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The Japanese Breast Cancer Society Clinical Practice Guidelines are published as timely guidance on clinical issues in breast cancer treatment in Japan. In the recent edition of these guidelines, we addressed a new clinical question 34 (CQ 34, systemic treatment part) "Is trastuzumab deruxtecan recommended for patients with unresectable or metastatic HER2-low breast cancer?" and a new future research question 7 (FRQ 7, pathological diagnosis part) "How is HER2-low breast cancer diagnosed for the indication of trastuzumab deruxtecan?". These questions address use of trastuzumab deruxtecan in patients with unresectable or metastatic HER2-low breast cancer who have previously received chemotherapy for metastatic disease. The strengths of evidence and recommendation were determined through a quantitative and qualitative systematic review using multiple outcomes, including efficacy and safety. We conclude that trastuzumab deruxtecan is recommended for this patient population (strength of recommendation: 1; strength of evidence: moderate; CQ34) and that HER2-low expression for the indication of trastuzumab deruxtecan should be diagnosed using companion diagnostics based on appropriate criteria (FRQ7)., (© 2024. The Author(s).)

Background: ER+HER2+ breast cancer requires most types of systemic therapies perioperatively. However, treatment resistance is often experienced. The current study investigated the predictive and prognostic value of intratumoral heterogeneity and conventional clinicopathological factors in patients with ER+HER2+ breast cancer., Methods: This research included two patient cohorts with ER+HER2+ breast cancer. Cohort A included patients who underwent surgery without neoadjuvant chemotherapy (NAC). Cohort B comprised patients who received NAC followed by surgery. Intratumoral heterogeneity was assessed via ER and HER2 double staining, and the number of cells stained with different patterns of ER and HER2 was counted., Results: In total, 11 of 92 tumors in cohort A and four of 45 tumors in cohort B consisted exclusively of double-positive (ER+ and HER2+) cells (homogeneous). The rest had different combinations of cells (heterogeneous). The pathological complete response (pCR) rates differed based on tumoral cell components but not intratumoral heterogeneity. The pCR rate of tumors with ER-HER2+ cells but without HER2- cells was higher than that of others (45.5% vs 4.3%; p = 0.0013). Low ER and PgR Allred scores indicated better pCR rates than high scores (p = 0.0005 and 0.024, respectively). Multivariate analysis showed that the ER Allred score and cell component of ER-HER2+ cells without HER2- cells were independent predictors of pCR (p = 0.0055 and 0.0081, respectively). In cohort B, posttreatment Ki67, but not pCR, was a prognostic factor of DFS and OS (p = 0.028 and 0.017, respectively). The prognostic value of combined posttreatment Ki67 and pCR was superior to that of either alone. Combined pCR and posttreatment Ki67 had an independent prognostic value for DFS and OS (p = 0.0068 and 0.0101, respectively)., Conclusions: In ER+HER2+ breast cancer, the presence of ER-HER2+ cells without HER2- cells was independently associated with pCR. Combined posttreatment Ki67 and pCR can be more precise in predicting prognosis than pCR alone., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Histopathological diagnosis is the ultimate method of attaining the final diagnosis; however, the observation range is limited to the two-dimensional plane, and it requires thin slicing of the tissue, which limits diagnostic information. To seek solutions for these problems, we proposed a novel imaging-based histopathological examination. We used the multiphoton excitation microscopy (MPM) technique to establish a method for visualizing unfixed/unstained human breast tissues. Under near-infrared ray excitation, fresh human breast tissues emitted fluorescent signals with three major peaks, which enabled visualizing the breast tissue morphology without any fixation or dye staining. Our study using human breast tissue samples from 32 patients indicated that experienced pathologists can estimate normal or cancerous lesions using only these MPM images with a kappa coefficient of 1.0. Moreover, we developed an image classification algorithm with artificial intelligence that enabled us to automatically define cancer cells in small areas with a high sensitivity of ≥0.942. Taken together, label-free MPM imaging is a promising method for the real-time automatic diagnosis of breast cancer., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Gene-protein assay (GPA), a combination of immunohistochemistry and dual in situ hybridization, allows simultaneous visualization of HER2 protein and gene on a single slide. We aimed to clarify the clinical significance of HER2 intratumoral heterogeneity (ITH) using GPA. We investigated the relationships between various HER2 ITH indicators and clinical course in 102 patients with HER2-positive breast cancer, treated with neoadjuvant trastuzumab and chemotherapy. Five representative microscopic images were captured from each GPA slide of pre-therapeutic biopsy materials. All evaluable cancer cells in the images were individually assessed for HER2 gene copy number and protein expression. Mean and coefficient of variation (CV) of both gene copy number and protein category were calculated, and each was divided into negative, equivocal, and positive. Based on their combined status, cancer cells were classified into nine types. Pathological complete response (pCR) to neoadjuvant treatments showed positive relationships to mean gene copy number (P < 0.001), mean protein category (P < 0.001), and proportion of gene- and protein-positive tumor cells (P < 0.001) and showed negative relationships to the CV of protein category (P < 0.001) and the proportion of gene-amplified but protein-negative tumor cells (P = 0.002). Two diagnostic models, created by combining clinicopathological factors and ITH indicators, showed excellent potential diagnostic ability for pCR (mean gene copy number and protein category CV; AUC = 0.837, proportion of gene- and protein-positive tumor cells; AUC = 0.831). HER2 ITH quantified by GPA is a potential predictive indicator for efficacy of HER2-targeted treatment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objective: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists., Methods: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics., Results: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753)., Conclusion: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Strain elastography for imaging lesion stiffness is being used as a diagnostic aid in the malignant/benign discrimination of breast diseases. While acquiring elastography in addition to B-mode images has been reported to help avoid performing unnecessary biopsies, intraductal lesions are difficult to discriminate whether they are malignant or benign using elastography. An objective evaluation of strain in lesions was performed in this study by measuring the elasticity index (E-index) and elasticity ratio (E-ratio) of lesions as semi-quantitative numerical indicators of the color distribution of strain. We examined whether ductal carcinoma in situ (DCIS) and intraductal papilloma could be distinguished using these semi-quantitative numerical indicators., Methods: In this study, 170 ultrasonographically detected mass lesions in 162 cases (106 malignant lesions and 64 benign lesions)-in which tissue biopsy by core needle biopsy and vacuum-assisted biopsy, or surgically performed histopathological diagnosis, was performed-were selected as subjects from among 1978 consecutive cases (from January 2014 to December 2016) in which strain elastography images were acquired, in addition to standard B-mode breast ultrasonography, by measuring the E-index and E-ratio., Results: The cut-off values for E-index and E-ratio in the malignant/benign discrimination of breast lesions were determined to be optimal values at 3.5 and 4.2, respectively, based on receiver operating characteristic (ROC) curve analysis. E-index sensitivity, specificity, accuracy, and AUC value (area under the curve) were 85%, 86%, 85%, and 0.860, respectively, while those for E-ratio were 78%, 74%, 74%, and 0.780, respectively. E-index yielded superior results in all aspects of sensitivity, specificity, accuracy, and AUC values, compared to those of E-ratio. The mean E-index values for malignant tumors and benign tumors were 4.46 and 2.63, respectively, indicating a significant difference (P < 0.001). E-index values of 24 DCIS lesions and 25 intraductal papillomas were 3.88 and 3.35, respectively, which showed a considerably close value, while the false-negative rate for DCIS was 29.2%, and the false-positive rate for intraductal papilloma was as high as 32.0%., Conclusion: E-index in strain elastography yielded better results than E-ratio in the malignant/benign discrimination of breast diseases. On the other hand, E-index has a high false-negative rate and false-positive rate for intraductal lesions, a factor which should be taken into account when making ultrasound diagnoses.

