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Background: Because a number of years may be required for normal cells to develop into carcinoma, genes involved in tumorigenesis and progression might differ among breast cancers in young women and those in older women. The present study sought to analyze subclonality during breast cancer evolution as well as diversity within each individual in our young patients' cohort. Methods: A total of 13 women aged <35 years at diagnosis with early breast cancer were recruited. Serial sections of breast samples consisting of synchronous invasive carcinoma, adjacent ductal carcinoma in situ (DCIS), normal breast tissue, and metastatic lymph nodes were collected and prepared for immunohistochemical analysis of estrogen receptor, progesterone receptor, HER2, and Ki67, and for extraction of genomic DNA. Germline and somatic gene alterations of genomic DNA were examined by targeted sequencing. Results: Genomic DNA from 13 blood samples and 36 breast tissues consisting of 14 invasive carcinomas, nine adjacent DCIS, 11 normal breast tissues, and two metastatic lymph nodes were successfully sequenced. Germline gene alterations including pathogenic variants and gene alterations that were not yet evaluated for their clinical significance were detected in all patients but one. Somatic gene alterations were identified in eight invasive carcinomas, five DCIS, and one metastatic lymph node. Different somatic gene alterations between invasive carcinoma and DCIS were detected in two patients. Somatic gene mutations were present in non-neoplastic tissues in three patients. No two patients had the same gene alterations. Conclusion: Our results reveal diversity within each individual during breast cancer progression. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Purpose Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. Methods In total, 143 patients with breast cancer who received docetaxel (75 mg/m(2)) or paclitaxel (175 mg/m(2))-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of >= G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. Results Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of >= G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of >= G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of >= G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. Conclusion Pegfilgrastim co-administration is an independent risk factor for >= G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.

Background: Because a number of years may be required for normal cells to develop into carcinoma, genes involved in tumorigenesis and progression might differ among breast cancers in young women and those in older women. The present study sought to analyze subclonality during breast cancer evolution as well as diversity within each individual in our young patients' cohort. Methods: A total of 13 women aged <35 years at diagnosis with early breast cancer were recruited. Serial sections of breast samples consisting of synchronous invasive carcinoma, adjacent ductal carcinoma in situ (DCIS), normal breast tissue, and metastatic lymph nodes were collected and prepared for immunohistochemical analysis of estrogen receptor, progesterone receptor, HER2, and Ki67, and for extraction of genomic DNA. Germline and somatic gene alterations of genomic DNA were examined by targeted sequencing. Results: Genomic DNA from 13 blood samples and 36 breast tissues consisting of 14 invasive carcinomas, nine adjacent DCIS, 11 normal breast tissues, and two metastatic lymph nodes were successfully sequenced. Germline gene alterations including pathogenic variants and gene alterations that were not yet evaluated for their clinical significance were detected in all patients but one. Somatic gene alterations were identified in eight invasive carcinomas, five DCIS, and one metastatic lymph node. Different somatic gene alterations between invasive carcinoma and DCIS were detected in two patients. Somatic gene mutations were present in non-neoplastic tissues in three patients. No two patients had the same gene alterations. Conclusion: Our results reveal diversity within each individual during breast cancer progression. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30-90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2-140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Purpose Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. Methods In total, 143 patients with breast cancer who received docetaxel (75 mg/m(2)) or paclitaxel (175 mg/m(2))-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of >= G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. Results Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of >= G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of >= G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of >= G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. Conclusion Pegfilgrastim co-administration is an independent risk factor for >= G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.

Purpose Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. Methods In total, 143 patients with breast cancer who received docetaxel (75 mg/m(2)) or paclitaxel (175 mg/m(2))-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of >= G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. Results Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of >= G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of >= G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of >= G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. Conclusion Pegfilgrastim co-administration is an independent risk factor for >= G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.

Background: Because a number of years may be required for normal cells to develop into carcinoma, genes involved in tumorigenesis and progression might differ among breast cancers in young women and those in older women. The present study sought to analyze subclonality during breast cancer evolution as well as diversity within each individual in our young patients' cohort. Methods: A total of 13 women aged <35 years at diagnosis with early breast cancer were recruited. Serial sections of breast samples consisting of synchronous invasive carcinoma, adjacent ductal carcinoma in situ (DCIS), normal breast tissue, and metastatic lymph nodes were collected and prepared for immunohistochemical analysis of estrogen receptor, progesterone receptor, HER2, and Ki67, and for extraction of genomic DNA. Germline and somatic gene alterations of genomic DNA were examined by targeted sequencing. Results: Genomic DNA from 13 blood samples and 36 breast tissues consisting of 14 invasive carcinomas, nine adjacent DCIS, 11 normal breast tissues, and two metastatic lymph nodes were successfully sequenced. Germline gene alterations including pathogenic variants and gene alterations that were not yet evaluated for their clinical significance were detected in all patients but one. Somatic gene alterations were identified in eight invasive carcinomas, five DCIS, and one metastatic lymph node. Different somatic gene alterations between invasive carcinoma and DCIS were detected in two patients. Somatic gene mutations were present in non-neoplastic tissues in three patients. No two patients had the same gene alterations. Conclusion: Our results reveal diversity within each individual during breast cancer progression. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30-90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2-140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.

