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Background: Several studies have recently reported that the relationships between serum vitamin D and the prognosis or the pathological response to neoadjuvant chemotherapy (NAC) in breast cancer. However, there are no data regarding the clinical impacts of the vitamin D in Japanese breast cancer patients so far., Patients and Methods: In the present study, a total of 250 patients with clinical Stage I-III primary breast cancer who were treated with NAC and subsequently underwent definitive surgery were included. Serum 25-hydroxvitamin D (25(OH)D) levels were evaluated using blood samples obtained before NAC., Results: The serum 25(OH)D was positively associated with age, and the serum 25(OH)D was significantly higher in postmenopausal women than that in pre/peri-menopausal women. Serum 25(OH)D level was not associated with the achievement of pathological complete response (pCR) in this cohort. The low 25(OH)D levels were significantly associated with shorter time to distant recurrence (TTDR). According to the univariate analysis, high clinical stage before NAC (cStage III) and low serum 25(OH)D level were significantly associated with the shorter TTDR, and pCR was significantly associated with the longer TTDR. According to a multivariate analysis, low serum 25(OH)D level were independent poor prognostic factors for TTDR., Conclusions: The low 25(OH)D levels were significantly associated with poorer prognosis in Japanese women with operable breast cancer patients treated with NAC., (© 2021. The Author(s).)

Salivary secretory carcinoma (SASC) is frequently associated with ETV6-neurotrophic tyrosine receptor kinase (NTRK) 3 fusion and more rarely with RET, MET, or ALK rearrangement. We aimed to elucidate the potential diagnostic utility of pan-tropomyosin receptor kinase (Trk) immunohistochemistry and its relationship with the fusion gene subtype in SASC. We examined 33 cases of SASC for immunoexpression of pan-Trk, ALK and ROS1, and gene rearrangement of the ETV6, NTRK3, and RET genes using fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Thirty (90.9%) of 33 SASCs harbored ETV6-NTRK3 fusion gene transcripts by RT-PCR and/or both ETV6 and NTRK3 gene rearrangements by FISH, and 3 cases (9.1%) had RET gene rearrangement. Most NTRK3-rearranged SASCs (27/33 cases; 81.8%) had conventional ETV6 exon 5-NTRK3 exon 15 fusion, whereas 2 cases (6.1%) had both the conventional fusion and a novel ETV6 exon 4-NTRK3 exon 15 fusion variant. In the remaining one case (3%), only FISH revealed both ETV6 and NTRK3 rearrangements, suggesting an ETV6-NTRK3 fusion with an as yet undetermined break point. All 30 SASCs with ETV6-NTRK3 fusion and/or NTRK3 rearrangement showed nuclear and cytoplasmic immunoreactivity for pan-Trk. In contrast, 3 SASCs with RET rearrangement showed negative or only weak cytoplasmic staining for pan-Trk. There was no case harboring ALK and ROS1 rearrangements. All 17 non-SASC tumors were negative for pan-Trk. The results suggest that nuclear and cytoplasmic immunoreactivity for pan-TRK may be helpful to identify ETV6-NTRK3-fused SASCs and to distinguish them from RET-rearranged SASCs and morphological mimics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late distant recurrence (DR) risk for breast cancer after 5-year adjuvant endocrine therapy., Patients and Methods: Among 560 postmenopausal women with pathological stage I-III estrogen receptor-positive (ER+) primary breast cancer, 383 women who had received 5-year adjuvant endocrine therapy without any recurrence at 5 years after surgery were included in this study. The CTS5 was calculated for each patient using a previously published formula, and the patients were stratified by their CTS5 values into the low-, intermediate- and high-CTS5 risk groups., Results: According to the CTS5, 205 (53.5%), 106 (27.7%) and 72 (18.8%) patients were classified into the low-, intermediate-, and high-CTS5 risk groups, respectively. A higher ER expression level was significantly associated with the low CTS5. The increased administration of adjuvant chemotherapy was significantly associated with a high CTS5. The occurrence of DR was higher in the intermediate and high CTS5 groups than in the low CTS5 group. The DRFS in the low CTS5 risk group was significantly better than that in the intermediate- or high-risk groups. In the ER-high or HER2-negative (HER2-) group, the DRFS in the low-risk group was significantly better than that of the intermediate- or high-risk groups. However, in the low-ER or HER2-positive group, there was no significant difference in DRFS among the three risk groups., Conclusions: In postmenopausal women with ER+ breast cancer, low CTS5 was considered to be associated with a very low risk of late DR. Thus, extended endocrine therapy may be unnecessary for patients with low CTS5 scores. Extended endocrine therapy should be offered for patients with intermediate or high CTS5 scores, especially those with high-ER and HER2- breast cancer.