Background: Although Ki67 has important clinical relevance in breast cancer, its assessment results vary according to assay due to differences in both analytical and interpretation processes. We aimed to validate the performance of anti-Ki67 antibody clone 30-9 by comparison with clone MIB-1 and to investigate utility of the image analysis system in Ki67 assessment using clinical breast cancer samples., Methods: A series of sequential tissue sections was prepared from formalin-fixed paraffin-embedded blocks of surgically resected breast cancer specimens from 50 patients. The tissue sections were stained immunohistochemically with anti-Ki67 antibodies, 30-9 and MIB-1, as well as with hematoxylin and eosin for morphological analysis. We scanned all the stained slides with Ventana iScan HT and selected the Ki67 counting areas based on morphological findings. Three pathologists independently studied images of the counting areas to determine Ki67-positive rates. In addition, the images of 30-9-stained slides were analyzed using the image analysis system, VENTANA Virtuoso., Results: Ki67-positive rates by 30-9 showed a strong correlation with those by MIB-1 for all pathologists (pathologist #1: r = 0.985, pathologist #2: r = 0.987, pathologist #3: r = 0.982). Between 30-9 and MIB-1, there was no significant difference of CV%, showing variabilities of Ki67-positive rates among pathologists. Ki67-positive rates showed a strong correlation between the image analytical values and the pathologist-counted median values (r = 0.952)., Conclusions: The performance of 30-9 is equivalent to that of MIB-1 in Ki67 assessment of breast cancer. The image analysis system can substitute for or support visual counting by a pathologist.

Background: Internal mammary and/or supraclavicular (IM-SC) lymph node (LN) recurrence without distant metastasis (DM) in patients with breast cancer is rare, and there have been few reports on its clinical outcomes., Methods: We enrolled 4237 patients with clinical stage I-IIIC breast cancer treated between January 2007 and December 2012. Clinicopathological features of patients with IM-SC LN recurrence and patients with DM were retrospectively reviewed., Results: With a median follow-up time 78 (range, 13-125) months after the primary operation, 14 (0.3%) had IM-SC LN recurrence without DM and 274 (6.5%) had DM at the first recurrence among 4237 patients. No statistical differences were found in the baseline characteristics of the primary tumor between the two groups. The 5-year overall survival (OS) rate after recurrence in patients with IM-SC LN recurrence was 51% compared with 27% in patients with DM (P = 0.040). In patients with IM-SC LN recurrence, clinically positive axillary LN at diagnosis and pathologically positive axillary LN at primary surgery were poor prognostic factors for distant disease-free survival (DDFS) (P = 0.004 and 0.007, respectively). Clinical and pathological axillary nodal status at primary surgery was associated with OS (P = 0.011 and 0.001, respectively)., Conclusions: Patients with IM-SC LN recurrence without DM who had no clinical and pathological axillary LNs involved at primary surgery had a favorable prognosis. A larger validation study is required.

Background: Second-look ultrasonography (US) is commonly performed for breast lesions detected using magnetic resonance imaging (MRI), but the identification rate of these lesions remains low. We investigated if US methods using anatomical breast structures can improve the lesion identification rate of MR-detected lesions and evaluated the diagnostic performance of fine-needle aspiration cytology (FNAC) of the second-look US using the above-mentioned method., Methods: We retrospectively assessed 235 breast lesions (hereinafter, "targets") subjected to second-look US following MRI between January 2013 and September 2015. US was employed using the conventional methods, and this assessment measured the positional relationships of lesions with regard to surrounding anatomical breast structures (glandular pattern, Cooper's ligaments, adipose morphology, and vascular routes). Associations were assessed among the following variables: the MRI findings, target size, identification rate, and main US indicators that led to identifying the target; FNAC results and MRI findings; MRI findings and histopathological findings; and FNAC results and histopathological findings. Moreover, the sensitivity and specificity of FNAC were determined., Results: The identification rate was 99%. The main US indicators leading to identification were a glandular pattern (28-30% of lesions) and other breast structures (~ 25% of lesions). FNAC was performed for 232 targets with the following results: sensitivity of 85.7%, specificity of 91.6%, PPV of 94.1%, NPV of 92.9%, false-negative rate of 14.3%, false-positive rate of 2.1%, and accuracy of 89.7%., Conclusions: Second-look US using anatomical breast structures as indicators and US-guided FNAC are useful for refining the diagnosis of suspicious breast lesions detected using MRI.

The Breast Cancer Clinical Practice Guidelines, 2018 edition, written in Japanese and organized by the Japanese Breast Cancer Society, were published in Japanese in May 2018. The process of making these guidelines, as well as the content, was largely changed and compared with previous editions. The concept of these guidelines is to act as a support tool for shared decision making between doctor and patient. The procedure of creating the guidelines referred to Minds Handbook for Clinical Practice Guideline Development 2014. This guideline, written in Japanese, consists of two booklets: (1) the epidemiology and diagnosis booklet covering screening, radiological, and pathological diagnosis and (2) the treatment booklet covering surgical therapy, radiation therapy, and systemic therapy. This review article consists of five parts, including the history of the Breast Cancer Clinical Practice Guidelines, the concept, process, content, and recommendation grade. I believe this brief summary concerning the Breast Cancer Clinical Practice Guidelines 2018 edition in English will be helpful for both Japanese and foreign investigators.

Individuals carrying pathogenic BRCA1 or BRCA2 mutations have an increased lifetime risk of breast and/or ovarian cancer. The incidence of breast cancer amongst disease-free BRCA mutation carriers under surveillance and the clinical and pathological characteristics of those who subsequently develop the disease remain unclear in Japan. We reviewed the records of 155 individuals with BRCA1 or BRCA2 mutations identified by genetic testing between January 2000 and December 2016. At the time of genetic testing, 26 individuals with one of these mutations had no history of breast cancer and were therefore enrolled in a surveillance program that included biannual ultrasonography, clinical breast examination, annual mammography, and conditional magnetic resonance imaging for the early detection of primary breast cancer. During the surveillance period, 5 individuals with BRCA1 or BRCA2 mutations were diagnosed with primary breast cancer. The mean surveillance duration until breast cancer diagnosis was 48 months. The incidence of primary breast cancer during surveillance in initially disease-free BRCA mutation carriers was 4.23%/year. In two cases, the tumors were only detectable on MRI. The case 5 patient who presented with a tumor that was detected by self-examination, which then grew rapidly, had stage IIB triple-negative breast cancer. In conclusion, our results show that some challenges exist in the early detection of breast cancers in BRCA1 or BRCA2 mutation carriers. There are also some difficulties in approaching those individuals in Japanese society.

