Publications by authors named "Shigehira Saji"

150 Publications

Systemic therapy and prognosis of older patients with stage II/III breast cancer: A large-scale analysis of the Japanese Breast Cancer Registry.

Eur J Cancer 2021 Sep 19;154:157-166. Epub 2021 Jul 19.

Department of Breast Oncology, Aichi Cancer Center, Nagoya, Japan. Electronic address:

Aim: This study aimed at investigating the real-world prognostic impact of systemic treatment in older patients with stage II/III breast cancer (BC).

Methods: This retrospective cohort study included patients with stage II/III primary BC, aged ≥55 years, and registered in the Japanese Breast Cancer Registry from 2004 to 2011. The clinicopathological characteristics, treatments, and prognosis of patients aged ≥75 years (older) were compared to those of younger patients.

Results: In total, 56,093 patients (12,727, ≥75 years; 17,860, 65-74 years; 25,506, 55-64 years) were enrolled. In the older group, 9.2% with a luminal (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), 32.9% with a triple-negative (TN, HR-/HER2-), and 27.4% with a HER2-positive (any-HR/HER2+) receptor were administered chemotherapy. In those with luminal cancer, the 5-year breast cancer-specific survival (BCSS) was approximately 95% in all age groups. Meanwhile, among those with TN and HER2-positive BC, the older group had a poorer BCSS. The 5-year overall survival (OS) was also poorer in the older group across all subtypes. Among older patients matched using clinicopathological factors, chemotherapy use was associated with improved OS in the luminal and HER2-positive subtypes.

Conclusions: Chemotherapy use was lower among older patients with stage II/III breast cancer. Those with TN and HER2-positive BC had a lower BCSS than their younger counterparts. Chemotherapy may be beneficial in improving the OS in older patients with luminal and HER2-positive BCs. Treatment for older patients should be individualized, based on tumor-related factors, quality of life, and the patient's health status.
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http://dx.doi.org/10.1016/j.ejca.2021.06.006DOI Listing
September 2021

Chromosomal translocation t(11;14) and p53 deletion induced by the CRISPR/Cas9 system in normal B cell-derived iPS cells.

Sci Rep 2021 Mar 4;11(1):5216. Epub 2021 Mar 4.

Department of Radiation Life Sciences, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

Multiple myeloma (MM) cells are derived from mature B cells based on immunoglobulin heavy chain (IgH) gene analysis. The onset of MM is often caused by a reciprocal chromosomal translocation (cTr) between chr 14 with IgH and chr 11 with CCND1. We propose that mature B cells gain potential to transform by reprograming, and then chromosomal aberrations cause the development of abnormal B cells as a myeloma-initiating cell during B cell redifferentiation. To study myeloma-initiating cells, we have already established normal B cell-derived induced pluripotent stem cells (BiPSCs). Here we established two BiPSCs with reciprocal cTr t(11;14) using the CRISPR/Cas9 system; the cleavage site were located in the IgH Eμ region of either the VDJ rearranged allele or non-rearranged allele of IgH and the 5'-upsteam region of the CCND1 (two types of BiPSC13 with t(11;14) and MIB2-6 with t(11;14)). Furthermore, p53 was deleted using the CRISPR/Cas9 system in BiPSC13 with t(11;14). These BiPSCs differentiated into hematopoietic progenitor cells (HPCs). However, unlike cord blood, those HPCs did not differentiated into B lymphocytes by co-culture with BM stromal cell. Therefore, further ingenuity is required to differentiate those BiPSCs-derived HPCs into B lymphocytes.
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http://dx.doi.org/10.1038/s41598-021-84628-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933289PMC
March 2021

Recommendations for the management of breast cancer patients during the COVID-19 pandemic from the Japan Breast Cancer Society.

Breast Cancer 2021 Mar 20;28(2):247-253. Epub 2021 Feb 20.

