Hirotsugu Isaka

Use of the neo-adjuvant exemestane in post-menopausal estrogen receptor-positive breast cancer: A randomized phase II trial (PTEX46) to investigate the optimal duration of preoperative endocrine therapy

PURPOSE The optimal treatment duration time and the causal relationship between neoadjuvant endocrine therapy and clinical response are not clear. Therefore, we conducted the present study to investigate the potential benefits of neoadjuvant exemestane therapy with the goal of identifying the optimal treatment duration. METHODS This study was conducted at three hospitals, as a multicenter, randomized phase II trial(UMIN000005668) of pre-operative exemestane treatment in post-menopausal women with untreated primary breast cancer. Fifty-one post-menopausal women with ER-positive and/or PgR-positive invasive breast cancer were randomly assigned to exemestane for 4 months or 6 months. Clinical response, pathological response, and decisions regarding breast-conserving surgery were the main outcome measures. RESULTS Of the 52 patients that enrolled, 51 patients underwent surgery. Of those, 26 and 25 patients had been treated with exemestane for 4 and 6 months, respectively. Treatments were performed at 3 hospitals in Japan between April 2008 and August 2010. The response rates as assessed by clinical examination were 42.3% and 48.0% for 4 and 6 months of treatment, respectively. Pathological responses (minimal response or better) were observed in 19.2% and 32.0% of patients, and breast-conserving surgery was performed on 50.0% and 48.0% of patients from the 4 and 6 month treatment groups, respectively. CONCLUSION The results of this study demonstrate that responses were equal to 4 or 6 months of exemestane treatment. Therefore, we propose that the rates of breast-conserving surgery could be maximized by 4 months of treatment. Furthermore, in addition to using exemestane as a preoperative treatment in post-menopausal women with ER-positive breast cancer, we envision administering the drug over the long term under careful clinical supervision.

Histopathological and clonal study of combined lobular and ductal carcinoma of the breast

Lobular carcinoma in situ (LCIS) clinically constitutes a risk factor for the subsequent development of either invasive lobular carcinoma (ILC) or invasive ductal carcinoma (IDC). In order to approach the possibility of this common precursor of both ILC and IDC, we investigated combined lobular and ductal carcinomas. Thirty‐two cases of lobular carcinoma were picked up out of 773 cases of operated breast carcinomas. The histopathological detailed re‐examination using immunostain of E‐cadherin and β‐catenin revealed a rather high frequency of combined lobular carcinomas than previous reports. Clinicopathologically, combined lobular carcinomas were younger and smaller than pure lobular carcinomas, and the cytological atypia was relatively low. These results suggested that combined lobular carcinomas could be detected in the earlier stage of breast cancer. Furthermore, the lobular and ductal components of combined carcinomas coexisted in the neighborhood and were distributed contiguously. The immunohistochemical phenotypes of both components were accorded in most combined cases. A genetic analysis using methylation‐specific PCR on the HUMARA gene demonstrated that the same allele was inactivated in both lobular and ductal components in all detectable cases of combined carcinoma. Therefore, it is reasonable to assume that both lobular and ductal components of combined carcinomas are clonal and derived from the LCIS as the common precursor lesion, which may contradict the conventional concept that the lobular and ductal carcinomas arise from distinct differentiation pathways.

Mammary ductoscopy by helical CT: initial experience.

BackgroundAn attempt was made to visualize minute intraductal lesions using helical CT in patients with abnormal nipple discharge.MethodsGalactography was performed, immediately followed by CT (ductal CT examination). Based on the image data obtained, ductal images were constructed on a workstation using a Pegasus viewer (ductal CT imaging). Since no criteria for diagnosis by this method are available, ductal CT images were diagnosed by reference to the known ductal fiberscopic findings1,2).ResultsDuctal CT examination was performed in 10 cases, in 9 of whom ductal CT images were successfully constructed. Pathological examination was performed in 8 cases. It was possible to observe the structure of the luminal surface on the constructed ductoscopic images from all directions, but the color tone or the presence or absence of hemorrhage could not be observed.ConclusionsIn the examination for abnormal nipple discharge, ductal CT examination was useful for intraductal observation. Currently, it is a method that allows for observation of the most minute intraductal lesions. However, some issues still remain unresolved. The results of this study suggest that further studies with more cases hold the promise of making ductal CT imaging a useful examination method.BACKGROUND An attempt was made to visualize minute intraductal lesions using helical CT in patients with abnormal nipple discharge. METHODS Galactography was performed, immediately followed by CT (ductal CT examination). Based on the image data obtained, ductal images were constructed on a workstation using a Pegasus viewer (ductal CT imaging). Since no criteria for diagnosis by this method are available, ductal CT images were diagnosed by reference to the known ductal fiberscopic findings. RESULTS Ductal CT examination was performed in 10 cases, in 9 of whom ductal CT images were successfully constructed. Pathological examination was performed in 8 cases. It was possible to observe the structure of the luminal surface on the constructed ductoscopic images from all directions, but the color tone or the presence or absence of hemorrhage could not be observed. CONCLUSIONS In the examination for abnormal nipple discharge, ductal CT examination was useful for intraductal observation. Currently, it is a method that allows for observation of the most minute intraductal lesions. However, some issues still remain unresolved. The results of this study suggest that further studies with more cases hold the promise of making ductal CT imaging a useful examination method.

