secondary endpoints were overall survival (OS), relapse-free survival, safety, health-related quality of life (HRQOL) and comprehensive geriatric assessment. Results: A total of 275 patients in the RCT group and 123 patients in the Cohort group, in total 398 patients, were enrolled in this study between October 2009 and October 2014. The median age was 74.0 years in the RCT group, 74.5 years in the Cohort group and the median follow-up time was 4.1 years and 3.2 years, respectively. Patients were classified as Stage I: 41.8%, 42.5%; IIA: 41.5 %, 40.8%; IIB: 13.5%, 13.3%; and IIIA: 1.5%. 3.3%, respectively (P = 0.51), there were no significant differences between the two groups. Treatment categories in the Cohort group were: (1) cH group; 43% (n = 52), (2) cH+CT group; 30% (n = 36), cOther group; 27% (n = 32). The planned analysis showed that DFS at 3 years was 91.4% in the RCT group vs 89.3% in the Cohort group (adjusted hazard ratio (HR) = 1.30; 95%CI, 0.72-2.35, P = 0.38). In patients in the cH+CT, cH and cOther group, DFS at 3 years was 92.3%, 89.2% and 82.5%, respectively. DFS in patients in the cH+CT and the cH group was significantly better than that of the cOther group (adjusted HR = 3.79; 95%CI = 1.35-10.64, P = 0.01). DFS in the cH group showed a better tendency compared with cOther (adjusted HR = 2.59; 95%CI, 0.87-7.73, P = 0.08). The incidence of grade 3/4 non-hematological adverse events in the RCT group was relatively higher compared with the Cohort group (18.5% vs 10.8 %, P = 0.05). Conclusion: The prognosis did not vary between the RCT and Cohort groups. H-containing regimens are often chosen for elderly patients with HER2-positive breast cancer. The prognosis of patients who received any H-containing regimen, even H monotherapy, was better than those who were not treated with H. Citation Format: Shinichi Baba, Masataka Sawaki, Yukari Uemura, Tsuyoshi Saito, Kokoro Kobayashi, Hiroaki Kawashima, Michiko Tsuneizumi, Noriko Sagawa, Hiroko Bando, Masato Takahashi, Miki Yamaguchi, Tsutomu Takashima, Takahiro Nakayama, Masahiro Kashiwaba, Toshiro Mizuno, Yutaka Yamamoto, Naruto Taira, Hiroji Iwata, Tatsuya Toyama, Koichiro Tsugawa, Yasuo Ohashi, Hirofumi Mukai. A cohort study to evaluate the efficacy and safety of postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT-cohort study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-02.

Background: The standard chemotherapy treatment strategy for patients with advanced/metastatic breast cancer (ABC) is the continuation of the same drug until tumor progression. However, despite continued antitumor effects, continuation of a drug often becomes difficult because of cumulative adverse events, such as peripheral neuropathy. Methods: This multicenter, randomized, Phase II study in patients with estrogen receptorpositive (ER+) human epidermal growth factor receptor 2-negative (HER2−) ABC aimed to compare 2 treatment strategies following induction therapy with 4-6 cycles of the combined use of weekly paclitaxel (wPTX) and bevacizumab (BV). Patients in Arm A continued with wPTX+BV, whereas patients in Arm B were switched from wPTX to maintenance endocrine therapy (endocrine+BV) until disease progression, followed by wPTX+BV re-induction. The primary endpoint was time to failure of strategy (TFS), defined as the time from randomization to a qualifying event (addition of a new agent not in the primary regimen, progressive disease during or after planned therapy, or death). Secondary endpoints were overall survival (OS), progression-free survival, safety, and quality of life (QoL). Sequential plasma and serum biomarkers were analyzed for predicting/monitoring the response. Result: Of 160 patients enrolled to receive induction therapy with wPTX+BV, 125 patients responded to treatment (complete response [CR], partial response [PR], or stable disease) and were randomized to either of the 2 treatment arms. Median follow-up was 21.3 months. Aromatase inhibitor (AI), fulvestrant, or AI with a luteinizing hormonereleasing hormone (LH-RH) analogue was used as maintenance endocrine therapy. The primary endpoint of TFS was 8.87 months (95% CI: 5.68-13.80) in the wPTX+BV continued group (Arm A) and 16.82 months (95% CI: 12.88-18.99) in the maintenance endocrine+BV group (Arm B) (hazard ratio [HR], 0.51; p Conclusion: This is the first study showing the benefit of maintenance endocrine therapy in patients with ER+ HER2− advanced breast cancer who responded to a fixed dose of chemotherapy. (UMIN: UMIN000012179; ClinicalTrials.gov: NCT01989780) Funding: Chugai Pharmaceutical CO., LTD. Citation Format: Shigehira Saji, Masahiro Kitada, Toshimi Takano, Masahiro Takada, Tohru Ohtake, Tatsuya Toyama, Yuichiro Kikawa, Yoshie Hasegawa, Tomomi Fujisawa, Masahiro Kashiwaba, Takanori Ishida, Rikiya Nakamura, Yutaka Yamamoto, Uhi Toh, Hiroji Iwata, Norikazu Masuda, Naruto Taira, Satoshi Morita, Shinji Ohno, Masakazu Toi. A randomized, multicenter, phase II study evaluating the efficacy of interventional maintenance endocrine therapy with bevacizumab following fixed cycles of bevacizumab plus paclitaxel in advanced/metastatic ER-positive HER2-negative breast cancer: JBCRG-M04 BOOSTER trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-01.

OBJECTIVE: The effect of trastuzumab(Tmab) or chemotherapy on cognitive function has not been fully understood, especially in elderly breast cancer patients. The RESPECT trial compared 1-year(yr) Tmab monotherapy with Tmab plus standard chemotherapy as adjuvant therapy in elderly patients with HER2-positive breast cancer. The primary objective was to verify the noninferiority of 1-yr Tmab monotherapy compared to Tmab plus chemotherapy in terms of disease-free survival, and the planned analysis showed that the difference of restricted mean survival time between two groups at 3 yrs was 0.45 months (Sawaki at ASCO2018). The goal of this report was to assess the impact of the treatment groups on longitudinal cognitive function. PATIENTS AND METHODS: The study was performed with patients from 99 hospitals in Japan. Elderly women with HER2-positive, stage I-IIIA invasive breast cancer surgery treated with clear resection margins were randomly assigned to either receive 1-yr Tmab or 1-yr Tmab plus standard chemotherapy. 15 institutions participated in the cognitive sub-study. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) at baseline and at 1 and 3 yrs after treatment. The primary outcome was the amount of change in the MMSE score from the baseline. A linear mixed-effects model was used for comparisons of change in the MMSE score between groups, controlling for time and baseline score. Secondary outcomes were the proportion of both suspected mild dementia (MMSE≤27) and dementia (MMSE≤23) at each time point. RESULTS: Between October 2009 and October 2014, 275 patients were enrolled in the RESPECT trial, and 57 patients were enrolled in the cognitive function sub-study with 2 patients subsequently excluded. The 55-patient sub-study comprised 29 patients assigned to the Tmab monotherapy group and 26 patients assigned to the Tmab plus chemotherapy group. Primary analysis revealed that change in the MMSE score was not significantly different between the two groups (difference −0.6 at 1 yr and −0.9 at 3 yrs; p=0.136), whereas the baseline score was the only significant factor that had an effect on the amount of change in the MMSE score (p CONCLUSION: Postoperative chemotherapy for elderly breast cancer patients was considered to have little effect on the onset of dementia during the follow-up period of 3 yrs. Further long-term observation is necessary to obtain a significant conclusion. Citation Format: Takahashi M, Sawaki M, Hagiwara Y, Uemura Y, Kawahara T, Shimozuma K, Ohashi Y, Saito T, Baba S, Kobayashi K, Mukai H, Taira N. Analysis of cognitive function in elderly HER2-positive breast cancer patients receiving either trastuzumab monotherapy or trastuzumab plus chemotherapy as a postoperative adjuvant treatment: A cognitive function sub-study of a randomized, open-label, phase 3 clinical trial (RESPECT trial) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-21.

