Showing papers by "Masakazu Toi published in 2019"

MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.

Abstract: At the MONARCH 3 interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (AI) significantly improved progression-free survival (PFS) and objective response rate (ORR) with a tolerable safety profile as initial treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). MONARCH 3 is a randomized, phase III, double-blind study of abemaciclib/placebo (150 mg twice daily, continuous) plus nonsteroidal AI (1 mg anastrozole or 2.5 mg letrozole, daily). A total of 493 postmenopausal women with HR+, HER2− ABC with no prior systemic therapy in this setting were enrolled. The primary endpoint was investigator-assessed PFS (final analysis after 240 events); other endpoints included response and safety evaluations. Here we analyze the final PFS data and update secondary endpoints. The abemaciclib arm had a significantly longer median PFS than the placebo arm (28.18 versus 14.76 months; hazard ratio [95% confidence interval], 0.540 [0.418–0.698]; p = .000002). The ORR was 61.0% in the abemaciclib arm versus 45.5% in the placebo arm (measurable disease, p = .003). The median duration of response was longer in the abemaciclib arm (27.39 months) compared to the placebo arm (17.46 months). The safety profile was consistent with previous reports. The most frequent grade ≥ 3 adverse events in the abemaciclib versus placebo arms were neutropenia (23.9% versus 1.2%), diarrhea (9.5% versus 1.2%), and leukopenia (8.6% versus 0.6%). Abemaciclib plus a nonsteroidal AI was an effective initial treatment with an acceptable safety profile for HR+, HER2− ABC. Patients with the most common form of breast cancer stand to benefit from taking a drug that blocks two cell cycle–regulating proteins in addition to hormonal therapy. In a phase III clinical trial, Stephen Johnston from the Royal Marsden NHS Foundation Trust in London, UK, and colleagues randomly gave 493 postmenopausal women with HR+/HER2− metastatic breast cancer a nonsteroidal aromatase inhibitor plus either a placebo or a drug called abemaciclib, a targeted inhibitor of CDK4 and CDK6. A planned interim analysis previously showed that abemaciclib was safe and effective. Johnson’s team now reports that abemaciclib nearly doubled the time women live without disease recurrence, from 15 months on placebo to 28 months on the drug. Additionally, responses were more common and lasted longer among women who received both abemaciclib and the hormonal therapy.

Insights Into Breast Cancer in the East vs the West: A Review

Abstract: Importance During the past few decades, the incidence of breast cancer (BC) has been increasing rapidly in East Asia, and BC is currently the most common cancer in several countries. The rising incidence is likely related to changing lifestyle and environmental factors in addition to the increase in early diagnosis with BC awareness and screening. The understanding and management of BC are generally based on research and data from the West. However, emerging differences in BC epidemiology and tumor and host biology in Asian populations may be clinically relevant. Observations A higher proportion of premenopausal BCs occur in Asia, although this factor is possibly an age-cohort effect. Although the relative frequencies of different immunohistochemical subtypes of BC may be similar between the East and West, the higher prevalence of luminal B subtypes with more frequent mutations inTP53may be confounded by disparities in early detection. In addition, Asian BCs appear to harbor a more immune-active microenvironment than BCs in the West. The spectra of germline mutations in BC predisposition genes and single-nucleotide polymorphisms contributing to BC risk vary with ethnicity as well. Differences in tolerability of certain cytotoxic and targeted agents used in BC treatment may be associated with pharmacogenomic factors, whereas the lower body mass of the average woman in East Asia may contribute to higher toxicities from drugs administered at fixed doses. Phenotypic characteristics, such as lower breast volume, may influence the type of surgery performed in East Asian women. On the other hand, increased breast density may affect the sensitivity of mammography in detecting BCs, limiting the benefits of screening mammography. Conclusions and Relevance Breast cancer has become a major health problem in Asia. The inclusion of more women from Asia in clinical trials and epidemiologic and translational studies may help unravel the interethnic heterogeneity of BCs and elucidate the complex interplay between environmental and intrinsic factors in its pathogenesis. These insights may help to refine prevention, diagnosis, and management strategies for BC in the setting of ethnic diversity.