Background: The TNM system, which reflects the anatomical extent of disease, was used for stage definition. In the recently published AJCC 8th edition, the new staging system of the clinical and pathological prognostic stage, which incorporates biological factors, is introduced., Patients and Methods: A total of 2622 patients with primary breast cancer at stage I-III were included in this study. The anatomic stage (aStage) and the pathological prognostic stage (ppStage) for each case were determined according to the definition of the AJCC 8th edition, and the influence of these stages on the prognosis was compared., Results: The stage distributions of aStage and ppStage were as follows: aStage, stage IA (54.8%), IB (1.1%), IIA (26.1%), IIB (9.2%), IIIA (5.6%), IIIB (0.1%), and IIIC (3.1%); and ppStage, stage IA (66.6%), IB (13.1%), IIA (11.1%), IIB (3.2%), IIIA (3.3%), IIIB (1.4%), and IIIC (1.2%). Compared with the aStage, the ppStage stayed the same in 1710 patients (65.2%), was downstaged in 778 patients (29.7%), and was upstaged in 134 patients. The pathological tumor size (pT2) and lymph node metastasis (pN1) were associated with downstaging, and histological grade 3 was associated with upstaging. ER positivity, PgR positivity, and HER2-positivity were significantly associated with downstaging, and the TN subtype was associated with upstaging. Both the aStage and ppStage were significantly associated with the prognosis; however, the Kaplan-Meier curves for the relapse-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival were better stratified by the ppStage., Conclusion: The ppStage reflects the prognosis of patients with early breast cancer more accurately than the aStage.

Background/aim: To evaluate the improvement in the prognosis by adjuvant trastuzumab in clinical practice and the risk factors for distant recurrence, we retrospectively investigated the prognosis of HER2-positive early breast cancer in our department before and after the introduction of adjuvant trastuzumab., Patients and Methods: Cohorts A and B included 161 and 182 cases, respectively, who underwent surgery before (2000-2007) and after (2008-2015) the introduction of adjuvant trastuzumab., Results: The rates of relapse-free and distant metastasis-free survival were significantly better in cohort B than in cohort A. The risk factors of distant recurrence found in cohort A, such as the presence of lymph node metastasis, lymphatic invasion, and a low histological grade, did not increase the risk in cohort B., Conclusion: Many risk factors seemed to have been negated by adjuvant trastuzumab administration. Therefore, further escalation of adjuvant treatment should be carefully considered., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: We explore the problems associated with the cell block (CB) method for receptor analysis in breast cancer metastases and propose a method for reporting the results., Study Design: Nine institutions used the CB method for the analysis of hormone receptors (HRs) and HER2 (human epidermal growth factor receptor 2) protein in cytological specimens of breast cancer metastases in routine practice. The stained slides were independently evaluated by 8 pathologists. Dual in situ hybridization assay was performed in cases of discordant results for HER2 protein. Based on the results, we propose a method for receptor scoring in the CB method., Results: Of 61 specimens, 57 contained tumor cells. Two or more pathologists disagreed on the results for the estrogen receptor, progesterone receptor, and HER2 protein in 3 (5.3%), 13 (22.8%), and 19 (33.3%) cases, respectively. The discrepant results for the HRs were attributed to the presence of a few positive cells or faintly stained cells. The high interobserver discordance rate for HER2 protein was explained by interobserver differences in the scoring criteria., Conclusion: The use of categorical scoring into positive and negative is recommended for evaluating the HR expressions. Use of strict criteria for HER2 protein 2+ and 3+ cases is recommended, as HER2-positive cases should not be missed., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

