Showing papers by "Masakazu Toi published in 2016"

Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3

Abstract: PurposeTwo recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2–overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment.MethodsArchival tumor samples from patients in BOLERO-1 and BOLERO-3 were analyzed using next-generation sequencing, immunohistochemistry, and Sanger sequencing.ResultsBiomarker data were available for 549 patients. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 samples and in 32% and 12% of BOLERO-3 samples, respectively. PI3K pathway was hyperactive (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) in 47% of BOLERO-1 and 41% of BOLERO-3 samples. In both studies, differential progression-free survival (PFS) benefits of everolimus were consistently observed in patient subgroups defined by their PI3K pathway st...

Evaluation of the Clinical Utility of the ICG Fluorescence Method Compared with the Radioisotope Method for Sentinel Lymph Node Biopsy in Breast Cancer

Abstract: Purpose This study compared the clinical utility of indocyanine green (ICG) fluorescence and radioisotope (RI) for sentinel lymph node (SLN) detection in breast cancer.

Circulating cell-free DNA-based epigenetic assay can detect early breast cancer

Abstract: Circulating cell-free DNA (cfDNA) has recently been recognized as a resource for biomarkers of cancer progression, treatment response, and drug resistance. However, few have demonstrated the usefulness of cfDNA for early detection of cancer. Although aberrant DNA methylation in cfDNA has been reported for more than a decade, its diagnostic accuracy remains unsatisfactory for cancer screening. Thus, the aim of the present study was to develop a highly sensitive cfDNA-based system for detection of primary breast cancer (BC) using epigenetic biomarkers and digital PCR technology. Array-based genome-wide DNA methylation analysis was performed using 56 microdissected breast tissue specimens, 34 cell lines, and 29 blood samples from healthy volunteers (HVs). Epigenetic markers for BC detection were selected, and a droplet digital methylation-specific PCR (ddMSP) panel with the selected markers was established. The detection model was constructed by support vector machine and evaluated using cfDNA samples. The methylation array analysis identified 12 novel epigenetic markers (JAK3, RASGRF1, CPXM1, SHF, DNM3, CAV2, HOXA10, B3GNT5, ST3GAL6, DACH1, P2RX3, and chr8:23572595) for detecting BC. We also selected four internal control markers (CREM, GLYATL3, ELMOD3, and KLF9) that were identified as infrequently altered genes using a public database. A ddMSP panel using these 16 markers was developed and detection models were constructed with a training dataset containing cfDNA samples from 80 HVs and 87 cancer patients. The best detection model adopted four methylation markers (RASGRF1, CPXM1, HOXA10, and DACH1) and two parameters (cfDNA concentration and the mean of 12 methylation markers), and, and was validated in an independent dataset of 53 HVs and 58 BC patients. The area under the receiver operating characteristic curve for cancer-normal discrimination was 0.916 and 0.876 in the training and validation dataset, respectively. The sensitivity and the specificity of the model was 0.862 (stages 0-I 0.846, IIA 0.862, IIB-III 0.818, metastatic BC 0.935) and 0.827, respectively. Our epigenetic-marker-based system distinguished BC patients from HVs with high accuracy. As detection of early BC using this system was comparable with that of mammography screening, this system would be beneficial as an optional method of screening for BC.

De-escalation of axillary surgery in early breast cancer

Abstract: Summary With the advent of sentinel lymph node biopsy, surgical methods for accurately staging the axilla in patients with early-stage breast cancer have become progressively less extensive, with formal axillary lymph node dissection confined to a dwindling group of patients. Although details of methods for sentinel lymph node biopsy have yet to be standardised, this technique is now widely practised and accepted as standard of care worldwide. In the past 5 years, attention has focused on minimisation of surgical morbidity by restricting further axillary surgery or considering radiotherapy in patients with a small tumour burden in their sentinel nodes. This change in approach to patients with positive sentinel lymph node biopsies has increased the complexity of axillary management, and any policy of de-escalation and avoidance of morbidity must not compromise patient outcomes. This trend for de-escalation has accompanied a shift in understanding of how any residual tumour burden can be adequately managed without surgical extirpation and reliance on effective adjuvant therapies. Indications for omission of completion axillary lymph node dissection in patients with two or fewer nodes containing macrometastases demand further clarification, together with the roles of preoperative imaging in defining axillary nodal burden, deselection of patients for sentinel lymph node biopsy, and provision of radiotherapy. Downstaging of biopsy-proven node-positive patients with neoadjuvant chemotherapy could safely permit sentinel lymph node biopsy alone when the index node has been successfully retrieved at surgery, while nodal deposits of any size continue to mandate completion axillary lymph node dissection. Developments in molecular imaging technologies and percutaneous biopsy techniques could potentially render sentinel lymph node biopsy redundant in the future.

