Publications by authors named "Takayuki Iwamoto"

88 Publications

Simultaneous hot and cold thyroid nodules: Which is malignant?

Clin Case Rep 2021 Mar 26;9(3):1810-1811. Epub 2021 Jan 26.

Department of General Medicine Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan.

Physicians should be aware of the risk of malignancy in patients with toxic multinodular goiter. Radionuclide scan cannot be used to predict the malignant potential of thyroid nodules. A comprehensive evaluation of imaging studies is needed.
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http://dx.doi.org/10.1002/ccr3.3843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981636PMC
March 2021

A Correlation Analysis Between Metabolism-related Genes and Treatment Response to S-1 as First-line Chemotherapy for Metastatic Breast Cancer: The SELECT BC-EURECA Study.

Clin Breast Cancer 2021 Feb 1. Epub 2021 Feb 1.

National Cancer Center Hospital East, Kashiwa, Japan.

Introduction: The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial.   PATIENTS AND METHODS: In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values.   RESULTS: Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure.

Conclusion: This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.
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http://dx.doi.org/10.1016/j.clbc.2021.01.018DOI Listing
February 2021

A Multicenter Study of Docetaxel at a Dose of 100 mg/m in Japanese Patients with Advanced or Recurrent Breast Cancer.

Intern Med 2021 Apr 16;60(8):1183-1190. Epub 2020 Nov 16.

Departments of Breast and Endocrine Surgery, Okayama University Hospital, Japan.

Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m in Japanese patients with advanced or recurrent breast cancer. Methods Japanese patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 μg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.
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http://dx.doi.org/10.2169/internalmedicine.5089-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112988PMC
April 2021

Relationships of physical and breast cancer phenotypes with three single-nucleotide polymorphisms (rs2046210, rs3757318, and rs3803662) associated with breast cancer risk in Japanese women.

Breast Cancer 2021 Mar 13;28(2):478-487. Epub 2020 Nov 13.

Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kitaku, Okayama, 700-8558, Japan.

Background: Recent genome-wide association studies have shown that many single-nucleotide polymorphisms (SNPs) are associated with breast cancer risk. However, it is often unclear how these SNPs are related to breast cancer. Analysis of associations between SNPs and phenotypes may be important for determining mechanisms of action, including carcinogenesis.

Methods: In previous case-control studies, we found three SNPs (rs2046210, rs3757318, and rs3573318) associated with breast cancer risk in Japanese women. Among these SNPs, two (rs2046210 and rs3757318) are located at 6q25.1, in proximity to the estrogen receptor 1 gene (ESR1). Using data from these studies, we examined associations between factors related to breast cancer risk, such as height, weight, and breast density, and the three SNPs in cases and controls. We also investigated whether the SNPs correlated with breast cancer features, such as estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type-2 (HER2) status, and clinical stage.

Results: There was a significant difference in mean height between risk and non-risk allele carriers for rs2046210 (156.0 ± 5.8 vs. 154.3 ± 5.5 cm, p = 0.002), and rs3757318 (155.8 ± 5.7 vs. 154.7 ± 5.6 cm, p = 0.035) in cases, but no significant associations between height and these SNPs in controls. There was also a significant difference in breast density between risk and non-risk allele carriers for rs2046210 (p = 0.040) and rs3757318 (p = 0.044) in cases. rs2046210 and rs3757318 risk allele carriers tended to have higher breast density in all subjects and in controls. In cases, rs3757318 risk allele carriers were also significantly more likely to be ER-negative compared to non-risk allele carriers (ER-positive rate: 77% vs. 84%, p = 0.036).

Conclusions: SNPs rs2046210 and rs3757318, which are associated with breast cancer risk in Japanese women, were significantly associated with height and high breast density, and this association was particularly strong in those with breast cancer. These findings suggest that SNPs in the ESR1 gene region affect phenotypes such as height and breast density.
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http://dx.doi.org/10.1007/s12282-020-01185-xDOI Listing
March 2021

Evaluation of Prognosis of Juvenile Differentiated Thyroid Carcinoma.