Purpose Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. Methods In total, 143 patients with breast cancer who received docetaxel (75 mg/m(2)) or paclitaxel (175 mg/m(2))-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of >= G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. Results Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of >= G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of >= G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of >= G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. Conclusion Pegfilgrastim co-administration is an independent risk factor for >= G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Background We investigated the usefulness of the minimum ADC value of primary breast lesions for predicting axillary lymph node (LN) status in luminal A-like breast cancers with clinically negative nodes in comparison with the mean ADC. Methods Forty-four luminal A-like breast cancers without axillary LN metastasis at preoperative clinical evaluation, surgically resected with sentinel LN biopsy, were retrospectively studied. Mean and minimum ADC values of each lesion were measured and statistically compared between LN positive (n = 12) and LN negative (n = 32) groups. An ROC curve was drawn to determine the best cutoff value to differentiate LN status. Correlations between mean and minimum ADC values and the number of metastatic axillary LNs were investigated. Results Mean and minimum ADC values of breast lesions with positive LN were significantly lower than those with negative LN (mean 839.9 +/- 110.9 vs. 1022.2 +/- 250.0 x 10(- 6) mm(2)/s, p = 0.027, minimum 696.7 +/- 128.0 vs. 925.0 +/- 257.6 x 10(- 6) mm(2)/s, p = 0.004). The sensitivity and NPV using the best cutoff value from ROC using both mean and minimum ADC were 100%. AUC of the minimum ADC (0.784) was higher than that of the mean ADC (0.719). Statistically significant negative correlations were observed between both mean and minimum ADCs and number of positive LNs, with stronger correlation to minimum ADC than mean ADC. Conclusions The minimum ADC value of primary breast lesions predicts axillary LN metastasis in luminal A-like breast cancer with clinically negative nodes, with high sensitivity and high NPV.

Background We investigated the usefulness of the minimum ADC value of primary breast lesions for predicting axillary lymph node (LN) status in luminal A-like breast cancers with clinically negative nodes in comparison with the mean ADC. Methods Forty-four luminal A-like breast cancers without axillary LN metastasis at preoperative clinical evaluation, surgically resected with sentinel LN biopsy, were retrospectively studied. Mean and minimum ADC values of each lesion were measured and statistically compared between LN positive (n = 12) and LN negative (n = 32) groups. An ROC curve was drawn to determine the best cutoff value to differentiate LN status. Correlations between mean and minimum ADC values and the number of metastatic axillary LNs were investigated. Results Mean and minimum ADC values of breast lesions with positive LN were significantly lower than those with negative LN (mean 839.9 +/- 110.9 vs. 1022.2 +/- 250.0 x 10(- 6) mm(2)/s, p = 0.027, minimum 696.7 +/- 128.0 vs. 925.0 +/- 257.6 x 10(- 6) mm(2)/s, p = 0.004). The sensitivity and NPV using the best cutoff value from ROC using both mean and minimum ADC were 100%. AUC of the minimum ADC (0.784) was higher than that of the mean ADC (0.719). Statistically significant negative correlations were observed between both mean and minimum ADCs and number of positive LNs, with stronger correlation to minimum ADC than mean ADC. Conclusions The minimum ADC value of primary breast lesions predicts axillary LN metastasis in luminal A-like breast cancer with clinically negative nodes, with high sensitivity and high NPV.

Background We investigated the usefulness of the minimum ADC value of primary breast lesions for predicting axillary lymph node (LN) status in luminal A-like breast cancers with clinically negative nodes in comparison with the mean ADC. Methods Forty-four luminal A-like breast cancers without axillary LN metastasis at preoperative clinical evaluation, surgically resected with sentinel LN biopsy, were retrospectively studied. Mean and minimum ADC values of each lesion were measured and statistically compared between LN positive (n = 12) and LN negative (n = 32) groups. An ROC curve was drawn to determine the best cutoff value to differentiate LN status. Correlations between mean and minimum ADC values and the number of metastatic axillary LNs were investigated. Results Mean and minimum ADC values of breast lesions with positive LN were significantly lower than those with negative LN (mean 839.9 +/- 110.9 vs. 1022.2 +/- 250.0 x 10(- 6) mm(2)/s, p = 0.027, minimum 696.7 +/- 128.0 vs. 925.0 +/- 257.6 x 10(- 6) mm(2)/s, p = 0.004). The sensitivity and NPV using the best cutoff value from ROC using both mean and minimum ADC were 100%. AUC of the minimum ADC (0.784) was higher than that of the mean ADC (0.719). Statistically significant negative correlations were observed between both mean and minimum ADCs and number of positive LNs, with stronger correlation to minimum ADC than mean ADC. Conclusions The minimum ADC value of primary breast lesions predicts axillary LN metastasis in luminal A-like breast cancer with clinically negative nodes, with high sensitivity and high NPV.