Background: This study aimed to evaluate the impact of previous local treatment on lymphatic drainage patterns in ipsilateral breast tumor recurrence (IBTR) based on our data on re-operative sentinel lymph node biopsy (re-SLNB) for IBTR., Methods: Between April 2005 and December 2016, re-SLNB using lymphoscintigraphy with Tc-99 m phytate was performed in 136 patients with cN0 IBTR. Patients were categorized into two groups: the AX group included 55 patients with previous axillary lymph node dissection; the non-AX group included 69 patients with previous SLNB and 12 patients with no axillary surgery. The whole breast irradiation (RT) after initial surgery had performed in 17 patients in the AX group and 27 patients in the non-AX group., Results: Lymphatic drainage was visualized in 80% of the AX group and 95% of the non-AX group (P < 0.01). The visualization rate of lymphatic drainage was associated with the number of removed lymph nodes in prior surgery. In the non-AX group, lymphatic drainage was visualized in 96% of patients without RT and 93% with RT. Lymphatic drainage was observed at the ipsilateral axilla in 98% of patients without RT and in 64% with RT (P < 0.0001). Aberrant drainage was significantly more common in patients with RT than without RT (60% vs. 19%, P < 0.001); it was observed mostly to the contralateral axilla (52% vs. 2%, P < 0.0001). In the AX group, patients with previous RT showed decreased lymphatic drainage to the ipsilateral axilla compared to those without RT (29% vs. 63%, P < 0.05) and increased aberrant drainage to the contralateral axilla (64% vs. 5%, P < 0.0001)., Conclusion: Lymphatic drainage patterns altered in re-SLNB in patients with IBTR and previous ALND and RT were associated with alterations in lymphatic drainage patterns.

Purpose: To clarify the long-term outcomes of breast calcifications after stereotactic vacuum-assisted breast biopsy (SVAB) and to develop strategy after SVAB., Methods: Subject comprised 594 patients with 615 calcifications who underwent SVAB. 371 (60.3%) lesions were diagnosed as benign, 38 (6.2%) as indeterminate, and 206 (33.5%) as malignant. We retrospectively reviewed post-biopsy courses of non-malignant lesions which were followed. A histopathological review was performed for false negatives to clarify the reasons., Results: Of the 308 patients with benign lesions, with a median follow-up time of 55.8 months, re-biopsy was performed for 11 (3.6%) due to changes of imaging, and 4 (1.3%) were diagnosed as breast cancer. Of the 36 patients with indeterminate lesion, re-biopsy was performed for 16 (44.4%), and 8 (22.2%) were diagnosed as breast cancer, while 20 (55.6%) showed no changes in imaging with a median follow-up time of 91.7 months without re-biopsy. Weak atypism of intraductal carcinoma may cause a false-negative diagnosis in SVAB for breast calcifications., Conclusions: When SVAB results in non-malignant, patients may be followed by annual screening, while re-biopsy needs to be performed for the patients with a discordant result of SVAB and with changes in an imaging finding during a follow-up.

Background: Immune responses play an important role in interrupting the progression of cancer cells. Tumor-infiltrating lymphocytes (TILs) are basic components of the immune system. In triple negative breast cancer, increased number of TILs is associated with excellent prognosis and response of chemotherapy. Here, we investigated whether TILs affect the efficacy of trastuzumab-based treatment in human epidermal growth factor receptor 2 (HER2)-positive breast cancer., Methods: The study included 97 patients with stage I-III HER2-positive breast cancer. All patients were preoperatively treated with an anthracycline-based combination regimen, followed by taxane with trastuzumab from 2009 to 2013. Pathological complete response (pCR) was defined as the disappearance of invasive cancer cells regardless of the presence of in situ components. TILs were evaluated using pre-therapeutic needle biopsy specimens. We assessed the percentage of the breast stroma with TILs over the total intratumoral stroma and classified the specimens in three grades: TILs1+ < 30%, TILs2+ 30-50%, and TILs3+ > 50%., Results: Overall, 80.4% of the specimens were TILs1+, 15.5% were TILs2+ and 4.1% were TILs3+. The pCR rate was 44.9% (35/78) in the TILs1+ cases, 80.0% (12/15) in the TILs2+ cases and 75.0% (3/4) in the TILs3+ cases. TILs were significantly associated with pCR (P = 0.0228). Multivariate analysis using TILs, hormone receptor (HR), nuclear grade (NG) and age indicated that TILs (OR 4.32, 95% CI 1.04-23.33, P = 0.0436) and HR (OR 8.76, 95% CI 3.30-25.44, P < 0.0001) were independent predictors for pCR., Conclusion: TILs are associated with the efficacy of trastuzumab-based treatment in HER2-positive breast cancer.

Purpose To evaluate the association between tumor shrinkage patterns shown with magnetic resonance (MR) imaging during neoadjuvant chemotherapy (NAC) and prognosis in patients with low-grade luminal breast cancer. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was obtained from all subjects. The low-grade luminal breast cancer was defined as hormone receptor-positive and human epidermal growth factor receptor 2-negative with nuclear grades 1 or 2. The patterns of tumor shrinkage as revealed at MR imaging were categorized into two types: concentric shrinkage (CS) and non-CS. Among 854 patients who had received NAC in a single institution from January 2000 to December 2009, 183 patients with low-grade luminal breast cancer were retrospectively evaluated for the development set. Another data set from 292 patients who had received NAC in the same institution between January 2010 and December 2012 was used for the validation set. Among these 292 patients, 121 patients with low-grade luminal breast cancer were retrospectively evaluated. Results In the development set, the median observation period was 67.9 months. Recurrence was observed in 31 patients, and 16 deaths were related to breast cancer. There were statistically significant differences in both the disease-free survival (DFS) and overall survival (OS) rates between patterns of tumor shrinkage (P < .001 and P < .001, respectively). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .001) and OS (P = .009) rate. In the validation set, the median follow-up period was 56.9 months. Recurrence was observed in 20 patients (16.5%) and eight (6.6%) deaths were related to breast cancer. DFS rate was significantly longer in patients with the CS pattern (72.8 months; 95% confidence interval [CI]: 69.9, 75.6 months) than in those with the non-CS pattern (56.0 months; 95% CI: 49.1, 62.9 months; P ≤ .001). The CS pattern was associated with an excellent prognosis (median OS, 80.6 months; 95% CI: 79.3, 81.8 months vs 65.0 months; 95% CI: 60.1, 69.8 months; P = .004). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .007) and OS (P = .037) rates. Conclusion The CS pattern as revealed at MR imaging during NAC had the only significant independent association with prognosis in patients with low-grade luminal breast cancer. © RSNA, 2017.

Background: The degree of pathological response to neoadjuvant chemotherapy (NAC) was correlated with the prognosis in breast cancer. There are few studies published on inter-observer variability in the assessment of pathological responses among pathologists., Methods: We collected 64 surgically resected specimens from patients who had received NAC. Three pathologists assessed the pathological responses and classified them into 7 grades according to grading system of the Japanese Breast Cancer Society. The levels of concordance among pathologists were categorized into 3 classes: full concordance (all pathologists gave the same grade), partial concordance (two of them gave the same grade), and discordance (all three gave different grades). The inter-observer agreement among pathologists was estimated using the percentage concordance and Cohen's kappa statistics., Results: Full concordance, partial concordance, and discordance were seen in 28 (43%), 33 (52%), and 3 (5%) specimens, respectively. In most of partial concordance specimens (30 out of 33), the pathological response grades differed by only one level. The kappa value was 0.59. The concordance rate with regard to pCR was 97%., Conclusions: Most of the judgments among pathologists differed within one level, but there is room for improving harmonization in the assessment of pathological responses.

