Real-world data analysis of perioperative chemotherapy patterns, G-CSF use, and FN status in patients with early breast cancer.

PURPOSE: This study aimed to describe perioperative chemotherapy patterns, granulocyte colony-stimulating factor (G-CSF) use, and febrile neutropenia (FN) status in patients with early breast cancer (EBC) using real-world data in Japan. METHODS: This retrospective observational study used anonymized claims data. The included patients were ≥ 18 years old, were female, and had breast cancer diagnosis and surgery records between January 2010 and April 2020. Measures included perioperative chemotherapy, G-CSF use (daily and primary prophylaxis [PP]), and FN and FN-related hospitalization (FNH), all examined annually. Perioperative chemotherapy was examined separately for human epidermal growth factor receptor 2-positive/negative (HER2±). A multivariate logistic regression was used to explore the factors associated with FNH. RESULTS: Of 32,597 patients, those with HER2 + EBC treated with anthracycline-based regimens followed by taxane + trastuzumab + pertuzumab increased since 2018, and those with HER2 - EBC treated with doxorubicin/epirubicin + cyclophosphamide followed by taxane and dose-dense regimens increased after 2014. The proportion of patients prescribed daily G-CSF declined after 2014, whereas that of pegfilgrastim PP increased. The incidence proportion of FN remained at approximately 24-31% from 2010 to 2020, while that of FNH declined from 14.5 to 4.0%. The odds of FNH were higher in those aged ≥ 65 years and lower with pegfilgrastim PP administration. CONCLUSION: Despite the increasing use of escalated regimens in the last 5-6 years, FNH continuously declined, and the odds of FNH were lower among patients treated with pegfilgrastim PP. These results may suggest the contribution of PP in part to suppressing FNH levels over the last 5-6 years.

Breast Cancer, Diabetes Mellitus and Glucagon-Like Peptide-1 Receptor Toward Exploring Their Possible Associations.

PURPOSE: Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology. METHODS: We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues. RESULTS: GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070). CONCLUSION: These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM patients.

Impact of Topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy.

PURPOSE: Triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy (NAC) harbor higher risk of relapse, and eventual demise compared to those who achieve pathologic complete response. Therefore, in this study, we assessed a panel of molecules involved in key pathways of drug resistance and tumor progression before and after NAC in TNBC patients, in order to clarify the underlying mechanisms. METHODS: We studied 148 TNBC Japanese patients treated with anthracycline/taxane-based NAC. KI67, Topoisomerase IIα (TopoIIα), PTEN, p53, Bcl2, vimentin, ABCG2/BCRP1, ABCB1/MDR1, and ABCC1/MRP1 were immunolocalized in surgical pathology materials before and after NAC. RESULTS: The status of vimentin and increasing labeling index (LI) of TopoIIα and KI67 in biopsy specimens were significantly associated with those who responded to NAC treatment. The abundance of p53 (p = 0.003), ABCC1/MRP1 (p = 0.033), ABCB1/MDR1 (p = 0.022), and a loss of PTEN (p < 0.0001) in surgery specimens following treatment were associated with pathologic parameters. TopoIIα, PTEN, and ABCC1/MRP1 status predicted pathologic response. In addition, the status of PTEN, ABCC1/MRP1, ABCB1/MDR1, Bcl2, and vimentin in surgical specimens was also significantly associated with adverse clinicopathological factors in surgery specimens, suggesting that these alterations could be responsible for tumor relapse in TNBC patients. CONCLUSION: KI67, TopoIIα, PTEN, and ABCC1/MRP1 status could predict treatment response and/or eventual clinical outcomes. These results could also provide an insight into the mechanisms of drug resistance and relapse of TNBC patients receiving NAC.

Randomized trial of aromatherapy versus conventional care for breast cancer patients during perioperative periods.