Background We investigated the usefulness of the minimum ADC value of primary breast lesions for predicting axillary lymph node (LN) status in luminal A-like breast cancers with clinically negative nodes in comparison with the mean ADC. Methods Forty-four luminal A-like breast cancers without axillary LN metastasis at preoperative clinical evaluation, surgically resected with sentinel LN biopsy, were retrospectively studied. Mean and minimum ADC values of each lesion were measured and statistically compared between LN positive (n = 12) and LN negative (n = 32) groups. An ROC curve was drawn to determine the best cutoff value to differentiate LN status. Correlations between mean and minimum ADC values and the number of metastatic axillary LNs were investigated. Results Mean and minimum ADC values of breast lesions with positive LN were significantly lower than those with negative LN (mean 839.9 +/- 110.9 vs. 1022.2 +/- 250.0 x 10(- 6) mm(2)/s, p = 0.027, minimum 696.7 +/- 128.0 vs. 925.0 +/- 257.6 x 10(- 6) mm(2)/s, p = 0.004). The sensitivity and NPV using the best cutoff value from ROC using both mean and minimum ADC were 100%. AUC of the minimum ADC (0.784) was higher than that of the mean ADC (0.719). Statistically significant negative correlations were observed between both mean and minimum ADCs and number of positive LNs, with stronger correlation to minimum ADC than mean ADC. Conclusions The minimum ADC value of primary breast lesions predicts axillary LN metastasis in luminal A-like breast cancer with clinically negative nodes, with high sensitivity and high NPV.

Breast cancer incidence in Japanese women has more than tripled over the past two decades. We have previously shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive, HER2-negative subtype. We conducted a case-control study; ER-positive, HER2-negative breast cancer patients who were diagnosed since 2011 and women without disease were recruited. Environmental factors, serum levels of testosterone and 25-hydroxyvitamin D, and common genetic variants reported as predictors of ER-positive breast cancer or found in Asian women were evaluated between patients and controls in pre-and postmenopausal women. To identify important risk predictors, risk prediction models were created by logistic regression models. In premenopausal women, two environmental factors (history of breastfeeding, and history of benign breast disease) and four genetic variants (TOX3-rs3803662, ESR1-rs2046210, 8q24-rs13281615, and SLC4A7-rs4973768) were considered to be risk predictors, whereas three environmental factors (body mass index, history of breastfeeding, and hyperlipidemia), serum levels of testosterone and 25-hydroxyvitamin D, and two genetic variants (TOX3-rs3803662 and ESR1-rs2046210) were identified as risk predictors. Inclusion of common genetic variants and serum hormone measurements as well as environmental factors improved risk assessment models. The decline in the birthrate according to recent changes of lifestyle might be the main cause of the recent notable increase in the incidence of ER-positive breast cancer in Japanese women.

Background: Breast cancer is the most common invasive cancer among women and its incidence is increasing. Risk assessment is valuable and recent methods are incorporating novel biomarkers such as mammographic density. Artificial neural networks (ANN) are adaptive algorithms capable of performing pattern-to-pattern learning and are well suited for medical applications. They are potentially useful for calibrating Full-Field Digital Mammography (FFDM) for quantitative analysis. This study uses ANN modeling to estimate volumetric breast density (VBD) from FFDM on Japanese women with and without breast cancer. Methods: ANN calibration of VBD was performed using phantom data for one FFDM system. Mammograms of 46 Japanese women diagnosed with invasive carcinoma and 53 with negative findings were analyzed using ANN models learned. ANN-estimated VBD was validated against phantom data, compared intra-patient, with qualitative composition scoring, with MRI VBD, and inter-patient with classical risk factors of breast cancer as well as cancer status. Results: Phantom validations reached an R2 of 0.993. Intra-patient validations ranged from R2 of 0.789 with VBD to 0.908 with breast volume. ANN VBD agreed well with BI-RADS scoring and MRI VBD with R2 ranging from 0.665 with VBD to 0.852 with breast volume. VBD was significantly higher in women with cancer. Associations with age, BMI, menopause, and cancer status previously reported were also confirmed. Conclusions: ANN modeling appears to produce reasonable measures of mammographic density validated with phantoms, with existing measures of breast density, and with classical biomarkers of breast cancer. FFDM VBD is significantly higher in Japanese women with cancer.

Background: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. Methods: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. Results: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. Conclusion: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

Breast cancer incidence in Japanese women has more than tripled over the past two decades. We have previously shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive, HER2-negative subtype. We conducted a case-control study; ER-positive, HER2-negative breast cancer patients who were diagnosed since 2011 and women without disease were recruited. Environmental factors, serum levels of testosterone and 25-hydroxyvitamin D, and common genetic variants reported as predictors of ER-positive breast cancer or found in Asian women were evaluated between patients and controls in pre-and postmenopausal women. To identify important risk predictors, risk prediction models were created by logistic regression models. In premenopausal women, two environmental factors (history of breastfeeding, and history of benign breast disease) and four genetic variants (TOX3-rs3803662, ESR1-rs2046210, 8q24-rs13281615, and SLC4A7-rs4973768) were considered to be risk predictors, whereas three environmental factors (body mass index, history of breastfeeding, and hyperlipidemia), serum levels of testosterone and 25-hydroxyvitamin D, and two genetic variants (TOX3-rs3803662 and ESR1-rs2046210) were identified as risk predictors. Inclusion of common genetic variants and serum hormone measurements as well as environmental factors improved risk assessment models. The decline in the birthrate according to recent changes of lifestyle might be the main cause of the recent notable increase in the incidence of ER-positive breast cancer in Japanese women.