Background: Overall survival (OS) is the established endpoint to evaluate the effects of drug treatment in comparative clinical trials of metastatic breast cancer. But assessing OS requires long follow-up periods and large sample size, which raise costs and create long delays in the drug approval process. Progression-free survival (PFS) or time to progression (TTP) is considered as a surrogate for OS and is often used as an alternative to OS. In some cancers the two endpoints are highly correlated, but in others they are not. Furthermore, the effect of breast cancer (BC) subtypes on the surrogacy of PFS/TTP for OS has not been completely defined. Method: A systematic literature review of randomized control trials was conducted to identify studies that reported both the hazard ratio (HR) of PFS/TTP and OS for BC subtypes {i.e. estrogen receptor (ER) positive, HER2 positive, and triple negative (TN)}. The correlation between the HR of PFS/TTP and OS was evaluated using weighted Spearman's rank correlation. Results: A total of 49 trials (34 phase III trials and 15 phase II trials) were selected for analysis. Among these trials, there were 8 comparison trials between one chemotherapy and another chemotherapy regimen, 18 comparison trials between chemotherapy and chemotherapy plus molecularly-targeted therapy, 9 comparison trials between one endocrine therapy and another endocrine therapy, and 5 comparison trials between endocrine therapy and endocrine therapy plus molecularly-targeted therapy. There were 17 trials reporting the HR of PFS/TTP and OS for ER positive, 16 trials for HER2 positive, and 9 trials for TN BC. Weighted Spearman's rank correlation revealed that coefficient between the HR of PFS/TTP and OS was 0.721(p Conclusion: There was a strong correlation between the HR of PFS/TTP and OS for ER positive BC, and a weak correlation between the HR of PFS/TTP and OS for HER2 positive and TN BC. The validity of using PFS/TTP as an OS surrogate marker was shown for metastatic BC, especially for ER positive BC. Citation Format: Tsukioki T, Taira N, Sakamaki K, Suzuki Y, Kajiwara Y, Hatono M, Takahashi Y, Kawata K, Kochi M, Iwamoto T, Ikeda H, Shien T, Doihara H. Progression-free survival or time to progression in comparative clinical trials of metastatic breast cancer as a potential surrogate for overall survival: A systematic review of 49 trials focusing on breast cancer subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-19.

Background : Isoflavones are phytoestrogens that may be effective in preventing osteoporosis, reducing cardiovascular events, and improving menopausal symptoms such as hot flash due to their estrogen-like actions. Isoflavones are currently used as a supplement for improving symptoms of menopause. Epidemiological studies have shown that ingestion of soy products may also reduce the risk of breast cancer, and antitumor effects on hormone receptor (HR)-positive breast cancer cells have been shown in vitro for equol, an isoflavone metabolite. Equol binds to estrogen receptors (ERα, β) and is thought to antagonize ERα-estradiol binding in the presence of estradiol. Since equol shows an antiestrogenic effect, similar to that of the hormonal agent tamoxifen, it is thought that equol acts as a selective estrogen receptor modulator (SERM), but the mechanism is still unclear. In this study, we evaluated the antitumor effects of equol alone and in combination with existing therapeutic agents in HR-positive breast cancer cells, and examined the mechanism of these effects. Methods : The antitumor effects of equol alone and in combination with hormone drugs (4-hydroxytamoxifen (Tam), fulvestrant (Ful)) and chemotherapeutic agents (paclitaxel (Ptx), doxorubicin (Dox)) were examined using a MTS assay. Combination indexes (CIs) were determined in HR-positive MCF-7, T-47D, and ZR-75-1 cell lines. The mechanisms of the drug effects were evaluated by Western blot for assessment of changes in chemoresistance factors at the protein level. Results : In MCF-7, T-47D and ZR-75-1 cells, there was a concentration-dependent antitumor effect of equol and of the other hormonal agents. CIs showed an antagonistic effect of equol with Tam and a synergistic effect with Ful in all cell lines. Equol also had an antagonistic effect with the two chemotherapeutic agents, with the strongest antagonism occurring at a low dose of equol. Western blot showed that ER, PgR, Cyclin D1 and Bcl-2 were upregulated via ER at a low concentration of equol, similarly to the effect of 17-β-estradiol (E2), and ER, PgR, Cyclin D1 and Bcl-2 were downregulated at a high concentration, similarly to the effect of Tam. In addition, ER, PgR and cyclin D1 were downregulated with the combination of equol and Tam, while the expression of Bcl-2, a chemoresistance factor, increased. Conclusion : These results suggest that equol has a concentration-dependent antitumor effect in HR-positive breast cancer cell lines and may antagonize the effect of existing therapeutic agents (hormone drugs and chemotherapeutic agents). In particular, it was considered that in combination of equol and Tam, the apoptosis inducing action of each drug was attenuated and antagonistic effect was shown. Citation Format: Hatono M, Ikeda H, Taira N, Suzuki Y, Kajiwara Y, Kawata K, Takahashi Y, Tsukioki T, Kochi M, Iwamoto T, Shien T, Doihara H. Effects of a soy isoflavone in breast cancer treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-05-06.

OBJECTIVE: The RESPECT trial compared 1-year trastuzumab monotherapy with trastuzumab plus standard chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients. Primary objective of this study was to verify the noninferiority of 1-year trastuzumab monotherapy to trastuzumab plus chemotherapy in terms of disease free survival, and the planned analysis showed that the difference of restricted mean survival time between two groups at 3 years was 0.45 months (reported by Sawaki at ASCO2018). This report assesses the patients-reported outcomes and health-related quality of life (HRQoL). PATIENTS AND METHODS: The study was done at 99 hospitals in Japan. Elderly women (70 to 80 years old) with HER2-positive, stageI-IIIA invasive breast cancer treated by surgery with clear resection margins were randomly assigned to receive either 1-year trastuzumab or 1-year trastuzumab plus standard chemotherapy, stratified by age, hormone-receptor status, pathological lymph node metastasis and institution. Patients completed questionnaires at baseline, 2 months, 1year, and 3 years after protocol treatment started. The primary outcome was global HRQoL assessed using Functional Assessment of Cancer Therapy-General (FACT-G) total score, and secondary outcomes were chemotherapy-induced peripheral neuropathy (CIPN), instrumental activities of daily living (IADL), anxiety, depression, and subjective happiness. We did the analyses by intention to treat, including patients who completed questionnaires at baseline before start of protocol treatment, and 5point or more change is meaningful in FACT-G total score. This study is registered with ClinicalTrials.gov, NCT01104935. RESULTS: Between Oct 2009 and Oct 2014, 275 patients were enrolled in the study, of whom 9 patients were excluded: 135 assigned to trastuzumab monotherapy and 131 assigned to trastuzumab plus chemotherapy. We detected significant difference between treatment groups for: clinically meaningful HRQoL deterioration rate at 2 months (31% for trastuzumab monotherapy vs 48% for trastuzumab plus chemotherapy; p=0.016) and at 1year (19% vs 38%; p=0.009), clinically meaningful HRQoL improvement rate at 2 months (38% for trastuzumab monotherapy vs 15% for trastuzumab plus chemotherapy; p CONCLUSION: Given the small advantage of adjuvant trastuzumab plus chemotherapy compared to trastuzumab monotherapy for elderly HER-2 positive breast cancer women, decisions about treatment should be informed by the risk for adverse health effects associated with chemotherapy. Citation Format: Kobayashi K, Taira N, Sawaki M, Sagawa N, Baba S, Saito T, Kawahara T, Hagiwara Y, Uemura Y, Shimozuma K, Ohashi Y, Mukai H. Patient-reported outcomes with trastuzumab monotherapy versus trastuzumab plus standard chemotherapy as a postoperative adjuvant therapy in HER2-positive elderly breast cancer patients (RESPECT): A randomized, open-label, phase 3 clinical trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-02.

