Michiko Tsuneizumi

Comparison of immune microenvironments between primary tumors and brain metastases in patients with breast cancer

Background Immune checkpoint inhibitors are reported to be effective in patients with brain metastases. However, detailed characteristics of the brain metastasis immune microenvironment remain unexplored. Results The median tumor-infiltrating lymphocyte (TIL) category in brain metastases was 5% (1–70%). In 46 pair-matched samples, the percentages of TILs were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.01). The numbers of CD4/CD8/Foxp3-positive cells were significantly higher in primary breast tumors than in brain metastases (paired t-test, P < 0.05 for all antibodies). In patients with triple-negative breast cancer specifically, low TIL numbers were associated with significantly shorter overall survival compared to high TIL numbers (log-rank test, P = 0.04). Materials and Methods We retrospectively identified 107 patients with breast cancer and brain metastases who had undergone surgery between 2001 and 2012 at 8 institutions, and collected 191 samples including brain metastases alone and primary tumors with pair-matched brain metastasis samples. Hematoxylin and eosin-stained slides were evaluated for TILs and categorized according to the extent of staining. Immunohistochemistry for CD4, CD8, Foxp3, PD-L1, PD-L2, and HLA class I was also performed. Conclusions There are significantly fewer TILs in brain metastases than in primary breast tumors.

Abstract P4-11-09: 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

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.

Abstract P3-10-01: Randomized phase III trial of taxanes versus S-1 as first-line chemotherapy for metastatic breast cancer (SELECT BC: CSPOR- MBC01)

Background: Treatment goals of metastatic breast cancer (MBC) are to prolong survival and improve health-related quality of life (HRQOL). Current standard first-line chemotherapy for MBC are the taxanes or anthracyclines; however treatment-related adverse events greatly reduce HRQOL. S-1 is an oral 5-fluorouracil derivative, and phase II trials showed good clinical efficacy and tolerability. We conducted a phase III randomized controlled trial to establish non-inferiority of S-1 in overall survival (OS) and superiority in HRQOL to taxanes, when given as first-line chemotherapy for MBC. Methods: Patients with HER2-negative non-life-threatening MBC, naive to chemotherapy for metastatic disease, were randomly assigned to the taxane or S-1 groups. In the taxane group, patients received docetaxel 60-75mg/m2 q3w, paclitaxel 80-100mg/m2 q1w, or paclitaxel 175 mg/m2 q3w according to institutional policy. In the S-1 group, patients received S-1 40–60 mg twice daily based on body surface area using a 28 days on;14 days off regimen. Treatment was repeated until tumor progression or for at least 6 cycles (taxane) or 4 cycles (S-1). After failure of the first-line protocol therapy, another cytotoxic agent was administered, based on the investigator’s discretion. HRQOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, the Patient Neurotoxicity Questionnaire (PNQ) and the EQ-5D at baseline and 3, 6, 12 months after the start of the treatment. The primary endpoint was OS. Secondary endpoints were time to treatment failure (TTF), adverse events, and HRQOL. Results: A total of 618 women were enrolled. After a median follow-up of 34.6 months, median OS was 37.2 months in the taxane group (n=309) and 35.0 months in the S-1 group (n=309) (hazard ratio [HR] 1.05, 95% confidence interval [CI] 0.86–1.27, non-inferiority test p=0.015). Median TTF was 8.9 months in the taxane group and 8.0 months in the S-1 group (HR 1.10, 95% CI 0.93–1.30, p=0.022). The incidence of the following grade 3-4 adverse events, allergic reaction, edema and sensory neuropathy, were statistically significantly more frequent in the taxane group (p=0.038, 0.0013 and 0.0077, respectively). Hematologic and non hematologic toxicities except above did not differ significantly between the two groups. The results of the EORTC QLQ-C30 under study treatment indicated that the S-1 was better than the taxanes in global health status/QOL (p=0.044), physical functioning (p=0.002), role functioning (p=0.002), emotional functioning (p=0.004), cognitive functioning (p=0.026), social functioning (p Conclusions: This study clearly demonstrated that S-1 was superior to taxanes in terms of HRQOL and toxicity, without compromising the prolonged OS. S-1 should be considered as a new standard for first-line chemotherapy for MBC. We are conducting another similar trial (UMIN000005449) that compares first-line anthracycline with S-1 in terms of OS and HRQOL. Citation Format: Takanori Watanabe, Kojiro Shimozuma, Kentaro Imi, Hiroyoshi Doihara, Hiromitsu Akabane, Hiroaki Ueo, Shinji Ohno, Masahiro Kashiwaba, Atsushi Fukuuchi, Kenichi Watanabe, Michiko Tsuneizumi, Hirotsugu Isaka, Yukari Uemura, Yasuo Ohashi, Hirofumi Mukai. Randomized phase III trial of taxanes versus S-1 as first-line chemotherapy for metastatic breast cancer (SELECT BC: CSPOR- MBC01) [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 P3-10-01.