Background: The efficacy and safety of continuing multiple anti-HER2 therapies in advanced breast cancer (ABC) patients remains unclear. This study investigated eribulin in combination with pertuzumab and trastuzumab for both taxane- and trastuzumab-pretreated HER2-positive ABC patients., Methods: In a single-institute, single-arm, open-label, phase II trial, HER2-positive ABC patients who had previously received taxanes and trastuzumab were treated with eribulin in combination with pertuzumab and trastuzumab. The pharmacokinetics of eribulin in this combination were assessed in 6 patients. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was objective response rate (ORR)., Results: A total of 30 patients (median age, 58 years; range, 31-76) were enrolled, with a median number of previous chemotherapy regimens of 3.5 (range: 1-9) in the metastatic setting. Pharmacokinetic parameters of eribulin in this combination were similar to previous reports of eribulin monotherapy. ORR was 34.8% (95% CI: 16.4-57.3, n = 23), and median progression-free survival was 42.6 weeks (95% CI: 20.3-51.9, n = 30). Clinical benefit rate was 60.9% (95% CI: 16.4-57.3). The most common grade 3/4 adverse event was neutropenia in 20 patients (66.7%). A dose reduction of eribulin was required in 27 patients due to adverse events, particularly grade 3 neutropenia., Conclusions: Eribulin in combination with pertuzumab and trastuzumab was well tolerated in heavily pretreated patients. Eribulin may be a viable treatment option when used in combination with pertuzumab and trastuzumab for HER2-positive ABC patients (UMIN Clinical Trial Registry identification number, UMIN000012375)., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Paclitaxel plays a central role in chemotherapy for breast cancer. Peripheral neuropathy, a well-known toxicity with paclitaxel, may be of interest in predicting the efficacy of paclitaxel therapy for patients with metastatic breast cancer. We performed a retrospective analysis assessing whether the early occurrence of peripheral neuropathy (EPN) was a predictive marker for better efficacy in patients with metastatic breast cancer receiving chemotherapy containing paclitaxel., Patients and Methods: Between January 2000 and August 2008, we examined the records of 168 patients with metastatic breast cancer treated with paclitaxel in our hospital. EPN was defined as a symptom of Grade 2 or more during first three months of treatment. The overall response rate (ORR) and time to treatment failure (TTF) in each group were analyzed retrospectively., Results: Of 168 patients with metastatic breast cancer who were treated with paclitaxel, EPN was documented in 101 patients (60.1%). The clinical benefit rate (CR, PR, and SD ≥ 6 months) was 72.3% in the EPN group and 49.3% in the non-EPN group (p = 0.002). The TTF of the EPN group (median 11.2 months, 95% CI: 9.5-12.9) was significantly longer than that of the non-EPN group (5.7 months, 95% CI: 4.6-6.8) (p<0.001). Multivariate analysis demonstrated that EPN (p<0.001), dose intensity of less than 70% (p<0.001), and the history of microtubule agents (p = 0.001) were the significant favorable prognostic factors for TTF., Conclusion: The early onset of peripheral neuropathy might be a robust predictor for TTF in patients with metastatic breast cancer treated with paclitaxel.

The present case is the first report in Japan in which a breast cancer was discovered as a result of prospective magnetic resonance imaging (MRI) screening study for BRCA1/2 mutation carriers who were free of breast or ovarian cancer. This case is significant and it verifies the importance of MRI screening in breast or ovarian cancer-free BRCA1/2 mutation carriers who do not exhibit positive mammographic or ultrasonographic findings.

Background: The definition of complete resection of ductal carcinoma in situ (DCIS) is difficult to standardize because of the high variety of surgical breast conserving procedures, specimen handling, and pathological examinations. Using strictly controlled criteria in a single institute, the present study aimed to determine the ipsilateral breast cancer rate when radiotherapy is omitted following complete resection of DCIS., Methods: We retrospectively examined 363 consecutive DCIS patients who underwent breast-conserving surgery, and of these, 125 (34.4%) had complete resection according to the criteria. We finally included 103 patients who omitted radiotherapy. Ipsilateral and contralateral breast cancer events were assessed., Results: The median follow-up period was 118 months. The incidences of ipsilateral and contralateral breast cancer and ipsilateral invasive breast cancer at 10 years were 10.8%, 9.1%, and 3.6%, respectively. No patient died of breast cancer., Conclusion: If complete resection of DCIS can be ensured, the annual incidence of ipsilateral breast cancer, even without irradiation, can be limited to approximately 1%, which equals the incidence of contralateral breast cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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: 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 10 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: Pathological complete response (pCR) with neoadjuvant chemotherapy (NAC) has been regarded as a surrogate endpoint for disease-free survival (DFS) and overall survival (OS) of patients with breast cancer. No consensus regarding the definition of pCR has been established; there are several definitions according to a variety of classifications. Eradication of cancer cells in both breast and lymph nodes has been better associated with improved prognosis than in the breast alone. Even in patients diagnosed as having clinically node-negative cancer before NAC, postoperative pathological examination often shows axillary lymph node metastases., Patients and Methods: Of the 771 patients with breast cancer who underwent NAC in the Cancer Institute Hospital between January 2000 and May 2009, 146 patients preoperatively diagnosed as having node-negative breast cancer were retrospectively evaluated. We have made the definition of clinically lymph node-negative (N0) as follows: first, ultrasonography before NAC did not show any lymphadenopathy. Second, a cytological procedure confirmed negative study for each patient when ultrasonography suggested lymphadenopathy., Results: The median observation period was 79.7 months, and the median age of the subjects was 51 years. Pathological examination at the time of the surgery showed lymph node metastases (ypN+) in 46 patients (31.5%). Histological therapeutic effects revealed ypT0/is in 9 patients (6.2%) and ypTinv in 137 (93.8%). Multivariate analysis demonstrated that younger age (49>), large tumor size, NG3, and ypN+ were significant poor prognostic factors for DFS (p = 0.020, p = 0.008, P = 0.022 and p = 0.010, respectively). Moreover, ypN+ was the only significant poor prognostic factor for OS (p = 0.022). The predictive factors of ypN+ in clinically lymph node-negative breast cancer were ypTinv (p = 0.036) and the luminal type (HR+ and HER2-) (p = 0.029)., Conclusion: The prognosis of clinically lymph node negative breast cancer depended on ypN+, which was associated with ypTinv and luminal subtype., Competing Interests: The authors have declared that no competing interests exist.

Background: The significance of the expression of aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, for predicting the recurrence of estrogen receptor (ER)-positive/human epidermal growth factor receptor type 2 (HER2)-negative breast cancer is still poorly understood. The value of ALDH1 in predicting the time of recurrence remains unknown., Methods: In total, 184 patients with early distant recurrence, 134 patients with late distant recurrence, and 321 control patients without recurrence for more than 10 years after starting initial treatment for ER-positive/HER2-negative breast cancer, registered in 9 institutions, were analyzed. We assessed relationships between ALDH1 and other clinicopathological features, and ALDH1 expression was compared among the three groups. The relationship between ALDH1 expression and overall survival after recurrence was also evaluated in each group., Results: The rates of ALDH1 expression positivity (more than 1 %) in the early, late, and no recurrence groups were 18.4 %, 13.4 %, and 8.4 %, respectively. ALDH1 expression correlated significantly with lymph node metastases (p = 0.048) and the Ki-67 labeling index (p < 0.001) in the early recurrence group. Multivariate analysis revealed ALDH1 expression to be significantly higher in the early recurrence group than in the no recurrence group (adjusted OR 2.140, 95 % CI 1.144-4.003, p = 0.016). Moreover, there was a significant difference in ALDH1 expression between the early and no recurrence groups receiving adjuvant endocrine therapy and chemotherapy (adjusted OR 4.625, 95 % CI 1.881-12.474, p < 0.001). However, there was no difference in ALDH1 expression between the late and no recurrence groups in univariate analysis (OR 1.507, 95 % CI 0.738-2.998, p = 0.253). In multivariate analysis, ALDH1 was not a factor independently predicting overall survival after the detection of recurrence (adjusted OR 1.451, 95 % CI 0.985-2.085, p = 0.059)., Conclusions: Among patients with ER-positive/HER2-negative breast cancer, ALDH1 expression was more common in those with early recurrence, and this expression was found to be associated with a more aggressive breast cancer phenotype than that in the patients without recurrence. Further study is needed to clarify the prognostic significance of the heterogeneity of cancer stem cells and to confirm their role in resistance to chemotherapy.

