Comparison of proportions and prognostic impact of pathological complete response between evaluations of representative specimen and total specimen in primary breast cancer after neoadjuvant chemoradiotherapy: an ancillary study of JCOG0306.

BACKGROUND: In JCOG0306 trial, a phase II study to examine the efficacy of neoadjuvant chemotherapy followed by radiation therapy (NAC-RT) to primary breast cancer, pathological complete response (pCR) was evaluated from specimens of the representative cross-section including the tumor center that had been accurately marked [representative specimen (RS) method]. In this ancillary study, we examined if the RS method was comparable to the conventional total specimen (TS) method, which is widely employed in Japan, to identify the pCR group showing excellent prognosis. METHODS: We obtained long-term follow-up data of 103 patients enrolled in JCOG0306 trial. As histological therapeutic effect, pCR (ypT0 and ypT0/is) and quasi-pCR [QpCR, ypT0/is plus Grade 2b (only a few remaining invasive cancer cells)] were evaluated with RS and TS methods. Concordance of pCR between these two methods and associations of the pCR with prognosis were examined. RESULTS: ypT0, ypT0/is, and QpCR were observed in 28 (27.2%), 39 (37.9%), and 45 (43.7%) patients with RS method, whereas these were 20 (19.4%), 25 (24.3%) and 40 (38.9%) with TS method, respectively. Between RS and TS methods, concordance proportions of ypT0 and ypTis were 92.2% and 86.4%, respectively. Risk of recurrence of ypT0/is group was lower than that of non-ypT0/is group (HR 0.408, 95% CI [0.175-0.946], P = 0.037) and risk of death of ypT0/is group was lower than that of non-ypT0/is group (HR 0.251, 95% CI [0.073-0.857], P = 0.027). The ypT0 and ypT0/is groups with RS method showed excellent prognosis similarly with those with TS method, and RS method was able to differentiate the OS and RFS between pCR and non-pCR than TS method significantly even if pCR was classified ypT0 or ypT0/is. With TS method, QpCR criteria stratified patients into the better and worse prognosis groupsmore clearly than pCR criteria of ypT0 or ypT0/is. CONCLUSIONS: RS method was comparable to TS method for the evaluation of pCR in the patients who received NAC-RT to primary breast cancer provided the tumor center was accurately marked. As pCR criteria with RS method, ypT0/is appeared more appropriate than ypT0.

A prediction model for early systemic recurrence in breast cancer using a molecular diagnostic analysis of sentinel lymph nodes: A large-scale, multicenter cohort study.

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay can quantify the cytokeratin 19 messenger RNA copy number as a proxy for sentinel lymph node (SN) metastasis in breast cancer. A large-scale, multicenter cohort study was performed to determine the prognostic value of the SN tumor burden based on a molecular readout and to establish a model for the prediction of early systemic recurrence in patients using the OSNA assay. METHODS: SN biopsies from 4757 patients with breast cancer were analyzed with the OSNA assay. The patients were randomly assigned to the training or validation cohort at a ratio of 2:1. On the basis of the training cohort, the threshold SN tumor burden value for stratifying distant recurrence was determined with Youden's index; predictors of distant recurrence were investigated via multivariable analyses. Based on the selected predictors, a model for estimating 5-year distant recurrence-free survival was constructed, and predictive performance was measured with the validation cohort. RESULTS: The prognostic cutoff value for the SN tumor burden was 1100 copies/µL. The following variables were significantly associated with distant recurrence and were used to construct the prediction model: SN tumor burden, age, pT classification, grade, progesterone receptor, adjuvant cytotoxic chemotherapy, and adjuvant anti-human epidermal growth factor receptor 2 therapy. The values for the area under the curve, sensitivity, specificity, and accuracy of the prediction model were 0.83, 63.4%, 81.7%, and 81.1%, respectively. CONCLUSIONS: Using the OSNA assay, the molecular readout-based SN tumor burden is an independent prognostic factor for early breast cancer. This model accurately predicts early systemic recurrence and may facilitate decision-making related to treatment.

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

PURPOSE: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes. METHODS: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status. RESULTS: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02). CONCLUSIONS: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.

Nuclear grade and comedo necrosis of ductal carcinoma in situ as histopathological eligible criteria for the Japan Clinical Oncology Group 1505 trial: an interobserver agreement study.

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.

Clinicopathological features of breast cancer patients with internal mammary and/or supraclavicular lymph node recurrence without distant metastasis.