Background: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. Methods: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. Results: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. Conclusion: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

Background: Breast cancer is the most common invasive cancer among women and its incidence is increasing. Risk assessment is valuable and recent methods are incorporating novel biomarkers such as mammographic density. Artificial neural networks (ANN) are adaptive algorithms capable of performing pattern-to-pattern learning and are well suited for medical applications. They are potentially useful for calibrating Full-Field Digital Mammography (FFDM) for quantitative analysis. This study uses ANN modeling to estimate volumetric breast density (VBD) from FFDM on Japanese women with and without breast cancer. Methods: ANN calibration of VBD was performed using phantom data for one FFDM system. Mammograms of 46 Japanese women diagnosed with invasive carcinoma and 53 with negative findings were analyzed using ANN models learned. ANN-estimated VBD was validated against phantom data, compared intra-patient, with qualitative composition scoring, with MRI VBD, and inter-patient with classical risk factors of breast cancer as well as cancer status. Results: Phantom validations reached an R2 of 0.993. Intra-patient validations ranged from R2 of 0.789 with VBD to 0.908 with breast volume. ANN VBD agreed well with BI-RADS scoring and MRI VBD with R2 ranging from 0.665 with VBD to 0.852 with breast volume. VBD was significantly higher in women with cancer. Associations with age, BMI, menopause, and cancer status previously reported were also confirmed. Conclusions: ANN modeling appears to produce reasonable measures of mammographic density validated with phantoms, with existing measures of breast density, and with classical biomarkers of breast cancer. FFDM VBD is significantly higher in Japanese women with cancer.

Background: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. Methods: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. Results: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. Conclusion: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

Background: Breast cancer is the most common invasive cancer among women and its incidence is increasing. Risk assessment is valuable and recent methods are incorporating novel biomarkers such as mammographic density. Artificial neural networks (ANN) are adaptive algorithms capable of performing pattern-to-pattern learning and are well suited for medical applications. They are potentially useful for calibrating Full-Field Digital Mammography (FFDM) for quantitative analysis. This study uses ANN modeling to estimate volumetric breast density (VBD) from FFDM on Japanese women with and without breast cancer. Methods: ANN calibration of VBD was performed using phantom data for one FFDM system. Mammograms of 46 Japanese women diagnosed with invasive carcinoma and 53 with negative findings were analyzed using ANN models learned. ANN-estimated VBD was validated against phantom data, compared intra-patient, with qualitative composition scoring, with MRI VBD, and inter-patient with classical risk factors of breast cancer as well as cancer status. Results: Phantom validations reached an R2 of 0.993. Intra-patient validations ranged from R2 of 0.789 with VBD to 0.908 with breast volume. ANN VBD agreed well with BI-RADS scoring and MRI VBD with R2 ranging from 0.665 with VBD to 0.852 with breast volume. VBD was significantly higher in women with cancer. Associations with age, BMI, menopause, and cancer status previously reported were also confirmed. Conclusions: ANN modeling appears to produce reasonable measures of mammographic density validated with phantoms, with existing measures of breast density, and with classical biomarkers of breast cancer. FFDM VBD is significantly higher in Japanese women with cancer.

Breast cancer incidence in Japanese women has more than tripled over the past two decades. We have previously shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive, HER2-negative subtype. We conducted a case-control study; ER-positive, HER2-negative breast cancer patients who were diagnosed since 2011 and women without disease were recruited. Environmental factors, serum levels of testosterone and 25-hydroxyvitamin D, and common genetic variants reported as predictors of ER-positive breast cancer or found in Asian women were evaluated between patients and controls in pre-and postmenopausal women. To identify important risk predictors, risk prediction models were created by logistic regression models. In premenopausal women, two environmental factors (history of breastfeeding, and history of benign breast disease) and four genetic variants (TOX3-rs3803662, ESR1-rs2046210, 8q24-rs13281615, and SLC4A7-rs4973768) were considered to be risk predictors, whereas three environmental factors (body mass index, history of breastfeeding, and hyperlipidemia), serum levels of testosterone and 25-hydroxyvitamin D, and two genetic variants (TOX3-rs3803662 and ESR1-rs2046210) were identified as risk predictors. Inclusion of common genetic variants and serum hormone measurements as well as environmental factors improved risk assessment models. The decline in the birthrate according to recent changes of lifestyle might be the main cause of the recent notable increase in the incidence of ER-positive breast cancer in Japanese women.