Background:It is unclear how to define responsiveness to endocrine therapy (ET) during the clinical course of advanced breast cancer (ABC), especially in evaluation of the effect of sequential ET. Objective:The goal of the study was to evaluate the efficacy of second line treatment of physician's choice (2nd-line TPC) for estrogen receptor-positive (ER+) and HER2-negative postmenopausal ABC with very low or low sensitivity to initial ET. Methods:A multicenter prospective observational cohort study was performed for 2nd-line TPCs. ABC with low sensitivity to initial ET was defined as recurrence within 5 years (yrs) during adjuvant ET or progression within 9 months (mo.) of initial ET. Similarly, ABC with very low sensitivity to initial ET was defined as recurrence within 2 yrs during adjuvant ET or progression within 3 mo. of initial ET. The expected clinical benefit rate (CBR: defined as patients who achieved CR, PR or SD for 24 weeks) was 50%. The null hypothesis of a CBR of 30% was tested with a one-sided α of 5%. 90% confidence intervals (CIs) were calculated for hypothesis tests. Results: A total of 56 patients (pts) were enrolled, but 7 were ineligible and one discontinued before starting the protocol treatment. The median age was 66 yrs (range: 41-88) and the median BMI was 23.4 kg/m2 (16.4-31.9). All pts were ER+ and 80% were PgR+. Most of pts had a baseline PS of 0 or 1, 90% had invasive ductal carcinoma, and 10% had invasive lobular carcinoma. Postoperative recurrence was detected in 84% and these pts had a median duration of adjuvant ET of 30.5 mo. (5.3-58.9). De novo stage IV ABC was present in 16%, with a median duration of first-line ET of 5 mo. (2.3-10.8). Adjuvant chemotherapy including anthracycline- and/or a taxane-containing regimen was administered in 58% (29/49). As adjuvant ET before initial recurrence, 34 pts received non-steroidal aromatase inhibitors (AIs) (88.0%), 1 received a steroidal AI (2.3%), and 3 received a selective estrogen receptor modulator (SERM). As first line ET in de novo stage IV, 7 pts (14%) were treated with AIs or a SERM (1 case). 2nd-line TPCs were also used, with 40 pts receiving fulvestrant (82%), 5 receiving SERMs (10%), 3 receiving a mTOR inhibitor plus a steroidal AI (6%), and one patient receiving an AI alone. The overall CBR was 44.9% (90% CI: 34.6-57.6, p=0.009), and CBR was similar across following subgroups (PgR+: n=39, 51.3%, 90% CI: 39.6-65.2, p=0.0016; very low sensitivity group: n=17, 58.8%, 90% CI: 42.0-78.8, p=0.003; non-visceral metastases: n=25, 40%, 90% CI; 34.1-65.9, p=0.0175). However, there were not statistically significant CBR in PgR- (n=10, 20.0%, 90% CI; 8.73-50.7, p=0.617), fulvestrant subgroup (n=40, 40.0 %, 90% CI; 29.2-54.2, p=0.063), low sensitive group (n=32, 37.5%, 90% CI; 26.0-53.6, p=0.1326), and visceral metastases (n=24, 48%, 90%CI; 28.2-60.3 p=0.072). The median PFS was 7.1 mo. (95% CI: 5.6-10.6). Conclusion:This study shows that 2nd line ETs was effective and might be a valid option in the sequence of treatments for postmenopausal women with ABC with low sensitivity to initial ET. It was suggested that PgR and visceral metastasis were significant predictive factors for CBR. Citation Format: Araki K, Fujisawa T, Sakamaki K, Kikawa Y, Iwamoto T, Sangai T, Shien T, Takao S, Nishimura R, Takahashi M, Aihara T, Mukai H, Taira N. Sequential second line endocrine therapy is still an effective strategy for postmenopausal ER+ and HER2- advanced breast cancer with low sensitivity to initial endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-09.

[Background] Past studies revealed that a moderate to high level of physical activity after diagnosis of breast cancer reduces both the risk of breast cancer-related death and death from all causes. Furthermore, some randomized studies suggested that exercise programs improve the percentage of patients who complete the chemotherapy and quality of life, and decrease fatigue, and adverse events. The issues to be determined include defining an established uniform exercise program and the efficacy of a long-term exercise program after breast cancer surgery. [Object] To elucidate the efficacy of a long-term exercise program and to verify the safety and feasibility of a uniform exercise program using an ‘existing social resource’ after primary therapy of breast cancer. [Design] A multi-center, randomized trial. [Method] Subjects: The subjects included patients who had completed treatment for primary breast cancer, including surgery and/or adjuvant chemotherapy. Patients with metastatic breast cancer were excluded. Randomization & intervention: The patients were randomly assigned to three groups. The first group followed an exercise program at Curves® that involved 30 minutes of exercise, including aerobics, weight training, and stretching 3 times a week for 4 months. The second group was given life-style guidance at least once that patients participate in a lecture program about recommended exercise at this point and the importance of weight control after diagnosis of breast cancer using a brochure. The third group served as controls that the patients receive a brochure used same one in the second group. The variables included age and weight. Outcome: The primary endpoint is level of physical activity at 1 year after randomization, and the secondary endpoints are the percentage of those completing the exercise program, patient reported outcomes (QOL, cancer or treatment associated symptoms, fatigue, depression, and anxiety), body mass index, bone density, and level of lymphedema. Period of research: The study will last 2 years beginning March 2016. Sample size: We plan to enroll 400 patients to detect 20% difference with 90% power. Additional study: Some biochemical markers in the blood will be evaluated to determine the mechanism of the effect of exercise on the human body. Citation Format: Kawada K, Taira N, Hatono M, Takahashi Y, Miyoshi Y, Nogami T, Iwamoto T, Motoki T, Sien T, Matsuoka J, Doihara H, Ikeda M, Ogasawara Y, Takabatake D, Yoshitomi S, Kiyoto S, Yamamoto S, Mizota Y, Oka K. Influence of exercise or educational programs on long-term physical activity by patients after surgery for primary breast cancer: A randomized trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-07-02.