PURPOSE: Several studies focused on the effect of aromatherapy on mood, quality of life (QOL), and physical symptoms in patients with cancer. We compared the effects on QOL, vital signs, and sleep quality between aromatherapy and conventional therapy during perioperative periods of the breast cancer patients in this study. METHODS: Patients were randomly assigned in a 2:1 ratio to receive aromatherapy or usual care. The primary endpoint was QOL, which was assessed using the quality of life questionnaire QLQ-C30, Version 3.0 of the European Organization for Research and Treatment of Cancer (EORTC) Study Group on quality of life. Secondary endpoints included the necessity of hypnotics, vital signs including blood pressure and heart rate and adverse events. In addition, we also summarized the patients' perception of the experience from a free description-type questionnaire. RESULTS: A total of 249 patients had breast cancer surgery and 162 patients gave physician consent and were recruited; 110 were randomly assigned to aromatherapy group (eight patients showed incomplete EORTC QLQ-C30) and 52 to control group (one patient showed incomplete EORTC QLQ-C30). There were no statistically significant differences between the aromatherapy group and control group in the EORTC QLQ-C30 at the surgery day. As for the results of the post-operation day 1, trends for differentiations of physical functioning and role functioning were detected between aromatherapy group and control group, but the differences did not reach statistical significance (p = 0.08 and 0.09). There were no significant differences of systolic and diastolic blood pressures between aromatherapy group and control group (p = 0.82 and 0.68). There was no statistically significant difference in heart rates between aromatherapy group (70.6 ± 11.0 bpm) and control group (71.2 ± 9.8 bpm) (p = 0.73). Likewise, the rate of hypnotic use was not statistically significant (p = 0.10). No adverse events were reported after aromatherapy and all impressions from aromatherapy group were positive with descriptors such as relaxed, comfortable, and enjoyable being common. CONCLUSION: The results showed no effects of aromatherapy on QOL, sleep quality, and vital sign. However, there was not any harm or adverse event for using aromatherapy. All impressions from self-reporting were positive such as relaxed, comfortable, and enjoyable by the aromatherapy group. Therefore, we can use aromatherapy during perioperative periods in order to meet the expectations of the patients.

[Selection of goal-directed information triggers removal of irrelevant information from working memory].

This study investigated the triggers for removing irrelevant information from working memory. Based on the perspective that removal is a unique process of updating working memory (Ecker et al., 2010), we hypothesized that the removal process begins after selection of task-relevant information. To test this hypothesis, we employed a modified Sternberg task that reflects the time-course for the removal of information. In a standard procedure of this task, the removal process is thought to be completed in approximately 1,500 ms after directing relevant information. If selection induces removal, removal might not end within 1,500 ms when selection requires more time. To increase the time for selection, we created a circumstance with high interference. Experiment 1 showed that removal was incomplete within 2,000 ms after directing relevant information. Experiment 2 showed that removal could be completed given more time. These results support the hypothesis that the trigger for the removal process is the completion of selection. This is in consistent with recent frameworks concerning executive functions.

Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas.

The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17ß-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17ßHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17ßHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs.

Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC.

Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study.

INTRODUCTION: The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8(+) TILs and FOXP3(+) TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these parameters before and after NAC in patients with triple-negative breast cancer (TNBC). METHODS: One hundred thirty-one TNBC patients who received NAC at three institutions were examined. CD8(+) TIL and FOXP3(+) TIL in residual tumors and biopsy specimens were evaluated by double-staining immunohistochemistry. The CD8(+) TIL and FOXP3(+) TIL status of the residual tumors was assessed, and the rates of their changes before and after NAC were calculated. RESULTS: TNBC patients with high CD8(+) TIL levels or a high CD8/FOXP3 ratio in residual tumors had significantly better recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) than patients with low values of these parameters. In multivariate analyses, CD8(+) TIL exhibited strong prognostic significance for RFS, with a hazard ratio (HR) of 3.09 (95 % confidence interval (CI) 1.537-6.614, P=0.0013). The CD8/FOXP3 ratio was also significantly correlated with RFS (HR=2.07, 95 % CI 1.029-4.436, P=0.0412). TNBC with larger residual tumor size and positive lymph node status, which are known prognostic factors, was independently associated with worse RFS (P=0.0064 and P=0.0015, respectively). High CD8(+) TIL levels were a markedly powerful indicator of improved BCSS, with an HR of 3.59 (95 % CI 1.499-9.581, P=0.0036). Nodal status was also associated with BCSS (P=0.0024). TNBC with a high rate of CD8(+) TIL changes was associated with significantly better RFS compared with the low group (P=0.011). Higher rates of changes in the CD8/FOXP3 ratio were significantly correlated with both better RFS and BCSS compared with lower rates (P=0.011 and P=0.023, respectively). CONCLUSIONS: This is the first study to demonstrate that high CD8(+) TIL and a high CD8/FOXP3 ratio in residual tumors and increment of these parameters following NAC and accurately predict improved prognosis in TNBC patients with non-pathological complete response following NAC. These parameters could serve as a surrogate one for adjuvant treatment in patients with residual disease in the neoadjuvant setting.