Breast cancer incidence in Japanese women has more than tripled over the past two decades. We have previously shown that this marked increase is mostly due to an increase in the estrogen receptor (ER)-positive, HER2-negative subtype. We conducted a case-control study; ER-positive, HER2-negative breast cancer patients who were diagnosed since 2011 and women without disease were recruited. Environmental factors, serum levels of testosterone and 25-hydroxyvitamin D, and common genetic variants reported as predictors of ER-positive breast cancer or found in Asian women were evaluated between patients and controls in pre-and postmenopausal women. To identify important risk predictors, risk prediction models were created by logistic regression models. In premenopausal women, two environmental factors (history of breastfeeding, and history of benign breast disease) and four genetic variants (TOX3-rs3803662, ESR1-rs2046210, 8q24-rs13281615, and SLC4A7-rs4973768) were considered to be risk predictors, whereas three environmental factors (body mass index, history of breastfeeding, and hyperlipidemia), serum levels of testosterone and 25-hydroxyvitamin D, and two genetic variants (TOX3-rs3803662 and ESR1-rs2046210) were identified as risk predictors. Inclusion of common genetic variants and serum hormone measurements as well as environmental factors improved risk assessment models. The decline in the birthrate according to recent changes of lifestyle might be the main cause of the recent notable increase in the incidence of ER-positive breast cancer in Japanese women.

Background: Breast cancer is the most common invasive cancer among women and its incidence is increasing. Risk assessment is valuable and recent methods are incorporating novel biomarkers such as mammographic density. Artificial neural networks (ANN) are adaptive algorithms capable of performing pattern-to-pattern learning and are well suited for medical applications. They are potentially useful for calibrating Full-Field Digital Mammography (FFDM) for quantitative analysis. This study uses ANN modeling to estimate volumetric breast density (VBD) from FFDM on Japanese women with and without breast cancer. Methods: ANN calibration of VBD was performed using phantom data for one FFDM system. Mammograms of 46 Japanese women diagnosed with invasive carcinoma and 53 with negative findings were analyzed using ANN models learned. ANN-estimated VBD was validated against phantom data, compared intra-patient, with qualitative composition scoring, with MRI VBD, and inter-patient with classical risk factors of breast cancer as well as cancer status. Results: Phantom validations reached an R2 of 0.993. Intra-patient validations ranged from R2 of 0.789 with VBD to 0.908 with breast volume. ANN VBD agreed well with BI-RADS scoring and MRI VBD with R2 ranging from 0.665 with VBD to 0.852 with breast volume. VBD was significantly higher in women with cancer. Associations with age, BMI, menopause, and cancer status previously reported were also confirmed. Conclusions: ANN modeling appears to produce reasonable measures of mammographic density validated with phantoms, with existing measures of breast density, and with classical biomarkers of breast cancer. FFDM VBD is significantly higher in Japanese women with cancer.

Background: Few studies have been performed on post-relapse survival in patients with the early and late distant recurrence in estrogen receptor (ER)-positive, HER2-negative breast cancer. Methods: A total of 205 patients with the early distant recurrence and 134 patients with the late distant recurrence of ER-positive, HER2-negative breast cancer who had undergone breast surgery or neoadjuvant chemotherapy between January 2000 and December 2004 were registered from nine institutions. Prognostic factors for post-relapse survival in patients with the early and late recurrence were analyzed. Results: Post-relapse survival was significantly longer in patients with the late recurrence than in patients with the early recurrence. Predictive factors for post-relapse survival in patients with the early recurrence were lack of adjuvant chemotherapy, a long disease-free interval, and long durations of endocrine therapies and chemotherapies after relapse. In patients with the late recurrence, post-relapse survival was significantly improved for those individuals with one metastatic organ at relapse and individuals who were treated with the first-line and subsequent endocrine therapies for prolonged periods. Moreover, ER expression in primary breast tumors of late recurrence patients was significantly higher with a duration of the first-line endocrine therapy >6 months than in those with a duration ≤6 months. Conclusion: Predictors for prognosis after relapse differed between patients with the early and late distant recurrence. Endocrine responsiveness after relapse is a key factor for improved post-relapse survival, and it is thus important to establish whether metastatic tumors are endocrine-resistant in ER-positive, HER2-negative recurrent breast cancer.