Department of Breast Oncology and Surgery, Tokyo Medical University Hospital, 6-7-1, Nishishinjuku, Shinjuku, Tokyo, 160-0023, Japan.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 remains a major global crisis and continues to spread relentlessly around the world. In Japan, the number of infected people has incrementally increased since April 2020. The COVID-19 pandemic has exerted a major impact not only on our daily lives but also on healthcare. As the infection continues to spread, many medical institutions have devoted all efforts to minimize the risk of infection not only for patients but also for medical personnel by prioritizing medical care, reserving treatment, and extending consultation intervals. Cancer treatment is one of the priorities for medical care even during an epidemic infection as there is a concern of decreasing curability or therapeutic effect from postponement. As the COVID-19 situation evolves rapidly, we created an informative triage to provide appropriate medical treatment to breast cancer patients. In this triage, we offer guidance on preparing for the impact of the COVID-19 pandemic in breast cancer patients, prioritizing triage and diagnostic procedures, and providing advice on surgical, radiation, and oncological treatments.
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http://dx.doi.org/10.1007/s12282-020-01214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895736PMC
March 2021

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 01;22(1):74-84

Cancer Institute Hospital, Tokyo, Japan.

Background: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer.

Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969.

Findings: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis.

Interpretation: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer.

Funding: Public Health Research Foundation (Japan), Taiho Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30534-9DOI Listing
January 2021

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

Breast Cancer Res Treat 2021 Feb 1;186(1):135-147. Epub 2020 Dec 1.

Chuo University, Tokyo, Japan.

Purpose: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes.

Methods: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status.

Results: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02).

Conclusions: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.
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http://dx.doi.org/10.1007/s10549-020-06018-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940338PMC
February 2021

Clinicopathological characteristics, practical treatments, prognosis, and clinical issues of older breast cancer patients in Japan.

Breast Cancer 2021 Jan 21;28(1):1-8. Epub 2020 Nov 21.

Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan.

Background: Minimal data are available to support the clinical management of older breast cancer patients. Consequently, the standard of care remains unclear. Our aim was to clarify the clinicopathological characteristics, practical treatments, and prognosis of older Japanese breast cancer patients and discuss clinical issues.

Methods: We reviewed 132,240 cases, diagnosed between 2004 and 2011, from the Japanese Breast Cancer Registry. Focusing on older patients, we compared data among three age groups: 75 years and over (n = 27,385), 65-74 years (n = 43,839), and 55-64 years (n = 61,016).

Results: Data revealed the proportions of mucinous and apocrine carcinoma were higher in older patients, and they more frequently had clinical stage II and III cancer. Their ER-positive rates were higher, in contrast to the lower HER2-positive, breast-conserving surgery (BCS), post-BCS irradiation, and adjuvant chemotherapy rates. Almost half of the older patients who underwent chemotherapy received CMF or oral 5FU, during hormone therapy, Tamoxifen was administered more frequently. The overall survival rate decreased with age, but the breast cancer-specific survival (BCSS) at 5 years remained similar. The rate of other cause of death in the oldest group was about a half, and more than double that in those aged 55-64 years.

Conclusions: We showed clinical data of older breast cancer patients in Japan. Their disease was more advanced at the time of diagnosis, post-BCS irradiation and primary systemic chemotherapy were omitted more frequently, and overall, BCSS was similar among age categories, although the rate of other causes of death was higher.
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http://dx.doi.org/10.1007/s12282-020-01188-8DOI Listing
January 2021

Risk of immunotherapy-related narcolepsy in genetically predisposed patients: a case report of narcolepsy after administration of pembrolizumab.

J Immunother Cancer 2020 10;8(2)

Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan

Background: Immune-related adverse events associated with immune checkpoint therapy cause autoimmune disease-like symptoms. People who carry specific genotypes or haplotypes of human leucocyte antigen (HLA) are known to be predisposed to develop autoimmune diseases including narcolepsy. Immunotherapy could be a trigger to develop narcolepsy in predisposing HLA positive patients.

Case Presentation: A 66-year-old woman with stage IVB endometrial carcinosarcoma experienced daytime sleepiness and temporary muscle weakness 14 days after the administration of an immune checkpoint inhibitor, pembrolizumab. These were consistent with the main symptoms of narcolepsy with cataplexy. This patient carried a highly predisposing HLA haplotype for narcolepsy; HLA-DQB1*06:02, DRB1*15:01, DQA1*01:02 and DRB5*01:01:01. A hypocretin-1/orexin-A concentration in the patient's cerebrospinal fluid was low at 9.6 pg/mL in ELISA, and 155.5 pg/mL in radioimmunoassay that was below the normal level of 200 pg/mL. Therefore, she was diagnosed with narcolepsy tentatively according to the International Classification of Sleep Disorders, third edition diagnostic criteria for narcolepsy. The onset of narcolepsy in the 60s is very rare, and narcoleptic symptoms in our patient were likely to be caused by pembrolizumab.

