Publications by authors named "Naoki Niikura"

78 Publications

Oral care and oral assessment guide in breast cancer patients receiving everolimus and exemestane: subanalysis of a randomized controlled trial (Oral Care-BC).

Ann Transl Med 2021 Apr;9(7):535

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Tokyo, Japan.

Background: Oral mucositis is a clinically significant adverse event linked to cancer therapy; it reduces the quality of life of patients and may result in the discontinuation of treatment and a poorer prognosis. Based on level 3 evidence, the Mucositis Study Group of Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology recommend oral care for all patients receiving cancer chemotherapy and radiotherapy, although no data from large-scaled randomized controlled trials support the efficacy of oral care in preventing oral mucositis. Therefore, this randomized, controlled, multicenter, open-label, phase III study sought to determine whether professional oral care reduces oral mucositis in everolimus and exemestane-treated estrogen receptor-positive metastatic breast cancer patients.

Methods: Altogether, 169 patients were randomized into the professional oral care (n=82) and control (n=87) groups. The professional oral care group received oral health instruction, professional mechanical tooth and tongue cleaning, gargling with a benzethonium chloride mouthwash, and dexamethasone ointment when grade 1 mucositis manifested. The control group received oral health instruction and gargling. Eight weeks after the everolimus and exemestane administration, the oral status (Oral Assessment Guide criteria) and oral mucositis status (Common Terminology Criteria for Adverse Events functional and clinical examinations) were evaluated.

Results: The incidence of oral mucositis of any grade and grade 2 severe mucositis was significantly lower in the professional oral care group, based on the Common Terminology Criteria for Adverse Events functional and clinical examinations. The total Oral Assessment Guide score, total Oral Assessment Guide grade, and Oral Assessment Guide score of teeth/dentures and mucous membranes were significantly different between the two groups. The Oral Assessment Guide grade for swallow, lip, teeth/dentures, mucous membrane, tongue, and saliva significantly correlated to oral mucositis severity.

Conclusions: Professional oral care may prevent oral mucositis and improve teeth/denture conditions in patients receiving everolimus and exemestane.
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http://dx.doi.org/10.21037/atm-20-6488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105828PMC
April 2021

Clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with ductal carcinoma in situ (DCIS): a multi-institutional retrospective cohort study.

Breast Cancer 2021 Jul 18;28(4):896-903. Epub 2021 Feb 18.

Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.

Background: We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS.

Patients And Methods: We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records.

Results: We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2-2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2-2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2-2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2-2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm.

Conclusion: We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.
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http://dx.doi.org/10.1007/s12282-021-01225-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213581PMC
July 2021

Secondary endpoints analysis in patients with estrogen receptor-positive metastatic breast cancer treated with everolimus and exemestane enrolled in Oral Care-BC.

BMC Cancer 2021 Jan 7;21(1):34. Epub 2021 Jan 7.

Department of Dentistry and Oral and Maxillofacial Surgery, Tokai University School of Medicine, Tokyo, Japan.

Background: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE.

Methods: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months.

Results: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI <  25 mg/m and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial.

Conclusions: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI <  25 mg/m, and who did not receive BMA while receiving EVE and EXE may have better prognoses.

Trial Registration: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov ( NCT02376985 ).
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http://dx.doi.org/10.1186/s12885-020-07746-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791872PMC
January 2021

Current Status of Advance Care Planning and End-of-life Communication for Patients with Advanced and Metastatic Breast Cancer.

Oncologist 2021 04 2;26(4):e686-e693. Epub 2021 Jan 2.

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

Background: Advance care planning (ACP) is a process that supports adults in understanding and sharing their personal values, life goals, and preferences regarding future medical care. We examined the current status of ACP and end-of-life (EOL) communication between oncologists and patients with metastatic breast cancer.

Materials And Methods: We conducted a survey among 41 institutions that specialize in oncology by using an online tool in October 2019. Participants (118 physicians) from 38 institutions completed a 39-item questionnaire that measured facility type and function; physicians' background and clinical approach, education about EOL communication, and understanding about ACP; and the current situation of ACP and EOL discussions.

Results: Ninety-eight responses concerning physicians' engagement in ACP with patients were obtained. Seventy-one (72%) answered that they had engaged in ACP. Among these, 23 (33%) physicians used a structured format to facilitate the conversation in their institutions, and only 6 (8%) settled triggers or sentinel events for the initiation of ACP. In the multivariable analysis, only the opportunity to learn communication skills was associated with physicians' engagement with ACP (odds ratio: 2.8, 95% confidence interval: 1.1-7.0). The frequency and timing of communication about ACP and EOL care with patients substantially varied among the oncologists. Communication about patients' life expectancy was less frequent compared with other topics.