Alteration of specific cytokine expression patterns in patients with breast cancer

Abstract: Systemic inflammation has been associated with aggressive tumor growth, invasion, and metastasis. Here we performed a comprehensive analysis of 26 kinds of inflammatory cytokine expression patterns among 185 patients with breast cancer and 54 healthy volunteers followed by chemometric analysis. We identified the specific cytokine expression patterns of breast cancer patients compared to healthy volunteers with (1) VEGF, IL-9, GM-CSF, IL-13, IL-4, and IFNγ, (2) IL-8, IL-10, IL-12, IL-5, IL-7, IL-1α, GCSF, IL-1β, and TNFα and (3) IL-2, Eotaxin, MIP1β, MIP1α, IL-17, and bFGF. Among the patients with breast cancer, we identified the specific cytokine signature of metastatic patients compared to non-metastatic patients. We also established a mathematical model for distinguishing patients with breast cancer from healthy volunteers and metastatic patients from non-metastatic patients. This cytokine network analysis could provide new insights into early intervention and effective therapeutic strategy for patients with breast cancer.

Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2–positive advanced breast cancer: Final results from MARIANNE

Abstract: Background In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses. Methods OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. Results The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm. Conclusions These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy.

Palbociclib in combination with letrozole in patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients

Abstract: In the double-blind, phase 3 PALOMA-3 study, palbociclib–fulvestrant significantly prolonged progression-free survival versus placebo–fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC) whose disease had progressed on prior endocrine therapy. The present study evaluated the efficacy, safety, and pharmacokinetics of palbociclib plus fulvestrant in Japanese patients enrolled in PALOMA-3. Pre/peri/postmenopausal women with HR+/HER2– MBC were randomized 2:1 to fulvestrant (500 mg) and either palbociclib (125 mg/day; 3 weeks on/1 week off; n = 347) or placebo (n = 174). Prespecified exploratory analyses compared the efficacy (data cutoff: October 23, 2015), safety, and pharmacokinetics (data cutoff: December 5, 2014) in Japanese women versus the overall population. A total of 35 Japanese women were randomized to palbociclib–fulvestrant (n = 27) or placebo–fulvestrant (n = 8). Median progression-free survival was 13.6 months (95% CI, 7.5–not estimable) in the Japanese palbociclib–fulvestrant group and 11.2 months (95% CI, 5.6–not estimable) in the placebo–fulvestrant group. The most common adverse event (AE) in Japanese patients was neutropenia (all grades, 93%); no discontinuations were due to an AE. Geometric mean trough concentration values (within-subject mean steady state) for palbociclib were similar for Japanese Asian (excluding Japanese), and non-Asian patients (84.4 ng/mL, 86.3 ng/mL, and 74.8 ng/mL, respectively). The results for the overall population and Japanese patients in PALOMA-3 suggest that palbociclib plus fulvestrant was effective and well tolerated in Japanese patients with HR+/HER2‒ MBC whose disease had progressed on prior endocrine therapy (Pfizer; NCT01942135).

Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study.

Abstract: PURPOSEIn PALOMA-2, palbociclib plus letrozole significantly improved progression-free survival (PFS) as initial treatment of estrogen receptor–positive/human epidermal growth factor receptor 2–neg...

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer

Abstract: Following publication of the original article [1], the authors reported the following errors in the article.

Efficacy of Scalp Cooling in Preventing and Recovering From Chemotherapy-Induced Alopecia in Breast Cancer Patients: The HOPE Study.

Abstract: Purpose: This study aimed to assess the efficacy of scalp-cooling devices in preventing chemotherapy-induced alopecia in Japanese breast cancer patients and investigate whether a scalp-cooling device improves hair volume recovery over a 12 weeks period after completing chemotherapy. Methods: This multicenter controlled trial included women with breast cancer undergoing chemotherapy in Japan between February 2016 and March 2018. The primary endpoint was the proportion of patients with no alopecia at the end of chemotherapy. The secondary endpoint included hair volume at 12 weeks after completing chemotherapy. Results: A total of 48 patients were enrolled; of them, 34 and 14 were sequentially allocated to the scalp-cooling group using the Paxman Hair Loss Prevention System and the control group, respectively. There was no significant difference in average age between the scalp-cooling and the control groups (50.0 ± 9.6 vs. 49.0 ± 9.0 years). More than 50% of patients in each group had stage II breast cancer (scalp-cooling group: 53.1%; control group: 64.3%), more than 90% received adjuvant chemotherapy (scalp-cooling group: 96.9%; control group: 92.9%), and more than 60% were treated with a docetaxel/cyclophosphamide regimen (scalp-cooling group: 75.0%; control group: 64.3%). There were more patients judged to have no alopecia at the end of chemotherapy in the scalp-cooling group than in the control group (26.7% [8/30] vs. 0% [0/13]; P = 0.011). The proportion of patients with alopecia who experienced an increase in hair volume of ≥50% within 12 weeks duration after chemotherapy was 85.7% (24/28) in the scalp-cooling group and 50.0% (6/12) in the control group. No patient developed serious adverse events related to the scalp-cooling device. Conclusions: The use of a scalp-cooling device prevented alopecia with acceptable safety for Japanese patients. In addition, scalp cooling resulted in faster recovery of hair volume after chemotherapy, even in patients for whom scalp cooling failed to prevent chemotherapy-induced alopecia.