Conclusions: This case suggests that treatment with immune checkpoint inhibitors potentially causes narcolepsy in genetically predisposed patients.
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http://dx.doi.org/10.1136/jitc-2020-001164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534705PMC
October 2020

Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.

Lancet 2020 10 20;396(10257):1090-1100. Epub 2020 Sep 20.

Breast Center, Department of Gynecology and Obstetrics and Comprehensive Cancer Center of the Ludwig-Maximilians-University, Munich, Germany.

Background: Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC.

Methods: This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II-III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m every week for 12 weeks followed by doxorubicin at 60 mg/m and cyclophosphamide at 600 mg/m every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ≥1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing.

Findings: Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20·6 months (IQR 8·7-24·9) in the atezolizumab plus chemotherapy group and 19·8 months (8·1-24·5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50-65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34-49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6-27; one-sided p=0·0044 [significance boundary 0·0184]). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57-79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38-61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4-35; one-sided p=0·021 [significance boundary 0·0184]). In the neoadjuvant phase, grade 3-4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group).

Interpretation: In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile.

Funding: F Hoffmann-La Roche/Genentech.
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http://dx.doi.org/10.1016/S0140-6736(20)31953-XDOI Listing
October 2020

Trend in Cancer incidence and mortality in Fukushima between 2008 and 2015.

J Epidemiol 2020 Sep 19. Epub 2020 Sep 19.

Radiation Medical Science Center for the Fukushima Health Management Survey, Fukushima Medical University.

BackgroundsCancer incidence in Fukushima Prefecture, especially thyroid cancer, has been a public concern, since the Tokyo Electric Power Company Fukushima Daiichi Nuclear Plants accident following the Great East Japan Earthquake on March 11, 2011; however, cancer incidence for Fukushima residents before and after the accident based on a population-based cancer registry (PBCR) has not been known to worldwide.MethodsWe obtained the corrected incidence data for invasive cancers newly diagnosed from 2008 to 2015, from the Fukushima Cancer Registry. We checked data quality indicators for PBCRs to confirm a comparability. We calculated age-standardized annual incidence and mortality of cancer for all-site, thyroid, and leukemia by calendar year and sex, as did for Tochigi Prefecture and all of Japan as a reference for comparison. We applied joinpoint trend analysis to test an apparent trend in incidence and mortality.ResultsThe corrected incidence data from the Fukushima Cancer Registry had sufficient quality comparable to other PBCRs. For the age-standardized annual incidence by sex and cancer type in Fukushima and Tochigi, we did not detect any joinpoint in trend with statistical significance. Cancer incidence gently increased from 2008 to 2015 nationwide. Incidence and mortality of cancer for Fukushima before the accident was very close to that for Tochigi.ConclusionsWe interpreted the incidence statistics of cancer for Fukushima residents between 2008 and 2015. Our results will provide fundamental statistics for subsequent researchers to assess the relationship between the disaster and cancer incidence among Fukushima residents in the long term.
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http://dx.doi.org/10.2188/jea.JE20200202DOI Listing
September 2020

Trastuzumab, pertuzumab, and eribulin mesylate versus trastuzumab, pertuzumab, and a taxane as a first-line or second-line treatment for HER2-positive, locally advanced or metastatic breast cancer: study protocol for a randomized controlled, non-inferiority, phase III trial in Japan (JBCRG-M06/EMERALD).

Trials 2020 May 7;21(1):391. Epub 2020 May 7.

Breast Oncology Center, The Cancer Institute Hospital of JFCR, 3-8-31 Ariake Koto-ku, Tokyo, 135-8550, Japan.

Background: Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2 mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade.

Methods/design: This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2 mBC who meet the following requirements: (1) age 20-70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m on days 1 and 8) or taxane (docetaxel 75 mg/m on day 1 or paclitaxel 80 mg/m on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested.

Discussion: If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2 mBC in Japan.

Trial Registration: ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.
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http://dx.doi.org/10.1186/s13063-020-04341-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206765PMC
May 2020

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.

Breast Cancer 2020 May 2;27(3):322-331. Epub 2020 Apr 2.

Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.

Purpose: We present the English version of The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition.

Methods: The JBCS formed a task force to update the JBCS Clinical Practice Guidelines, 2015 edition, according to Minds Handbook for Clinical Practice Guideline Development 2014. First, we set multiple outcomes for each clinical question (CQ). Next, quantitative or qualitative systematic review was conducted for each of the multiple outcomes, and the strength of recommendation for the CQ was taken into consideration during meetings, with the aim of finding a balance between benefit and harm. Finalized recommendations from each session were confirmed through discussion and voting at the recommendation decision meeting.