Conclusion: The opportunity to improve EOL communication skills promoted physicians' engagement with ACP among patients with metastatic/advanced breast cancer. However, there were still substantial variabilities in the method, frequency, and timing of ACP and EOL communication among the oncologists.

Implications For Practice: This study found that the opportunity to improve end-of-life (EOL) communication skills promoted physicians' engagement in advance care planning (ACP) among patients with metastatic/advanced breast cancer. All oncologists who treat said patients are encouraged to participate in effective education programs concerning EOL communication skills. In clinical practice, there are substantial variabilities in the method, frequency, and timing of ACP and EOL communication among oncologists. As recommended in several clinical guidelines, the authors suggest a system that identifies patients who require conversations about their care goals, a structured format to facilitate the conversations, and continuous measurement for improving EOL care and treatment.
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http://dx.doi.org/10.1002/onco.13640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018302PMC
April 2021

Stability of HER2 Status by Dual-color in Situ Hybridization Before and After Neoadjuvant Chemotherapy in Breast Cancer.

Tokai J Exp Clin Med 2020 Dec 20;45(4):176-181. Epub 2020 Dec 20.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Objective: Trastuzumab may convert human epidermal growth factor receptor-2 (HER2)-positive primary breast tumors to HER2-negative tumors after chemotherapy. This study determined whether trastuzumab increases the number of patients with conversion to HER2-negative status and assessed the effect of neoadjuvant chemotherapy.

Methods: We retrospectively reviewed 46 patients diagnosed with HER2-overexpression in primary breast cancers at Tokai University Hospital, receiving neoadjuvant chemotherapy by immunohistochemistry and fluorescence in situ hybridization (FISH). Surgical specimens of patients achieving less than pathological complete response (pCR) were verified for sufficient residual tissue to evaluate post-treatment HER2 status by dual-color in situ hybridization (DISH).

Results: pCR was achieved in 8 of the 46 (17.4%) patients. The residual tumor was sufficient for a ssessing post-treatment HER2 status in 25 patients. DISH of pretreatment specimens confirmed HER2 amplification prior to therapy. Of the 25 HER2-positive patients, DISH revealed 3 were HER2 negative in pretreatment specimens. No post-treatment tumors were HER2-negative according to DISH in HER2-positive pre-treatment tumors. Among HER2-negative pretreatment tumors, 1 post-treatment tumor was HER2 positive and 2 had stable HER2 status.

Conclusion: HER2 status determined by DISH was stable between pretreatment breast tumors and residual tumors. However, a small discrepancy regarding HER2 status determined by immunohistochemistry and DISH existed.
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December 2020

Prediction of pathological complete response after neoadjuvant chemotherapy in breast cancer by combining magnetic resonance imaging and core needle biopsy.

Surg Oncol 2020 Dec 6;35:447-452. Epub 2020 Oct 6.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan.

Background: Pathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI.

Methods: In this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated.

Results: Of the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis.

Conclusion: In cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.
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http://dx.doi.org/10.1016/j.suronc.2020.10.002DOI Listing
December 2020

Students' Input on Preparing a Weekly Calendar of Individual Students in the Breast Surgery Clinical Clerkship.

Tokai J Exp Clin Med 2020 Sep 20;45(3):117-120. Epub 2020 Sep 20.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Background; Until 2018, the Breast and Endocrine surgery had no student calendar. A questionnaire survey was conducted on how students felt by creating a weekly schedule of individual students from 2019.

Method: 6th-year elective courses, targeted at students who selected Breast and Endocrine surgery clinical clerkship. The schedule clarifies the contents of the training as follows; outpatient visits, small group study (preparation for graduation and national exams including mammography reading), simulator training, and surgery. The questionnaire adopted an anonymous five-point evaluation method (5; I think very much; 4; Somewhat I think; 3; Normal; 2; Somewhat I don't think; 1; I don't think), and provided a free text box. The following seven questions were asked; A. I was able to send a good training, B. I was useful for studying national and graduation exams, C. Time constraints were appropriate, D. I could fully experience surgery, E. Appropriately experienced outpatients, F. Assignments (presented at conference) appropriate, G. I was interested in Breast and Endocrine surgery.

Results: Average values were A. 4.7, B. 4.9, C. 4.6, D. 4.9, E. 4.8, F. 4.7, G. 4.7. However, C and F received low ratings of 1 and 2. In the free text box, there were favorable opinions such as the fact that it was good to prepare for the national examination and that reading mammography was helpful. Conversely, there were some negative opinions, such as a time spent outpatient was too long, a difference in enthusiasm among the instructors, and a hope to see more at the first visit and to cope with the procedure.