Changes in Recurrence Score by neoadjuvant endocrine therapy of breast cancer and their prognostic implication.

Abstract: Background Neoadjuvant endocrine therapy (NET) can improve surgical outcomes in postmenopausal patients with hormone receptor-positive breast cancer. The Ki67 labelling index after NET has a better prognostic power than that at baseline. However, it remains unknown whether a multigene assay with post-treatment samples could predict the prognosis better than that with pretreatment samples. Methods The prognostic value of the multigene assay Oncotype DX Recurrence Score (RS) was investigated using pretreatment and post-treatment samples from a multicentre NET trial, JFMC34-0601 (UMIN C000000345), where exemestane was given at 25 mg/day for 24 weeks. Results Both pretreatment and post-treatment RSs were significantly associated with disease-free survival (DFS) (p=0.005 and 0.002, respectively). The combination of pretreatment and post-treatment RSs was also a predictor of DFS (p=0.002) and superior to preoperative endocrine prognostic index (PEPI). Furthermore, combined RS was the only independent prognostic factor in the multivariate analysis among the three RSs (p=0.04). In addition, combined RS could differentiate early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group, suggesting possible differential treatment strategies based on the risk categories indicated by the combined RS. Conclusions The combination of pretreatment and post-treatment RSs could provide pivotal information for predicting DFS and differentiating early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group in patients with hormone receptor-positive breast cancer. A larger study is required to validate the results.

Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR.

Abstract: Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.

Cryosurgery for primary breast cancers, its biological impact, and clinical outcomes.

Abstract: Recently, a number of new minimally invasive image-guided percutaneous ablation treatments, including cryoablation, radiofrequency ablation, microwave ablation, high-intensity focused ultrasound, laser ablation, and irreversible electroporation have been developed. Several studies have shown the feasibility and safety of these cryoablation therapies for the treatment of benign breast tumors and small invasive breast cancer. Although the complete response rate of cryoablation for breast cancer is reported to be relatively good, most studies enrolled a small number of patients, and so reliable conclusions could not be drawn. In this review, we introduce the mechanisms of action of cryoablation, and summarize the current literature on the efficacy and safety of cryoablation for breast cancer. Cryoablation also induces an immunomodulatory effect, which is an interesting topic of research in the era of immune checkpoint inhibitors. Cryoablation for primary tumor may enhance the treatment effect of immune checkpoint inhibitors in patients with breast cancer. Further investigations of this new therapeutic strategy are needed.

Gene expression profile of peripheral blood mononuclear cells may contribute to the identification and immunological classification of breast cancer patients

Abstract: It has been reported that the gene expression profile of peripheral blood mononuclear cells (PBMCs) exhibits a unique gene expression signature in several types of cancer. In this study, we aimed to explore the breast cancer patient-specific gene expression profile of PBMCs and discuss immunological insight on host antitumor immune responses. We comprehensively analyzed the gene expression of PBMCs by RNA sequencing in the breast cancer patients as compared to that of healthy volunteers (HVs). Pathway enrichment analysis was performed on MetaCoretm to search the molecular pathways associated with the gene expression profile of PBMCs in cancer patients compared with HVs. We found a significant unique gene expression signature, such as the Toll-like receptor (TLR) 3- and TLR4-induced Toll/interleukin-1 receptor domain-containing adapter molecule 1 (TICAM1)-specific signaling pathway in the breast cancer patients as compared to that of healthy volunteers. Distinctive immunological gene expression profiles also showed the possibility of classifying breast cancer patients into subgroups such as T-cell inhibitory and monocyte-activating groups independent of known phenotypes of breast cancer. These preliminary findings suggest that evaluation of gene expression patterns of PBMCs might be both a less invasive diagnostic procedure and a useful way to reveal immunological insight of breast cancer, including biomarkers for cancer immunotherapy, such as immune checkpoint inhibitor therapy.