Treatment of low-risk ductal carcinoma in situ: is nothing better than something?

Abstract: Summary The heterogeneous nature of ductal carcinoma in situ has been emphasised by data for breast-cancer screening that show substantial increases in the detection of early-stage non-invasive breast cancer but no noteworthy change in the incidence of invasive and distant metastatic disease. Indolent non-progressive forms of ductal carcinoma in situ are managed according to similar surgical strategies as high-risk disease, with extent of resection dictated by radiological and pathological estimates of tumour dimensions. Although adjuvant treatments might be withheld for low-risk lesions, surgical treatments incur potential morbidity, especially when mastectomy and breast reconstruction are done for widespread low-grade or intermediate-grade ductal carcinoma in situ. Low rates of deaths from breast cancer coupled with overdiagnosis within screening programmes have prompted a fundamental rethink of approaches to the management of both low-risk and high-risk ductal carcinoma in situ. Changes include active surveillance for low-risk lesions and a watchful waiting policy with intervention when invasive local recurrence after breast-conserving surgery is detected. Prediction of ipsilateral invasive recurrence is likely to be improved by integration of molecular biomarkers with conventional histopathological parameters. Moreover, further genetic interrogation of ductal carcinoma in situ might lead to a reclassification of some low-grade lesions as non-cancerous entities.

Photoacoustic mammography capable of simultaneously acquiring photoacoustic and ultrasound images.

Abstract: We have constructed a prototype photoacoustic mammography system (PAM-02) capable of simultaneously acquiring photoacoustic (PA) and ultrasound (US) images. Each PA, US, and fused PA/US image can be acquired over a wide area of the breast using the scanning module of a US transducer, a PA detector, and optical prisms. The resolution of the PA images exhibits improvement from 2 to 1 mm compared to images acquired using our previous prototype. The maximum scan area of PAM-02 is 90 mm along the horizontal axis and 150 mm along the vertical axis. In a phantom experiment, the available depth was at least 45 mm. A representative example of the application of the PAM-02 prototype in clinical research at Kyoto University is presented and shows S-factor images, which are considered an approximation parameter related to hemoglobin saturation of tumor-related blood vessels. We confirmed the applicability of the system for anatomical and biological research.

Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy.

Abstract: Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment. In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601). Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14 % and 52 % of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25 % vs 67 % for clinical response, p = 0.011, N = 51; 0 % vs 41 % for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not. Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE. UMIN C000000345 (2006/03/06)

Genomic tumor evolution of breast cancer

Abstract: Owing to recent technical development of comprehensive genome-wide analysis such as next generation sequencing, deep biological insights of breast cancer have been revealed. Information of genomic mutations and rearrangements in patients’ tumors is indispensable to understand the mechanism in carcinogenesis, progression, metastasis, and resistance to systemic treatment of breast cancer. To date, comprehensive genomic analyses illustrate not only base substitution patterns and lists of driver mutations and key rearrangements, but also a manner of tumor evolution. Breast cancer genome is dynamically changing and evolving during cancer development course from non-invasive disease via invasive primary tumor to metastatic tumor, and during treatment exposure. The accumulation pattern of base substitution and genomic rearrangement looks gradual and punctuated, respectively, in analogy with contrasting theories for evolution manner of species, Darwin’s phyletic gradualism, and Eldredge and Gould’s “punctuated equilibrium”. Liquid biopsy is a non-invasive method to detect the genomic evolution of breast cancer. Genomic mutation patterns in circulating tumor cells and circulating cell-free tumor DNA represent those of tumors existing in patient body. Liquid biopsy methods are now under development for future application to clinical practice of cancer treatment. In this article, latest knowledge regarding breast cancer genome, especially in terms of ‘tumor evolution’, is summarized.