Background: Tumor infiltrating lymphocytes (TIL) in subtypes of breast cancer may provide clinically important information on chemotherapy response and prognosis. However, the standardized methodology for immunohistochemical (IHC)-TIL has not yet been established, reproducible and objective method of evaluation of TIL such as gene expression profiles is warranted. We evaluated whether IHC-TIL level was associated with gene expression profiles and whether such profiles could be used to predict chemotherapy response and prognosis according to subtypes of breast cancers. Methods: To select TIL associated genes, we used 40 samples with both IHC-TIL information and gene expression profiling data. The degree of TIL at the edges of the tumor mass, in the tumor mass, or in the stroma surrounding the expanding mammary ducts packed by carcinoma cells was evaluated as score 0, 1, and 2, when TIL was not unrecognizable (0%), sparse (0 << 50%) and dense (50% ≤), respectively. We selected 22 genes as the TIL-gene signature (GS), by comparing expression profiles between TIL score 2 and 0 tumors. We showed the associations between the TIL-GS levels and subtypes of breast cancers (Estrogen receptor: ER / Human Epidermal growth factor 2: HER2). The chemotherapy sensitivity analysis was performed on cohorts of 625 patients with stage I–III breast cancer who received neo adjuvant chemotherapy (NAC) based on Anthracycline and Taxane containing regimen. Data from 1,586 tumors were used to evaluate the association between distant metastasis free survival (DMFS) and the TIL-GS in a Kaplan-Meier analysis. Results: The TIL-GS for ER negative (-)/HER2- and HER2 positive (+) cases were significantly higher expression level than luminal types (p-value Conclusions: Higher TIL-gene signature of 22 genes appeared to be associated with aggressive subtypes and pCR rate (except luminal-low) of breast cancers. This approach may improve the reproducibility of assessment on tumor TIL level and thus serve the clinical applications for breast cancers. Citation Format: Kochi M, Niikura N, Iwamoto T, Bianchini G, Mizoo T, Nogami T, Shien T, Motoki T, Taira N, Masuda S, Doihara H, Fujiwara T, Tokuda Y, Matsuoka J. Tumor Infiltrating lymphocytes (TIL) related genomic signature associated with chemotherapy response and prognosis in subtypes of breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-14.

Background: There is a high risk of under-reporting subjective toxicities by physicians, even when collected prospectively in clinical trials. It has been recommended to include patient reported measures regarding symptoms in prospective clinical comparative effectiveness trials. However, there have been few reports of agreement in endocrine related symptoms between patient and physician reporting. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 06 (N-SAS BC 06) is a multicenter, randomized clinical trial of postmenopausal, hormone receptor-positive breast cancer patients, with a two-stage (preoperative and postoperative) enrollment, and intervention. The primary aim was to evaluate the need for adjuvant chemotherapy in the treatment of postmenopausal breast cancer patients who responded to neoadjuvant treatment with Letrozole (LET) for 24-28 weeks. After surgery, responders were randomized into two arms receiving either chemotherapy plus LET, or LET alone. The primary endpoint was disease-free survival, and the secondary endpoints included adverse events, quality of life and health economic evaluation. This study enrolled 497 subjects from the N-SAS BC 06 who were evaluated by Patient Reported Outcomes (PROs). The concordance rate between Clinician Reported Outcomes (CROs) and PROs in their endocrine symptoms during neoadjuvant endocrine therapy was examined. Symptoms were collected prospectively by physicians using the Common Toxicity Criteria for Adverse Events at enrollment, i.e., baseline, and 4 and 16 weeks after starting neoadjuvant LET. Patients also completed the FACT-G (General), B (Breast), ES (Endocrine Symptoms), and HADS. The endocrine symptoms according to the PROs, included nausea, hot flushes, cold sweats, headaches, and HADS-Depression score. In FACT, "Not at all" was used to express the absence of the symptoms, and "A little bit", "Some-what", "Quite a bit", and "Very much" were used to express the presence of symptoms. The HADS-Depression score threshold was 10/11. According to the CROs, grade 0 was defined as the absence of symptoms and grade 1 or more was defined as the presence of symptoms. Cohen's kappa was used to determine the concordance between CROs and PROs. The sensitivity of CROs was also calculated. Results: The calculated point estimates of Cohen's kappa at Weeks 4 and 16 after starting neoadjuvant LET were 0.12 and 0.01 for nausea, 0.16 and 0.18 for hot flushes, 0.12 and 0.09 for cold sweats, 0.03 and 0.02 for headaches, and 0.11 and 0.11 for dysthymia/depression, respectively; the concordance was quite low. The sensitivity of CROs at Weeks 4 and 16 after starting neoadjuvant LET was 0.07 and 0.03 for nausea, 0.16 and 0.17 for hot flushes, 0.1 and 0.08 for cold sweats, 0.03 and 0.03 for headaches, and 0.11 and 0.1 for dysthymia/depression, respectively; the sensitivity was quite low. Conclusion: This study showed that there were big differences between CROs and PROs in endocrine symptoms associated with endocrine therapy for breast cancer and that physicians could not obtain sufficient information on the endocrine symptoms. It is recommended that PROs be used to evaluate adverse events caused by endocrine therapy. Citation Format: Fujisawa T, Iwata H, Sakai T, Nakamura R, Hasegawa Y, Ohtani S, Kashiwaba M, Taira N, Toyama T, Masuda N, Yamamoto Y, Kihara K, Shimozuma K, Ohashi Y, Mukai H. Endocrine-related symptoms during neoadjuvant endocrine therapy for breast cancer: Agreement between patient and physician reporting in a prospective clinical trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-02.

Background: There are few randomized clinical trials examining adjuvant treatment in elderly breast cancer patients. While obtaining informed consent is essential for participation in clinical studies, there is little information on the frequency of agreement to participate among elderly patients. Furthermore, elderly patients might have specific reasons to decline participation. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized clinical trial in women over 70 years with HER2-positive primary breast cancer. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with the combination of trastuzumab and chemotherapy. Key inclusion criteria were as follows: women between 70 and 80 years old with HER2-positive breast cancer; underwent curative operation; stage I to IIIA; with sufficient organ function. Patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, health-related quality of life, and cost effectiveness (NCT01104935). It was not possible to predict the number of patients who would agree to participate. In order to comprehensively assess the effect of postoperative adjuvant therapy, we evaluated the reasons why eligible patients declined to participate. The patients were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). This study examined the obtaining of informed consent for N-SAS BC 07 and the reasons for declining participation, and compared the clinicopathological backgrounds between the N-SAS BC 07 and 07-Cohort groups. Results: 398 eligible patients have been recruited. Informed consent to participate in N-SAS BC 07 has been obtained from 275 patients (69%) and 123 patients (31%) who declined to participate in the RCT have been registered in the 07-Cohort. The common reasons to decline participation in the RCT were "cannot choose the treatment option (55%)", "refused chemotherapy (16%)", "wanted chemotherapy (9%)", "anxious about clinical studies (9%)" and "family opposition (8%)". The mean ages of the patients in N-SAS BC 07 and 07-Cohort were 73.9 and 74.6 years old, respectively. There were no differences in stage, surgical procedure, lymph node metastasis, or co-morbidities between the groups. ER-positive rate was higher in 07-Cohort group compared with N-SAS BC 07 group (53% vs. 37%, p=0.017, χ2 test). Conclusion: While we expected the number of registrants to be small, since N-SAS BC 07 investigated whether elderly patients with HER2-positive breast cancer should undergo chemotherapy, almost 70% of the patients accepted informed consent. The most common reason to decline participation in N-SAS BC 07 was "cannot choose the treatment option" and the majority refused chemotherapy. Furthermore, ER-positivity was higher in the 07-Cohort group, which suggested that ER expression in the patients with HER2-positive breast cancer might influence their decision to participate in the study or to choose the treatment option. Citation Format: Sagara Y, Sawaki M, Taira N, Saito T, Kashiwaba M, Iwata H, Kobayashi K, Nakayama T, Bando H, Mizuno T, Yamamoto Y, Tsuneizumi M, Takahashi M, Yamaguchi M, Kawashima H, Takashima T, Uemura Y, Hozumi Y, Sagawa N, Mukai H, Ohashi Y. A randomized clinical trial of postoperative adjuvant therapy for elderly breast cancer patients: Conditions of obtaining informed consent and reasons for declining participation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-18-01.