Acta Med Okayama 2020 Oct;74(5):401-406

Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama 700-8558, Japan.

Differentiated thyroid carcinoma (DTC) in juvenile patients is often an extensive and aggressive disease with a high frequency of recurrence. However, the prognosis is excellent, with a low mortality rate even when advanced disease is present, although prognostic factors and treatment strategy remain uncertain. Between April 2004 and March 2017, 33 juvenile patients (< 30 years old) were diagnosed with DTC and treated at our institution. We retrospectively investigated prognosis and factors including sex, reason for discovery, treatment, pathological factors and treatment progress to clarify the risk factors. All patients underwent curative surgical treatment. Pathologically, lymph node metastasis was identified in 25 patients (75%). Thirteen patients (39%) had bilateral cervical metastasis. In addition, 9 (27%) had more than 10 metastatic lymph nodes. The 2 patients with more than 20 metastatic lymph nodes were treated with radioactive iodine (RAI). Five patients (15%) had local recurrences and received surgery. There have been no further recurrences or deaths. However, no factors were determined to significantly predict the recurrence of juvenile DTC. Local recurrent disease was treated with surgery and/or RAI until remission, and survival was excellent in juvenile DTC.
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http://dx.doi.org/10.18926/AMO/60799DOI Listing
October 2020

Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments.

Breast Cancer Res Treat 2021 Jan 9;185(2):307-316. Epub 2020 Oct 9.

Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Purpose: Epidemiological studies have suggested that intake of soy isoflavones is associated with a reduced risk of development of breast cancer and an improved prognosis in patients with breast cancer. In addition, basic research has demonstrated the antitumor effects of these compounds on breast cancer cell lines. However, the detailed effects of the intake of equol, which is one of the metabolites of the soy isoflavones, are yet to be clarified on the risk of development and recurrence of breast cancer and its interactions with drugs used for treating breast cancer. This study aimed to determine the antitumor effects of equol and investigate the impact of adding equol to therapeutic agents for breast cancer using breast cancer cell lines.

Methods: We examined the antitumor effect of equol on breast cancer cell lines using MTS assay. We also studied the combined effect of equol and the existing hormonal or chemotherapeutic agents using combination index. We evaluated the expressions of the related proteins by Western blot analysis and correlated the findings with the antitumor effect.

Results: Equol showed bi-phasic protumor and antitumor effects; at a low concentration, it promoted the tumor growth in hormone receptor-positive cell lines, whereas antitumor effects were generally observed when an excessive amount of dose unexpected in the blood and the tissue was administered. When used with tamoxifen, equol might have some antagonistic effect, although it depends on equol concentration and the type of cancer cells.

Conclusions: We confirmed that equol has dual action, specifically a tumor growth-promoting effect and an antitumor effect. Although the results suggested that equol might exert an antagonistic effect against tamoxifen depending on the concentration, equol did not exert an antagonistic effect on other therapeutic agents.
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http://dx.doi.org/10.1007/s10549-020-05957-zDOI Listing
January 2021

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

Influences of preoperative metformin on immunological factors in early breast cancer.

Cancer Chemother Pharmacol 2020 07 12;86(1):55-63. Epub 2020 Jun 12.

Department of General Thoracic Surgery and Breast and Endocrine Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 7008558, Japan.

Purpose: Metformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer.

Method: We evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen.

Result: There was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08).

Conclusion: Preoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.
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http://dx.doi.org/10.1007/s00280-020-04092-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338817PMC
July 2020

NSAS-BC02 substudy of chemotherapy-induced amenorrhea (CIA) in premenopausal patients who received either taxane alone or doxorubicin(A) cyclophosphamide(C) followed by taxane as postoperative chemotherapy.

Breast Cancer Res Treat 2020 Jul 28;182(2):325-332. Epub 2020 May 28.

Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan.

Background: Chemotherapy-induced amenorrhea (CIA) is one of the critical side effects from the chemotherapy in premenopausal patients with breast cancer. The goals of our study are the following: (1) to investigate the factors affecting the incidence of CIA; and (2) to evaluate the prognostic role of CIA in premenopausal patients with breast cancer.