Results: The recommendations, the strength of recommendation and the strength of evidence were determined based on systemic literature reviews and the meta-analyses for each CQ.

Conclusion: The JBCS updated the Clinical Practice Guidelines for systemic treatment of breast cancer.
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http://dx.doi.org/10.1007/s12282-020-01085-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062371PMC
May 2020

Breast Cancer Provider Interval Length in Fukushima, Japan, After the 2011 Triple Disaster: A Long-Term Retrospective Study.

Clin Breast Cancer 2020 04 6;20(2):e127-e150. Epub 2019 Sep 6.

Department of Surgery, Minamisoma Municipal General Hospital, Minamisoma, Fukushima, Japan.

Background: Minimizing the interval from symptom onset to treatment commencement is essential for a favorable outcome among breast cancer (BC) patients. This study examined whether provider interval (time elapsed from first consultation to treatment initiation) lengthened among BC patients after Japan's 2011 earthquake, tsunami, and nuclear disaster in Fukushima. Factors associated with the length of postdisaster interval and whether the interval was associated with BC stage were also investigated.

Patients And Methods: So-so District (study site) was an area damaged by the 2011 disasters. Data of all BC patients who made their first medical consultation and received initial treatment at the core medical institutions in the area 5 years before or after the disaster were extracted from patient medical records. We used several regression approaches to fulfill our study objectives.

Results: We included 263 (140 predisaster and 123 postdisaster) patients. After adjustment for covariates, the interval did not significantly change after the disaster compared to before the disaster. Those with 4 or 5 cohabiting family members experienced a shorter interval after the disaster than those with 0 or 1 cohabiting family members (relative length, 0.47; 95% confidence interval, 0.28-0.78). Those with an interval of > 60 days had lower odds of stage III or IV cancer after the disaster than those with an interval of < 30 days (odds ratio, 0.09; 95% confidence interval, 0.01-0.84).

Conclusion: Overall, provider interval did not lengthen after the disaster. However, those with fewer cohabiting family members might have experienced a longer total interval. Cancer stage may not necessarily reflect the influence of interval on patient outcome.
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http://dx.doi.org/10.1016/j.clbc.2019.07.008DOI Listing
April 2020

Cluster of differentiation 8 and programmed cell death ligand 1 expression in triple-negative breast cancer combined with autosomal dominant polycystic kidney disease and tuberous sclerosis complex: a case report.

J Med Case Rep 2019 Dec 24;13(1):381. Epub 2019 Dec 24.

Department of Polycystic Kidney Research, Kyorin University shool of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.

Background: Autosomal dominant polycystic kidney disease is defined as an inherited disorder characterized by renal cyst formation due to mutations in the PKD1 or PKD2 gene, whereas tuberous sclerosis complex is an autosomal dominant neurocutaneous syndrome caused by mutation or deletion of the TSC2 gene. A TSC2/PKD1 contiguous gene syndrome, which is caused by a chromosomal mutation that disrupts both the TSC2 and PKD1 genes, has been identified in patients with tuberous sclerosis complex and severe early-onset autosomal dominant polycystic kidney disease. The tumor tissue of patients with breast cancer with contiguous gene syndrome has a high mutation burden and produces several neoantigens. A diffuse positive immunohistochemistry staining for cluster of differentiation 8 in the T cells of breast cancer tissue is consistent with neoantigen production due to high mutation burden.

Case Presentation: A 61-year-old Japanese woman who had been undergoing dialysis for 23 years because of end-stage renal failure secondary to autosomal dominant polycystic kidney disease was diagnosed as having triple-negative breast cancer and underwent mastectomy in 2015. She had a history of epilepsy and skin hamartoma. Her grandmother, mother, two aunts, four cousins, and one brother were also on dialysis for autosomal dominant polycystic kidney disease. Her brother had epilepsy and a brain nodule. Another brother had a syndrome of kidney failure, intellectual disability, and diabetes mellitus, which seemed to be caused by mutation in the CREBBP gene. Immunohistochemistry of our patient's breast tissue showed cluster of differentiation 8 and programmed cell death ligand 1 positivity.