Purpose: Although improved long-term prognoses for patients with metastatic breast cancer (MBC) have been demonstrated, few reports address overall survival (OS) with sufficient follow-up. Furthermore, the relevance of immunohistological subtypes to OS in MBC has not been clarified., Methods: We evaluated, retrospectively, the OS of patients who had been initiated on systemic therapy for MBC between 2000 and 2008., Results: The subjects of this study were 527 patients with MBC treated by systemic therapy. The median survival time (MST) was 55.5 months. The MST for each immunohistological subtype was as follows: luminal, 59.9 months; luminal-HER2, not reached; triple-negative, 18.6 months; and HER2-enriched, 49.9 months. According to multivariate analysis, metastasis-free intervals of ≥2 years and treatment with anthracycline for MBC were predictive of better OS. The predictors of shorter OS included disease progression after first-line treatment for MBC, triple-negative, and all histological factors, except papillotubular carcinoma, with liver metastasis, and having three or more initial metastatic sites., Conclusions: The prognosis of the patients with MBC in this series was better than that reported before 2000, which is probably attributable to the use of novel, improved pharmacological agents. For example, luminal-HER2 tumors can be treated using both aromatase inhibitors and trastuzumab. Because of the lower toxicities, it is now possible to administer these agents for longer periods, resulting in better prognoses.

Histological assessment of the therapeutic response to neoadjuvant therapy gives us information regarding the efficacy of a given treatment in individual patients. Such information is useful for guiding selection of appropriate therapeutic strategies after surgery. In many studies of neoadjuvant chemotherapy (NAC) for breast cancer, both the histological therapeutic effect in the primary lesion and the lymph node metastatic status are significantly related to prognosis. The histological assessment of therapeutic response helps determine prognosis in breast cancer treated with NAC; however, methodological problems remain. There are many different histological criteria currently used to assess therapeutic response. Even when the same criteria are used, use of different methods for examination of surgical material can cause different results for the same patient case. When histological therapeutic effect is determined in daily clinical practice, pathologists have to describe the criteria used and their examination methods. Histological criteria for evaluation of therapeutic response and methods for examination of surgical materials after neoadjuvant therapy must be standardized in the near future.

Background: Axillary dissection omission for sentinel lymph node-negative patients has been a practice at Cancer Institute Hospital, Japanese Foundation for Cancer Research since 2003. We examined the long-term results of omission of axillary dissection in sentinel lymph node-negative patients treated at our hospital, as well as their axillary lymph node recurrence characteristics and outcomes., Methods: Our study included 2,578 patients with cTis or T1-T3N0M0 primary breast cancer for whom dissection was omitted because they were sentinel lymph node negative. The median observation period was 75 months., Results: In sentinel lymph node-negative patients for whom dissection was omitted, the rates of axillary lymph node recurrence, distant recurrence, and breast cancer mortality were 0.9, 2, and 1 %, respectively. Eighteen patients underwent additional dissection if axillary lymph node recurrence was observed at the first recurrence. Four triple-negative (TN) patients experienced distant recurrence after additional dissection. All four patients were administered anticancer agents after axillary lymph node recurrence and experienced recurrence within 1 year of additional dissection. The axillary lymph node recurrence rate was 0.8 % for luminal and 4.5 % for TN subtypes., Conclusions: The long-term prognoses of patients for whom dissection was omitted owing to negative sentinel lymph node metastases were similar to those reported previously-low recurrence and mortality rates. The frequency of axillary lymph node recurrence and the post-recurrence outcome differed between luminal and TN cases, with recurrence being more frequent in patients with the TN subtype. TN patients also had poorer prognoses, even after receiving additional dissection and anticancer agents after recurrence.

To establish a prognostic prediction system, we examined the relationships between prognosis and histological therapeutic effect or ypTNM classification in 258 breast cancer patients who received neoadjuvant chemotherapy. The case distribution according to therapeutic effect was nine patients (3.5%) with Grade 0, 169 (65.5%) with Grade 1, 58 (22.5%) with Grade 2, and 22 (8.5%) with Grade 3. The 5-year overall survival (OS) rate by therapeutic effect was 56% in Grade 0, 81% in Grade 1, 87% in Grade 2, and 96% in Grade 3. The higher the therapeutic effect the better the prognosis, with a significant difference among the groups (P = 0.008). The case distribution according to ypTNM classification was 20 patients (7.8%) with Stage 0, 83 (32.2%) with Stage I, 77 (29.8%) with Stage II, and 78 (30.2%) with Stage III. The 5-year OS rate by ypTNM classification was 95% in Stage 0, 94% in Stage I, 89% in Stage II, and 59% in Stage III. While prognosis was mostly comparable in Stages 0 and I, in the other stages it became significantly worse as residual cancer increased (P < 0.001). The prognosis of breast cancer patients with neoadjuvant chemotherapy can be predicted by histological therapeutic effect and staging classification of residual cancer., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: Although human epidermal growth factor receptor 2 (HER2) is a significant clinical biomarker for breast cancer, the HER2 testing involves a complicated evaluation process. We devised an easy method for HER2 gene testing and investigated its utility., Methods: HER2 testing was performed by immunohistochemistry (IHC) and dual-color in situ hybridization (DISH) on surgical specimens from 50 patients with invasive breast cancer. DISH was evaluated by two methods. One was the DISH count method in which the HER2 and CEP17 signals were counted and the HER2/CEP17 signal ratio was calculated. The other was the DISH-easy method in which pathologists only observed slices without counting the signals. The DISH-easy method was performed by two pathologists. We analyzed the correlations between the DISH-easy method and the DISH count method by each pathologist and calculated the inter-observer concordance rate of the DISH-easy method., Results: The results from two pathologists using the DISH-easy method corresponded to the IHC results (P < 0.01) and the DISH count method results (P < 0.01). All cases determined to be negative using the DISH-easy method were also negative via the DISH count method with a corresponding rate of 100 % for both pathologist A (34/34) and B (32/32). Most of the results for the positive cases also corresponded; the correspondence rate of pathologist A was 100 % (8/8) and 89 % for B (8/9). The inter-observer concordance rate was 81 % (κ = 0.65)., Conclusions: The DISH-easy method is simple and useful for HER2 testing regardless of proficiency of the evaluators.