Methods: We conducted a post hoc retrospective substudy to examine the incidence of the CIA and the relationship between CIA and prognosis in NSAS-BC02 that compared taxane alone to Doxorubicin(A) Cyclophosphamide(C) followed by taxane in postoperative patients with node-positive breast cancer RESULTS: Of 395 premenopausal women, 287 (72.7%) had CIA due to protocol treatment. Regarding type of protocol regimen, proportion of CIA was 76.9% in AC Paclitaxel(P), 75.2% in AC Docetaxel(D), 62.8% in PTX, and 75.2% in DTX. Predictive factors of CIA were age increase by 5 years (OR 1.50), ER positivity (OR 2.08), and HER2 3 + ( OR 0.40) according to logistic regression analysis. According to the log rank test and the Cox proportional hazards model, CIA group had significantly better disease-free survival than non-CIA group (P < .0001). However, according to time-dependent Cox model that was used to reduce guarantee-time bias, CIA was not a statistically significant prognostic factor in both ER-positive and ER-negative patients.

Conclusion: Treatment with taxane alone caused high frequency of CIA in premenopausal women with breast cancer. CIA did not turn out to be an independent prognostic factor, taking guarantee-time bias into consideration. Further clinical studies are needed to validate these findings.
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http://dx.doi.org/10.1007/s10549-020-05692-5DOI Listing
July 2020

The efficacy of sequential second-line endocrine therapies (ETs) in postmenopausal estrogen receptor-positive and HER2-negative metastatic breast cancer patients with lower sensitivity to initial ETs.

Breast Cancer 2020 Sep 11;27(5):973-981. Epub 2020 May 11.

Department of Breast and Endocrine Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Purpose: Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET.

Methods: This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24 weeks.

Results: Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6-57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6-65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0-78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1-65.9, p = 0.018) groups. The median progression-free survival was 7.1 months (95% CI: 5.6-10.6).

Conclusion: Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.
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http://dx.doi.org/10.1007/s12282-020-01095-yDOI Listing
September 2020

Biomarkers of neoadjuvant/adjuvant chemotherapy for breast cancer.

Chin Clin Oncol 2020 06 13;9(3):27. Epub 2020 Mar 13.

Department of Breast Oncology, Miyake Ofuku Clinic, Okayama, Japan.

The improvement of tumor biomarkers prepared for clinical use is a long process. A good biomarker should predict not only prognosis but also the response to therapies. In this review, we describe the biomarkers of neoadjuvant/adjuvant chemotherapy for breast cancer, considering different breast cancer subtypes. In hormone receptor (HR)-positive/human epidermal growth factor 2 (HER2)-negative breast cancers, various genomic markers highly associated with proliferation have been tested. Among them, only two genomic signatures, the 21-gene recurrence score and 70-gene signature, have been reported in prospective randomized clinical trials and met the primary endpoint. However, these genomic markers did not suffice in HER2-positive and triple-negative (TN) breast cancers, which present only classical clinical and pathological information (tumor size, nodal or distant metastatic status) for decision making in the adjuvant setting in daily clinic. Recently, patients with residual invasive cancer after neoadjuvant chemotherapy are at a high-risk of recurrence for metastasis, which, in turn, make these patients best applicants for clinical trials. Two clinical trials have shown improved outcomes with post-operative capecitabine and ado-trastuzumab emtansine treatment in patients with either TN or HER2-positive breast cancer, respectively, who had residual disease after neoadjuvant chemotherapy. Furthermore, tumor-infiltrating lymphocytes (TILs) have been reported to have a predictive value for prognosis and response to chemotherapy from the retrospective analyses. So far, TILs have to not be used to either withhold or prescribe chemotherapy based on the absence of standardized evaluation guidelines and confirmed information. To overcome the low reproducibility of evaluations of TILs, gene signatures or digital image analysis and machine learning algorithms with artificial intelligence may be useful for standardization of assessment for TILs in the future.
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http://dx.doi.org/10.21037/cco.2020.01.06DOI Listing
June 2020

Recurring radiation-induced angiosarcoma of the breast that was treated with paclitaxel chemotherapy: a case report.