We propose a computer-aided diagnostic (CAD) system that uses time-intensity curves to distinguish between benign and malignant mammary tumors. Many malignant tumors show a washout pattern in time-intensity curves. Therefore, we designed a program that automatically detects the position with the strongest washout effect using the technique, such as the subtraction technique, which extracts only the washout area in the tumor, and by scanning data in 2×2 pixel region of interest (ROI). Operation of this independently developed program was verified using a phantom system that simulated tumors. In three cases of malignant tumors, the washout pattern detection rate in images with manually set ROI was ≤6%, whereas the detection rate with our novel method was 100%. In one case of a benign tumor, when the same method was used, we checked that there was no washout effect and detected the persistent pattern. Thus, the distinction between benign and malignant tumors using our method was completely consistent with the pathological diagnoses made. Our novel method is therefore effective for differentiating between benign and malignant mammary tumors in dynamic magnetic resonance images.

Background: Squamous cell carcinoma (SCC) of the breast is a rare and generally aggressive disease that accounts for less than 0.1% of all breast carcinomas. Although SCCs have distinct morphological features, their origin and cytogenetic profile are not well understood., Methods: Five patients with SCC were studied. The tumor area that was predominantly composed of SCC components was macrodissected and DNA was extracted. In three cases, an invasive or noninvasive ductal carcinoma of no special type (NST) component was also present. NST-component DNA was also extracted. The tumor DNA was used for array comparative genomic hybridization analysis using a high-density oligonucleotide microarray. The cytogenetic profile of the SCC components was compared with each other and with the paired NST component in three of the five cases., Results: The cytogenetic profile of the SCC components indicated large intertumoral heterogeneity. There were between 2 and 160 copy number alterations per case, and no common copy number alterations were identified. The cytogenetic profiles of the paired SCC and NST components were similar but not identical. Although, in one case, a larger number of copy number aberrant regions were detected in the SCC component than the NST component. In this case, all the NST component aberrations were present in the SCC component. This implies that the SCC component originated from the NST component. There were no common SCC component-specific aberrations in the three NST-component cases., Conclusion: Our results demonstrate the cytogenetic inter- and intratumoral heterogeneity of SCC of the breast. Our comparison of cytogenetic profiles indicated that the SCC component originated from the NST component in one case.

Background: Estrogen receptor (ER)/GATA3/Forkhead box A1 (FOXA1) network is necessary for the ERα functional signature. High FOXA1 expression indicates a good prognosis in ER-positive breast cancer. However, little is known about the significance of FOXA1 and GATA3 expression in neoadjuvant endocrine therapy (NAE). The aim of this study is to investigate their predictive potential for NAE and their expression changes after NAE., Methods: FOXA1 and GATA3 expression was evaluated using immunohistochemistry in 66 patients with ER-positive/HER2-negative breast cancer who had been treated with NAE. The association between biological marker expressions and the efficacy of NAE and their expression changes after NAE were analyzed., Results: The median pre-treatment FOXA1 and GATA3 expressions were 94.6 and 90 %. Pre-treatment FOXA1 expression was positively correlated with GATA3 (P = 0.0003) and progesterone receptor (PgR) (P = 0.0138). There was no correlation between pre- or post-treatment FOXA1 and GATA3 expressions and the efficacy of NAE. Post-treatment Ki67 expression was significantly lower in tumors with partial response (PR) (P = 0.0007). In terms of the changes of the expression, PgR, Ki67, and FOXA1 expression significantly decreased after NAE (P < 0.0001, P < 0.0001, and P < 0.0001, respectively)., Conclusions: FOXA1 and GATA3 expression was not correlated with the efficacy of NAE, but FOXA1 expression was significantly reduced after NAE.