Acceptability of a touch screen tablet psychosocial survey administered to radiation therapy patients in Japan

Abstract: Background Studies in western clinical settings suggest that touch screen computer surveys are an acceptable mode of collecting information about cancer patients’ wellbeing

Pattern of RECK CpG methylation as a potential marker for predicting breast cancer prognosis and drug-sensitivity

Abstract: The membrane-anchored glycoprotein RECK negatively regulates multiple metalloproteinases and is frequently downregulated in tumors. Forced RECK expression in cancer cells results in suppression of tumor angiogenesis, invasion, and metastasis in xenograft models. A previous methylome study on breast cancer tissues detected inverse correlation between RECK CpG methylation (in an intron-1 region) and relapse-free survival. In this study, we focused on another region of the RECK CpG island (a promoter/exon-1 region) and found an inverse correlation between its methylation and RECK-inducibility by an HDAC inhibitor, MS275, among a panel of breast cancer cell lines (n=15). In clinical samples (n=62), RECK intron-1 methylation was prevalent among luminal breast cancers as reported previously (26 of 38 cases; 68%) and particularly enriched in tumors of the ER+PR- subclass (10 of 10 cases) and of higher histological grades (Grade 2 and 3; 28 of 43 cases; P=0.006). In about a half of these cases, promoter/exon-1 methylation was absent, and hence, RECK may be inducible by certain drugs such as MS275. Our results indicate the value of combined use of two RECK methylation markers for predicting prognosis and drug-sensitivity of breast cancers.

Clinical benefit of nomogram for predicting positive resection margins in breast conserving surgery

Abstract: Purpose Previously, we reported a nomogram for the prediction of positive resection margin (RM) after breast conserving surgery (BCS). This study was conducted to evaluate the clinical usefulness of the nomogram. Methods Prospective patients who underwent operations using the nomogram between July 2012 and August 2013 (nomogram group; N = 260) were compared with past control patients who underwent operations between July 2010 and October 2011 and underwent frozen section biopsy (FSB) without use of the nomogram (N = 266). In the nomogram group, an intraoperative assessment of RM using FSB was only performed when the nomogram score was higher than predefined cut-off (>80). In addition, we conducted retrospective analysis of additional 181 patients who received BCS in another institute (Kyoto University Hospital). These patients did not undergo FSBs for RMs. Results Of 260 patients, 161 (61.9%) presented low nomogram scores and avoided FSB. The surgical decision to use the nomogram did not significantly increase reoperation rate due to positive RM compared with the control FSB group (4.6% vs. 3.8%, p = 0.47). The surgery time was significantly reduced by 18.1% (mean 14.7 min) in nomogram group (p Conclusions We showed that our nomogram is useful to reduce FSBs without increasing reoperation rate for surgeons who perform routine FSBs. For most surgeons, it can give useful information about the possibility of tumor-positive RMs.

The effects of frozen gloves and socks on paclitaxel-induced peripheral neuropathy among patients with breast cancer: A self-controlled clinical trial.

Abstract: 10022Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect with no proven effective treatment or prevention. In this prospective study, we aimed to eva...

Vascular registration in photoacoustic imaging by low-rank alignment via foreground,background and complement decomposition

Abstract: Photoacoustic (PA) imaging has been gaining attention as a new imaging modality that can non-invasively visualize blood vessels inside biological tissues. In the process of imaging large body parts through multi-scan fusion, alignment turns out to be an important issue, since body motion degrades image quality. In this paper, we carefully examine the characteristics of PA images and propose a novel registration method that achieves better alignment while effectively decomposing the shot volumes into low-rank foreground (blood vessels), dense background (noise), and sparse complement (corruption) components on the basis of the PA characteristics. The results of experiments using a challenging real data-set demonstrate the efficacy of the proposed method, which significantly improved image quality, and had the best alignment accuracy among the state-of-the-art methods tested.