Background: Multiple anti-HER2 therapies have improved the outcome for patients with HER2-positive breast cancer. However, optimal management has yet to be established for lapatinib (LAP)- and trastuzumab (Tmab)-resistant disease progression. Data from our institution were reviewed to contribute to the search for best practices., Patients and Methods: Between June 2009 and March 2013, 74 HER2-positive advanced breast cancer (ABC) patients were treated with LAP with capecitabine (LAPCAP). Patients re-treated with Tmab-based chemotherapies were identified, with a focus on baseline characteristics, chemotherapies, and efficacy. The study focused on the clinical outcomes of 50 patients re-treated with Tmab after LAPCAP-resistant disease progression (LAPCAP-PD), with an assessment of tumor response and clinical benefit (CB). Progression-free survival (PFS) was used as a predictive surrogate marker for the efficacy of Tmab rechallenge., Results: All patients were pretreated with Tmab- and LAP-based chemotherapies. At a median follow-up of 7.9 months, PFS was 4.6 months, and overall survival was 33.7 months after LAPCAP-PD. Rechallenges with Tmab-based chemotherapies included gemcitabine (GEM) in 23 patients, vinorelbine in 14, taxanes in 5, endocrine treatments in 2, and others. The CB rate was 32%, including complete response for 1, partial response for 3, and > 6 months of stable disease for 12. Although the median PFS was longer for patients treated with microtubule inhibitors (MTIs) than with GEM, various chemotherapies had different efficacy regardless of whether or not previous LAPCAP had CBs., Conclusion: Tmab rechallenge combined with not only MTIs but also an antimetabolite agent is effective against some LAPCAP-PD HER2-positive ABC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Highly malignant tumors express high levels of the minichromosome maintenance 2 (MCM2) protein, which is associated with advanced tumor grade, advanced stage, and poor prognosis. In a previous study, we showed that Friend leukemia virus (FLV) envelope protein gp70 bound MCM2, impaired its nuclear translocation, and enhanced DNA-damage-induced apoptosis in FLV-infected hematopoietic cells when the cells expressed high levels of MCM2. Here, we show that MCM2 is highly expressed in clinical samples of invasive carcinoma of the breast, especially triple-negative breast cancer (TNBC), and in cancer stem cell (CSC) marker-positive breast cancer cells. To generate a cancer therapy model using gp70, we introduced the gp70 protein into the cytoplasm of murine breast cancer cells that express high levels of MCM2 by conjugating the protein transduction domain (PTD) of Hph-1 to gp70 (Hph-1-gp70). Hph-1-gp70 was successfully transduced into the cytoplasm of breast cancer cells. The transduced protein enhanced the DNA damage-induced apoptosis of cancer cells in vitro and in vivo. Therefore, an MCM2-targeted strategy using Hph-1-gp70 treatment to induce DNA damage might be a successful therapy for highly malignant breast cancers such as TNBC and for the eradication of CSC-like cells from breast cancer tissue.

Background: One-step nucleic acid amplification (OSNA) examines lymph node metastasis in a semiquantitative manner with molecular biology techniques. In this study, we conducted a whole-node analysis of non-sentinel lymph nodes (SLNs) using the OSNA method in SLN metastasis-positive breast cancer patients., Methods: With the OSNA method, we compared the rates of positivity of non-SLN metastasis in cases with both SLN micro- and macrometastases., Results: The rates of non-SLN metastasis positivity in those with SLN micrometastasis and macrometastasis were 44% and 48%, respectively, and this difference was not significant. When the study of non-SLN metastasis positivity was focused only on macrometastases, the rates of non-SLN metastasis positivity in patients with SLN micrometastasis and macrometastasis were 19% and 22%, respectively, and there was no significant difference., Conclusion: Regardless of the copy number of SLN metastases, non-SLN metastases were found in approximately half of the cases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to extensively analyze the signaling pathway molecules in breast cancer and to explore candidate biomarkers for clinicopathological relevance., Methods: We assessed the expression of key factors in cell signaling, namely p-AKT, cyclin D1, P27, p-p70S6 K, p-4EBP1, and p-MAPK/ERK, within 338 invasive breast cancer patients. These factors were immunohistochemically examined in tumor tissues and assessed by staining score. Staining scores were analyzed by a clustering method to devise a new classification based on pathway activity. We investigated the relationships among staining scores, the clustering classification, and patient characteristics., Results: The proportion of patients displaying high expression levels were as follows: p-AKT, 75%; cyclin D1, 12%; P27, 53%; p-p70S6 K, 37%; p-4EBP1, 19%; and p-MAPK/ERK, 3%. Patients were classified into two groups on the basis of staining scores. Group 1 (39%) included more positive cases for p-4EBP1, p-MAPK/ERK, and p-p70S6 K and fewer positive cases for P27 and cyclin D1 than Group 2 (61%). The clustering classification was significantly related to subgrouping by hormone receptor and HER2 (P < 0.001), nuclear grade (P < 0.001) and histological subtype (P = 0.034). A strong positive correlation was identified between p-AKT and P27, cyclin D1 and P27, p-p70S6 K and p-4EBP1, p-p70S6 K and p-MAPK/ERK, and between p-4EBP1 and p-MAPK/ERK. Levels of p-p70S6 K were significantly related to recurrence in both univariate (RR = 0.75, P < 0.001) and multivariate (RR = 0.71, P = 0.049) analyses., Conclusions: The present study helps us to understand the characteristics of signaling pathway status in breast cancers. Moreover, p-p70S6 K expression may be of use in predicting clinical outcome.

We classified ipsilateral breast tumor recurrences (IBTRs) based on strict pathological rules. Ninety-six women who were surgically treated for IBTR were included. IBTRs were classified according to their origins and were distinguished based on strict pathological rules: relationship between the IBTR and the primary lumpectomy scar, surgical margin status of the primary cancer, and the presence of in situ lesions of IBTR. The prognosis of these subgroups were compared to that of new primary tumors (NP) in the narrow sense (NPn) that occurred far from the scar. Distant-disease free survival of IBTR that occurred close to the scar with in situ lesions and a negative surgical margin of the primary cancer (NP occurred close to the scar, NPcs) was similar to that of NPn. In contrast, IBTR that occurred close to the scar without in situ lesions (true recurrence (TR) that arose from residual invasive carcinoma foci, TRinv) had significantly poorer prognosis than NPn. IBTR that occurred close to the scar with in situ lesions and a positive surgical margin of the primary cancer (TR arising from a residual in situ lesion, TRis) had more late recurrences than NPcs. Precise pathological examinations indicated four distinct IBTR subtypes with different characteristics., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Objective: We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation., Research Design and Methods: This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014., Main Outcome Measures: TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated., Results: The median age was 65 (42 - 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), de novo metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder., Conclusions: Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, de novo metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.

Background: The clinicopathological importance of Ki-67 in breast cancers has been intensely studied; however, there have been few systematic large studies of patients treated with predefined adjuvant therapy. Further, Ki-67 evaluation methodology differed among studies, which prevents Ki-67 from being used for clinical practice. We performed a large systematic study using routinely processed tissues and compared various scoring methods., Methods: Representative slides of archival tissue blocks of 442 consecutive invasive breast cancers from women treated with adjuvant tamoxifen monotherapy and having a long follow-up period were subjected to immunohistochemistry using anti-Ki-67 monoclonal antibody, Mib-1. Both the average score across the section and the score at the hottest spot were assessed., Results: Ki-67 evaluated at the hottest spot, not the average score across the section, independently predicted poor clinical outcomes of patients with hormone receptor-positive/HER2-negative cancer. Ki-67 was not a predictor of clinical outcome in patients with triple-negative breast cancer. Overall, high Ki-67 level significantly correlated with classic unfavorable clinicopathological factors, correlating negatively with the status of estrogen receptor (ER)-α and progesterone receptor (PR), and positively with HER2 status and grade. ER-β status positively correlated with the Ki-67 level., Conclusions: Ki-67 evaluation at the hottest spot was superior to that determined by average score across the section as a predictor of outcome in patients with hormone receptor-positive/HER2-negative breast cancers treated with endocrine monotherapy. The different result obtained in patients with triple-negative carcinomas needs to be further investigated.