Impact of the Number of Iterations in Compressed Sensing Reconstruction on Ultrafast Dynamic Contrast-enhanced Breast MR Imaging.

Abstract: Purpose To assess the impact of the number of iterations of compressed sensing (CS) reconstruction on the kinetic parameters and image quality in dynamic contrast-enhanced (DCE)-MRI of the breast, with prospectively undersampled CS-accelerated scans. Materials and methods Breast examinations including ultrafast DCE-MRI using CS were conducted for 21 patients. Images were reconstructed with different numbers of iterations. The peak enhancement ratio of the aorta and wash-in slope, initial area under the curve, and Ktrans of the breast lesions were measured. The root mean square error and structural similarity between the images using 50 iterations and images with a lower number of iterations were evaluated as criterion for quantitative image evaluation. Results Using an insufficient number of iterations, the contrast-enhanced effect was highly underestimated. In all semi-quantitative parameters, the number of iterations that stabilized the parameters in malignant lesions was higher than that in benign lesions. At least 15 iterations were needed for semi-quantitative parameters. For Ktrans, there were no significant differences between 10 and 50 iterations in both malignant and benign lesions. Conclusion The kinetic parameters using ultrafast DCE-MRI with CS are affected by the number of iterations, especially in malignant lesions. However, if the images are reconstructed with an adequate number of iterations, ultrafast DCE-MRI with CS can be a powerful technique having high temporal and spatial resolution.

A snapshot of surgical resident training in Japan: results of a national-level needs assessment survey

Abstract: To evaluate the status of surgical training in Japan through a national-level needs assessment. A survey was sent to all 909 graduating residents (GRs) and their 611 program directors (PDs) for the year 2016. A working group of surgical educators from around the country was formed under the education committee of the Japan Surgical Society. The survey items were developed by consensus of this working group. The survey investigated the knowledge and problems of the current curriculum, and the status of the current residency training. The response rates were 56.3% of the GRs and 76.8% of the PDs. Among the participants, 47.6% of the GRs and 29.4% of the PDs believed that the residency curriculum did not match the clinical experience. Over 80% of the GRs and PDs agreed on the importance of training outside of the OR, whereas only 13% of the GRs had received such training regularly. Trainees also reported a lower satisfaction rate about the opportunity to train outside of the OR. This national-level needs assessment of surgical training in Japan identified several gaps in the curriculum. These results provide valuable data to assist the ongoing efforts for surgical residency curriculum improvement.

Abstract 4458: Clinical significance ofPIK3CAandESR1mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant

Abstract: BACKGROUND: Mutations in PIK3CA and ESR1 have been implicated in resistance to endocrine therapy in HR+ metastatic breast cancer. Herein, we assessed the clinical significance of PIK3CA and ESR1 mutations from ctDNA and FFPE samples from patients treated with abemaciclib plus fulvestrant and placebo plus fulvestrant. METHODS: Baseline plasma samples (n = 334) and FFPE tumor samples (n = 434) from 669 patients enrolled in MONARCH 2 were analyzed. Extracted DNA was analyzed by droplet digital PCR for four hotspot mutations of PIK3CA (E542K; E545K; H1047L; H1047R) and ESR1 (D538G; Y537C; Y537N; Y537S). Samples that failed DNA QC or where mutation status could not be determined were excluded from analysis. RESULTS:PIK3CA mutations were detected in 96 (40.3%) of 238 plasma samples and 133 (39.9%) of 333 FFPE samples. H1047R was the most frequent mutation followed by E545K, E542K, and H1047L. The concordance of PIK3CA mutations in ctDNA and FFPE samples was 62.8%. ESR1 mutations were detected in 190 (64.4%) of 295 plasma samples and 15 (4.4%) of 344 FFPE samples. D538G was the most frequent mutation followed by Y537C, Y537N, and Y537S. The concordance of ESR1 mutations in ctDNA and FFPE samples was 37.1%; this rate of detection of ESR1 mutations in ctDNA and FFPE samples is explained in part by the site of the biopsy (primary vs metastatic). Co-mutations in PIK3CA and ESR1 were observed in 86 (36.1%) plasma and 5 (1.5%) FFPE samples. Finally, we examined the relationship of PIK3CA and ESR1 mutation status and benefit from abemaciclib therapy as shown in Table 1. CONCLUSIONS:PIK3CA and ESR1 mutations in ctDNA but not in archived FFPE samples correlated with response to abemaciclib, confirming the potential use of ctDNA analysis. The addition of abemaciclib to fulvestrant in MONARCH 2 demonstrated improvement in PFS regardless of PIK3CA or ESR1 status; however, the magnitude of benefit was numerically greater for patients with tumors harboring PIK3CA/ESR1 mutations. Citation Format: Sara M. Tolaney, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Eva-Maria Grischke, Antonio Llombart-Cussac, Hatem Soliman, Lacey M. Litchfield, Sameera Wijayawardana, Tammy Forrester, Valerie M. Jansen, George W. Sledge. Clinical significance of PIK3CA and ESR1 mutations in ctDNA and FFPE samples from the MONARCH 2 study of abemaciclib plus fulvestrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4458.