The Impact of Treatment Preferences in Second-Line Chemotherapy on the Prognosis of HER2-Negative Metastatic Breast Cancer

Objective: We assessed the impact of treatment preferences in second-line chemotherapy on breast cancer prognosis using the SELECT BC study. Methods: The SELECT BC study was performed in patients with HER2-negative metastatic breast cancer treated with initial chemotherapy. From these patients, 618 were assigned to 2 groups (S-1 group, 309; taxane group, 309). The S-1 and taxane groups were each subdivided into 3 groups: crossover group, protocol-recommended group, and other group, and the analysis of overall survival (OS) was performed using Cox regression with inverse probability weighting, to adjust for postrandomization confounding. Results: In the taxane group, the OS of the crossover group (39.6 months) was better than that of the protocol-recommended group (35.7 months) and the other chemotherapy group (36.9 months) (vs. the protocol-recommended group, HR 0.72 [95% CI 0.52-0.98], p = 0.037; vs. the other chemotherapy group, HR 0.71 [95% CI 0.43-1.18], p = 0.183). In the S-1 group, there was no statistically significant difference in OS between the 3 groups. Conclusion: The study of the combination of first-line chemotherapy and second-line chemotherapy showed that S-1 might be recommended as a second-line chemotherapy in patients in whom taxane was the primary chemotherapy.

Abstract 4138: Immunological profile of metastatic or recurrent breast cancer patients

Background: We previously reported about immune suppression in breast cancer patients at this meeting. In brief, tumor tissue specimens and peripheral blood mononuclear cells (PBMC) were analyzed in 50 early or advanced breast cancer (BC) patients. To compare between 38 early and 12 advanced BC cases, CD163-positive tumor cells and CCR4-positive tumor cells were detected more frequently in advanced cases than in early cases. Regulatory T (Treg) cells in PBMC significantly increased in percentage of the population in 37 BC patients than in 21 healthy volunteers (AACR 2011). In addition, several cytokines were examined in that cohort and plasma IL-17A had significantly higher levels in early BC than in advanced BC (AACR 2013). Then, we examined their prognosis and immunological profile. Patients and methods: Treg cells were examined by counting CD4+CD25highCD127low/-cells in PBMC with flow cytometry analysis. Immunohistochemical evaluation of tumor specimens was performed with monoclonal antibodies of HLA-ABC and DR, CD56, CD68, CD83, CD163 and CCR4. The number of stained cells was analyzed using a semiquantitative ordinal scale ranging from 0 to 3 (0, +/-, ++, +++). Human IL-2, IL-4, IL-6, IL-10, TNF, INFγ and IL-17A were measured using cytometric beads array system. Most patients received chemotherapy, hormonal therapy, and/or anti-HER2 therapy on the basis of intrinsic subtype and breast irradiation after breast-conserving surgery. Results and discussions: At the median follow-up of 7 years after blood sample collection, only 2 operable patients relapsed and 3 patients including 2 cases of stage IV died of disease. Of 5 cases of stage IV or recurrent BC, CD163 and/or CCR4 were strongly stained positive in tumor cells. There were significant differences of staining intensity in CD163 and CCR4-positive tumor cells between those cases and the rest 45 cases (p Conclusion: Targeted therapy against M2 macrophage or CCR4 is considered as a promising strategy of advanced breast cancer. Citation Format: Shigeru Imoto, Takayuki Ueno, Hirotsugu Isaka, Hiroki Ito, Kaisuke Miyamoto, Tomohiro Chiba, Hiroshi Kamma. Immunological profile of metastatic or recurrent breast cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4138.

Abstract 3484: Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues

Background: Hormone receptors and proliferation markers are critical parameters for treatment selection of breast cancer patients. The expression of different parameters are currently assessed separately in different tissue sections but it is unclear how different parameters are co-expressed in a single cell in breast cancer tissues. Samples and Methods: Breast cancer tissues from fifty-one patients with ER-positive HER2-negative breast cancer were analyzed. Expressions of ER and PgR were assessed in association with Ki67 using dual fluorescence immunohistochemistry with specific antibodies: SP-1 (abcam, Tokyo), 1E2 (Roche Diagnostics GmBH, Germany), and MIB1 (Dako Japan, Tokyo), respectively. More than 500 cancer cells were assessed in each tissue. Expression levels of each marker in a single cell were semi-quantitatively assessed by MetaMorph image analyzer (Molecular Devices Japan, Tokyo). All statistical analyses were performed using JMP ver.8.01 (SAS Institute Japan, Tokyo). Results: To validate the system, Ki67 LI in breast cancer tissues were compared between this system and the regular DAB system. The two systems showed a good concordance (p Conclusion: PgR status in Ki67-positive proliferating cells is associated with histological grade in ER positive HER2-negative breast cancers. Our results suggest that different driving systems give different expression patterns of PgR and Ki67 at a single cell level, which may distinguish between luminal A and luminal B cancers. Citation Format: Takayuki Ueno, Hirotsugu Isaka, Hiroki Itoh, Kaisuke Miyamoto, Manami Kitamura, Shigeru Imoto. Analysis of in situ expression of hormone receptors and proliferation marker at a single cell level in breast cancer tissues. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3484.