Analysis of tumor infiltrating lymphocytes in HER2-positive primary breast cancer treated with neoadjuvant lapatinib and trastuzumab: The NeoLath study (JBCRG-16).

Abstract: 599Background: The presence of tumor-infiltrating lymphocytes (TILs) is associated with better outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) patient...

Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs

Abstract: Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs.

Abstract 4149: Direct immune cell contact to basal-like triple negative breast cancer cells evokes downregulation of EGFR and PD-L1

Abstract: BACKGROUND: We previously reported that direct co-culture of triple negative breast cancer cell line MDA-MB-231 and immune cells results in reduction of EGFR expression on cell surface of MDA-MB-231 (AACR 2015 #2349). However, a role of reduction of EGFR on MDA-MB-231 via co-culture with immune cells still remains unclear. Therefore, we evaluated a role of reduction of EGFR on MDA-MB-231 at the immunological point of view by testing expression of immune related genes including PD-L1. METHODS: In order to verify the importance of direct immune cell contact to breast cancer cell, MDA-MB-231 cells were co-cultured directly or indirectly with THP-1 cells (human monocytic cell line) at 1:50 cellular ratios. In order to study indirect co-culture assay, we used cell culture insert to avoid direct cancer cell-immune cell contact. We analyzed gene expression by quantitative real time PCR and membrane protein expression by flow cytometry of EGFR, also other HER family on MDA-MB-231 which is directly or indirectly co-cultured with THP-1. We also evaluated the expression of immune related genes including PD-L1. RESULTS: Both mRNA and protein level of EGFR on MDA-MB-231 cells directly co-cultured with THP-1 were significantly decreased as compared to those with indirectly co-cultured MDA-MB-231 cells. There are no significant differences in EGFR expression between indirectly co-cultured MDA-MB-231 cells and control MDA-MB-231 cells. Importantly, PD-L1 expression on MDA-MB-231 cells directly co-cultured with THP-1 was significantly decreased as compared to that with indirectly co-cultured MDA-MB-231 cells. CONCLUSION: It has been reported that PD-L1 expression in cancers is regulated by phosphatidylinositol 3-kinase (PI3K) and Akt signaling. Thus, our findings may give a novel insight on regulation of PD-L1 expression on cancer cells in tumor microenvironment that tumor infiltrated immune cell directly contact with cancer cells and EGFR down-regulation leads to reduction of PD-L1 expression on cancer cells. Further investigation is needed to elucidate the mechanism of reduction of EGFR by direct immune cell contact to cancer cells and its interaction with modulation of PD-L1 expression. This will provide novel aspects for immune therapy of breast cancer patients. Citation Format: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Masakazu Toi. Direct immune cell contact to basal-like triple negative breast cancer cells evokes downregulation of EGFR and PD-L1. [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 4149.

Patient-reported outcomes (PROs) from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/- pertuzumab (P) vs trastuzumab + taxane (HT) for HER2-positive advanced breast cancer.

Abstract: 593Background: MARIANNE (NCT01120184) is a randomized, phase III study of T-DM1 +/- P vs HT in pts with HER2-positive advanced breast cancer (BC). Methods: Pts with previously treated inoperable lo...

For choosing axillary treatment, and adjuvant hormonal treatment.