Discussion: Preparing a weekly calendar of individual students generally yielded satisfactory results, but also highlighted the potential for future improvements in clinical clerkship.
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September 2020

Breast cancer survival among Japanese individuals and US residents of Japanese and other origins: a comparative registry-based study.

Breast Cancer Res Treat 2020 Nov 20;184(2):585-596. Epub 2020 Aug 20.

Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.

Background: Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO).

Method: Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan-Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status.

Results: We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45-0.47 for Japanese and 0.66 [95% CI 0.59-0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51-0.55] for Japanese and 0.53 [95% CI 0.52-0.74] for USJ).

Conclusions: In stage I-III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.
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http://dx.doi.org/10.1007/s10549-020-05869-yDOI Listing
November 2020

Annual report of the Japanese Breast Cancer Registry for 2017.

Breast Cancer 2020 Sep 24;27(5):803-809. Epub 2020 Jul 24.

Department of Breast Surgery, Kyorin University Hospital, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.

Background: The Japanese Breast Cancer Society Registry started in 1975; it was transferred to the registry platform of the National Clinical Database in 2012. We provide the annual data and an analysis of the Breast Cancer Registry for 2017.

Methods: Patients' characteristics and pathological data of the 95,203 registered Japanese breast cancer patients from 1,427 institutes in 2017 were obtained. Trends in age at diagnosis and pathological stage were determined during the most recent 6 years (2012-2017).

Results: The mean onset age was 60.2 years with bimodal peaks at 45-49 years and 65-69 years. A short-term trend of the most recent 6 years of data caused the second, older peak. At diagnosis, 32.4% of breast cancer patients were premenopausal. The distribution of stages revealed that the proportion of early stage breast cancer (stage 0-I) increased up to 60%. At the initial diagnosis, 2.2% of patients presented with metastatic disease. Sentinel node biopsy without axillary node dissection was performed without neoadjuvant chemotherapy (NAC) in 68.8%, and with NAC in 31.1%, of patients. For patients without NAC, lymph node metastasis was less than 3% if the tumor size was less than 1 cm. The proportion of node-negativity decreased to 79.5% when tumor size was 2.1-5 cm.

Conclusions: This analysis of the registry provides new information for effective treatment in clinical practice, cancer prevention, and the conduct of clinical trials. Further development of the registry and progress in collecting prognostic data will greatly enhance its scientific value.
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http://dx.doi.org/10.1007/s12282-020-01139-3DOI Listing
September 2020

A Case of Unknown Primary Cancer with a Tumor Formed in the Retroperitoneum: A Case Report.

Tokai J Exp Clin Med 2020 Jul 20;45(2):69-74. Epub 2020 Jul 20.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Background: Cancer of unknown primari (CUP) are said to account for 2% of all carcinomas. Here we report a rare case of CUP confined to the retroperitoneum.

Case Presentation: A 51-year-old man consulted a nearby physician for back pain. The malignant tumor could not be denied by MRI, and she was referred to our hospital. CT and MRI revealed uneven enhanced tumor structures protruding into the L2/3 disc. Part of the tumor was continuous with the left iliopsoas muscle. A CT-guided needle biopsy was performed. Histologically, the sheet-like proliferation of atypical cells was observed. Immunohistochemistry showed that atypical cells were positive for cytokeratin AE1&3, CK7, CD10, GATA3, glypican 3, Hep Par 1, carbonic anhydrase 9 (focal), and vimentin (focal) but negative for CK20, CD56, chromogranin A, synaptophysin, TTF1, HMB45, melan A, and PSA. The pathological diagnosis was poorly differentiated carcinoma. However, it was difficult to determine the primary site from the pathological findings. Positron emission tomography (PET) scan showed no distant metastases. He was diagnosed as poorly differentiated cancer localized to the lumbar spine from the retroperitoneum. Paclitaxel plus carboplatin (TC) was started. After completing 3 kr of TC, she was hospitalized urgently due to worsening lumbago. CT and MRI at admission showed an increase in the main lesion and exacerbation of bone invasion. Radiation therapy was given for curative purposes. Eventually, he died seven months after visiting our hospital and five months after starting TC therapy.

Conclusions: CUP has various disease states, and it is necessary to finish the examination immediately and shift to treatment. More effective treatment including immune checkpoint inhibitor for CUP is needed in the future.
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July 2020

Myxofibrosarcoma that Developed Rapidly in the Breast of an Elderly Man and Recurred Early after Surgery: A Case Report.