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 1083: Host-tumor immune response for early breast cancer patients treated with radiofrequency ablation therapy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA [Background] We demonstrated immune suppression of regulatory T (Treg) cells in preoperative breast cancer (BC) patients at AACR 2011. Last year we also reported at this meeting that Th17 cells might have some potential to control tumor progression in the same cohort. Modern treatment of operable BC consists of breast surgery, drug therapy and radiation therapy. [Aim] To explore new strategy of BC treatment, we conducted a phase II study on radiofrequency ablation (RFA) in early BC between 2009 and 2013. Twenty patients were enrolled. To examine host-tumor immune response under thermal ablation therapy, Treg cells in peripheral blood mononuclear cells (PBMC) and plasma IL-17A were measured. [Patients and methods] Blood samples were collected from 13 patients before RFA and at the time of 1 month after RFA. Treg cells were examined by counting CD4+CD25highCD127low/-cells in PBMC. Plasma IL-17A was measured using cytometric beads array system. Statistical significance was analyzed using Mann-Whitney U-test. [Results] As of November 2013, all patients were free of recurrence. The percentages of Treg cells had no significant change in 13 patients before and after RFA (2.8% versus 2.7% of CD4-positive cells at mean value). In addition, there was no statistical difference in levels of plasma IL-17A before and after RFA (76 pg/ml versus 116 pg/ml at mean level). [Discussion] Unexpectedly, RFA had no favorable immune response in BC patients, because we observed significant decrease in percentages of Treg cells after breast surgery. The reason is that most patients had T1 tumor and Luminal A-like BC. They had lower percentages of Treg cells in comparison to those of tumor-bearing patients reported previously (2.8% versus 4.2%). [Conclusion] RFA is a promising alternative to breast surgery. However, it may make little effect on host-tumor immune response in favorable subtype of early BC. Citation Format: Shigeru Imoto, Noriko Nakatsugawa, Takayuki Ueno, Hiroki Ito, Kentaro Imi, Kaisuke Miyamoto, Manami Kitamura, Hirotsugu Isaka, Tetsuya Nakatsura. Host-tumor immune response for early breast cancer patients treated with radiofrequency ablation therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1083. doi:10.1158/1538-7445.AM2014-1083

Abstract 450: Host-tumor immune response for breast cancer patients.

We demonstrated immune suppression of regulatory T cells (Treg) and M2 macrophage in breast cancer (BC) patients at AACR 2011. In summary, to compare between 38 early and 12 advanced BC cases, CD163-positive tumor cells and CCR4-positive tumor cells were detected more frequently in advanced cases than in early cases. Treg cells in PBMC significantly increased in percentage of the population in 37 BC patients than in 21 healthy volunteers. To explore host-tumor immune response, several cytokines were examined in the same cases. Plasma from 32 early and 9 advanced BC cases was preoperatively obtained. Human IL-2, IL-4, IL-6, IL-10, TNF, INFγ, and IL-17A were measured using cytometric beads array system. Statistical significance was analyzed using Mann-Whitney U-test. Plasma IL-17A had significantly higher levels in early BC than in advanced BC (103 pg/ml v.s. 51 pg/ml at mean level). Th17 cells may have some potential to control tumor progression in BC. In conclusions, induction of host-tumor immune response due to chemotherapy and anti-HER2 therapy and release from immune suppression such as CCR4 monoclonal antibody are important issues to explore a new strategy for BC patients. Citation Format: Shigeru Imoto, Noriko Nakatsugawa, Hirotsugu Isaka, Hiroki Ito, Kentaro Imi, Kaisuke Miyamoto, Tetsuya Nakatsura. Host-tumor immune response for breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 450. doi:10.1158/1538-7445.AM2013-450

Paradigm shift in axilla surgery for breast cancer patients treated with sentinel node biopsy

BackgroundSentinel node biopsy (SNB) is a standard technique for the diagnosis of regional lymph node metastases in clinically node-negative breast cancer patients. In the case of pathologically negative sentinel lymph nodes (SLN), axillary lymph node dissection (ALND) can be avoided.MethodsRecent clinical studies on SNB in breast cancer were reviewed regarding the pathological and molecular diagnosis of SLN, the tools used to predict non-SLN metastases, the prognostic significance of isolated tumor cells (ITC) and micrometastases (MIC), and axilla surgery.ResultsITC or MIC in SLN was associated with worse survival in patients treated with SNB alone or SNB followed by ALND. However, this effect was limited and adjuvant therapy improved survival. If T1 and one SLN-positive breast cancer patients are treated with whole-breast irradiation and adjuvant therapy, additional ALND may not be necessary.ConclusionsSNB without ALND can be adopted for patients with a small number of SLN metastases. Although the lack of apparent regional lymph node recurrence, similar to tumor dormancy, cannot be fully explained, ALND should be performed in cases that are highly suspected to be non-SLN metastases.