Background: Health-related quality of life (HRQoL) is one of the important outcomes in cancer control trials and has increasingly become the one of the primary foci. Obtaining informed consent from participants is essential for participation in randomized controlled trials (RCTs), but the participation in these RCTs may directly influence HRQoL, because treatment options are determined according to the allocation schedule. To date, only a few studies have compared HRQoL between clinical trial participants and decliners. Patients and Method: The National Surgical Adjuvant Study of Breast Cancer 07 (N-SAS BC 07) is a randomized controlled trial in women with HER2-positive primary breast cancer who are over 70 years of age. The primary aim was to investigate the benefit of trastuzumab monotherapy compared with combination therapy using trastuzumab and chemotherapy. The study concept and design were published in concept paper (Sawaki M. et al., Jpn J Clin Oncol. 2011). In this study, patients were randomized to receive either trastuzumab plus chemotherapy or trastuzumab monotherapy. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival, relapse-free survival, safety, HRQoL, comprehensive geriatric assessment (CGA) and cost effectiveness (protocol ID; NCT01104935). HRQoL and CGA were assessed at registration (baseline), 2 month, 1 year, and 3 years after the start of protocol treatments using the Functional Assessment of Cancer Therapy-General (FACT-G), Hospital Anxiety and Depression Scale (HADS), EuroQol 5 Dimension (EQ-5D), Tokyo Metropolitan Institute of Gerontology (TMIG) index of competence, and the Philadelphia Geriatric Center (PGC) Morale Scale. The patients who declined to participate in N-SAS BC 07 were registered in a cohort study to prospectively evaluate the subsequent treatment options and prognosis (07-Cohort). The same questionnaire that was used in N-SAS BC 07 was used in 07-Cohort to evaluate HRQoL and CGA at entry. Results: Patients were enrolled from October 2012 to October 2016. During this period, 275 and 123 patients were registered in N-SAS BC 07 and 07-Cohort, respectively. The mean age at entry of the patients in the N-SAS BC 07 and 07-Cohort groups was 73.9 and 74.6 years, respectively. The questionnaire response rates at baseline in the patients in N-SAS BC 07 and 07-Cohort groups were 89% and 82%, respectively. There were no significant differences in FACT-G, HADS, EQ-5D, or TMIG index of competence at baseline between the groups, but the mean (standard deviation) scores of PGC Morale Scale in N-SAS BC 07 and 07-Cohort groups were 10.8 (3.3) and 9.9 (3.7), respectively, with the scores being significantly greater in the N-SAS BC 07 group (p=0.020, t-test). Conclusion: The PGC Morale Scale provides a multidimensional approach to assess the psychological state of older people. This study indicated that participation in the RCT did not affect the baseline QoL of elderly patients but suggested that the baseline QoL of the RCT participants was better than decliners. Citation Format: Saito T, Sawaki M, Hozumi Y, Sagawa N, Iwata H, Kashiwaba M, Kawashima H, Kobayashi K, Taira N, Takashima T, Takahashi M, Tsuneizumi M, Nakayama T, Baba S, Bando H, Mizuno T, Yamaguchi M, Yamamoto Y, Uemura Y, Ohashi Y, Mukai H. A randomized controlled trial of postoperative adjuvant therapy for elderly breast cancer patients: Comparison of health-related quality of life between clinical trial participants and decliners. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-09.

Background: Whether adjuvant chemotherapy is required for patients with intermediate-risk endocrine-responsive postmenopausal breast cancer remains unknown. The New primary Endocrine-therapy Origination Study (NEOS: N-SAS BC06 study: UMIN 000001090 (http://www.umin.ac.jp/) was a randomized controlled trial to verify the necessity of adjuvant chemotherapy in node-, ER+, and HER2- postmenopausal breast cancer patients who responded to neoadjuvant endocrine therapy. The primary registration and primary treatment have finished. This report evaluated clinical responses and radiological findings in the neoadjuvant LET treatment phase of 6 months. Methods: Patients meeting eligibility criteria received LET preoperatively in weeks 24-28 after primary enrollment. Patients evaluated as complete response (CR), partial response (PR) or stable disease (SD) by each investigators underwent secondary enrollment and will be divided at random into two arms, an arm given LET for 4.5-5 years after chemotherapy and another arm given only LET for 4.5-5 years. Patients evaluated as progressive disease during LET treatment will receive discretionary treatment. The primary endpoint was disease-free survival and secondary endpoints were overall survival, clinical response rate in neoadjuvant treatment phase, pathological response, breast-conserving surgery rate, DFS/OS in subgroups according to clinical response, safety, HRQOL, and cost-effectiveness. Results: Between May 2008 and June 2013, 905 patients entered primary registration. We excluded 42 patients without confirmed data. The 863 included patients’ characteristics at baseline are: median age: 63 years old, median Body Mass Index (BMI):23.90, T1c:37%, T2:63%, and PgR+:79%, and 74% of patients had planned breast-conserving surgery (BCS). The clinical responses were evaluated with calipers, ultrasound and MRI (or CT) at the baseline and end of treatment before surgery. Clinical response rates were 2, 48, 46 and 4% in CR, PR, SD and PD, respectively. Excluding those who could not enter secondary registration according to the protocol, 83 (56.1%) of 148 patients with planned total mastectomy were converted to BCS according to final radiological evaluations before surgery. The correlation between the tumor size on MRI (r=0.87) after neoadjuvant LET and the pathological invasive tumor size was stronger than with other modalities (r=0.68, 0.57, 0.33 by CT, US and calipers, respectively). On univariate analysis, a small tumor size (T1c rather than T2), PgR+, HER2:2+ and a high BMI at the baseline were significantly correlated with the clinical response. On multivariate analysis, PgR + (HR: 1.13, 95%CI: 1.01-1.27, p=0.032) and a small tumor size (HR: 1.11, 95%CI: 1.03-1.17, p=0.003) were significant independent predictors of the clinical response. Conclusion: This is the first clinical report of neoadjuvant hormone therapy for early breast cancer. Neoadjuvant LET therapy improved BCS rates. MRI was useful for predicting the residual pathological invasive tumor size. PgR + and a small tumor size at the baseline were significant independent predictors of the clinical response. Citation Format: Takehiko Sakai, Hiroji Iwata, Yoshie Hasegawa, Rikiya Nakamura, Hiromitsu Akabane, Shoichiro Ohtani, Masahiro Kashiwaba, Naruto Taira, Tatsuya Toyama, Yutaka Yamamoto, Tomomi Fujisawa, Norikazu Masuda, Takuhiro Yamaguchi, Hirofumi Mukai, Yasuo Ohashi. First report of clinicopathological analysis in neoadjuvant treatment phase in NEOS: A randomized study of adjuvant endocrine therapy with or without chemotherapy for postmenopausal breast cancer patients who responded to neoadjuvant letrozole [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-14-01.