The impact of age on the risk of ipsilateral breast tumor recurrence after breast-conserving therapy in breast cancer patients with a > 5 mm margin treated without boost irradiation

Abstract: The boost irradiation to the tumor bed following whole-breast irradiation (WBI) reduced the risk of ipsilateral breast tumor recurrence (IBTR). However, in Japan, almost all patients with a margin ≤5 mm receive boost irradiation to the tumor bed, but the decision to perform boost irradiation for those with a margin > 5 mm is dependent on the institution. Thus, institutional guidelines on utilizing boost irradiation for patients aged ≤40 or ≤ 50 years vary. We investigated the IBTR rate to assess the appropriate age for boost irradiation to the tumor bed with a margin > 5 mm. From January 1993 to December 2010, 419 patients with early-stage breast cancer and negative margins (> 5 mm) after breast-conserving surgery received WBI without boost irradiation. The Gray test was used to compare the cumulative incidence of IBTR among patients aged ≤40, 41–50, and ≥ 51 years. Hazard ratios were estimated using the Fine and Gray models. Furthermore, as a subgroup analysis, we investigated whether IBTR depended on the use of systemic therapy, such as anthracycline or taxane regimens. The median follow-up time was 9.3 years. In multivariate analysis, only age predicted IBTR (p = 0.047). The 10-year IBTR rate was 15.7% in patients aged ≤40, 3.8% in those aged 41–50, and 2.0% in patients aged ≥51 years. The difference between patients aged ≤40 and 41–50 years was statistically significant (p = 0.045), whereas the difference between patients aged 41–50 and ≥ 51 years was not significant (p = 0.21). In our institutional surgical setting, when boost irradiation is performed only for patients with a margin ≤5 mm, the IBTR rate after WBI without boost irradiation was significantly higher in patients aged ≤40 years, suggesting that boost irradiation should be used for patients in this age group.

Pharmacogenomic-pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer.

Abstract: An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers. The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities. Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks. TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.

Distribution pattern of FDG uptake using ring-type dedicated breast PET in comparison to whole-body PET/CT scanning in invasive breast cancer.

Abstract: This study aimed to investigate the incidence of rim uptake (RU) or multifocal uptake (MU) by invasive breast cancers on a ring-type dedicated breast positron emission tomography (dbPET) scanner compared with whole-body PET (wbPET) scanner imaging and to correlate uptake patterns with pathological features and prognosis. Between 2009 and 2011, 76 lesions in 74 patients with primary invasive breast cancers were included. Each patient underwent dbPET and wbPET scanning on the same day after administration of 18F-fluorodeoxyglucose (FDG). The images were evaluated to identify specific uptake patterns (RU and MU). Their association with pathological characteristics and prognosis was analyzed. On dbPET, RU and MU patterns were observed in 18 lesions (24%) and 28 lesions (37%), respectively. On wbPET, RU and MU patterns were observed in six lesions (8%) and 17 lesions (22%), respectively. Lesions with RU on dbPET were of higher grade than lesions without RU (P = 0.024) and a higher Ki-67 index (mean; 31% vs. 18%, P = 0.015). They tended to be triple-negative (33% vs. 12%, P = 0.046) and less likely to be luminal A subtype (17% vs. 47%, P = 0.020). On wbPET, however, no significant differences in these markers were seen between RU and non-RU. The MU pattern did not correlate with pathological characteristics in either scanner. Lesions with RU or MU were not significantly associated with disease-free survival. DbPET can identify detailed FDG distribution patterns of breast cancer better than wbPET. Breast cancer with RU on dbPET was associated with higher grade and triple-negative subtype.

Correction to: Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer (BMC Cancer (2019) 19 (517) DOI: 10.1186/s12885-019-5687-0)

Abstract: Following publication of the original article [1], the authors reported the following errors in the article.