Can we improve breast cancer mortality in Okinawa? Consensus of the 7th Okinawa Breast Oncology Meeting.

The rate of breast cancer mortality in Okinawa has gradually been increasing up to 2010. Now Okinawa has the second worst mortality rate in Japan, in part due to the enormous dietary changes resulting from the post-World War II US military occupation, high incidence of obesity, high non-optimal treatment rate, and low breast-cancer screening rate. To reduce breast cancer mortality in Okinawa, we established the Okinawa Breast Oncology Meeting (OBOM) in 2012. At the 7th OBOM held on January 10th, 2014, we discussed the breast cancer mortality in Okinawa focusing on lifestyle, breast cancer screening and optimal treatments. The Okinawan women who were overweight and/or obese during premenopausal and postmenopausal ages had a statistically significant higher risk of breast cancer development compared to those with non-overweight and/or obese women. The traditional diet of Okinawa consists of foods low in calories but rich in nutritional value. Therefore, we recommend Okinawan people not to forget the Okinawan traditional lifestyle, and to reduce their bodyweight to prevent breast cancer. One of the main goals of the OBOM is to raise breast cancer screening attendance rates to 50% (29.2% in 2010). We should standardize the quality control for breast cancer screening in Okinawa. It is important to continue enlightening the Okinawan population to receive optimal treatment. In addition, we are striving to establish systematic medical cooperation between the hospitals specializing in breast cancer treatment with rural hospitals. The OBOM group endeavors to contribute to the improvement of breast cancer mortality in Okinawa.

Intratumoral androgen metabolism and actions in invasive lobular carcinoma of the breast.

Invasive lobular carcinoma (ILC) accounts for approximately 10% of all breast carcinomas and is characterized by higher levels of androgen receptor (AR) compared to invasive ductal carcinoma (IDC). Despite this potentially androgen-responsive environment, the combined importance of AR and androgen metabolism in non-neoplastic lobules and lobular carcinoma remains unknown. Therefore, in this study, we evaluated the status of pivotal androgen-producing enzymes 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5) and 5α-reductase type 1 (5αRed1) in 178 cases of ILC and surrounding histologically non-neoplastic lobular tissue using immunohistochemistry. Androgen receptor prevalence was higher but androgenic enzymes lower in ILC than non-neoplastic lobules. In ILC cases the status of 5αRed1 and 17ßHSD5 was inversely correlated with tumor size (P = 0.0053) and nuclear grade (P = 0.0290), and significantly associated with better overall survival of the patients (P = 0.0059). Based on these findings, we hypothesized that androgen signaling could act as a tumor suppressor. As previous studies suggested that androgens might partially act by increasing levels of the estrogen inactivating enzyme 17ß-hydroxysteroid dehydrogenase type 2 (17ßHSD2) in IDC tissues, this was reasonably considered a potential mechanism of androgen actions. Significantly positive correlation was detected between the status of androgenic enzymes and 17ßHSD2 (P < 0.0001) and intratumoral 17ßHSD2 was inversely correlated with tumor size in ILC (P = 0.0075). These correlations suggest one protective mode of androgen action could be through modulation of estrogen metabolism. Results of our present study indicated that androgen-producing enzymes could play pivotal protective roles in AR-enriched ILC cases.

Tumor-infiltrating CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with pathological complete response to neoadjuvant chemotherapy.