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.

Prognostic impact and possible pathogenesis of lymph node metastasis in ductal carcinoma in situ of the breast.

PURPOSE: Ductal carcinoma in situ (DCIS)-preinvasive breast cancer-with lymph node metastasis can clinically be treated as different stages: occult invasive cancer with true metastasis (T1N1) or pure DCIS with iatrogenic dissemination (TisN0). In this retrospective cohort study, we aimed to elucidate the prognostic impact and possible pathogenesis of nodal metastasis in DCIS to improve clinical management. METHODS: Subjects were comprised of 427 patients with routine postoperative diagnosis of DCIS who underwent sentinel node (SN) biopsy using molecular whole-lymph-node analysis. Clinicopathological characteristics and prognosis were compared between SN-positive and -negative patients. Primary tumour tissues of SN-positive patients were exhaustively step-sectioned to detect occult invasions, and predictive factors for occult invasion were investigated. Median follow-up time was 73.6 months. RESULTS: Of the 427 patients, 19 (4.4%) were SN-positive and 408 (95.6%) were SN-negative. More SN-positive patients received adjuvant systemic therapy than SN-negative patients (84.2% vs. 5.4%). Seven-year distant disease-free survivals were favourable for both cohorts (SN-positive, 100%; SN-negative, 99.7%). By examining 1421 slides, occult invasion was identified in 9 (47.4%) of the 19 SN-positive patients. Tumour burdens in SN and incidence of non-SN metastasis were similar between patients with and without occult invasion, and no predictive factor for occult invasion was found. CONCLUSIONS: Node-positive DCIS has favourable prognosis with adjuvant systemic therapy. Half of the cases may be occult invasive cancer with true metastasis. In practical settings, clinicians may have to treat these tumours as node-positive small invasive cancers because it is difficult to predict the pathogenesis without exhaustive primary tumour sectioning.

Characteristics of adverse events of endocrine therapies among older patients with breast cancer.

PURPOSE: To clarify the profile of adverse events from endocrine therapies in older patients. METHODS: We surveyed 15 subjective symptoms including hot flashes, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, lethargy, forgetfulness, depressive state, irritated state, genital bleeding, leukorrhea increase, vaginal dryness, bone fracture, and weight gain by a questionnaire among 2044 patients over 55 years old (total number of answered sheets, 8875) and compared the results according to age (56-69 years old vs. ≥ 70 years old) and type of therapy (aromatase inhibitors (AIs) vs. selective estrogen receptor modulators (SERMs)). Among patients 56-69 years old, 6093 and 314 responses were from patients treated with AIs (1477 patients) and SERMs (123 patients), respectively, and 2292 and 176 responses were from those ≥ 70 years old treated with AIs (581 patients) and SERMs (51 patients), respectively. RESULTS: In patients ≥ 70 years old, sweating, knuckle stiffness, knee/shoulder joint pain, limb numbness, and lethargy were significantly more frequent/severe with AIs than with SERMs. In those aged 56-69, knuckle stiffness and vaginal dryness were significantly more frequent with AIs than with SERMs, but the opposite occurred for hot flashes, leukorrhea increase, genital bleeding, and weight gain. CONCLUSIONS: Among patients ≥ 70 years old, many symptoms were significantly more frequent/severe with AIs than with SERMs, compared with those aged 56-69, which suggests a difference in the profile of adverse events according to the type of endocrine therapy and the patient's age. It is important to consider the benefits and risks of each treatment to optimize endocrine therapy for older patients.

Pattern of Tumor Shrinkage during Neoadjuvant Chemotherapy Is Associated with Prognosis in Low-Grade Luminal Early 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.

Intraoperative Nomograms, Based on One-Step Nucleic Acid Amplification, for Prediction of Non-sentinel Node Metastasis and Four or More Axillary Node Metastases in Breast Cancer Patients with Sentinel Node Metastasis.