Abstract P6-16-08: Prognostic factor of HER2-positive breast cancer patients developed brain metastasis: A multicenter retrospective analysis

Background: HER2-positive breast cancer has a high risk of developing brain metastasis compared to other subtypes of breast cancer. However, the clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine clinicopathological factors associated with prognosis of HER2-positive patients developed brain metastasis. Methods: A retrospective large dataset of 432 HER2-positive patients who were diagnosed with brain metastases between 2001 and 2012 were collected from 24 institutions of the Japan Clinical Oncology Group: Breast Cancer Study Group. We assessed the clinicopathological factors associated with prognosis of these populations with brain metastases. Results: The median age of the 432 patients was 54 years (range, 20–86 years). Of the patients, 162 patients (37.5%) had ER-positive/HER2-positive (ER+HER2+) breast cancer and 270 patients (62.5%) had ER-negative/HER2-positive (ER-HER2+) breast cancer. Nineteen of the 162 patients with ER+HER2+ (12%) and 53 of the 270 patients with ER-HER2+ (20%) underwent surgery for brain metastases. After the diagnosis of brain metastasis, 108 patients with ER+HER2+ (63%) and 175 patients with ER-HER2+ (64%) received HER2-targeting agents, including trastsuzumab and/or lapatinib. The median brain metastasis-free survival period from the diagnosis of primary breast cancer was 33.5 month in both subtypes. In 63.4% of patients with ER+HER2+subtype and 75.6% of patients with ER-HER2+, brain metastases were detected within 2 years after development of first distant metastasis. Eighty-four patients with ER+HER2+ subtype (52%) and 133 patients with ER-HER2+ (49%) had more than 3 brain metastases at the diagnosis. The median survival period after developing brain metastasis was 16.5 months (95% confidence interval [CI], 11.9–21.1 months) in patients with ER+HER2+ and 11.5 months (95% CI, 9.1–13.8 months) in patients with ER-HER2+ ( p = 0.117). Patients with more than 3 brain metastases had significantly shorter OS period than patients with equal or less than 3 brain metastases in both of ER+HER2+ ( p p = 0.018). According to receiving HER2-targeting agents, patients receiving both of trastsuzumab and lapatinib had significantly longer survival period than patients who had received trastsuzumab alone, lapatinib alone, or no HER2-targeting agent ( p Conclusions: Our results showed that HER2-positive patients with more than 3 brain metastases at the diagnosis had poor prognosis regardless of ER-positivity, and receiving both of trastsuzumab and lapatinib might improve their survival. Further studies are needed to determine the best treatment strategy including these HER2-targeting agents for these populations. Citation Format: Naoki Hayashi, Naoki Niikura, Norikazu Masuda, Seiki Takashima, Rikiya Nakamura, Ken-Ichi Watanabe, Chizuko Kanbayashi, Mayumi Ishida, Yasuo Hozumi, Michiko Tsuneizumi, Naoto Kondo, Yoichi Naito, Yayoi Honda, Akira Matsui, Tomomi Fujisawa, Risa Oshitanai, Hiroyuki Yasojima, Hideko Yamauchi, Shigehira Saji, Hiroji Iwata. Prognostic factor of HER2-positive breast cancer patients developed brain metastasis: A multicenter retrospective analysis [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 P6-16-08.