[Background] Based on the results of a case-control study performed in Japan (Okayama and Kagawa), it was revealed that gene polymorphisms of the estrogen receptor (single nucleotide polymorphisms, SNPs), ESR1/6q25.1-rs2046210 and SNPs of rs3757318 were closely related to breast cancer risk in Japanese women, and that the odds ratio per allele of individual SNPs were 1.37 [95% CI: 1.1 - 1.7] and 1.33 [1.04 - 1.7], respectively (San Antonio Breast Cancer Symposium 2012, Mizoo et al.). We analyzed the relationship of ESR1/6q25.1-rs2046210 and rs3757318 SNPs with the clinical characteristics of breast cancer patients. [Methods] Among the patients enrolled in the case-control study, 508 breast cancer patients who underwent genotyping for ESR1/6q25.1-rs2046210 and rs3757318 were analyzed as the subjects. SNPs were analyzed using the TaqMan genotyping assay® for blood samples. To analyze the relationship of genotypes (AA/GG, GG) with age at diagnosis, height, weight, BMI, age of menarche, birth history, pathological degree of progression and estrogen receptor, t-test and chi-square test were used. [Results] The genotypes of rs2046210 are AA (12%), AG (41%) and GG (46%), and the patients with the risk allele (AA/AG) had significantly higher height (p = 0.0015, t-test) and lower Body Mass Index (BMI) (p = 0.0022, t-test). The genotypes of rs3757318 are AA (8%), AG (39%) and GG (53%), and the patients with the risk allele (AA/AG) were characterized by significantly lower BMI (p = 0.041, t-test), no birth history (p = 0.0473, chi-square) and negative hormone receptor (p = 0.0128, chi-square). Overall, tendencies related to increased height, lower BMI and negative estrogen receptor were confirmed for the risk alleles of rs2046210 and rs3757318. [Conclusion] It was suggested that SNPs of rs2046210 and rs3757318 might be related to the development of estrogen-receptor-negative breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-10.

Background: Sensory loss or paresthesia due to division of the intercostobrachial nerve (ICBN) is a complication of axillary lymph node dissection (ALND). Preservation of the ICBN may be of value, but few prospective studies have shown an impact of preservation on sensory changes or health related quality of life (HRQOL) after breast cancer surgery. Methods: Prospective study was performed to evaluate the association of ICBN preservation with sensory change and HRQOL at 1 (baseline), 6, 12 and 24 months after breast cancer surgery in 140 patients. The sensory examination included dysesthesia, paresthesia, abnormal touch and pain sensation in the upper arm. Results: Division of the ICBN did not influence the frequency or severity of subjective dysesthesia and paresthesia. There was no marked difference in touch or pain sensation at baseline between patients with a preserved (group P) and divided (group D) ICBN. In group P, the percentage of patients aware of a sensory deficit or loss decreased with time, and that of patients aware of a hypersensitive sensation increased. These changes did not occur in group D, leading to a significant difference between the groups at 24 months. The main difference between the groups was the area with reduced touch or pain sensation. This area decreased with time in group P, but not in group D. ICBN preservation or division did not influence HRQOL. Conclusion: ICBN preservation in ALND has a benefit of a reduced area with long-term axillary hypoesthesia, but has no influence on improvement of pain and HRQOL. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-14-07.

[Background] Lifestyle, including diet and physical activity, and birth/breastfeeding history are known to affect the risk for breast cancer. A correlation between single nucleotide polymorphisms (SNPs) and breast cancer risk has also been suggested in some reports, but the gene-environment interaction with breast cancer risk has not been examined widely. [Methods] The subjects were 476 breast cancer patients and 528 controls who attended a health check and had no history of breast cancer. Lifestyle was examined using a questionnaire with 48 questions about diet, physical activity, smoking habits, alcohol intake, and birth/breastfeeding history, etc. Based on past reports, we analyzed 6 SNPs (TNRC9-rs3803662, LSP1/11q-rs3817198, MAP3K1-rs889312, 8q24-rs13281615, 5p12-rs981782, and TGFβ1-rs1800470) using blood samples, and calculated age-adjusted odds ratios in a multiple logistic regression analysis. [Results] The study was performed from December 2010 to November 2011. Lifestyle factors (age-adjusted odds ratio, [95% confident interval]) found to have a significant correlation with development of breast cancer included BMI (1.041, [1.00–1.08]), smoking history (2.28, [1.45–3.65]), small number of births (1.18, [1.05–1.34]), no exercise during leisure time (1.36, [1.06–1.77]), low intake of green and yellow vegetables (1.69, [1.01–2.85]), and low intake of mushrooms (1.58, [1.05–2.39]). Stratified analysis based on menopause status showed that smoking history (1.85, [1.00–3.49]) and low intake of green and yellow vegetables (2.5, [1.03–5.88]) were significant risk factors before menopause, and that smoking history (2.28, [1.45–3.65]), low intake of green and yellow vegetables (2.24, [1.09–4.68]), no exercise during leisure time (1.67, [1.19–2.36]), small number of births (1.49, [1.25–1.78]), and no breastfeeding history (1.03, [1.01–1.06]) were significant risk factors after menopause. The results of SNP analysis suggested that TNRC9-rs3803662 was a significant risk factor in women before menopause (2.29, [1.25–4.25]). However, in multivariate analysis including lifestyle factors and SNPs, only smoking history emerged as a significant risk factor in women before menopause. [Conclusion] A correlation between lifestyle and breast cancer risk was found in this study, consistent with previous findings. Lifestyle and environmental factors such as births and breastfeeding may be more important than SNPs as risk factors for breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-10.

Background It has not been established if adjuvant chemotherapy is required for patients with intermediate-risk endocrine-responsive postmenopausal breast cancer. The NEOS is a randomized controlled trial to verify the necessity of adjuvant chemotherapy in patients with node-negative, ER-positive, and HER2−negative postmenopausal breast cancer who responded to neoadjuvant endocrine therapy. For neoadjuvant letrozole (LET), the protocol specified that an interim analysis should be performed to avoid lack of benefit to patients if no therapeutic effects, which were anticipated before the start of the study, were obtained. Methods: Patients who complied with the eligibility criteria were administered LET preoperatively in weeks 24–28 after primary enrollment. Patients evaluated as complete response (CR), partial response (PR) or stable disease (SD) underwent secondary enrollment and will be divided at random into two arms, an arm given LET for 4.5-5 years after chemotherapy and another arm given only LET for 4.5-5 years. Patients evaluated as progressive disease during LET treatment will receive discretionary treatment. For neoadjuvant LET, the number of patients requiring interim analysis of efficacy was calculated as 140 based on the assumption that the threshold response rate of CR+PR+SD was 75% and its expected response rate was 85% in patients who completed neoadjuvant LET, and that the one-sided level of significance was 5% and the statistical power was 90%. When the hypothesis that the rate of CR+PR+SD was less than 75% was not rejected at a significance level of 5%, the study was discontinued and when it was rejected, the study was continued. Results: As of June 2011, 140 patients in 39 centers had completed neoadjuvant LET. The median age was 64 years old (range: 50–75) and the median Body Mass Index (BMI) was 23.90 (±3.77). According to MRI or CT scan, CR occurred in 2 (1.4%), PR in 57 (40.7%), and SD in 59 patients (42.1%). The rate of CR+PR+SD among the 140 patients was 84.3% (90% confidence interval: 78.6−88.7). In ultrasonography, 47 patients (33.6%) showed a decrease in the long diameter of 30% or more in a mono-dimensional measurement and 52 patients (37.1%) showed a decrease in volume of 50% or more in a three-dimensional measurement. The neoadjuvant LET effects showed no differences in patients with a BMI of less than 20, 20–25, and more than 25. No serious adverse events were observed. Discussion: The rate of patients who achieved CR+PR+SD by neoadjuvant LET complied adequately with the continuation criteria for the study. We will present the results for 205 patients who could be evaluated for efficacy and safety of neoadjuvant LET as of May 2011. This study was supported by Public Health Research Foundation. Clinical Trial Registration Information: UMIN (http://www.umin.ac.jp/), Study ID: 000001090 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-15-01.