Surg Case Rep 2020 Jan 16;6(1):25. Epub 2020 Jan 16.

Department of Breast and Endocrine surgery in Okayama University Japan Hospital, 2-5-1 Shikatacho Kitaku, Okayama-shi, Okayama-ken, 700-8558, Japan.

Background: Angiosarcoma of the breast is very rare and can be divided into primary and secondary angiosarcoma. Radiation-induced angiosarcoma (RIAS) is classified as secondary angiosarcoma. Diagnosis of RIAS is difficult due to its rarity, and the interpretation of pathological imaging is complicated. In the National Comprehensive Care Network (NCCN) guidelines, the first choice of treatment is surgery with negative margins. Adjuvant radiotherapy (RT) for close soft tissue margins should be considered. Preoperative or adjuvant chemotherapy of nonmetastatic disease is not recommended for angiosarcoma. We report a case of RIAS, which was impossible to diagnose with core needle biopsy (CNB) but was diagnosed by excisional biopsy. The patient was then administered adjuvant chemotherapy using conjugated paclitaxel (PTX).

Case Presentation: A 62-year-old woman noticed a tumor in her right breast. She had a history of right breast cancer and had undergone breast-conserving surgery, RT, and tamoxifen therapy 8 years previously. CNB, which was performed twice, was inconclusive. The tumor was surgically excised and pathological analysis yielded a diagnosis of angiosarcoma. She then underwent a right mastectomy. One month after she underwent right mastectomy, a nodule reappeared on the skin of her right breast, and excisional biopsy revealed recurrence of angiosarcoma. A few weeks later another nodule reappeared near the post-operative scar and excisional biopsy revealed recurrence of angiosarcoma. We assumed that surgical therapy was insufficient because the patient experienced relapse of angiosarcoma after complete mastectomy. After the second recurrence, we treated her with systemic chemotherapy using PTX. There was no evidence of recurrence 8 months after chemotherapy.

Conclusion: Although angiosarcoma is difficult to diagnose, many patients have a poor prognosis. Therefore, prompt treatment intervention is desired. Moreover, there is little evidence regarding adjuvant therapy of angiosarcoma since it is a rare disease. We consider that adjuvant therapy helped to effectively prevent recurrence in the patient after complete excision.
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http://dx.doi.org/10.1186/s40792-020-0790-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965539PMC
January 2020

Influence of breast density on breast cancer risk: a case control study in Japanese women.

Breast Cancer 2020 Mar 24;27(2):277-283. Epub 2019 Oct 24.

Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama, 700-8558, Japan.

Background: Mammography is the standard examination for breast cancer screening of woman aged ≥ 40 years. High breast density on mammography indicates that mammary gland parenchyma occupy a high percentage of the breast. The objective of this study was to investigate factors associated with breast density and the risk of high breast density for breast cancer.

Methods: A multicenter case-control study was performed in 530 patients and 1043 controls. Breast density was classified as C1-C4 using the Breast Imaging Reporting and Data System (BI-RADS). Clinical factors were obtained from questionnaires or medical records, and the influence of each factor (breast density, menopausal status, body mass index (BMI), parity, presence or absence of breastfeeding history, age at menarche, age at first birth, and familial history of breast cancer) on breast cancer risk in all patients was calculated as an age-adjusted odds ratio (OR). Multivariate logistic regression analyses were then performed in all patients and in pre- and postmenopausal and BMI-stratified groups using factors with a significant age-adjusted OR as adjustment factors.