Background: Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment. Methods: In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601). Results: Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14 % and 52 % of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25 % vs 67 % for clinical response, p = 0.011, N = 51; 0 % vs 41 % for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not. Conclusions: Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following e

Purpose: Recent studies have indicated that constitutive NF-κB activity could be involved in the proliferation of triple-negative breast cancer. Methods: NF-κB/p65 expression and the effects of the NF-κB inhibitor, (-)-DHMEQ were examined in triple-negative MDA-MB-231 breast cancer cells. Women with triple-negative breast cancer treated with neoadjuvant chemotherapy between 2002 and 2012 were retrospectively analyzed. Expression of NF-κB/p65, Bcl2 and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens, and predictive factors for neoadjuvant chemotherapy and prognosis were analyzed. Results: NF-κB/p65 was dominantly expressed in the cytoplasm in MDA-MB-231 cells. Of 34 triple-negative breast cancer patients, positive staining for NF-κB/p65 expression was detected in the nuclei of a few cells in 7 tumors before neoadjuvant chemotherapy, although expression of NF-κB/p65 in the cytoplasm was detected in almost all tumor cells of 33 tumors. Expression levels of NF-κB/p65 were not associated with response to neoaduvant chemotherapy, although expression levels of cytoplasmic NF-κB/p65 intensity were significantly decreased in post-treatment tumor samples compared with those in pretreatment samples. All patients whose tumors showed strong cytoplasmic NF-κB/p65 expression before neoadjuvant chemotherapy are currently disease-free. Conclusion: Our results suggest that strong cytoplasmic NF-κB/p65 expression could be a prognostic marker in triple-negative breast cancer.

Background: Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies. Methods: A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated. Results: Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms. Conclusions: Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.

Purpose: To compare the morphology and minimum apparent diffusion coefficient (ADC) values among breast cancer subtypes. Methods: Ninety-three patients, who underwent breast MRI and collectively had 98 pathologically proven invasive carcinomas, were enrolled. Morphology was evaluated according to BIRADS-MRI. Minimum ADC was measured. Morphology and minimum ADC were compared among subtypes. Multivariate logistic regression analyses were used to identify the characteristics associated with different subtypes. Results: Oval/round shape was significantly associated with triple-negative (TN) cancer (TN vs. non-TN: 90.9% vs. 45.2%; p = 0.0123). Rim enhancement was significantly less frequent in Luminal A (Luminal A vs. non-Luminal A: 34.2% vs. 76.1%; p = 0.0003). The minimum ADC of Luminal A was significantly higher than that of Luminal B (HER2-negative) (834 vs. 748 x 10^-6 mm2/s; p <0.025). The minimum ADC of the TN-special type was significantly higher than that of TN-ductal (997 vs. 702 x 10^-6 mm2/s; p <0.025). On the multivariate analysis comparing the characteristics associated with Luminal A vs. Luminal B (HER2-negative), the internal enhancement characteristics of the mass and minimum ADC were significant factors. Conclusion: Morphology and minimum ADC would be useful in distinguishing breast cancer subtypes.

Background: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. Methods: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than ten years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. Results: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. Conclusion: Predictors of early and late distant recurrence might differ according to menopausal status and age.

Background: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. Methods: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than ten years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. Results: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. Conclusion: Predictors of early and late distant recurrence might differ according to menopausal status and age.

Background: Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies. Methods: A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated. Results: Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms. Conclusions: Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.

Purpose: To compare the morphology and minimum apparent diffusion coefficient (ADC) values among breast cancer subtypes. Methods: Ninety-three patients, who underwent breast MRI and collectively had 98 pathologically proven invasive carcinomas, were enrolled. Morphology was evaluated according to BIRADS-MRI. Minimum ADC was measured. Morphology and minimum ADC were compared among subtypes. Multivariate logistic regression analyses were used to identify the characteristics associated with different subtypes. Results: Oval/round shape was significantly associated with triple-negative (TN) cancer (TN vs. non-TN: 90.9% vs. 45.2%; p = 0.0123). Rim enhancement was significantly less frequent in Luminal A (Luminal A vs. non-Luminal A: 34.2% vs. 76.1%; p = 0.0003). The minimum ADC of Luminal A was significantly higher than that of Luminal B (HER2-negative) (834 vs. 748 x 10^-6 mm2/s; p <0.025). The minimum ADC of the TN-special type was significantly higher than that of TN-ductal (997 vs. 702 x 10^-6 mm2/s; p <0.025). On the multivariate analysis comparing the characteristics associated with Luminal A vs. Luminal B (HER2-negative), the internal enhancement characteristics of the mass and minimum ADC were significant factors. Conclusion: Morphology and minimum ADC would be useful in distinguishing breast cancer subtypes.

Purpose: To compare the morphology and minimum apparent diffusion coefficient (ADC) values among breast cancer subtypes. Methods: Ninety-three patients, who underwent breast MRI and collectively had 98 pathologically proven invasive carcinomas, were enrolled. Morphology was evaluated according to BIRADS-MRI. Minimum ADC was measured. Morphology and minimum ADC were compared among subtypes. Multivariate logistic regression analyses were used to identify the characteristics associated with different subtypes. Results: Oval/round shape was significantly associated with triple-negative (TN) cancer (TN vs. non-TN: 90.9% vs. 45.2%; p = 0.0123). Rim enhancement was significantly less frequent in Luminal A (Luminal A vs. non-Luminal A: 34.2% vs. 76.1%; p = 0.0003). The minimum ADC of Luminal A was significantly higher than that of Luminal B (HER2-negative) (834 vs. 748 x 10^-6 mm2/s; p <0.025). The minimum ADC of the TN-special type was significantly higher than that of TN-ductal (997 vs. 702 x 10^-6 mm2/s; p <0.025). On the multivariate analysis comparing the characteristics associated with Luminal A vs. Luminal B (HER2-negative), the internal enhancement characteristics of the mass and minimum ADC were significant factors. Conclusion: Morphology and minimum ADC would be useful in distinguishing breast cancer subtypes.