The aim of this study was to elucidate the clinicopathological and prognostic significance of the expressions of insulin-like growth factor II mRNA-binding protein-3 (IMP3) and epidermal growth factor receptor (EGFR) in phyllodes tumors (PTs). Immunohistochemical staining for IMP3 and EGFR was performed in 130 cases of primary PTs (83 benign, 28 borderline, 19 malignant), 34 recurrent/metastatic PTs, and 26 fibroadenomas (FAs). Among the primary tumors, a high expression of IMP3 was significantly more frequently present in malignant PTs (17/19, 89%) than in the FAs (0/26, 0%), benign PTs (0/83, 0%) and borderline PTs (3/28, 11%). The recurrent and metastatic lesions of malignant PTs also showed high IMP3 expression (3/5 [60%] and 6/6 [100%], respectively). Most malignant PTs showed strong IMP3 expression at the interductal area or more diffusely, whereas weak and focal (low) expression of IMP3 was limited to the periductal area in FAs and benign PTs. EGFR overexpression was significantly correlated with tumor grade and high IMP3 expression. Overexpressions of IMP3 and EGFR were significantly associated with shorter periods of metastasis-free and disease-free survival. The results suggest that high expressions of IMP3 and EGFR with a characteristic staining pattern may be helpful for both identifying malignant PT and predicting the prognosis of these tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: Although 8-73 % of breast cancer patients who receive adjuvant endocrine therapy discontinue it, discontinuation is little studied in Asian breast cancer patients., Materials and Methods: To determine frequency and reasons for discontinuation at a single institution, we reviewed records and database information for women with hormone receptor-positive breast cancer who were treated at the National Kyushu Cancer Center 2001-2006, defining "persistence" as continued endocrine treatment (even when physicians decided to stop because of recurrent disease or severe adverse effects), and "discontinuation" as ending therapy due to patient's wishes., Results: Among 686 patients who started adjuvant endocrine therapy, 607 patients (88 %) persisted, 79 patients (12 %) discontinued. Of the 79 patients who discontinued, 37 (46 %) did so because of side effects, 26 (33 %) stopped appointments, 11 (14 %) stopped for "no particular reason", 4 (5 %) to get pregnant, and 1 (1 %) for economic reasons. The rate of persistence was higher in patients with lymph node involvement than in those without lymph node involvement (92 vs. 87 %; P = 0.03)., Conclusions: Clinicians should discuss side effects with patients, both as part of informed consent and to prepare them to continue therapy, and should be aware that over time, patients' reasons for discontinuation change.

Background: A certain number of patients have extracapsular invasion (ECI) at the sentinel lymph node (SLN), but only a few reports describe its clinical significance. This study aimed to determine the clinical significance of ECI at SLN in breast cancer patients with involved SLN., Methods: This study evaluated ECI at SLN in 131 consecutive SLN-positive patients who underwent axillary lymph node dissection between 2003 and 2008 at the National Kyushu Cancer Center with regard to their long-term prognosis and non-SLN metastasis., Results: Of the 131 patients, 46 (35 %) tested positive for ECI at SLN. Of these 46 patients, 61 % (28/46) had non-SLN metastasis compared with 28 % (24/85) in ECI-negative group (χ (2) test; P < 0.001). Multivariate analysis showed that ECI at SLN is significantly predictive for non-SLN metastasis [hazard ratio (HR) 3.2; 95 % confidence interval (CI) 1.4-7.1; P = 0.005]. The 5-year recurrence-free survival (RFS) rates were 71.3 % in the ECI-positive group and 89.9 %in the ECI-negative group (P = 0.001, log-rank test). Cox-regression analysis showed that ECI at SLN independently predicts lower RFS (HR 4.5; 95 % CI 1.8-11.7; P = 0.002)., Conclusions: The findings show that ECI at SLN is an independent predictor of both non-SLN metastasis and poor prognosis for breast cancer patients with involved SLN. The clinical significance of ECI at SLN in operable-stage breast cancer warrants further study.