Clinical Predictive Factors for the Efficacy of Everolimus in Patients With Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer: A Multicenter Retrospective Cohort Study in Japan.

Abstract: Purpose:To investigate the clinical predictive factors for the efficacy of everolimus (EVE) for advanced/metastatic breast cancer (AMBC).Methods:Routine practice data of consecutive patients with A...

In silico analysis-based identification of the target residue of integrin α6 for metastasis inhibition of basal-like breast cancer.

Abstract: Metastasis causes death in breast cancer patients. To inhibit breast cancer metastasis, we focused on integrin α6, a membrane protein that contributes to cell migration and metastasis. According to in silico analysis, we identified Asp-358 as an integrin α6-specific vertebrate-conserved residue and consequently as a potential therapeutic target. Because Asp-358 is located on the surface of the β propeller domain that interacts with other molecules for integrin α6 function, we hypothesized that a peptide with the sequence around Asp-358 competitively inhibits integrin α6 complex formation. We treated basal-like breast cancer cells with the peptide and observed reductions in cell migration and metastasis. The result of the immunoprecipitation assay showed that the peptide inhibited integrin α6 complex formation. Our immunofluorescence for phosphorylated paxillin, a marker of integrin-regulated focal adhesion, showed that the peptide reduced the number of focal adhesions. These results indicate that the peptide inhibits integrin α6 function. This study identified the functional residue of integrin α6 and designed the inhibitory peptide. For breast cancer patients, metastasis inhibition therapy may be developed in the future based on this study.

Digital artery deformation on movement of the proximal interphalangeal joint.

Abstract: This study aimed to characterize in vivo human digital arteries in three-dimensions using photoacoustic tomography in order to understand the specific mechanism underlying arterial deformation asso...

Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 12 weeks' exemestane exposure in patients with estrogen receptor-positive breast cancer: A multicenter, open-label, phase II study.

Abstract: Our aim was to investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane alone followed by tailored treatment, either continued exemestane monotherapy or exemestane plus docetaxel-cyclophosphamide (TC) combination therapy, in postmenopausal patients with primary invasive estrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I-IIIA breast cancer and Ki67 labeling index ≤30%. In this open-label phase II study, patients initially received exemestane 25 mg/d for 12 weeks. Responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 labeling index ≤5% after treatment, or stable disease with Ki67 labeling index ≤5% both before and after treatment. For the subsequent 12 weeks, exemestane monotherapy was continued for responders (group A), whereas nonresponders received exemestane plus four cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (group B). Clinical response rate (ie the proportion of patients with CR or PR) at 24 weeks was the primary endpoint. Of 64 patients provisionally enrolled between December 2010 and May 2016, 58 (median age 60 years) started the study treatment. Five patients discontinued treatment in the initial exemestane monotherapy period, and 39 completed the study treatment. Clinical response rates at 8-12 and 24 weeks were 71% (10/14, 95% confidence interval [CI] 41.9%-91.6%) and 57% (8/14, 95% CI 28.9%-82.3%), respectively, in group A, and 16% (4/25, 95% CI 4.5%-36.1%) and 56% (14/25, 95% CI 34.9%-75.6%), respectively, in group B. Grade ≥3 adverse events were reported in 8% (1/15) and 53% (20/38) in group A and group B, respectively. The tailored treatment maintained the favorable clinical response to exemestane alone in responders and improved clinical response in nonresponders. TRIAL NUMBER: UMIN000004752 (UMIN Clinical Trials Registry).

Association of drug-related polymorphisms with palbociclib-related neutropenia: Pharmacogenetic analysis of PALOMA-2/-3 (P2/3).

Abstract: 1060Background: The most common PAL treatment related adverse event is neutropenia. ABCB1 and ERCC1 variants are associated with increased chemotherapy drug exposure and CYP3A7*1C may be associated...

Estrogen induces mammary ductal dysplasia

Abstract: Mammary ductal dysplasia is a phenotype observed in precancerous lesions and early-stage breast cancer. However, the mechanism of dysplasia formation remains elusive. Here we show, by establishing a novel dysplasia model system, that estrogen, a female hormone, has the potential to cause mammary ductal dysplasia. We injected estradiol (E2), the most active form of estrogen, daily into scid mice with a defect in nonhomologous end joining repair and observed dysplasia formation with cell proliferation at day 30. Moreover, we found that isoflavones inhibited E2-induced dysplasia formation. Our dysplasia model system provides insight into the mechanistic understanding of breast tumorigenesis, and the development of breast cancer prevention.