Background: The treatment for metastatic breast cancer (MBC) is usually systemic therapy decided by the hormone and HER2 status of primary breast cancer lesion. There are some reports about the discrepancy in hormone and HER2 status between primary and metastatic lesion in these days. We have reported previously that the expression of ALDH-1 which considered the pathological markers of breast cancer stem cell in axillary lymph node matastases is a significant predictor of poor outcome in primary breast cancer patients (Figure 1). We evaluated the role of surgery in the diagnosis and treatment of a solitary pulmonary nodule (SPN) in breast cancer patients and demonstrated the significance of analyzing the immunopathological features in metastatic breast cancer lesion. Methods: Between 1990 and 2006, 17 patients (PM) with SPN which were diagnosed breast cancer metastases underwent complete pulmonary resection and 36 MBC patients (AP) underwent autopsy after breast cancer related death in our hospitals. We retrospectively analyzed clinicopathological features and the expression of ER, HER2, Ki-67 and ALDH-1 in both primary and metastatic breast cancer lesions. Results: The median age of PM patients was 53 (range 30-80). All PM patients had not other metastases and had undergone curative breast cancer operation. The pulmonary operation were partial pulmonary resection in 15(88%) and lobectomy in 2 (12%) patients. The median disease free survival (DFS) was 63 months (range 9-175). Median overall survival (OS) was 181 months and the median OS after pulmonary operation was 48 months. The median DFS and OS of AP patients were 21 and 43 months. All AP patients had multiple visceral metastases. We compared the immunohistlogical status between primary and metastatic lesion and evaluated the colletation with these status in metastatic lesion and prognosis in all patients. Conclusion: Pulmonary resection was effective to diagnose and the OS after resection was relatively long in PM patients. We report the value of the expression of ER, HER2, Ki67 and ALDH-1 in distant metastatic lesions. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-20.

Background: Neoadjuvant therapy for locally advanced breast cancer has the potential to improve surgical therapeutic outcomes without sacrificing the survival advantages of adjuvant therapy. However, determining whether ER+ patients (pts) will respond to neoadjuvant (NA) chemotherapy (CT) or hormone therapy (HT) can be difficult. Not all ER+ pts respond to NACT, while response to NAHT can vary across ER+ pts. Thus, the ability to select pts more likely to benefit from NAHT would represent progress in clinical management of breast cancer. NEOS is a randomized phase III study assessinglong-term prognosis of ER+ primary breast cancer with/without adjuvant CT following NAHT (UMIN 000001090, http://www.umin.ac.jp/). We used archived core biopsy tumor samples from the NEOS study to validate the RS result as a predictor of clinical response and its association with successful breast conserving surgery (BCS) in pts treated with 6 months of NAHT. Methods: NEOS enrolled 904 postmenopausal pts with ER+, HER2-, clinically node negative (cN0) breast cancer to evaluate whether adjuvant CT was necessary for pts who responded to NAHT. In this current study, we enrolled pts with tumors ≥2cm from the NEOS study. Biopsy samples of 333 pts were assessed for the Oncotype DX assay. Response to NAHT was recorded as complete/partial response (CR/PR), or stable/progressive disease (SD/PD). Primary endpoint of this study was to evaluate clinical response (CR/PR) to NA letrozole between pts with low ( Results: The analysis included 294 pts with median age of 63 yrs, median tumor size of 25mm, and 66% were nuclear grade 1. 156 (53.0%), 83 (28.6%) and 54(18.4%) cases were low, intermediate, and high RS groups by Oncotype DX, respectively. Six (2%), 126 (42.8%), 149 (50.3%), 13 (4.4%) cases experienced CR, PR, SD, PD as clinical response, respectively, similar to that of all NEOS pts. Clinical response rate was 54%, 42% and 22% in low, intermediate, and high RS groups, respectively. The proportion of pts with clinical response was significantly higher in the low RS group vs the high RS group (p Conclusion: The Oncotype DX RS test in core biopsy samples is validated as a predictive assay for clinical response of NAHT in postmenopausal, ER+/HER2-, cN0, primary early breast cancer pts. Further results on the association of RS results with BCS outcomes following NAHT will be presented. These results when combined with previously published data on RS in NACT studies help guide pts with ER+, HER2- breast cancer with NAHT vs NACT treatment options to maximize clinical response. Citation Format: Yamamoto Y, Iwata H, Masuda N, Fujisawa T, Toyama T, Kashiwaba M, Ohtani S, Taira N, Sakai T, Hasegawa Y, Nakamura R, Akabane H, Shibahara Y, Sasano H, Yamaguchi T, Sakamaki K, Chao C, McCullough D, Sugiyama N, Ohashi Y. TransNEOS: Validation of the oncotype DX recurrence score (RS) testing core needle biopsy samples from NEOS as predictor of clinical response to neoadjuvant endocrine therapy for postmenopausal estrogen receptor positive (ER+), HER2 negative (HER2-) breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-03.

Background: Genomic biomarkers have been widely adopted to assist in clinical decision making regarding chemotherapy use in estrogen receptor (ER)-positive, HER2-negative breast cancer. First generation genomic signatures (FGGS) serve predominately as prognostic biomarkers and secondarily have a role in prediction of chemotherapy response. The majority of the FGGSs provide similar prognostic information which mainly capture in different ways tumor proliferation. While several studies have compared the prognostic value of FGGSs to clinico-pathological variables, few studies have performed a similar comparison for their predictive value. For this reason, we aimed to compare both the prognostic and predictive value of histological grade and the genomic marker. Methods: We retrieved publicly available cDNA microarray data from 1,373 primary ER+/HER2- breast cancers (n=721 treated with various or unknown, n=350 untreated node negative, n=302 treated with neoadjuvant chemotherapy). We developed a genomic signature simulated from recurrence online (http://www.recurrenceonline.com/) to calculate recurrence score and recurrence risk using pre-defined sets of genes by cDNA microarray (B Gyorffy Breast Cancer Res Treat 2012). Breast cancers were categorized as low, intermediate or high risk for distant recurrence using grade and genomic signature. We compared the prognostic and predictive information provided by histological grade to the genomic signature. The outcome of interest in untreated patient was distant event free survival. The outcome of interest in the anthracycline-taxane treated patients was pathological complete response (pCR) in breast and axilla. Results: Fifty five, 28 and 17% breast cancers were classified as low, intermediate and high risk by genomic signature and 22, 59 and 19% as grade I, II and III respectively. The genomic signature classified 11% of grade I/II cancers (126/1108) and only 42% of grade III cancers (112/265) as high risk, and 29% of GradeIII (77/265) as low risk. Univariate analysis in the untreated cohort, showed both histological grade (overall p=0.007) and the genomic signature (p Interpretation: The genomic signature was better at identifying low risk cases compared to histological grade alone. There was no difference in prediction of NAC response between either biomarker. Better predictive biomarkers for NAC response are needed. Citation Format: Takayuki Iwamoto, Catherine Kelly, Giampalo Bianchini, Takeo Mizoo, Tomohiro Nogami, Takayuki Motoki, Tadahiko Shien, Naruto Taira, Naoki Hayashi, Naoki Niikura, Toshiyoshi Fujiwara, Hiroyoshi Doihara, Junji Matsuoka. Assessment of the prognostic and predictive ability of a gene signature compared to histological grade in estrogen receptor positive, HER2 negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-09.