Immunohistochemical determination of ER/PR status has been the gold standard in clinical practice of breast cancer for decades. A cut-off of '1%' is commonly used; however, this is not supported by strict evidence. How the proportion of ER/PR-positive cells influences the response to endocrine therapy has been scarcely reported, either. To address these issues, 486 and 663 invasive breast cancer cases treated with or without adjuvant tamoxifen respectively (median follow-up period, 12.8 years) were enrolled, and effect of tamoxifen treatment was compared among ER/PR-positive or -negative groups immunohistochemically determined using various cut-offs. Tamoxifen significantly improved 5 years disease-free survival in ER/PR-positive, but not in ER/PR-negative, cases even using immunohistochemical >0% cut-off. Cases with ≥67% ER/PR expressing cells responded to tamoxifen by far the best. Patients having tumors without any ER/PR-positive cells should be excluded from endocrine therapy, whereas this therapy should be strongly recommended for those with ≥67% ER/PR-positive cells., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Cancer in sclerosing adenosis includes the following 2 types: cancer genuinely arising from sclerosing adenosis and cancer arising near a sclerosing adenosis lesion and infiltrating into it. This study aimed to elucidate the features of the former by comparing both types., Methods: This study included 28 lesions in 27 cases of cancer in sclerosing adenosis for which surgery was performed during a 2-year period from January 2006 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We determined the proportions of cancer in sclerosing adenosis relative to the overall lesion of ductal carcinoma in situ. They were compared for 13 clinico-pathological factors by dividing the lesions into 2 groups: those involving cancer in 50 % or more (cancer in sclerosing adenosis predominant type-inner type) and those involving cancer in less than 50 % (cancer out of sclerosing adenosis predominant type-outer type)., Results: There were 20 lesions (71 %) of the inner type and 8 lesions (29 %) of the outer type. The comparison between the 2 types revealed significant differences in the following 3 factors. Bilateral breast cancer was observed in 5 cases (26 %) of the inner type and in none (0 %) of the outer type, indicating that there were significantly more cases of bilateral breast cancer for the inner type (p = 0.04). Regarding the subtypes of ductal carcinoma in situ, there were significantly more cases of the non-comedo type for the inner type (p = 0.002). Significantly fewer cases were positive for human epidermal growth factor receptor type 2 (HER2) for the inner type (p = 0.007)., Conclusion: The results of this study suggest that cancer genuinely arising in sclerosing adenosis may often have biological features of bilateral breast cancer, non-comedo type in subtype, and being negative for HER2.

This study is aimed to identify clinical predictors, other than HER2 overexpression, for the response to lapatinib plus capecitabine (LAPCAP) in patients with HER2-positive advanced breast cancer (HER2ABC). Data from our medical records of 76 patients from June 2009 to March 2013 were analyzed. Evaluations of these patients with HER2ABC treated with LAPCAP included baseline characteristics, dose modifications, efficacy, and incidence of adverse events (AEs). With a median follow-up of 20 months, the median number of prior therapies for ABC before LAPCAP was 2 (range 0-13), and 66 patients had previously received trastuzumab. For LAPCAP, the overall response rate was 21 %, and the clinical benefit rate was 60 %. During the initial 12-month observation period, 93 % of patients had AEs. The most common AE was hand-foot syndrome (HFS) in 55 patients. Progression-free survival (PFS) was better in patients who had HFS than in those who did not (p = 0.0002). Since HFS is a well-known AE associated with CAP, whether CAP dose affected PFS or not was investigated, but no positive relationship was found. Since several studies with EGFR-targeted agents have suggested a positive correlation between cutaneous toxicities and outcomes, whether the incidence of any AEs affected PFS or not was explored among 76 patients. HFS, diarrhea, and rash were significant favorable factors (p = 0.0002, 0.0088, and 0.0011). The median PFS of patients who had all three AEs was 13.2 months, compared with 2.6 months for those who did not (p = 0.00000174). Mucocutaneous toxicities may be predictors of the response to LAP in patients with HER2ABC.

Background: The TNM classification of the Unio Internationalis Contra Cancrum was revised for the seventh edition. The major change concerning breast cancer is a change in the stages for patients with T0 or T1N1miM0. In the present study, the seventh edition of the TNM classification was validated in breast cancer., Methods: The stages of 416 breast cancer patients, treated at our hospital in 1996, were classified according to the TNM classification, sixth and seventh editions, and their prognoses were compared., Results: Case distribution using the sixth edition was stage 0, 56 cases (13.5 %); stage I, 158 cases (38.0 %); stage II, 130 [A, 102; B, 28] cases (31.2 [A, 24.5; B, 6.7] %); and stage III, 72 [A, 31; B, 8; C, 33] cases (17.3 [A, 7.5; B, 1.9; C, 7.9] %). According to the seventh edition, the stages for 20 patients, accounting for 19.6 % of IIA cases according to the sixth edition, decreased from IIA to IB. The 10-year overall survivals were stage 0, 91.1 %; stage I, 88.6 %; stage II, 80.8 %; and stage III, 63.9 % according to the sixth edition; and stage 0, 91.1 %; stage I, 88.8 %; stage II, 79.1 %; and stage III, 63.9 % according to the seventh edition. Although no significant differences were seen among the survival rates for stages 0 to II according to the sixth edition, there was a significant difference between stage I and II according to the seventh edition (p = 0.026)., Conclusion: The latest revision of the TNM classification is appropriate for breast cancer from the perspective of prognosis.

Background: HER2 is a prognostic factor in breast cancer, and is predictive of the effects of HER2-targeted drugs. HER2 tests are essential in invasive and metastatic breast cancer. Dual-color in-situ hybridization (DISH) is a novel genetic test, and we investigated its utility in HER2 testing in breast cancer., Methods: Using DISH and two FISH methods (FISH method 1, FISH method 2) with representative slices of surgical specimens from 134 invasive breast cancer patients, we performed HER2 gene testing and compared the results for HER2 gene/CEP17 signal ratio and HER2 gene diagnosis., Results: Of 134 patients, either the HER2 gene or the CEP17 signal could not be counted in 2 patients by DISH, in 1 patient by FISH method 1, and in 1 patient by FISH method 2. HER2 gene/CEP17 signal ratios were strongly correlated in DISH and FISH method 1 (R = 0.85, P < 0.05). Agreement of DISH and FISH method 1 for HER2 gene diagnosis was 98.5 % for all patients, irrespective of gene amplification (κ = 0.97). HER2 gene/CEP17 signal ratios were strongly correlated in DISH and FISH method 2 (R = 0.87, P < 0.05). Agreement of DISH and FISH method 2 for HER2 gene diagnosis was 94.1 % for gene amplification patients, 98.4 % for gene non-amplification patients, and 96.2 % for all patients (κ = 0.92)., Conclusions: DISH is useful for HER2 gene testing in breast cancer, and is recommended as a new option for assessing HER2 status.