Tokai J Exp Clin Med 2020 Jul 20;45(2):53-57. Epub 2020 Jul 20.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Background: Myxofibrosarcoma is a rare disease occurring subcutaneously in the limbs. We report a case of a rapidly growing myxofibrosarcoma in the breast of an elderly man that recurred early after surgery.

Case Presentation: A 73-year-old man presented with a breast mass. Physical findings showed a large tumor in the right breast, and malignancy was suspected on ultrasonography. Computed tomography (CT) revealed tumor invasion into the pectoralis major and pectoralis minor muscles. Positron emission tomography/CT showed no abnormality in other organs. Needle biopsy results excluded breast cancer but did not provide a definitive diagnosis. However, the tumor grew rapidly before further results were available, so emergency mastectomy was performed. The final pathological diagnosis was high-grade myxofibrosarcoma. Postoperative radiotherapy was started because of remnant tumor. The wound became worsened and swollen, and needle biopsy 10 days after the start of therapy indicated recurrence. Radical resection and thoracoplasty were performed. Postoperative pathological specimens showed no residual tumor. Radical radiation therapy was resumed. The patient has shown no recurrence after an year.

Conclusions: It is important to consult a soft tissue oncologist for tumors in the breast and perform appropriate examination and treatment if soft tissue tumors cannot be ruled out.
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July 2020

Annual report of the Japanese Breast Cancer Society registry for 2016.

Breast Cancer 2020 Jul 11;27(4):511-518. Epub 2020 May 11.

Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8606, Japan.

The Japanese Breast Cancer Society (JBCS) registry began data collection in 1975, and it was integrated into National Clinical Database in 2012. As of 2016, the JBCS registry contains records of 656,896 breast cancer patients from more than 1400 hospitals throughout Japan. In the 2016 registration, the number of institutes involved was 1422, and the total number of patients was 95,870. We herein present the summary of the annual data of the JBCS registry collected in 2016. We analyzed the demographic and clinicopathologic characteristics of registered breast cancer patients from various angles. Especially, we examined the registrations on family history, menstruation, onset age, body mass index according to age, nodal status based on tumor size and subtype, and proportion based on ER, PgR, and HER2 status. This report based on the JBCS registry would support clinical management for breast cancer patients and clinical study in the near future.
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http://dx.doi.org/10.1007/s12282-020-01081-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297705PMC
July 2020

Taste alterations in patients with breast cancer following chemotherapy: a cohort study.

Breast Cancer 2020 Sep 16;27(5):954-962. Epub 2020 Apr 16.

Division of Dental Informatics and Radiology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Japan.

Background: Chemotherapy-induced taste and smell alterations in cancer patients are associated with multiple adverse effects, namely, malnutrition, weight loss, and a diminished quality of life. The aim of this prospective study was to identify the incidence of taste alterations following epirubicin and cyclophosphamide (EC) chemotherapy in patients with breast cancer without previous history of cancer or chemotherapy.

Methods: Forty-one patients undergoing EC chemotherapy for breast cancer at Tokai University Hospital were included. A subjective (questionnaire) and an objective (filter paper disk method) assessment for 5 basic tastes were administered on day 4 post-chemotherapy and immediately before the subsequent cycle of chemotherapy for each cycle, in addition to an olfactory evaluation and oral examination. The correlation between subjective and objective taste alterations and factors influencing these alterations were analyzed by statistical means.

Results: The mean incidence of subjective taste alteration on the 4th day after chemotherapy was 53%. In each of the 4 cycles, taste alterations decreased to about 9.0% immediately before the next cycle. A significant correlation between subjective and objective assessments was seen only for salty taste, suggesting important differences in subjective versus objective assessment outcomes. A multivariate analysis indicated that age and body surface area influenced taste alterations.

Conclusions: EC chemotherapy induced taste alterations in more than 50% of patients, which decreased to less than 10% immediately before the next chemotherapy cycle. A combination of objective and subjective assessments is essential to evaluate taste alterations induced by EC chemotherapy. These could be used in routine clinical practice.
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http://dx.doi.org/10.1007/s12282-020-01089-wDOI Listing
September 2020

Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial.

Oncologist 2020 02 8;25(2):e223-e230. Epub 2019 Oct 8.

Department of Dentistry and Oral and Maxillofacial Surgery, Tokai University School of Medicine, Tokyo, Japan.

Background: The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus-induced oral mucositis.

Materials And Methods: This randomized, multicenter, open-label, phase III study evaluated the efficacy of POC in preventing everolimus-induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8-week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2-sided type I error rate of 5% and 80% power to detect 25% risk reduction.