BACKGROUND: One-step nucleic acid amplification (OSNA) for cytokeratin 19 messenger RNA is an intraoperative diagnostic procedure for the detection of lymph node metastasis. OBJECTIVE: This study aimed to construct intraoperative nomograms using OSNA for the prediction of non-sentinel lymph node (NSLN) metastasis and four or more axillary lymph node (ALN) metastases. METHODS: Of the 4736 breast cancer patients (T1-3, N0) who underwent sentinel lymph node (SLN) biopsy and had SLNs examined intraoperatively with OSNA, 623 with SLN metastasis treated with completion ALN dissection (cALND) were retrospectively analyzed, and were randomly divided into training (n = 312) and validation (n = 311) sets. RESULTS: Of the clinicopathological parameters available preoperatively and intraoperatively, the multivariate analysis of the training set revealed that clinical tumor size and total tumor load (TTL) determined by OSNA were significantly associated with NSLN metastasis, and that clinical tumor size, number of macrometastatic SLNs, and TTL were significantly associated with four or more ALN metastases. Nomograms for NSLN metastasis and four or more ALN metastases were constructed using these parameters, and their area under the receiver operating characteristic curve (AUC) of the validation set were both 0.70, with a diagnostic accuracy similar to that of previously reported postoperative nomograms. CONCLUSIONS: We constructed intraoperative nomograms using OSNA for the prediction of NSLN metastasis and four or more ALN metastases. These nomograms are as accurate as the conventional postoperative nomograms and might be helpful for decision making regarding the indication for cALND or the choice of adjuvant chemotherapeutic regimens and radiation field.

A new molecular-based lymph node staging classification determines the prognosis of breast cancer patients.

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can detect metastasis in a whole lymph node based on cytokeratin 19 mRNA copy number. This cohort study aimed to establish an OSNA-based nodal staging (pN(mol)) classification for breast cancer. METHODS: The cohort consisted of 1039 breast cancer patients who underwent sentinel node (SN) biopsy using the OSNA assay. Cutoff value of the SN tumour burden stratifying distant disease-free survival (DDFS) was determined, and predictive factors for DDFS and breast cancer-specific survival (BCSS) were investigated. pN(mol) classification of the SN status was defined as: pN0(mol)(sn), SN negative; pN1mi(mol)(sn), SN positive and tumour burden

Lesion Size on Ultrasonography Predicts Potential Invasion in Ductal Carcinoma in situ Preoperatively Diagnosed by Breast Needle Biopsy.

Ductal carcinoma in situ (DCIS) of the breast has no potential to metastasize, but over 20% of cases preoperatively diagnosed as DCIS are upstaged on final pathology. The rates of upstaging and the predictors for invasion on final pathology were evaluated. For 240 primary breast cancers, radiological findings on mammography, ultrasonography, and magnetic resonance imaging were investigated along with pathological and clinical information. Univariate and multivariate analyses were performed to identify predictors of potential invasion. Of the 240 breast cancers, 68 (28.3%) showed invasion on final pathology, and 5 (2.5%) had sentinel node metastasis. The multivariate analysis identified five independent predictors: non-mass lesions >2.4 cm on ultrasonography (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.02-7.95, p=0.047), comedo-type histology (OR 6.89, 95% CI 1.89-25.08, p<0.01), solid-type histology (OR 7.97, 95% CI 2.08-30.49, p<0.01), palpable mass (OR 2.63, 95% CI 1.05-6.64, p=0.04), and bloody nipple discharge (OR 4.61, 95% CI 1.20-17.66, p=0.02). These five predictors were associated with invasion on final pathology and may help select candidates for sentinel node biopsy.

Prognostic significance of histological therapeutic effect in preoperative chemotherapy for breast cancer.

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.

Impact of immunohistological subtypes on the long-term prognosis of patients with metastatic breast cancer.

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.

Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptors status or adjuvant endocrine therapy.