The anti-tumor immune response was recently reported to play a critical role in the chemotherapeutic sensitivity of breast cancer. Therefore, we investigated the correlation between CD8+ and FOXP3+ tumor-infiltrating lymphocytes and the pathological complete response (pCR) following neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), in conjunction with neoangiogenesis, basal and proliferation markers. CD8+ and FOXP3+ lymphocytes were assessed in biopsy specimens by double-staining immunohistochemistry, in combination with immunostaining of vasohibin-1, CD31, EGFR, CK5/6, and Ki-67. Earlier age, pre-menopausal status, smaller tumor size, and high Ki-67 were significantly associated with pCR, as in high CD8+, high CD8+/FOXP3+ ratio, and low vasohibin-1 positive ratio. Multivariate analysis did reveal that a high CD8+/FOXP3+ ratio was a strong predictor of pCR with an odds ratio of 5.32 (P = 0.005). High Ki-67 was also significantly associated with pCR (P = 0.002). TNBCs with a high CD8+/FOXP3+ ratio and high Ki-67 had the highest pCR rate (70%) following NAC. However, the pCR rate of the patients with low CD8+/FOXP3+ ratio and low Ki-67 was only 5%. The pCR rates of a high CD8+/FOXP3+ ratio and low Ki-67 patients and those with a low CD8+/FOXP3+ ratio and high Ki-67 were 24 and 21%, respectively. TNBCs with a high CD8+/FOXP3+ ratio were more sensitive to anthracycline and taxane-based chemotherapeutic regimens, and the CD8+/FOXP3+ ratio in conjunction with Ki-67 could predict pCR following NAC in TNBC. This predictor may represent a new surrogate for testing the efficacy of investigational agents in the neoadjuvant setting.

Androgenic pathways in the progression of triple-negative breast carcinoma: a comparison between aggressive and non-aggressive subtypes.

One of the active intracellular pathways/networks in triple-negative breast carcinoma (TNBC) is that of the androgen receptor (AR). In this study, we examined AR and androgen-metabolising enzyme immunoreactivity in subcategories of TNBC to further elucidate the roles of androgenic pathways in TNBC. We utilised formalin-fixed paraffin-embedded breast cancer samples from ductal carcinoma in situ (DCIS) and invasive ductal carcinoma patient cohorts. We then used immunohistochemistry to classify these samples into basal-like and non-basal samples and to assess interactions between AR, androgen-metabolising enzymes and proliferation. To further substantiate our hypothesis and provide mechanistic insights, we also looked at the expression and regulation of these factors in publically available microarray data and in a panel of TNBC AR-positive cell lines. DCIS was associated with higher levels of AR and enzymes (p < 0.02), although a similar difference was not noticed in basal and non-basal samples. AR and enzymes were correlated in all states. In TNBC cell lines (MDA-MD-453, MFM-223 and SUM185-PE), we found that DHT treatment up-regulated 5αR1 and 17ßHSD5 suggesting a mechanistic explanation for the correlations observed in the histological samples. Publicly available microarray data in TNBC cases suggested similar patterns to those observed in histological samples. In the majority of settings, including publically available microarray data, an inverse association between AR and proliferation was detected. These findings suggest that decreases in AR and androgen-metabolising enzymes may be involved in the increased biological aggressiveness in TNBC development.

The correlation between body mass index and breast cancer risk or estrogen receptor status in Okinawan women.

Dietary changes resulting from the post-World War II occupation of Okinawa by the US military have been largely deleterious, resulting in a marked increase of obesity among Okinawan residents. In this study, we examined the association between BMI and the risk of developing breast cancer according to the menstruation status and age, and the correlation between BMI and expression of estrogen receptor (ER). Breast cancer cases were 3,431 females without any personal or family history of breast cancer. Control subjects were 5,575 women drawn from the clinical files of Nahanishi Clinic. We found that women, who were overweight or obese, regardless of menopausal stage, had a higher risk of breast cancer compared to women with normal weight and this difference was statistically significant (p < 0.001, respectively). This risk was especially apparent in older (> 40 years) overweight or obese women. The women who were overweight or obese during postmenopausal ages were at higher risk of ER-positive breast cancer compared to women with normal weight. Results of our present study clearly indicate that increased BMI was associated with increased risk of developing breast cancer in Okinawan women, regardless of menopausal status. In addition, there was statistically significant correlation between BMI and ER expression in the postmenopausal period. Given the obesity epidemic associated with the extreme sociological and dietary changes brought about by the post-war occupation of Okinawa, the present study provides essential guidelines on the management, treatment and future breast cancer risk in Okinawa.