For breast cancer patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), sentinel lymph node (SN) biopsy has been proposed as an axillary staging procedure in selected patients with a higher likelihood of having occult invasive lesions. With detailed histological examination of primary tumors and molecular whole-node analysis of SNs, we aimed to validate whether this selective application accurately identifies patients with SN metastasis. The subjects were 336 patients with a preoperative needle-biopsy diagnosis of DCIS who underwent SN biopsy using the one-step nucleic acid amplification assay in the period 2009-2011. The incidence and preoperative predictors of upstaging to invasive disease on final pathology and SN metastasis, and their correlation, were investigated. Of the 336 patients, 113 (33.6%) had invasive disease, and 6 (1.8%) and 17 (5.0%) had macro- and micrometastasis in axillary nodes respectively. Of the 113 patients with invasive disease, 4 (3.5%) and 9 (8.0%) had macro- and micrometastasis. Predictors of invasive disease included palpability, mammographic mass, and calcifications (spread >20 mm), and intraductal solid structure, but no predictor was found for SN metastasis. Therefore, even though occult invasive disease was found at final pathology, most of the patients had no metastasis or only micrometastasis in axillary nodes. Predictors of invasive disease and SN metastasis were not completely consistent, so the selective SN biopsy for patients with a higher risk of invasive disease may not accurately identify those with SN metastasis. More accurate application of SN biopsy is required for patients with a preoperative diagnosis of DCIS., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

The standardized assessment of Ki67 labeling index (LI) is of clinical importance to identify patients with primary breast cancer who could benefit from chemotherapy. In this study, we evaluated the interobserver concordance of Ki67 LI assessment. Six surgical pathologists participated and all the slides were prepared from archival breast cancer tissues fixed in 10% buffered formalin for 24 h and stained with MIB-1. Three independent studies were conducted. In the first study, 30 stained slides were assessed using two different methods: the scoring system, with a positive rate scored from 1 (0-9%) to 10 (90-100%) by visual estimate; and the counting method, with approximately 1000 cells counted in hot spots. In the second study, 20 tumors with Ki67 LI 5-25% were assessed, and in the third study, 15 printed photographs of stained slides were assessed to avoid variations by selecting different fields. In study 1, the counting system (intraclass correlation coefficient [ICC], 0.66 [95% confidence interval 0.52-0.78]) demonstrated a better correlation than the scoring system (ICC, 0.57 [0.42-0.72]). In study 2, the assessment for Ki67 LI of 5-25% demonstrated a correlation (ICC, 0.68 [0.50-0.81]) similar to that of study 1 (unrestricted range of Ki67 LI). In study 3, the assessment of Ki67 LI by counting yielded a good concordance (ICC, 0.94 [0.88-0.97]). In conclusion, there was better concordance with the counting system, and concordance was high when the assessed field was predetermined, indicating that the selection of the evaluation area is critical for obtaining reproducible Ki67 LI in breast cancer., (© 2013 Japanese Cancer Association.)

Aims: Secretory carcinoma (SC) is a rare histological type of breast cancer, and ETV6-NTRK3 gene fusion is highly specific to it. The differential diagnoses of SC include acinic cell carcinoma (ACCA) and cystic hypersecretory carcinoma (CHC), as well as invasive ductal carcinoma (IDC). For patients with these rare but distinctive histological subtypes, SC and its histopathological mimics should be differentiated from each other. However, differential markers have not yet been assessed systematically, and we aimed to identify and evaluate novel and existing markers., Methods and Results: We reviewed 19 cases diagnosed initially as SC using integrated diagnostic techniques, including morphology, immunohistochemistry and molecular pathology, and validated promising markers in 445 breast cancers. We reclassified 19 formerly diagnosed 'SCs' into nine SCs, three ACCAs, three CHCs, three IDCs and one microglandular adenosis. We confirmed that ETV6-NTRK3 gene rearrangement and amylase positivity are good diagnostic markers for SC and ACCA, respectively. Vacuolar staining for adipophilin, positivity for α-lactalbumin and negativity for ETV6 rearrangement are diagnostic markers for CHC., Conclusions: In this study, we propose a panel of four markers (ETV6 rearrangement, amylase, α-lactalbumin and adipophilin) for distinguishing SC, ACCA, CHC and IDC. This simple but robust panel will serve pathologists well as a practical guide for reaching an appropriate diagnosis., (© 2013 John Wiley & Sons Ltd.)

Background: For patients with breast cancer treated with preoperative chemotherapy, residual tumour burden in lymph nodes is the strongest prognostic factor. However, conventional pathological examination has limitations that hinder the accurate and reproducible measurement. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method for detecting nodal metastasis. In this prospective multicentre trial, we assessed the performance of the OSNA assay in detecting nodal metastasis after chemotherapy., Methods: In total, 302 lymph nodes from 80 breast cancer patients who underwent axillary dissection after chemotherapy were analysed. Each node was cut into two or four slices. One piece or alternate pieces were evaluated by pathology, and the other(s) were examined using the OSNA assay. The results of the two methods were compared. Stromal fibrosis, histiocytic aggregates, and degenerated cancer cells were regarded as chemotherapy-induced histological changes., Results: The overall accuracy, sensitivity, and specificity of the OSNA assay compared with the reference pathology were 91.1%, 88.3%, and 91.7%, respectively. Of the 302 lymph nodes, 66 (21.9%) exhibited chemotherapy-induced histology. For these nodes, the accuracy, sensitivity, and specificity were 90.9%, 88.9%, and 93.3%, respectively., Conclusion: The OSNA assay can detect the residual tumour burden as accurately as conventional pathology, although chemotherapy-induced histological changes are present.

By definition, ductal carcinoma in situ (DCIS) - pre-invasive breast cancer - does not metastasize to the lymph nodes. However, since the introduction of molecular whole-node analysis using the one-step nucleic acid amplification assay for sentinel node (SN) biopsies, the number of patients with DCIS and SN metastasis has increased. The pathogenesis and clinical management of DCIS with SN metastasis remain controversial. In this case-control study, in order to elucidate the pathogenesis of SN metastasis in DCIS, we compared occult invasions between the SN-positive and SN-negative DCIS and investigated predictive factors of occult invasion. The subjects were 24 patients selected from 285 patients with a routine postoperative diagnosis of DCIS who had undergone SN biopsy using the one-step nucleic acid amplification whole-node assay between 2009 and 2011. Of these 24 patients, 12 were SN-positive, and 12 were SN-negative. The 12 SN-negative patients make up the control group and were selected from the 273 SN-negative patients based on patient characteristics. All paraffin blocks of the primary tumor from each patient were step-sectioned with 500-μm intervals until the block was exhausted and histopathologically examined. We analyzed 1830 step-sectioned slides and found occult invasions were more frequent in the SN-positive group (7/12, 58.3%) than in the SN-negative group (3/12, 25.0%). All occult invasions were <5 mm. There was no correlation between occult invasion and SN tumor burden, non-SN metastasis, or patient characteristics. Our results suggest true metastasis from occult invasion may be a potent pathogenesis indicating nodal metastasis in postoperatively diagnosed DCIS. Patient follow-up is required to elucidate the prognostic impact of nodal metastasis and occult invasion., (© 2013 Japanese Cancer Association.)