Conclusions: Programmed cell death ligand 1 checkpoint therapy may be effective for recurrence of triple-negative breast cancer in a patient with autosomal dominant polycystic kidney disease and tuberous sclerosis complex.
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http://dx.doi.org/10.1186/s13256-019-2274-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929341PMC
December 2019

The Japanese Breast Cancer Society clinical practice guidelines for surgical treatment of breast cancer, 2018 edition.

Breast Cancer 2020 Jan 12;27(1):4-8. Epub 2019 Dec 12.

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.

We have prepared the Japanese Breast Cancer Society clinical practice guidelines (CPGs) for surgical treatment of breast cancer, 2018 update after a systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. The CPG committee for surgical treatment of breast cancer, composed of breast surgeons and plastic surgeons treating breast cancer, has developed the CPGs. Eight clinical questions (CQs) were selected and divided roughly into the following five categories: (1) breast surgery in initial therapy (CQs 1-3); (2) axillary surgery in initial therapy (CQs 4-5); (3) breast reconstruction in initial therapy (CQ 6); (4) surgical treatment for recurrent and metastatic breast cancer (CQs 7-8); and (5) others. Recommendations for these CQs were decided by the GRADE grid method. In addition, 4 outlines, 14 background questions (BQs), and 12 future research questions (FQs) were also selected. Statements for these BQs and FQs are provided. We developed the updated CPGs for surgical treatment of breast cancer, 2018, which include 8 CQs and recommendations. As a decision-making tool for the understanding and treatment of breast cancer, these guidelines will help surgical oncologists dealing with breast cancer, medical staff, and patients, along with their family members.
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http://dx.doi.org/10.1007/s12282-019-01030-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134293PMC
January 2020

Genotype-Guided Tamoxifen Dosing in Hormone Receptor-Positive Metastatic Breast Cancer (TARGET-1): A Randomized, Open-Label, Phase II Study.

J Clin Oncol 2020 02 10;38(6):558-566. Epub 2019 Dec 10.

Keio University School of Medicine, Tokyo, Japan.

Purpose: In patients taking tamoxifen, the genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome.

Methods: Patients who needed first-line tamoxifen therapy were enrolled. Based on individual genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes.

Results: Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM 51.1 nM; < .0001) and were also higher compared with wt/wt patients (72.0 nM; = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months ( = .43).

Conclusion: In patients with -variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The genotype solely cannot explain individual variability in the efficacy of tamoxifen.
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http://dx.doi.org/10.1200/JCO.19.01412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030889PMC
February 2020

Factors associated with prolonged overall survival in patients with postmenopausal estrogen receptor-positive advanced breast cancer using real-world data: a follow-up analysis of the JBCRG-C06 Safari study.

Breast Cancer 2020 May 6;27(3):389-398. Epub 2019 Dec 6.

Breast Oncology Center, The Cancer Institute Hospital of JFCR, Tokyo, 135-8550, Japan.

Background: Assessing survival risk is important for discussing treatment options with estrogen receptor-positive (ER+) advanced breast cancer (ABC) patients. However, there are few reports from large-scale databases on the survival risk factors in ER+ ABC. The Safari study (UMIN000015168) was a retrospective, multicenter cohort study involving 1072 Japanese patients receiving fulvestrant 500 mg mostly as a second- or later-line endocrine therapy for ER+ ABC. The follow-up data after the Safari study were examined, focusing on any relationship between clinicopathological factors and overall survival (OS) in ER+ ABC patients.

Methods: OS in patients with ER+ ABC was analyzed by univariate and multivariate analyses with a Cox proportional hazards model in this study.

Results: A total of 1031 cases were evaluable for OS analysis. Multivariate analysis showed that younger age (< 60 years), longer time from ABC diagnosis to fulvestrant use (≥ 3 years), no prior palliative chemotherapy before fulvestrant use, and progesterone receptor (PgR) negativity (PgR-) were significantly correlated with prolonged OS (median 7.0 years). For cases with histological or nuclear grade data, lower histological or nuclear grades were also correlated with longer OS. In recurrent metastatic cases, long disease-free interval (DFI) was not correlated with longer OS.

Conclusions: In ER+ ABC patients whose treatment history included fulvestrant, younger age, longer time from ABC diagnosis to fulvestrant use, no prior palliative chemotherapy use, PgR-, and lower histological or nuclear grade correlated positively with prolonged OS.
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http://dx.doi.org/10.1007/s12282-019-01029-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196081PMC
May 2020

The Japanese Breast Cancer Society Clinical Practice Guidelines, 2018 edition: the tool for shared decision making between doctor and patient.