Results: Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; p = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; p = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction.

Conclusion: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. Clinical trial identification number: NCT02069093.

Implications For Practice: The Oral Care-BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus.
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http://dx.doi.org/10.1634/theoncologist.2019-0382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011665PMC
February 2020

[Two Cases of Pneumocystis Pneumonia during Adjuvant Chemotherapy for Breast Cancer].

Gan To Kagaku Ryoho 2019 Dec;46(12):1887-1890

Dept. of Endocrine and Breast Surgery, Tokai University School of Medicine.

In recent years, human immunodeficiency virus(HIV)-negative Pneumocystis pneumonia(PCP)onset has been occasionally seen in breast cancer. In particular, dose-dense epirubicin and cyclophosphamide(EC: ddEC)therapy, in which EC is administered every 2 weeks, has been generally used in clinical practice for early stage breast cancers. PCP may develop before and during postoperative chemotherapy. We report the cases of 2 patients who developed PCP during postoperative adjuvant chemotherapy. Case 1: A 62-year-old woman, who underwent postoperative EC therapy, developed PCP during the 4th EC cycle. During EC therapy, steroids(prednisolone[PSL])were administered at an average dose of 11.4mg/day, and the number of lymphocytes at the initiation of the 4th EC cycle was 516/mL. Case 2: After receiving 4 cycles of postoperative ddEC, a 27-year-old woman developed PCP after 1 cycle of docetaxel(DTX)administration. During ddEC therapy, PSL was administered at a dose of 17.14mg/day, and the number of lymphocytes at DTX administration was 311/mL. The onset of PCP is presumed to be related to the steroid dose administered and the number of lymphocytes. Therefore, determining effective indicators in patients at a high risk of PCP onset is important.
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December 2019

Rare Finding of Bilateral Pseudoangiomatous Stromal Hyperplasia of the Breast: A Case Report.

Tokai J Exp Clin Med 2019 Dec 20;44(4):73-79. Epub 2019 Dec 20.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

A 49-year-old woman, with a medical history of rheumatism, was admitted to our hospital with chief complaints of bilateral enlargement and redness of breasts. She underwent weekly breast examinations. Mammography findings were reported as category 3 for both breasts. Breast ultrasonography, magnetic resonance imaging, and chest contrast computed tomography revealed a massive tumor in the left BD region, however, there were no findings for suspected malignancy. Needle biopsy did not yield histologically malignant cells in both breasts. Mammary interstitium was edematous, and capillary-like slit structures were observed. The stroma stained with alcian blue and destained with hyaluronidase treatment. Since the stroma tested positive for vimentin, calponin, and CD34 and negative for CD31, the patient was diagnosed as (PASH). Because both breasts had similar diagnosis based on histopathologic findings, bilateral mastectomy was performed. Details about the origin of bilateral PASH are unknown but it may be related to the development of rheumatoid arthritis. Additionally, systemic autoimmune diseases like rheumatism may be the reason for repeated contraction and enlargement of PASH.
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December 2019

ASO Author Reflections: Impact of Radiotherapy for Breast Cancer is Changing in the Modern Era.

Ann Surg Oncol 2019 12 11;26(Suppl 3):780-781. Epub 2019 Oct 11.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan.

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http://dx.doi.org/10.1245/s10434-019-07941-4DOI Listing
December 2019

Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial.

Oncologist 2019 Oct 8. Epub 2019 Oct 8.

Department of Dentistry and Oral and Maxillofacial Surgery, Tokai University School of Medicine, Tokyo, Japan.

Background: The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus-induced oral mucositis.

Materials And Methods: This randomized, multicenter, open-label, phase III study evaluated the efficacy of POC in preventing everolimus-induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8-week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2-sided type I error rate of 5% and 80% power to detect 25% risk reduction.

Results: Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction.

Conclusion: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. : NCT02069093.

Implications For Practice: The Oral Care-BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus.
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http://dx.doi.org/10.1634/theoncologist.2019-0382DOI Listing
October 2019

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

A population-based recurrence risk management study of patients with pT1 node-negative HER2+ breast cancer: a National Clinical Database study.

Breast Cancer Res Treat 2019 Dec 26;178(3):647-656. Epub 2019 Aug 26.

Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8606, Japan.

Purpose: Recurrence risk management of patients with small (≤ 2 cm), node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains challenging. We studied the effects of adjuvant chemotherapy and/or trastuzumab and survival outcomes among these patients, using data from the population-based Japanese National Clinical Database (NCD).