Background: Based on the results of a case-control study performed in Japan (Okayama and Kagawa), it was revealed that gene polymorphisms of the estrogen receptor (single nucleotide polymorphisms, SNPs), ESR1/6q25.1-rs2046210 and rs3757318, were closely related to breast cancer risk in Japanese women, and that the odds ratios per allele of individual SNPs were 1.37 [95% CI: 1.1 - 1.7] and 1.33 [1.04 - 1.7], respectively (San Antonio Breast Cancer Symposium 2012, Mizoo et al.). To examine the effects of these SNPs on the pathogenic mechanism of breast cancer, we analyzed the relationship of SNPs with reproductive/physiological factors (age of menarche and number of births), physical factors (height and Body Mass Index [BMI]), family history and mammographic breast density. Methods: Among the patients enrolled in the case-control study, the patients who could be evaluated regarding their lifestyle, SNPs and mammographic breast density were divided into the case group (N = 394) and the control group (N = 511) as the dataset for the study. SNPs were analyzed using the TaqMan genotyping assay® for blood samples. In the analysis of the relationship between SNPs and breast cancer risk, the odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using logistic regression analysis. For the analysis of the relationship between SNPs and the factors, t-test and chi-square test were used. Results: In our dataset, the age-adjusted OR [95% CI] of ESR1/6q25.1-rs2046210 and rs3757318 were 2.22 [1.41 - 3.55] (AA vs. GG) and 2.12 [1.2 - 3.8] (AA vs. GG), respectively, suggesting that they would be significant risk factors. As a result of analyzing the relationship between SNPs and other factors, a significantly lower BMI was observed for the risk allele AA/AG of rs2046210, compared to GG (p = 0.014, t-test). Regarding the mammographic breast density, a significantly higher proportion of mammary glands with high density was confirmed for the risk allele AA/AG of rs2046210, compared to GG (p = 0.0389, chi-square test). The tendency towards a high mammographic breast density in the rs2046210 risk allele AA/AG was also confirmed based upon a stratified analysis of the case and control groups before and after menopause, and a significant correlation was observed, especially before menopause (p = 0.026, chi-square test). Conclusion: Mammographic high breast density is generally considered as one of the breast cancer risks, and it was suggested that gene polymorphisms of ESR1/6q25.1-rs2046210 might affect mammographic breast density. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-01-07.

Background: Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers since they can be treated with anti-estrogen therapies. However, ER-positive breast cancers have low sensitivity to chemotherapy and the survival benefitof chemotherapy is limited. Microtubule associated protein-tau (MAPT) plays an important role in taxane sensitivity. In a previous study we showed that ER signaling influenced MAPT expression and that fulvestrant, an estrogen receptor antagonist, downregulated MAPT and reversed resistance to taxane in MAPT-and ER-positive breast cancer cells (SABCS 2009, Abstract 2118). In clinical treatment for breast cancer, the advantages and disadvantages of combination treatment with endocrine therapy and chemotherapy have long been discussed. Several studies have shown that endocrine therapy has an antagonistic effect on chemotherapy, which suggests that concurrent use of a hormone drug and a chemotherapeutic agent should be avoided clinically. However, most of these studies used tamoxifen (TAM) and anthracycline regimens. The effects of combination treatment using new hormone therapies, such as aromatase inhibitors or fulvestrant, and chemotherapeutic agents have not been examined thoroughly. In this study we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents in vitro and in vivo. Methods: In vitro, the effects of different combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-FU) and three hormone drugs (TAM, 4-hydroxytamoxifen (4OH-TAM), and fulvestrant) were examined in ER-positive breast cancer cell lines (MCF-7, ZR75-1) using CalcuSyn software. The cells were also exposed to hormone drugs and changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1 (MRP1), and MAPT were examined. In vivo, xenografts were created using MCF-7 cells transplanted into BALB/c nu/nu mice. Tumor sizes were evaluated after the mice were treated with tamoxifen alone, fulvestrant alone, docetaxel alone, and combinations of these drugs. Results: Combination treatment with fulvestrant and all chemotherapeutic agents in vitro showed a synergistic effect regardless of the fulvestrant dose. In contrast, TAM showed an antagonistic effect with all the chemotherapeutic agents, with the strongest antagonism occurring at a low dose of TAM. 4OH-TAM showed an antagonistic effect with doxorubicin and 5-FU, and a synergistic effect with taxanes and vinorelbine. In the analysis of chemoresistant factors, Bcl2 and MAPT were downregulated by fulvestrant, but upregulated by TAM and 4OH-TAM. In vivo, the combination of fulvestrant and docetaxel showed the strongest inhibitory effect on tumor growth. Conclusion: TAM and 4OH-TAM had different effects in combination with chemotherapeutic agents. Fulvestrant downregulated ER and chemoresistant factors such as Bcl2 and MAPT, which are regulated via ER. Fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents in vitro and in vivo. These results suggest that combination therapy with fulvestrant and chemotherapeutic agents may be effective for ER-positive breast cancers. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-01-01.

Background: Taxanes are important drugs in treatment of breast cancer. These drugs bind to tubulin and suppress spindle microtubule dynamics, which leads to cell cycle arrest in the G2/M phase followed by apoptosis. However, resistance to taxane therapy prevents some patients from benefiting from these drugs. Several mechanisms of taxane resistance have been described, including the involvement of microtubule-associated protein-tau (MAPT). MAPT binds to the same pocket as taxanes in microtubules and obstructs the function of the drug. Estrogen receptors (ER) are transcriptional factors that play an important role in the development and progression of breast cancer. However, the relationship between ER and MAPT in breast cancer is not entirely clear. In this study we examined the correlation between MAPT expression and the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT at the protein level in these cells. We also examined combination therapy with hormone drugs and taxanes.Methods: The correlation between MAPT expression and sensitivity to taxanes was examined in 12 human breast cancer cell lines using real time PCR, western blotting analysis and an MTS assay. Following small interfering RNA (siRNA) knockdown of MAPT expression, the alteration of cellular sensitivity to taxanes was examined by MTS assay, flow cytometry and immunofluorescence. To examine the relationship between ER and MAPT, ER expression was knocked down with siRNA or stimulated with 17-β-estradiol in MAPT- and ER-positive cell lines (MCF-7 and ZR75.1, respectively). The cells were also treated with hormone drugs (tamoxifen and ICI182,780) and changes in MAPT protein expression were examined.Results: Six cell lines showed high MAPT mRNA expression and four showed high MAPT protein expression; that is, expression at the mRNA level did not always correlate with that at the protein level. MAPT mRNA expression did not correlate with taxane resistance, but expression of MAPT protein isoforms under 70 kDa correlated with taxane resistance. Downregulation of MAPT increased sensitivity to taxanes. MAPT protein expression was decreased by ER knockdown and increased by 17-β-estradiol stimulation. The MAPT protein level was also increased by tamoxifen, but decreased by ICI182,780. Combination treatment of taxanes with ICI182,780 showed a strong synergistic effect, but similar treatment with tamoxifen had an antagonistic effect in both cell lines.Conclusions: Expression of MAPT protein isoforms under 70 kDa correlates with taxane resistance in breast cancer cells. MAPT expression is influenced by ER in breast cancer and ICI182,780, a selective ER inhibitor, can reverse the resistance to taxanes in both MAPT- and ER-positive breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2118.