Background: Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies. Methods: A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated. Results: Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms. Conclusions: Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.

Background: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. Methods: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than ten years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. Results: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. Conclusion: Predictors of early and late distant recurrence might differ according to menopausal status and age.

Background: Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies. Methods: A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated. Results: Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms. Conclusions: Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.

Purpose: To compare the morphology and minimum apparent diffusion coefficient (ADC) values among breast cancer subtypes. Methods: Ninety-three patients, who underwent breast MRI and collectively had 98 pathologically proven invasive carcinomas, were enrolled. Morphology was evaluated according to BIRADS-MRI. Minimum ADC was measured. Morphology and minimum ADC were compared among subtypes. Multivariate logistic regression analyses were used to identify the characteristics associated with different subtypes. Results: Oval/round shape was significantly associated with triple-negative (TN) cancer (TN vs. non-TN: 90.9% vs. 45.2%; p = 0.0123). Rim enhancement was significantly less frequent in Luminal A (Luminal A vs. non-Luminal A: 34.2% vs. 76.1%; p = 0.0003). The minimum ADC of Luminal A was significantly higher than that of Luminal B (HER2-negative) (834 vs. 748 x 10^-6 mm2/s; p <0.025). The minimum ADC of the TN-special type was significantly higher than that of TN-ductal (997 vs. 702 x 10^-6 mm2/s; p <0.025). On the multivariate analysis comparing the characteristics associated with Luminal A vs. Luminal B (HER2-negative), the internal enhancement characteristics of the mass and minimum ADC were significant factors. Conclusion: Morphology and minimum ADC would be useful in distinguishing breast cancer subtypes.

Background: Most studies analyzing prognostic factors for late relapse have been performed in postmenopausal women who received tamoxifen or aromatase inhibitors as adjuvant endocrine therapy for estrogen receptor (ER)-positive breast cancer. Methods: A total of 223 patients (108 premenopausal and 115 postmenopausal) with early distant recurrence and 149 patients (62 premenopausal and 87 postmenopausal) with late distant recurrence of ER-positive, HER2-negative breast cancer who were given their initial treatment between 2000 and 2004 were registered from nine institutions. For each late recurrence patient, approximately two matched control patients without relapse for more than ten years were selected. Clinicopathological factors and adjuvant therapies were compared among the three groups by menopausal status and age. Results: Factors predicting early recurrence in premenopausal women were large tumor size, high lymph node category and high tumor grade, whereas predictors for late recurrence were large tumor size and high lymph node category. In postmenopausal women under 60 years of age, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, low PgR expression and high Ki67 labeling index (LI), while predictors for late recurrence were large tumor size and high lymph node category. On the other hand, in postmenopausal women aged 60 years or older, factors predicting early recurrence were bilateral breast cancer, large tumor size, high lymph node category, high tumor grade, low ER expression and high Ki67 LI, whereas predictors for late recurrence were high lymph node category, low ER expression and short duration of adjuvant endocrine therapy. Conclusion: Predictors of early and late distant recurrence might differ according to menopausal status and age.

Objectives: To determine the added discriminative value of detailed quantitative characterization of background parenchymal enhancement in addition to the tumor itself on dynamic contrast-enhanced (DCE) MRI at 3.0 Tesla in identifying "triple-negative" breast cancers. Materials and Methods: In this Institutional Review Board-approved retrospective study, DCE-MRI of 84 women presenting 88 invasive carcinomas were evaluated by a radiologist and analyzed using quantitative computer-aided techniques. Each tumor and its surrounding parenchyma were segmented semi-automatically in 3-D. A total of 85 imaging features were extracted from the two regions, including morphologic, densitometric, and statistical texture measures of enhancement. A small subset of optimal features was selected using an efficient sequential forward floating search algorithm. To distinguish triple-negative cancers from other sub-types, we built predictive models based on support vector machines. Their classification performance was assessed with the area under receiver operating characteristic curve (AUC) using cross-validation. Results: Imaging features based on the tumor region achieved an AUC of 0.782 in differentiating triple-negative cancers from others, in line with the current state of the art. When background parenchymal enhancement features were included, the AUC increased significantly to 0.878 (p<0.01). Similar improvements were seen in nearly all subtype classification tasks undertaken. Notably, amongst the most discriminating features for predicting triple-negative cancers were textures of background parenchymal enhancement. Conclusions: Considering the tumor as well as its surrounding parenchyma on DCE-MRI for radiomic image phenotyping provides useful information for identifying triple-negative breast cancers. Heterogeneity of background parenchymal enhancement, characterized by quantitative texture features on DCE-MRI, adds value to such differentiation models as they are strongly ass

Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype. Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) < 14 %) and 22 as luminal B (Ki67 LI a parts per thousand yen 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype. It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.