Abstract: Consensus formation is crucial for advancing clinical practice and moving clinical investigations such as clinical trials forward. The treatment of breast cancer, in particular, requires many highly sophisticated and complex decisions to be made regarding diagnosis, therapy, safety, and quality of life, and treatment must also be flexible enough to incorporate diagnostic and therapeutic advances. The St. Gallen 2015 consensus on improving the management of early breast cancer provided many new and clinically relevant ideas in this respect [1], especially in the areas of local therapy, adjuvant hormone therapy for premenopausal primary breast cancer, and use of multi-gene assay. Here, we review and discuss these specific issues and consider what the next paradigm will be in the near future. The importance of systemic therapy for positive axilla was highlighted by 90 % of panelists responding affirmatively to the question ‘‘Is sentinel node (SN) biopsy appropriate in a patient who is clinically node positive at presentation and is down staged after chemotherapy?’’ and 90 % of panelists responding negatively to the question ‘‘Can axillary lymph node dissection (ALND) be avoided in a SN-positive patient in patients with mastectomy?’’. Adopting a recommendation to allow SN biopsy after neoadjuvant chemotherapy for baseline node-positive patients, keeping in mind surgical issues such as the falsenegative rate, would have clear implications in that it would change current local therapy practices, especially among those who plan to offer breast conservation after neoadjuvant therapy. Conceptually, axillary clearance may be avoidable if node-positive status converts to node-negative status after systemic therapy. However, in current practice, when node-positive status remains after systemic therapy, ALND is inevitable for controlling local disease. Another key question on the role of local therapy is whether, in patients with macro-metastases in 1–2 SNs, completion axillary dissection can be safely omitted after (1) mastectomy with no radiotherapy planned, (2) mastectomy with radiotherapy planned, (3) conservative resection with radiotherapy on standard tangents, and (4) conservative resection with radiotherapy on high tangents, including the lower axilla. All panelists responded ‘‘no’’ to the first question, which suggests that radiation is indispensable for axilla-conserving therapy (ACT). Sixty-seven percentage of the panelists responded ‘‘yes’’ to the third question and 94 % responded ‘‘yes’’ to the fourth question, indicating that ACT may be possible for cases with involvement of 1–2 SNs if radiation treatment is performed on high tangents, including the lower axilla. In fact, based on Z0011, EORTC/AMARO, and other studies, the penetration speed of ACT may differ by country as well as by institution. It seems to be reasonable to implement these Electronic supplementary material The online version of this article (doi:10.1007/s12282-015-0662-3) contains supplementary material, which is available to authorized users.

Cancer Genomics and Biology 2015 – Meeting Report.

Abstract: The Cancer Genomics and Biology 2015 meeting embodied a three way collaboration among colleagues from the Global Cancer Genomics Consortium (GCGC), the Unifaith Cancer Institute China and Jiujiang University of China. The meeting marks the fifth and the last meeting of GCGC, which was formed in 2010. Previous four GCGC meetings have been held at the Tata Memorial Center- Mumbai, Institute of Molecular Medicine-Lisbon, and Graduate Medical School Kyoto University-Kyoto. In contrast to the genomic themes of the previous meetings, the 2015 conference theme was at the interface of laboratory and translation research and emerging therapeutics as reflected in the shared interests of all three collaborative entities – Cancer Genomics and Biology 2015. This year's conference was co-organized by the Jiujiang University at the Run Run Shaw building, Jiujiang University, Jiujiang City, China, on November 13 and 14, 2015. The conference attracted over 174 participants with 13 platform presentations. Scientific sessions included a plenary and five platform scientific sessions with themes ranging from biomarkers, stem cells and markers of the tumor microenvironment, proteomics and epigenetics, big data, to hormone and expression profiles. The meeting concluded with closing remarks by conference co-chairs emphasizing with the need to broaden membership across the globe, establishing priorities, and redrafting a white paper to launch a new consortium.

A New Concept for Axillary Treatment of Primary Breast Cancer Using Indocyanine Green Fluorescence Imaging

Abstract: Sentinel lymph node (SLN) biopsy using fluorescence indocyanine green (fICG) method can visualize lymphatic vessels by real-time imaging and is technically straightforward. Identification and false-negative rates of SLN biopsy using fICG ranged from 93 to 100 % and 0 to 10 %, respectively, which were comparable to blue dye or radioisotope method. Four SLNs should be removed for the accurate staging of the axillary lymph node status. The fICG method seems to be advantageous for effective SLN dissection by the intraoperative visualization of a sentinel node bed. However, the number of SLNs removed can be adjusted by the risk of lymph node metastasis. SLN biopsy after preoperative systemic therapy (PST) in patients with clinical node positive is still challenging. There may be some advantage in fICG method for SLN detection after PST because the fICG method can identify an average of three SLNs. A prospective study to evaluate the accuracy of SLN identification using fICG after PST in node-positive patients is now warranted.