Results: Age-adjusted ORs for breast cancer were significant for breast density, BMI, parity, and breast feeding, but not for age at menarche, age at first birth, or family history of breast cancer. In multivariate analysis, there was a significant correlation between breast density and breast cancer in postmenopausal women (OR for C1 vs. C2 1.90 [95% CI 1.34-2.70]; C1 vs. C4 2.85 [95% CI 1.10-7.16]). This correlation was also significant in patients in the third BMI quartile (22.3-24.5 kg/m) (OR for C1 vs. C4 8.76 [95% CI 2.38-42.47]); and fourth BMI quartile (>24.5 kg/m) (OR for C1 vs. C2 1.92 [95% CI 1.17-3.15]; C1 vs. C4 11.89 [95% CI 1.56-245.17]).

Conclusion: Breast density on mammography is a risk factor for breast cancer after adjustment for other risk factors. This risk is particularly high in postmenopausal women and those with a high BMI.
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http://dx.doi.org/10.1007/s12282-019-01018-6DOI Listing
March 2020

Evaluation of Therapeutic Target Gene Expression Based on Residual Cancer Burden Classification After Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer.

Clin Breast Cancer 2020 04 9;20(2):117-124.e4. Epub 2019 Sep 9.

Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Introduction: Patients with residual disease usually have a poor prognosis after neoadjuvant chemotherapy for breast cancer. The aim of this study was to explore therapeutic targets and potential additional adjuvant treatments for patients with residual disease after standard neoadjuvant chemotherapy.

Patients And Methods: We retrieved publicly available complementary DNA microarray data from 399 human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer samples from patients who underwent standard neoadjuvant chemotherapy. We analyzed the messenger RNA (mRNA) expression levels of key breast cancer markers and therapeutic target genes according to residual cancer burden (RCB) classification: RCB-0/I, RCB-II, and RCB-III.

Results: Among hormone receptor-positive samples, there were more luminal A tumors by PAM50 (Prediction Analysis of Microarray 50 [Prosigna], aka Prosigna Breast Cancer Prognostic Gene Signature Assay) in RCB-III than in RCB-0/I and RCB-II (P < .01). The mRNA expressions of ESR1 and PGR were significantly higher, and that of MKI67 was lower in RCB-II and RCB-III than in RCB-0/I. The mRNA expression of cyclin D1 was up-regulated in RCB-III and that of CDKN2A was down-regulated in RCB-III (P = .027 and < .01). Among triple-negative (TN) samples, RCB-III had higher clinical stage and more lymph node-positive samples than RCB-0/1 and RCB-II (P < .01). In both subtypes, VEGF-C expression was significantly higher in RCB-III than in RCB-0/I and RCB-II.

Conclusion: In hormone receptor-positive breast cancer, biological features such as luminal A were associated with RCB; this trend was not observed in TN breast cancer. Further, some targeted therapies should be tested as new strategies after standard neoadjuvant chemotherapy in future clinical trials.
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http://dx.doi.org/10.1016/j.clbc.2019.07.001DOI Listing
April 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

[Endoscopic treatment for gastric carcinoid tumor in a patient with type A gastritis complicated with autoimmune polyendocrine syndrome: a case report].

Nihon Shokakibyo Gakkai Zasshi 2019 ;116(8):654-659

Department of Gastroenterology, Kansai Rosai Hospital.

A 42-year-old female developed type 1 diabetes mellitus at the age of 16 years and received insulin therapy. Esophagogastroduodenoscopy revealed an atrophic change localized in the gastric body and a small, protruding gastric lesion. Biopsy revealed that this lesion was gastric neuroendocrine tumor. Hence, the patient underwent en bloc resection by endoscopic submucosal resection with a ligation device. As the patient presented both autoimmune gastritis and type 1 diabetes mellitus, she was diagnosed with type 4 autoimmune polyendocrine syndrome. We report this case considering that only few cases of gastric neuroendocrine tumor with autoimmune gastritis (type A gastritis) complicated with autoimmune polyendocrine syndrome have been reported till date.
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http://dx.doi.org/10.11405/nisshoshi.116.654DOI Listing
September 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

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

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan.

Acta Med Okayama 2018 Aug;72(4):369-374

Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama 700-8558,

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.
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http://dx.doi.org/10.18926/AMO/56172DOI Listing
August 2018

Advance care planning in metastatic breast cancer.