[Observing grasping action from egocentric perspective modulates observer's visual attention].

Previous studies demonstrated that observing another person's grasp action modulated the observer's attention to the object in a manner congruent with another person's action goal. These studies suggest that this grasp-cueing effect results from representation of the observer's understanding of action intention in the mirror neuron system. This system serves as the neural mechanism underlying action-oriented goals, regardless of whether they are those of the observer or others. The present study examined whether the grasp-cueing effect emerged even when a grasp action was observed from an egocentric (observer's own) perspective. Reaction times were faster when the target was presented over the object that was congruent with the action goal implied by the size of the hand aperture. This indicated that the grasp cueing effect occurred when the stimulus was observed from an egocentric perspective, consistent with the view that this effect resulted from the observer's understanding of action intention as represented in the mirror neuron system.

Hexokinase II in breast carcinoma: a potent prognostic factor associated with hypoxia-inducible factor-1α and Ki-67.

Hypoxia-inducible factor-1α (HIF-1α) mediates adaptive responses to changes under tissue hypoxia in carcinoma cells by controlling the expression of various target genes. Previous studies have demonstrated that HIF-1α is associated with adverse clinical outcome in breast carcinoma patients, but details of HIF-1α's role have remained largely unknown. Therefore, in this study, we examined the expression profiles of HIF-1α-induced genes in 10 breast carcinoma cases using microarray data. As a result, we demonstrated that the status of hexokinase II (HKII) was associated with carcinoma recurrence in patients with these genes. The enzyme HKII is involved in the first, and rate-limiting, step of glycolysis, but its clinical significance has not yet been examined in breast carcinoma. Therefore, we immunolocalized HKII in 118 breast carcinomas, and HKII immunoreactivity was detected in 44% of the cases. It is significantly associated with histological grade, Ki-67 labeling index and HIF-1α immunoreactivity. Also, HKII status is significantly associated with increased risk of recurrence and adverse clinical outcome in breast cancer patients. Subsequent multivariate analysis demonstrated that HKII status was an independent prognostic factor for disease-free survival of patients. These results all suggest that HKII is induced by HIF-1α and plays important roles in the proliferation and/or progression of breast carcinoma possibly through increased glycolytic activity. The status of HKII is therefore considered a potent prognostic factor in human breast cancer patients.

Androgenic pathway in triple negative invasive ductal tumors: its correlation with tumor cell proliferation.

Triple negative breast cancer (TNBC) is defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 negativity. Patients with TNBC frequently undergo an aggressive clinical course due to the unavailability of specific targeted therapies. Androgen receptor (AR) was reported to be expressed in up to 60% of TNBC cases but there have been controversies as to the roles of androgen signaling through AR in TNBC. Therefore, in this study, we analyzed the status of AR in combination with androgen synthesizing enzymes (5α-reductase type 1 (5αR1) and 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5)] in order to further understand androgenic actions in TNBC. Androgen receptor, 5αR1, and 17ßHSD5 were immunolocalized in a cohort of 203 TNBC patients from Thailand and Japan. We then correlated the findings with clinicopathological characteristics (age, stage, tumor diameter, lymph node invasion, metastatic spread, Ki-67 labeling index, disease-free survival, and overall survival) of the patients. Univariate analysis revealed that AR+/enzyme+ cases were associated with a significantly lower Ki-67 labeling index than AR-/enzyme- samples. Multivariate analysis indicated the presence of significant positive correlations between AR and enzyme status in tumor cells, and between tumor diameter, lymph node invasion, and distant metastasis. Significant negative correlations were also detected between Ki-67 labeling index and AR status (P = 0.04) or 5αR1 (P < 0.001). Cox proportional hazards analysis showed that Ki-67 labeling index and stage were the only factors predicting disease-free and overall survival of the patients, although univariate Kaplan-Meier analysis revealed AR/5αR1 negativity suggested a more adverse clinical course up to 80 months after surgery. These results suggest that the presence of androgen synthesizing pathways in addition to AR expression in tumor cells could confer a better clinical outcome through suppression of cell proliferation.

Clinical significance following breast conservation therapy with or without irradiation in breast cancer patients.