Breast Cancer 2020 Jan 22;27(1):1-3. Epub 2019 Nov 22.

Department of Radiation Oncology, Shiga General Hospital, Moriyama, Japan.

The Breast Cancer Clinical Practice Guidelines, 2018 edition, written in Japanese and organized by the Japanese Breast Cancer Society, were published in Japanese in May 2018. The process of making these guidelines, as well as the content, was largely changed and compared with previous editions. The concept of these guidelines is to act as a support tool for shared decision making between doctor and patient. The procedure of creating the guidelines referred to Minds Handbook for Clinical Practice Guideline Development 2014. This guideline, written in Japanese, consists of two booklets: (1) the epidemiology and diagnosis booklet covering screening, radiological, and pathological diagnosis and (2) the treatment booklet covering surgical therapy, radiation therapy, and systemic therapy. This review article consists of five parts, including the history of the Breast Cancer Clinical Practice Guidelines, the concept, process, content, and recommendation grade. I believe this brief summary concerning the Breast Cancer Clinical Practice Guidelines 2018 edition in English will be helpful for both Japanese and foreign investigators.
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http://dx.doi.org/10.1007/s12282-019-01021-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134297PMC
January 2020

The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer Screening and Diagnosis, 2018 Edition.

Breast Cancer 2020 Jan 16;27(1):17-24. Epub 2019 Nov 16.

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

This article updates readers as to what is new in the Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer Screening and Diagnosis, 2018 Edition. Breast cancer screening issues are covered, including matters of breast density and possible supplemental modalities, along with appropriate pre-operative/follow-up diagnostic breast imaging tests. Up-to-date clinical practice guidelines for breast cancer screening and diagnosis should help to provide patients and clinicians with not only evidence-based breast imaging options, but also accurate and balanced information about the benefits and harms of intervention, which ultimately enables shared decision making about imaging test plans.
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http://dx.doi.org/10.1007/s12282-019-01025-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134289PMC
January 2020

The Japanese Breast Cancer Society Clinical Practice Guideline for radiation treatment of breast cancer, 2018 edition.

Breast Cancer 2020 Jan 28;27(1):9-16. Epub 2019 Oct 28.

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Purpose: The Japanese Breast Cancer Society (JBCS) Clinical Practice Guideline was revised in 2018. This article describes the revise points in the section on radiation therapy (RT).

Methods And Materials: The JBCS formed task force to update the JBCS Clinical Practice Guideline 2015 edition. Background questions (BQs) deal with standard treatments of breast cancer in clinical practice. Clinical questions (CQs) highlight the important treatments in which controversy remains. The task force for RT section addressed the 10 BQs, the 10 CQs, and the 4 Future reseach questions (FQs). For each CQ, systematic literature reviews and meta-analyses were conducted, and recommendations, strength of recommendation and strength of evidence were determined according to the protocol in Morizane et al. (Minds Handbook for Clinical Practice Guideline Development, 2014).

Results: The recommendations, the strength of recommendation and the strength of evidence were determined based on the systematic literature reviews and the meta-analyses for each CQ.

Conclusion: The JBCS updated the Clinical Practice Guideline. RT represents a significant portion of the breast cancer treatment, and these recommendations regarding RT will be useful in individualized, shared decision making between physicians and patients.
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http://dx.doi.org/10.1007/s12282-019-01019-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134303PMC
January 2020

Distinct gene expression profiles between primary breast cancers and brain metastases from pair-matched samples.

Sci Rep 2019 09 16;9(1):13343. Epub 2019 Sep 16.

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Our objectives were to determine whether clinic-pathological markers and immune-related gene signatures in breast cancer exhibit any change upon brain metastasis and whether previously reported genes significantly associated with brain metastases and the epithelial-mesenchymal transition (EMT) were reproducible and consistent in our dataset. Sixteen pair-matched samples from primary breast cancers and brain metastases diagnosed were collected from the Japan Clinical Oncology Group Breast Cancer Study Group. Gene expression profiles for immune-, brain metastases-, and EMT-related genes were compared between primary breast cancers and brain metastases. Potential therapeutic target genes of 41 FDA-approved or under-investigation agents for brain metastases were explored. Immune-related signatures exhibited significantly lower gene expression in brain metastases than in primary breast cancers. No significant differences were detected for the majority of genes associated with brain metastases and EMT in the two groups. Among 41 therapeutic target candidates, VEGFA and DNMT3A demonstrated significantly higher gene expression in brain metastases. We found that distinct patterns of gene expression exist between primary breast cancers and brain metastases. Further studies are needed to explore whether these distinct expression profiles derive from or underlie disease status and compare these features between metastases to the brain and other sites.
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http://dx.doi.org/10.1038/s41598-019-50099-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746866PMC
September 2019

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.