Objective: How breast cancer subtypes should affect treatment decisions for breast cancer patients with brain metastases is unclear. We analyzed local brain metastases treatments and their outcomes according to subtype in patients with breast cancer and brain metastases., Methods: We reviewed records and database information for women treated at the National Kyushu Cancer Center between 2001 and 2010. Patients were divided into three breast cancer subtype groups: Luminal (estrogen receptor positive and/or progesterone receptor positive, but human epidermal growth factor receptor 2 negative); human epidermal growth factor receptor 2 positive and triple negative (estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor 2 negative)., Results: Of 524 advanced breast cancer patients, we reviewed 65 (12%) with brain metastases and records showing estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status, as well as outcome data; there were 26 (40%) Luminal, 26 (40%) had human epidermal growth factor receptor 2 and 13 (20%) had triple negative subtypes. There was no statistical difference in the number of brain metastases among subtypes; however, rates of stereotactic radiosurgery or surgery for brain metastases differed significantly by subtype (human epidermal growth factor receptor 2: 81%, Luminal: 42% and triple negative: 47%; P = 0.03). Patients having the human epidermal growth factor receptor 2 subtype, a performance status of ≤1 and ≤4 brain metastases, who underwent systemic therapy after brain metastases and underwent stereotactic radiosurgery or surgery, were predicted to have longer overall survival after brain metastases. Multivariate analysis demonstrated that not having systemic therapy and not having the human epidermal growth factor receptor 2 subtype were independent factors associated with an increased risk of death (hazard ratio 2.4, 95% confidence interval 1.01-5.6; P = 0.05 and hazard ratio 2.9, 95% confidence interval 1.5-5.8; P = 0.003, respectively)., Conclusion: Our study showed that local brain treatments and prognosis differed by subtype in breast cancer patients with brain metastases., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: It is unclear whether individualized treatments based on biological factors have improved the prognosis of recurrent breast cancer. The purpose of this study is to evaluate the survival improvement of patients with recurrent breast cancer after the introduction of third generation aromatase inhibitors (AIs) and trastuzumab., Methods: A total of 407 patients who received first diagnosis of recurrent breast cancer and treatment at National Kyushu Cancer Center between 1992 and 2008 were retrospectively evaluated. As AIs and trastuzumab were approved for clinical use in Japan in 2001, the patients were divided into two time cohorts depending on whether the cancer recurred before or after 2001. Cohort A: 170 patients who were diagnosed between 1992 and 2000. Cohort B: 237 patients who were diagnosed between 2001 and 2008. Tumor characteristics, treatments, and outcome were compared., Results: Fourteen percent of cohort A and 76% of cohort B received AIs and/or trastuzumab (P < 0.001). The median overall survival (OS) times after breast cancer recurrence were 1.7 years and 4.2 years for these respective cohorts (P < 0.001). Both the time period and treatment of AIs and/or trastuzumab for recurrent disease were significant prognostic factors in multivariate analysis (cohort B vs. cohort A: HR = 0.70, P = 0.01; AIs and/or trastuzumab for recurrent disease: yes vs. no: HR = 0.46, P < 0.001). When patients were categorized into 4 subgroups by the expression of hormone receptor (HR) and HER-2 status, the median OS times of the HR-positive/HER-2-negative, HR-positive/HER-2-positive, HR-negative/HER-2-positive, and HR-negative/HER-2-negative subtypes were 2.2, 2.4, 1.6, and 1.0 years in cohort A and 4.5, 5.1, 5.0, and 1.4 years in cohort B., Conclusions: The prognosis of patients with recurrent breast cancer was improved over time following the introduction of AIs and trastuzumab and the survival improvement was apparent in HR- and/or HER-2-positive tumors.

We report a case of HER-2-positive advanced inflammatory breast cancer with invasive micropapillary component showing a complete response to trastuzumab and paclitaxel treatment. A 37-year-old woman was referred to our hospital for right breast swelling with broad skin redness and right axillary tumor. Ipsilateral infraclavicular and contralateral axillary lymph nodes swelling were also recognized. The histopathological findings of core-needle biopsy specimens from primary breast tumor and ipsilateral axillary lymph node were invasive ductal carcinoma with a micropapillary component. Immunohistochemical examination gave a negative result for estrogen receptor (ER)/progesterone receptor (PgR), and overexpression of HER-2 (Hercep Test 3+). Advanced inflammatory breast cancer with an invasive micropapillary component was diagnosed (T4d N3 M1 (LYM), stage IV). The patient was treated with combination chemotherapy using weekly paclitaxel and trastuzumab. After administration of three courses, the breast swelling, skin redness, and lymph node swelling disappeared completely. She maintained complete remission of disease for 12 months and was judged to have a clinically complete response by the RECIST criteria. Invasive micropapillary carcinoma is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and poor prognosis. This is the first reported case of advanced inflammatory breast cancer with an invasive micropapillary component showing a clinically complete response to trastuzumab-containing treatment. This report suggests trastuzumab-containing chemotherapy is a promising therapy for HER-2-positive advanced invasive micropapillary carcinoma.