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.

Quantitative digital image analysis of tumor-infiltrating lymphocytes in HER2-positive breast cancer.

As visual quantification of the density of tumor-infiltrating lymphocytes (TILs) lacks in precision, digital image analysis (DIA) approach has been applied in order to improve. In several studies, TIL density has been examined on hematoxylin and eosin (HE)-stained sections using DIA. The aim of the present study was to quantify TIL density on HE sections of core needle biopsies using DIA and investigate its association with clinicopathological parameters and pathological response to neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The study cohort comprised of patients with HER2-positive breast cancer, all treated with neoadjuvant anti-HER2 therapy. DIA software applying machine learning-based classification of epithelial and stromal elements was used to count TILs. TIL density was determined as the number of TILs per square millimeter of stromal tissue. Median TIL density was 1287/mm2 (range, 123-8101/mm2). A high TIL density was associated with higher histological grade (P = 0.02), estrogen receptor negativity (P = 0.036), and pathological complete response (pCR) (P < 0.0001). In analyses using receiver operating characteristic curves, a threshold TIL density of 2420/mm2 best discriminated pCR from non-pCR. In multivariate analysis, high TIL density (> 2420/mm2) was significantly associated with pCR (P < 0.0001). Our results indicate that DIA can assess TIL density quantitatively, machine learning-based classification algorithm allowing determination of TIL density as the number of TILs per unit area, and TIL density established by this method appears to be an independent predictor of pCR in HER2-positive breast cancer.

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.

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.

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.

Non-invasive evaluation of axillary lymph node status in breast cancer patients using shear wave elastography.

Less invasive procedures are currently required to examine the axillary lymph node status. Shear wave elastography with acoustic radiation force impulse provides objective and reproducible quantification of the intrinsic property of the soft tissue. In this study, we measured shear wave velocity of the axillary lymph nodes of patients with breast cancer using Virtual Touch Tissue Quantification (VTTQ). The degree of lymph node metastasis was evaluated by measuring the expression level of cytokeratin 19 (CK19) mRNA, a specific marker for breast cancer cells. The one-step nucleic acid amplification (OSNA) was used to determine the copy number of CK19 mRNA in 149 lymph node specimens of 149 primary breast cancer patients. Axillary lymph node status according to OSNA (copy number/µl) were categorized as 0-249 copies (-), 250-5,000 copies (+), and copy number > 5,000 (++). A category (-) represents no metastasis in the axillary lymph node. There were 121 patients with OSNA-, 9 with OSNA+ and 19 with OSNA++. The average velocities according to OSNA categories were 1.64 ± 0.42 m/second for OSNA-, 2.25 ± 0.78 m/second for OSNA+, and 2.79 ± 0.98 m/second for OSNA++. There were significant differences in the shear wave velocity between OSNA- and OSNA+ (P = 0.040) or OSNA++ (P < 0.001). The most optimal cutoff velocity to distinguish benign from metastasis is 1.44 m/second, as determined using the receiver operating characteristic method. The shear wave velocity measured with VTTQ could provide clinically useful information about axillary lymph node metastasis in patients with primary breast cancer.

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.

Breast ultrasonographic and histopathological characteristics without any mammographic abnormalities.

OBJECTIVE: We evaluated ultrasonographic findings and the corresponding histopathological characteristics of breast cancer patients with Breast Imaging Reporting and Data System (BI-RADS) category 1 mammogram. METHODS: We retrospectively reviewed the ultrasonographic findings and the corresponding histopathological features of 45 breast cancer patients with BI-RADS category 1 mammogram and 537 controls with mammographic abnormalities. We evaluated the ultrasonographic findings including mass shape, periphery, internal and posterior echo pattern, interruption of mammary borders and the distribution of low-echoic lesions, and the corresponding histopathological characteristics including histological classification, hormone receptor and human epidermal growth factor receptor 2 status of invasive ductal carcinoma and ductal carcinoma in situ, histological grade, mitotic counts and lymphovascular invasion in individual cases of BI-RADS category 1 mammograms and compared with those of the control group. RESULTS: The ultrasonographic characteristics of the BI-RADS category 1 group were characterized by a higher ratio of round shape (P< 0.001), non-spiculated periphery (P= 0.021), non-interruption of mammary borders (P< 0.001) and non-attenuation (P= 0.011) compared with the control group. A total of 52.6% of low-echoic lesions were associated with spotted distribution in the BI-RADS 1 group, whereas 25.8% of low-echoic lesions were associated with spotted distribution in the control group (P= 0.012). As for histopathological characteristics, there was a statistically higher ratio of triple-negative subtype (P= 0.021), and this particular tendency was detected in histological grade 3 in the BI-RADS category 1 group (P= 0.094). CONCLUSION: We evaluated ultrasonographic findings and the corresponding histopathological characteristics for BI-RADS category 1 mammograms and noted significant differences among these findings in this study. Evaluation of these ultrasonographic and histopathological characteristics may provide a more accurate ultrasonographic screening system for breast cancer in Japanese women.

Retrospective analysis of mammographic findings for Japanese women: a potential predictor for breast malignancies.

This purpose of this study was to retrospectively stratify the risks of malignancy according to the mammographic characteristics of Japanese women. We studied the mammographic findings of 1267 Japanese women. We characterized malignant phenotypes according to mass shape, margin and mass density, and by shape and distribution of calcified foci, and to obtain possible predictors for malignancies according to age groups. Lobular and irregular mass shape, no circumscribed margin and higher density turned out to be more powerful predictors for malignancy than other radiological factors (P < 0.001, respectively). The ratio of the cases detected as a mass in those between 21 and 49 years was lower than that of other age groups. In addition, the presence of calcifications and no mammographic abnormalities were the most powerful predictors for malignancies in the young age groups (P < 0.001, respectively). The peak age of breast cancer is between 40 and 49 years in Japan. In the present study, subtle differences were found in the mammographic results for young and old women, in contrast to those of women in the USA and Europe. The results of this study might enable more accurate prediction of biological behavior of the breast lesions in Japanese women.