Cancer Med 2019 Sep 30;8(12):5468-5481. Epub 2019 Jul 30.

Department of Surgery (Breast Surgery), Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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/m and cyclophosphamide 600 mg/m 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).
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http://dx.doi.org/10.1002/cam4.2423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745863PMC
September 2019

MLH1 germline mutation associated with Lynch syndrome in a family followed for more than 45 years.

BMC Med Genet 2019 05 2;20(1):67. Epub 2019 May 2.

Department of Surgery, Hoshi General Hospital, 59-1 Mukaikawahara Koriyama city, Fukushima, 963-8501, Japan.

Background: Lynch syndrome, is an autosomal dominantly inherited disease that predisposes individuals to a high risk of colorectal cancers, and some mismatch-repair genes have been identified as causative genes. The purpose of this study was to investigate the genomic rearrangement of the gene in a family with Lynch syndrome followed for more than 45 years.

Case Presentation: The family with Lynch syndrome is family N, who received colorectal cancer treatment for 45 years. The proband of family N had multiple colorectal and uterine cancers. Because the proband met the diagnostic Amsterdam criteria and was Microsatellite instability (MSI) - positive, we performed genetic testing several times. However, germline mutations in MLH1 and MSH2 genes were not found by long-distance PCR or RT-PCR/direct sequencing analysis within the 45-year follow-up. MLPA analysis showed that the genomes of the proband and proband's daughter contained a deletion from exon 4 through exon 19 in the MLH1 gene. Her son's son and her daughter's son were found to be carriers of the mutation.

Conclusions: For carriers of mismatch-repair gene mutation among families with Lynch syndrome, the onset risk of associated cancers such as uterine cancer is particularly high, including colorectal cancer. The diagnosis of carriers among non-onset relatives is important for disease surveillance.
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http://dx.doi.org/10.1186/s12881-019-0792-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498505PMC
May 2019

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

ESMO Open 2019 27;4(1):e000476. Epub 2019 Feb 27.

Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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.
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http://dx.doi.org/10.1136/esmoopen-2018-000476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435245PMC
February 2019

Progesterone receptor expression in proliferating cancer cells of hormone-receptor-positive breast cancer.

Tumour Biol 2018 Nov;40(10):1010428318811025

1 Department of Breast Surgery, School of Medicine, Kyorin University, Tokyo, Japan.

Breast cancer has been suggested to have two distinct driving mechanisms: the hormone receptor and the growth factor receptor pathways. We hypothesized that each driving system produces a different expression pattern of estrogen-regulated genes, such as progesterone receptor, in proliferating cells. Progesterone receptor and Ki67 expressions were assessed by dual-fluorescence immunohistochemistry in estrogen-receptor-positive breast cancer tissues. Two distinct proliferating cell populations were observed: progesterone-receptor-positive and progesterone-receptor-negative. In the training cohort, tissues with progesterone-receptor-positive proliferating cells were associated with lower grade and better disease-free survival (p = 0.0055 and 0.0026, respectively). These associations were confirmed in the validation cohort from the neoadjuvant endocrine trial JFMC34 (p = 0.033 and 0.0003, respectively). In the validation cohort, patients with progesterone-receptor-positive proliferating cells responded better to endocrine therapy and had a lower Oncotype DX Recurrence Score. In the multivariate analysis, progesterone receptor status of proliferating cells, but not progesterone receptor or Ki67 alone, was an independent predictor of disease-free survival in both cohorts (p = 0.0043 and 0.0026). In conclusion, the progesterone receptor status of proliferating cancer cells was associated with histological grade and Recurrence Score, and a potent prognostic factor in estrogen-receptor-positive breast cancers. Results suggest that different driving systems generate different expression patterns of progesterone receptor in proliferating cancer cells. Further studies are warranted to validate the findings.
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http://dx.doi.org/10.1177/1010428318811025DOI Listing
November 2018
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