BACKGROUND: Bcl-2 plays an anti-apoptotic role, resulting in poor clinical outcome or resistance to therapy in most tumor types expressing Bcl-2. In breast cancer, however, Bcl-2 expression has been reported to be a favorable prognostic factor. The positive correlation of Bcl-2 with estrogen receptor (ER)/progesterone receptor (PR) status, and endocrine therapy frequently given for hormone receptor-positive tumors, may obscure the independent pathobiological role of Bcl-2. We constructed a large systematic study to determine whether Bcl-2 has an independent role in breast cancer. METHODS: Bcl-2 expression was immunohistochemically evaluated and compared with other clinicopathological factors, including clinical outcome, in 1081 breast cancer cases with long follow-up, separately analyzing 634 cases without any adjuvant therapy and 447 cases with tamoxifen monotherapy. The χ (2)-test for independence using a contingency table, the Kaplan-Meier method with the log-rank test, and a Cox proportional hazards model were used for the comparison of clinicopathological factors, assessment of clinical outcome, and multivariate analyses, respectively. RESULTS: In both patient groups, Bcl-2 expression strongly correlated with positive ER/PR status, low grade, negative human epidermal growth factor receptor 2 (HER2) status, and small tumor size, as previously reported. Bcl-2 expression did not independently predict clinical outcome in patients with ER-positive and/or PR-positive tumors or in those who received tamoxifen treatment; however, it was an independent unfavorable prognostic factor in patients with ER-negative/PR-negative or triple-negative (ER-negative/PR-negative/HER2-negative) tumors who received no adjuvant therapy. The latter was even more evident in postmenopausal women: those with hormone receptor-negative or triple-negative tumors lacking Bcl-2 expression showed a favorable outcome. CONCLUSION: Bcl-2 expression is an independent poor prognostic factor in patients with hormone receptor-negative or triple-negative breast cancers, especially in the absence of adjuvant therapy, suggesting that the anti-apoptotic effect of Bcl-2 is clearly exhibited under such conditions. The prognostic value of Bcl-2 was more evident in postmenopausal women. The present findings also highlight Bcl-2 as a potential therapeutic target in breast cancers lacking conventional therapeutic targets such as triple-negative tumors. The favorable prognosis previously associated with Bcl-2-positive breast cancer probably reflects the indirect effect of frequently coexpressed hormone receptors and adjuvant endocrine therapy.

The significance of combined CK5/6 and p63 immunohistochemistry in predicting the risks of subsequent carcinoma development in intraductal papilloma of the breast.

Prediction of subsequent risks of breast carcinoma (BC) development in intraductal papilloma (IDP) has remained controversial with the exception of atypical papilloma (AP). The potential value of immunohistochemistry (IHC) of cytokeratin 5/6 [CK5/6] and p63 have been proposed but its standardization has also remained controversial. We studied 17 patients initially diagnosed as IDP or AP who subsequently developed BC with 34 age-matched controls. We compared histological features, results of IHC (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2], p63, CK5/6, Ki67), and ultrasound findings. Univariate conditional logistic regression analysis revealed that the status of both CK5/6 and p63/CK5/6 were significantly associated with subsequent BC development (P < 0.05). BC development in CK5/6 positive patients was 17.9% and p63/CK5/6 double positive patients 8.6%, respectively. Ultrasound evaluation was not significantly associated with any of the parameters examined and subsequent carcinoma development. Despite CK5/6 positivity, the subsequent incidence of BC development was nearly 20%. However p63/CK5/6 double positive status could predict a significantly lower subsequent carcinoma incidence, indicating a more accurate prognostic utility. Combining p63/CK5/6 with histological findings could be easily applied and could predict the subsequent BC development of the patients diagnosed as IDP at biopsy.

Four types of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery: classification of IBTR based on precise pathological examination.

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.

Extensive analysis of signaling pathway molecules in breast cancer: association with clinicopathological characteristics.

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.

Incidence and prediction of invasive disease and nodal metastasis in preoperatively diagnosed ductal carcinoma in situ.

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.

Lapatinib-associated mucocutaneous toxicities are clinical predictors of improved progression-free survival in patients with human epidermal growth factor receptor (HER2)-positive advanced breast cancer.

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.

Clinicopathological significance of 'atypical ductal proliferation' in core needle biopsy of the breast.

Atypical ductal proliferation or ADP has been used in histopathological diagnosis of core needle biopsy (CNB) but its details have not been well studied. Therefore, we examined the clinicopathological characteristics of the initial CNB cases diagnosed as 'ADP ' who subsequently turned out to be malignant, and compared the findings to those that did not. Among 101 cases initially diagnosed as ADP in CNB, the second biopsy revealed no carcinoma (38), ductal carcinoma in situ (DCIS) (45) and invasive carcinoma (18). Significant differences were detected between those which turned out to be carcinoma and those that did not, in the status of myoepithelial cells identified by p63 immunohistochemistry (P = 0.026) and ultrasound (US) categories (P < 0.001). We further compared the histopathological characteristics of those initially diagnosed as ADP and subsequently as DCIS or invasive ductal carcinoma (IDC) with those initially diagnosed as such. DCIS or IDC cases initially diagnosed as ADP had significantly lower Ki67 labeling index (P < 0.01, P < 0.01) and histological grade using Van nuys prognostic index (P < 0.01) or Nottingham histological grades (P < 0.01) respectively than those initially as DCIS or IDC. An assessment of myoepithelial components with US findings might contribute to determine the subsequent clinical algorithm of the patients diagnosed as ADP at initial CNB.