Methods: We identified a cohort of 2736 breast cancer patients with HER2+ pT1N0 disease: 489 pT1a, 642 pT1b, and 1623 pT1c. The median observation period was 76 months, and the 5-year follow-up rate was 48.2%. The number of events was 212 for disease-free survival (DFS), 40 for breast cancer-specific survival, and 84 for overall survival (OS).

Results: There were 24.5% of pT1a, 51.9% of pT1b, and 63.3% of pT1c patients who were treated systemically after surgery. OS in pT1b (logrank test; p = 0.03) and DFS in pT1c (logrank test; p < 0.001) were significantly improved in treated compared with untreated patients. In the Cox proportional hazards model, treated patients had significantly longer OS than untreated patients in pT1b (hazard ratio (HR) 0.20) and pT1c (HR 0.54) groups. Estrogen receptor-negative tumors was also a significant predictor of survival in pT1c (HR 2.01) but not pT1ab patients. Furthermore, HR was greater in patients aged ≤ 35 years (3.18) compared to that in patients aged 50-69 years in the pT1b group.

Conclusions: NCD data revealed that systemic treatment improved OS in pT1bc but not in pT1a node-negative HER2+ breast cancer patients. Future observational research using big-sized data is expected to play an important role in optimizing treatment for patients with early-stage breast cancer.
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http://dx.doi.org/10.1007/s10549-019-05413-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817748PMC
December 2019

Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.

Medicine (Baltimore) 2019 Aug;98(32):e16770

Division of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-hirokoji, Kamigyo-ku, Kyoto.

Background: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD.

Patients And Methods: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals.

Trial Registration: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.
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http://dx.doi.org/10.1097/MD.0000000000016770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708609PMC
August 2019

Distinction of IgG4-related mastitis from breast cancer: a case report.

Surg Case Rep 2019 Jul 31;5(1):123. Epub 2019 Jul 31.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.

Background: Immunoglobulin (Ig) G4-related sclerosing disease is a pathological concept proposed in Japan during the early 2000s. This lesion-forming disease may exhibit characteristics of a systemic disease but often affects a single organ. To date, IgG4-related sclerosing disease in the mammary gland, or IgG4-related mastitis (IgG4-RM), has rarely been reported.

Case Presentation: Here, we describe the case of a female patient who was admitted to our hospital with the main complaints of left breast and axillary lymphadenopathy. A careful diagnostic imaging examination led to an initial suspicion of breast cancer. However, a needle biopsy led to a diagnosis of IgG4-RM. Subsequently, the patient was successfully treated with predonin.

Conclusions: The treatment requirements for breast cancer and IgG4-RM differ considerably. This is a good example of a case wherein unnecessary surgical treatment, which is indicated for breast cancer, was avoided by needle biopsy. Accordingly, the patient was appropriately treated with steroids following a correct diagnosis.
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http://dx.doi.org/10.1186/s40792-019-0681-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669223PMC
July 2019

Taxane-based combinations as adjuvant chemotherapy for node-positive ER-positive breast cancer based on 2004-2009 data from the Breast Cancer Registry of the Japanese Breast Cancer Society.

Breast Cancer 2020 Jan 20;27(1):85-91. Epub 2019 Jul 20.

Division of Breast Surgical Oncology, Department of Surgery, Showa University, Tokyo, Japan.

Background: Adding taxane to an anthracycline-based regimen improves survival in node-positive breast cancer patients, as shown by clinical trials and meta-analyses. However, no studies have analyzed the number of metastatic lymph nodes in patients with estrogen receptor (ER)-positive cancer. This study investigated whether adding a taxane to an anthracycline-based regimen improved prognosis in node-positive, ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients in a real-world setting.

Methods: Using Japanese Breast Cancer Society registry data, we compared disease-free survival (DFS) of patients with ER-positive, HER2-negative breast cancer, excluding those receiving neoadjuvant chemotherapy, between those who received an anthracycline-based regimen followed by a taxane-based regimen (A + T) and those who received only an anthracycline-based regimen (A w/o T), stratified by lymph node status. A Cox proportional hazards model was used to evaluate DFS in both groups.

Results: There were 4566 eligible patients with ER-positive, HER2-negative breast cancer. During the median follow-up period of 60 months, there were 481 recurrences and 149 deaths. There was no significant difference in DFS between the A + T and A w/o T groups among patients with 1-3 positive nodes, while there was a significant difference among patients with ≥ 4 positive nodes.