BACKGROUND: We retrospectively examined the clinical outcome of irradiated versus non-irradiated groups of Japanese breast cancer patients according to their clinical and histopathological characteristics following breast-conserving therapy. METHODS: We retrospectively evaluated a total of 1197 Japanese female breast cancer patients (598 irradiated and 599 non-irradiated) who received breast-conserving therapy. The median age of the patients was 54 years (range: 24-99 years). We retrospectively examined the local recurrence-free survival rates in those with or without post-operative irradiation according to age, surgical margin status and histopathological characteristics including histological grade, estrogen receptor expression and HER2 status. RESULTS: Local recurrence-free survival rates in the irradiated group were significantly higher than those in the non-irradiated group, especially in surgical margin-positive [hazard ratio (HR): 0.334, 95% confidence interval: 0.14-0.79, P = 0.001], estrogen receptor-positive (HR: 0.249, 95% confidence interval: 0.11-0.54, P < 0.001), HER2-negative (HR: 0.382, 95% confidence interval: 0.21-0.69, P = 0.001) and non-triple-negative (HR: 0.382, 95% confidence interval: 0.21-0.69, P = 0.001) breast cancer patients. CONCLUSION: The results indicated that irradiation after breast-conserving therapy is strongly recommended in Japanese breast cancer patients, especially those with surgically positive margins, estrogen receptor-positive tumors and HER2-negative invasive breast cancers.

A non-invasive modality: the US virtual touch tissue quantification (VTTQ) for evaluation of breast cancer.

OBJECTIVE: We evaluated the biologic features of breast tissues using a newly developed non-invasive diagnostic system, named virtual touch tissue quantification. METHODS: A total of 180 patients including 115 invasive ductal carcinoma, 30 ductal carcinoma in situ, 4 mucinous carcinoma, 7 invasive lobular carcinoma, 8 fibroadenoma, 12 fibrocystic change and 4 intraductal papilloma were studied at Nahanishi Clinic, Okinawa. We first compared the results of virtual touch tissue quantification according to each histologic subtype and determined the optimal cutoff values for virtual touch tissue quantification to distinguish benign from malignant tissues, using the receiver operating characteristic method. In addition, we also examined the correlation between virtual touch tissue quantification velocities and Ki-67, estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2 in cases of invasive ductal carcinoma using linear regression analyses and Student's t-test. RESULTS: Virtual touch tissue quantification velocities were statistically higher in malignant cases than in benign cases (P < 0.05, respectively) and the best cutoff value for the virtual touch tissue quantification velocity which could differentiate benign from malignant cases was 2.89 m/s. There were statistically significant correlations between the virtual touch tissue quantification velocity and the Ki-67 labeling index (r = 0.338, r(2) = 0.114 and P < 0.001) and significant inverse correlations between virtual touch tissue quantification and the estrogen receptor (r = -0.311, r(2) = 0.097 and P < 0.001) or progesterone receptor (r = -0.361, r(2) = 0.131 and P < 0.001) status of invasive ductal carcinoma. There were also significant differences of the average velocities between human epidermal growth factor receptor 2-positive (6.39 ± 1.44 m/s) and -negative (4.43 ± 1.41 m/s) cases (P < 0.001). CONCLUSION: Virtual touch tissue quantification could be a valuable clinical tool for estimating breast cancer pathology in a non-invasive fashion.

The challenge to reduce breast cancer mortality in Okinawa: consensus of the first Okinawa breast oncology meeting.

Breast cancer mortality is gradually increasing in Okinawa. The 1st Okinawa Breast Oncology Meeting was held on 6 July 2012 and discussions on how to curb the rising trend were focused on breast cancer screening, adjuvant treatment, socioeconomic and geographic issues, and the problem of complementary and alternative medicine. The consensus of the 1st Okinawa Breast Oncology Meeting was that ultrasonography screening is an acceptable screening system for Okinawan women because of the geographic disadvantage of having many small islands and rural areas. Educational and economic support is needed for women in rural areas to get correct information, for access to urban areas and to be treated by evidence-based optimal therapy for breast cancer. In addition, new approaches are needed for Okinawan people to successfully educate patients to correctly interpret evidence-based information.