Chin Clin Oncol 2018 Jun;7(3):33

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Kita-Ku, Okayama, Japan.

End-of-life care requires improvement. For a good death, patients consider five factors important: managing physical symptoms, avoiding a useless prolongation of dying, having good self-esteem, relieving burdens on the family, and deepening ties with loved ones. Four out of those 5 are accomplished by the implementation of advance care planning (ACP). ACP is not simply a formal writing of a patient's preferences about end-of-life treatment, but it is a process of communication between a patient, their family and care providers. There are few studies on ACP for patients with metastatic breast cancer. However, data on seriously ill patients support ACP's favorable effects on end of life care outcomes for not only patients, but family members and care providers as well. The observed keys to success for ACP were trained facilitators, education of the medical staff, inclusion of family and surrogate members, and a system to support ACP. ACP should be regarded as a standard of care to improve the quality of life of patients with metastatic breast cancer.
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http://dx.doi.org/10.21037/cco.2018.06.03DOI Listing
June 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

CSF-1/CSF-1R axis is associated with epithelial/mesenchymal hybrid phenotype in epithelial-like inflammatory breast cancer.

Sci Rep 2018 06 21;8(1):9427. Epub 2018 Jun 21.

Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Inflammatory breast cancer (IBC) is a rare subtype of breast cancer, accounting for 8-10% of breast cancer-associated deaths in the US. Clinical hallmarks of IBC include tumor emboli in lymphatic vessels and E-cadherin overexpression, which supports a type of metastasis referred to as cell cluster-based metastasis, prevalent in IBC. In contrast, we previously reported epithelial-to-mesenchymal transition (EMT)-based progression of IBC, utilizing in vivo xenografts and in vitro Matrigel culture models. To address these two contradictory concepts of IBC metastasis, we used Matrigel culture to induce EMT in a panel of IBC cells. Results revealed Matrigel culture induced vimentin expression in SUM149 and SUM190 IBC cells at the transcriptional and protein levels while maintaining the expression of E-cadherin, a phenomenon referred to as partial EMT. Transcriptional profiling revealed that expression of colony-stimulating factor 1 (CSF-1) was induced in Matrigel culture. When the receptor tyrosine kinase of CSF-1 (CSF-1R) was inhibited by CSF-1R inhibitor BLZ945, the partial EMT was reversed in a dose-dependent manner, indicating that the CSF-1/CSF-1R axis plays a key role in controlling partial EMT. This observation may help reconcile the two contradictory theories of IBC metastasis, EMT vs cell cluster-based metastasis.
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http://dx.doi.org/10.1038/s41598-018-27409-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013474PMC
June 2018

Current Multidisciplinary Approach to Fertility Preservation for Breast Cancer Patients.

Acta Med Okayama 2018 Apr;72(2):137-142

Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama 700-8558, Japan.

Adverse effects on fertility are a significant problem for premenopausal breast cancer patients. Since April 2009, we have been referring young patients for fertility counseling provided by a multidisciplinary team. Here we evaluated the efficacy and safety of our current fertility preservation approach. We retrospectively analyzed the cases of 277 patients < 45 years old at diagnosis, which was made between 2009 and 2016. Seventy-two (26%) patients received fertility counseling. Seventeen (6%) of the 277 patients decided to preserve their fertility before starting adjuvant systemic therapy. Six (35%) patients underwent oocyte cryopreservation, and 11 (65%) married patients opted for embryo cryopreservation. There were no pregnancies among the patients undergoing oocyte cryopreservation, whereas 3 (27%) of the patients who opted for embryo cryopreservation became pregnant. Two (12%) patients stopped endocrine therapy after 2 years in an effort to become pregnant, but their breast cancers recurred. Though the problem of fertility loss for breast cancer patients is important and we should assess the infertility risk for all patients, we should also consider the prognosis. In June 2016, we launched a prospective multicenter cohort study to evaluate the efficacy and safety of fertility preservation in greater detail.
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http://dx.doi.org/10.18926/AMO/55854DOI Listing
April 2018

Non-Hypervascular Hypointense Hepatic Nodules during the Hepatobiliary Phase of Gadolinium-Ethoxybenzyl-Diethylenetriamine Pentaacetic Acid-Enhanced MRI as a Risk Factor of Intrahepatic Distant Recurrence after Radiofrequency Ablation of Hepatocellular Carcinoma.