Conclusions: In patients with ER-positive, HER2-negative breast cancer, adding taxane to an anthracycline regimen did not improve DFS in patients with metastasis in 1-3 lymph nodes. We considered that the group without the addition of taxane might be present in patients with ER-positive, HER2-negative lymph node metastases.
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http://dx.doi.org/10.1007/s12282-019-00997-wDOI Listing
January 2020

Predictive and prognostic value of stromal tumour-infiltrating lymphocytes before and after neoadjuvant therapy in triple negative and HER2-positive breast cancer.

Eur J Cancer 2019 09 11;118:41-48. Epub 2019 Jul 11.

Department of Breast Surgical Oncology, St. Luke's International Hospital, Tokyo, Japan. Electronic address:

Aim: Lymphocyte predominant breast cancer (BC) is associated with higher pathological complete response (pCR) rate after neoadjuvant therapy (NAT) and favorable outcome in triple negative breast cancer (TNBC) and HER2+ BC. The predictive and prognostic impact of stromal tumour-infiltrating lymphocytes (TILs) after NAT and the change of TILs before (pre-) and after (post-) NAT are not well studied. We aimed to assess the predictive and prognostic value of pre- and post-NAT TILs, as well as their pharmacodynamics modulation and their change for TNBC and HER2+ BC.

Materials And Methods: Two-hundred and nine consecutive patients (n = 80 TNBC, n = 129 HER2+ BC) who received NAT between 2001 and 2009 in a single institution were included. We evaluated the association between pre-NAT TILs and pCR, and the association between pre- and post-NAT TILs, as well as their immunodynamics change with relapse-free survival (RFS) for patients with residual disease (RD).

Results: Low pre-NAT TILs compared to int/high were significantly associated with lower pCR rate (TNBC: 4.0% vs 43.6%; HER2+ BC: 26.0% vs 51.9%). The median follow-up period was 98 months. In TNBC with RD, low pre-NAT TILs showed significant association with shorter RFS (HR = 3.844 [1.190-12.421], p = 0.024) in multivariate analysis. Low post-NAT TILs showed borderline significant association with shorter RFS (HR = 2.836 [0.951-8.457], p = 0.061). The change in TILs was not associated with RFS. In HER2+ BC, low pre-NAT TILs were not associated with RFS.

Conclusion: In TN and HER2+ BCs, low pre-NAT TILs tumours had a low likelihood of achieving pCR. In TNBC with RD, both low pre- and post-NAT TILs were associated with shorter RFS. These results suggest that TILs information should be taken into account when additional therapies may be given in the post-neoadjuvant setting.
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http://dx.doi.org/10.1016/j.ejca.2019.05.014DOI Listing
September 2019

Anthracycline could be essential for triple-negative breast cancer: A randomised phase II study by the Kanagawa Breast Oncology Group (KBOG) 1101.

Breast 2019 Oct 15;47:1-9. Epub 2019 Jun 15.

Department of Translational Oncology, St. Marianna University School of Medicine, Kawasaki, Japan. Electronic address:

Background: It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment.

Methods: The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated.

Results: Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively).

Conclusion: TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC.
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http://dx.doi.org/10.1016/j.breast.2019.06.003DOI Listing
October 2019

Role of Postmastectomy Radiotherapy After Neoadjuvant Chemotherapy in Breast Cancer Patients: A Study from the Japanese Breast Cancer Registry.

Ann Surg Oncol 2019 Aug 17;26(8):2475-2485. Epub 2019 May 17.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan.

Background: The role of postmastectomy radiotherapy (PMRT) in breast cancer patients receiving neoadjuvant chemotherapy (NAC) is controversial. We aimed to evaluate the effectiveness of radiotherapy in patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry.

Methods: We enrolled patients who received NAC and mastectomy for cT1-4 cN0-2 M0 breast cancer. We evaluated the association between radiotherapy and outcomes, locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) based on ypN status by multivariable analysis.

Results: Of the 145,530 patients, we identified 3226 who met the inclusion criteria. Among ypN1 patients, no differences were found in LRR, DDFS, or OS between groups with and without radiotherapy (p = 0.72, p = 0.29, and p = 0.36, respectively). Radiotherapy was associated with improved LRR-free survival (p < 0.001), DDFS (p = 0.01), and OS (p < 0.001) in patients with ypN2-3. Multivariable analysis demonstrated that use of radiotherapy was independently associated with improved LRR [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.45-0.82, p = 0.001] and OS [HR 0.69, 95% CI 0.53-0.89, p = 0.004) for ypN2-3 patients only. The association between radiotherapy and OS was not statistically significant among ypN0 (p = 0.22) and ypN1 patients (p = 0.51).