Objectives: To determine the added discriminative value of detailed quantitative characterization of background parenchymal enhancement in addition to the tumor itself on dynamic contrast-enhanced (DCE) MRI at 3.0 Tesla in identifying "triple-negative" breast cancers. Materials and Methods: In this Institutional Review Board-approved retrospective study, DCE-MRI of 84 women presenting 88 invasive carcinomas were evaluated by a radiologist and analyzed using quantitative computer-aided techniques. Each tumor and its surrounding parenchyma were segmented semi-automatically in 3-D. A total of 85 imaging features were extracted from the two regions, including morphologic, densitometric, and statistical texture measures of enhancement. A small subset of optimal features was selected using an efficient sequential forward floating search algorithm. To distinguish triple-negative cancers from other sub-types, we built predictive models based on support vector machines. Their classification performance was assessed with the area under receiver operating characteristic curve (AUC) using cross-validation. Results: Imaging features based on the tumor region achieved an AUC of 0.782 in differentiating triple-negative cancers from others, in line with the current state of the art. When background parenchymal enhancement features were included, the AUC increased significantly to 0.878 (p<0.01). Similar improvements were seen in nearly all subtype classification tasks undertaken. Notably, amongst the most discriminating features for predicting triple-negative cancers were textures of background parenchymal enhancement. Conclusions: Considering the tumor as well as its surrounding parenchyma on DCE-MRI for radiomic image phenotyping provides useful information for identifying triple-negative breast cancers. Heterogeneity of background parenchymal enhancement, characterized by quantitative texture features on DCE-MRI, adds value to such differentiation models as they are strongly ass

Recent studies have indicated that response to chemotherapy and the prognostic impact of a pathologic complete response (pCR) after neoadjuvant chemotherapy differ among breast cancer subtypes. Women with Stage I to III breast cancer treated with anthracycline and taxane-based neoadjuvant chemotherapy (four cycles of docetaxel every 3 weeks followed by four cycles of FEC every 3 weeks) between 2006 and 2011 were retrospectively analyzed. Trastuzumab was concurrently added to docetaxel for HER2-positive breast cancer. Expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67 was examined by immunohistochemistry in pre- and post-treatment specimens. Predictive factors for neoadjuvant chemotherapy and prognosis were analyzed by breast cancer subtype. Of 64 patients, 30 (47 %) were ER-positive (ER+) HER2-negative (HER2-), including eight as luminal A (Ki67 labeling index (LI) < 14 %) and 22 as luminal B (Ki67 LI a parts per thousand yen 14 %) subtypes, 11 (17 %) were ER+ HER2-positive (HER2+), 12 (19 %) were ER-negative (ER-) HER2+, and 11 (17 %) were ER- HER2-. The clinical response rates were significantly higher in luminal B, ER+ HER2+, and ER- HER2+ subtypes compared with luminal A subtype. Patients whose tumors contained high Ki67 expression effectively responded to neoadjuvant chemotherapy. Ki67 LI was a predictive marker for pCR, and all patients whose tumors achieved pCR are currently disease-free. Furthermore, high Ki67 expression in post-treatment tumors was strongly correlated with poor disease-free and overall survival regardless of subtype. It is necessary to establish additional strategies to improve survival for patients whose residual tumors show high Ki67 expression after neoadjuvant chemotherapy.

Objectives: To determine the added discriminative value of detailed quantitative characterization of background parenchymal enhancement in addition to the tumor itself on dynamic contrast-enhanced (DCE) MRI at 3.0 Tesla in identifying "triple-negative" breast cancers. Materials and Methods: In this Institutional Review Board-approved retrospective study, DCE-MRI of 84 women presenting 88 invasive carcinomas were evaluated by a radiologist and analyzed using quantitative computer-aided techniques. Each tumor and its surrounding parenchyma were segmented semi-automatically in 3-D. A total of 85 imaging features were extracted from the two regions, including morphologic, densitometric, and statistical texture measures of enhancement. A small subset of optimal features was selected using an efficient sequential forward floating search algorithm. To distinguish triple-negative cancers from other sub-types, we built predictive models based on support vector machines. Their classification performance was assessed with the area under receiver operating characteristic curve (AUC) using cross-validation. Results: Imaging features based on the tumor region achieved an AUC of 0.782 in differentiating triple-negative cancers from others, in line with the current state of the art. When background parenchymal enhancement features were included, the AUC increased significantly to 0.878 (p<0.01). Similar improvements were seen in nearly all subtype classification tasks undertaken. Notably, amongst the most discriminating features for predicting triple-negative cancers were textures of background parenchymal enhancement. Conclusions: Considering the tumor as well as its surrounding parenchyma on DCE-MRI for radiomic image phenotyping provides useful information for identifying triple-negative breast cancers. Heterogeneity of background parenchymal enhancement, characterized by quantitative texture features on DCE-MRI, adds value to such differentiation models as they are strongly