Dig Dis 2017 17;35(6):574-582. Epub 2017 Oct 17.

Department of Gastroenterology, Ikeda Municipal Hospital, Ikeda, Japan.

Background: Non-hypervascular hypointense hepatic nodules during the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI have been reported to be associated with intrahepatic distant recurrence (IDR) after hepatectomy or radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). IDR is categorized into hypervascular transformation of non-hypervascular hypointense hepatic nodules and new intrahepatic recurrence. The aim of this study was to evaluate the relationship between non-hypervascular hypointense hepatic nodules on Gd-EOB-DTPA-enhanced MRI and IDR after RFA, focusing on new intrahepatic recurrence.

Methods: Ninety-one consecutive patients with 115 HCCs undergoing pretreatment Gd-EOB-DTPA-enhanced MRI and RFA for treatment of HCC were enrolled.

Results: Of the 91 patients who underwent RFA for HCC, 24 had non-hypervascular hypointense hepatic nodules on pretreatment Gd-EOB-DTPA-enhanced MRI. Recurrences were observed in 15 and 19 patients with and without non-hypervascular hypointense hepatic nodules, respectively. Of the 15 recurrences in patients with non-hypervascular hypointense hepatic nodules, 10 patients had new intrahepatic recurrences. The cumulative incidence of new intrahepatic recurrence was significantly higher in patients with non-hypervascular hypointense hepatic nodules than in those without non-hypervascular hypointense hepatic nodules (p < 0.0001). Multivariate analysis revealed that the presence of non-hypervascular hypointense hepatic nodules and Child-Pugh score were independent risk factors for new intrahepatic recurrence.

Conclusions: Non-hypervascular hypointense hepatic nodules during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI were a useful predictive factor for IDR, particularly for new intrahepatic recurrence, after RFA.
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http://dx.doi.org/10.1159/000480185DOI Listing
January 2018

Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer.

Breast Cancer Res Treat 2018 01 13;167(1):39-47. Epub 2017 Sep 13.

Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan.

Purpose: The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes.

Methods: We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies.

Results: Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30-3.14, P = 0.025).

Conclusions: TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.
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http://dx.doi.org/10.1007/s10549-017-4502-3DOI Listing
January 2018

Bone metastasis-related signaling pathways in breast cancers stratified by estrogen receptor status.

J Cancer 2017 9;8(6):1045-1052. Epub 2017 Apr 9.

Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Breast cancer bone metastasis (BCBM)-specific genes have been reported without considering biological differences based on estrogen receptor (ER) status. The aims of this study were to identify BCBM-specific genes using our patient dataset and validate previously reported BCBM-specific genes, and to determine whether ER-status-related biological differences matter in identification of BCBM-specific genes. We used Affymetrix GeneChips to analyze 365 primary human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer specimens. Genes that were differentially expressed between patients who developed bone metastasis and those who developed non-bone metastasis were identified using Cox proportional hazards model, and differential expression of gene sets was assessed using gene set analysis. We performed gene set analysis to determine whether biological function associated with bone metastasis were different by ER status using 2,246 functionally annotated gene sets assembled from Gene Ontology data base. Among 16,712 probe sets, 592 were overexpressed in the bone metastasis cohort compared to the non-bone-metastasis cohort (false discovery rate ≤ 0.05). However, no BCBM-specific genes met our significance tests when the cancers were stratified by ER status. In ER-positive and ER-negative breast cancers, 151 and 125 gene sets, respectively, were overexpressed for BCBM and the majority of BCBM-related pathways were different. Of significant gene sets, only 13 gene sets were overlapped between ER-positive and -negative cohorts. ER-positive and ER-negative breast cancers have different biological pathways in BCBM development. We have yet to explore BCBM-related biomarkers and targets considering the biological features associated with BCBM depending on the ER status.
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http://dx.doi.org/10.7150/jca.13690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436258PMC
April 2017

Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers.