Conclusions: The results from this nationwide database study did not show significant associations between PMRT and improved survival among ypN0 and ypN1 patients. Radiotherapy may be beneficial only for ypN2-3 breast cancer patients who receive NAC and mastectomy in the modern era.
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http://dx.doi.org/10.1245/s10434-019-07453-1DOI Listing
August 2019

Impact of Subtype on Survival of Young Patients With Stage IV Breast Cancer.

Clin Breast Cancer 2019 06 29;19(3):200-207.e1. Epub 2019 Jan 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Background: Although younger age is a negative prognostic factor for patients with early stage breast cancer, data regarding the outcomes of young patients with stage IV disease are limited. We evaluated differences in overall survival (OS) according to age and disease subtype among patients with stage IV breast cancer.

Patients And Methods: Using Surveillance, Epidemiology, and End Results (SEER) data, we identified 6,302 patients aged < 60 years with de novo stage IV breast cancer between 2010 and 2014. We examined age-specific OS among hormone receptor (HR)-positive (HR)/human epidermal growth factor receptor 2 (HER2)-negative (HER2), HR/HER2-positive (HER2), HR-negative (HR)/HER2, and triple-negative cases using log-rank tests and Cox proportional hazards models, adjusting for relevant clinical and demographic variables.

Results: Compared with patients aged 40 to 59 years, patients aged < 40 years (n = 944; 15%) had a higher proportion of HER2 cancers and a lower proportion of HR/HER2 disease (P < .001), but a similar proportion of triple-negative disease. Patients aged < 40 years also experienced significantly longer survival, with a median OS of 45 months (vs. 33 months). Further, after stratification by subtype, patients aged < 40 years experienced significantly longer survival, except in the setting of triple-negative disease. These survival differences persisted in adjusted analyses.

Conclusions: Compared with those aged 40 to 59 years, patients with de novo metastatic breast cancer aged < 40 years experienced significantly longer survival, except in the setting of triple-negative disease. Distinct treatment-related or biological factors may exist between earlier stage and metastatic breast cancers; further examination of the potential reasons for our findings are warranted.
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http://dx.doi.org/10.1016/j.clbc.2019.01.005DOI Listing
June 2019

Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results.

Breast Cancer 2019 Jan 27;26(1):106-112. Epub 2018 Jul 27.

Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Background: Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months.

Methods: This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months.

Results: At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur.

Conclusions: Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.
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http://dx.doi.org/10.1007/s12282-018-0896-yDOI Listing
January 2019

A randomized, open-label, Phase III trial of pertuzumab retreatment in HER2-positive locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab and chemotherapy: the Japan Breast Cancer Research Group-M05 PRECIOUS study.

Jpn J Clin Oncol 2018 Sep;48(9):855-859

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

The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.
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http://dx.doi.org/10.1093/jjco/hyy097DOI Listing
September 2018

Comparison of Ki-67 labeling index measurements using digital image analysis and scoring by pathologists.

Breast Cancer 2018 Nov 29;25(6):768-777. Epub 2018 Jun 29.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa, Japan.

Background: Routine analysis of Ki-67 is not widely recommended for clinical decision-making because of poor reproducibility. Furthermore, counting numerous cells can be laborious for pathologists. Digital image analysis for immunohistochemical analysis was recently developed; however, the clinical efficacy of the Ki-67 index obtained using image analysis is unknown.

Methods: We retrospectively identified female patients with breast cancer with immunohistochemical Ki-67 and survival data using the pathology database at the Tokai University, Japan. Ki-67 expression was scored by three pathologists. Slides were scanned and converted to virtual slides; Ki-67-positive cells were counted using image analysis. Ki-67 indices obtained by the pathologist's scoring and image analysis were evaluated by 2 × 2 analysis. Relationships between Ki-67 index and survival outcomes were evaluated using the Kaplan-Meier method and compared using the log-rank test.

Results: Based on the 2 × 2 analysis, Ki-67 index obtained using image analysis was moderately correlated with the pathologist's scoring for all patients (κ 0.41; sensitivity, 0.573; specificity, 0.878). Poorer relapse-free survival was associated with high Ki-67 index than with low Ki-67 index for estrogen receptor-positive, human epidermal growth factor receptor 2-negative, and stage I or II patients scored by pathologists (p < 0.001) and obtained using image analysis (p = 0.031).

Conclusions: The Ki-67 indices obtained using image analysis were moderately correlated with those scored by pathologists. Digital image analysis can be effective for measuring Ki-67 values, because they are associated with relapse-free survival in estrogen receptor-positive, human epidermal growth factor receptor 2-negative, and patients at stage I or II.
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http://dx.doi.org/10.1007/s12282-018-0885-1DOI Listing
November 2018
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