Oncotarget 2017 Apr;8(16):26122-26128

Department of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan.

Background: The purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers.

Results: Thirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P < 0.001). Post-Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P < 0.001 and 0.041, respectively).

Materials And Methods: Core needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre- and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed.

Conclusions: IHC based post-Ki67 levels may have distinct predictive power compared with the naïve IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.
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http://dx.doi.org/10.18632/oncotarget.15385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432244PMC
April 2017

Feasibility of Extracted-Overlay Fusion Imaging for Intraoperative Treatment Evaluation of Radiofrequency Ablation for Hepatocellular Carcinoma.

Liver Cancer 2016 Oct 14;5(4):269-279. Epub 2016 Sep 14.

Department of Radiology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.

Background And Aims: Extracted-overlay fusion imaging is a novel computed tomography/magnetic resonance-ultrasonography (CT/MR-US) imaging technique in which a target tumor with a virtual ablative margin is extracted from CT/MR volume data and synchronously overlaid on US images. We investigated the applicability of the technique to intraoperative evaluation of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).

Methods: This retrospective study analyzed 85 HCCs treated with RFA using extracted-overlay fusion imaging for guidance and evaluation. To perform RFA, an electrode was inserted targeting the tumor and a virtual 5-mm ablative margin overlaid on the US image. Following ablation, contrast-enhanced US (CEUS) was performed to assess the ablative margin, and the minimal ablative margins were categorized into three groups: (I) margin <0 mm (protrusion), (II) margin 0 to <5 mm, and (III) margin ≥5 mm. Margin assessment was based on the positional relationship between the overlaid tumor plus margin and the perfusion defect of the ablation zone. Tumors in group I underwent repeat ablation until they were in groups II or III. The final classifications were compared with those obtained by retrospectively created fusion images of pre- and post-RFA CT or MR imaging (CT-CT/MR-MR fusion imaging).

Results: Treatment evaluation was impossible using CEUS in six HCCs because the tumors were located far below the body surface. Of the remaining 79 HCCs, the categorizations of minimal ablative margins between CEUS extracted-overlay fusion imaging and CT-CT/MR-MR fusion imaging were in agreement for 72 tumors (91.1%) (Cohen's quadratic-weighted kappa coefficient 0.66, good agreement, p<0.01).

Conclusions: Extracted-overlay fusion imaging combined with CEUS is feasible for the evaluation of RFA and enables intraoperative treatment evaluation without the need to perform contrast-enhanced CT.
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http://dx.doi.org/10.1159/000449338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075812PMC
October 2016

A Phase I Trial of 100 mg/m2 Docetaxel in Patients with Advanced or Recurrent Breast Cancer.

Acta Med Okayama 2016 Oct;70(5):425-427

Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan.

Docetaxel is a standard treatment for patients with advanced or recurrent breast cancer. The recommended dose is 60 to 100 mg/m2. Previous study have shown that the tumor response rates of patients who received docetaxel monotherapy at doses of 60, 75, and 100 mg/m2 were 22.1% , 23.3% , and 36.0% , respectively, and there was a significant relationship between the dose and response. In Europe and the United States, docetaxel is approved at a dose of 100 mg/m2, and Japanese guidelines also recommend a dose of 100 mg/m2. However, the approved dose in Japan is up to 75 mg/m2. We have launched a phase I trial evaluating 100 mg/m2 docetaxel in patients with advanced or relapsed breast cancer. The major eligibility criteria are as follows: age 20 years, pathologically diagnosed breast cancer, recurrent or advanced breast cancer, a good performance status, and HER2 [human epidermal growth factor receptor 2] negative. The primary endpoint is demonstrated safety of 100 mg/m2 docetaxel. This study will clarify whether 100mg/m2 docetaxel can be administrated safely in Japanese patients with advanced or recurrent breast cancer.
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http://dx.doi.org/10.18926/AMO/54607DOI Listing
October 2016