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Purpose: We studied the long-term outcomes of invasive micropapillary carcinoma (IMPCs) of the breast in relation to stromal tumor infiltrating lymphocytes (sTILs), prognostic biomarkers and clinicopathological features., Methods: Stage I-III IMPCs treated with upfront surgery at our institution (January 2000 and December 2016) were included. Central pathology review was performed and sTILs (including zonal distribution and hot spot analysis) and tumor-associated plasma cells (TAPC) were evaluated. Expression of P53, BCL2, FOXP3, and WT1, which are variably linked to breast cancer prognosis, was measured by immunohistochemistry using tissue microarrays. Time-to-event endpoints were distant recurrence free interval (DRFI) and breast cancer-specific survival (BCSS)., Results: We included 111 patients of whom 59% were pure IMPCs. Standard clinicopathological features were comparable between pure and non-pure IMPCs. Overall, the mean sTILs level was 20% with higher proportion of sTILs present at the invasive front. There were no significant differences between pure- and non-pure IMPCs in sTILs levels, nor in the spatial distribution of the hot spot regions or in the distribution of TAPC. Higher sTILs correlated with worse DRFI (HR = 1.55; p = 0.0172) and BCSS (HR = 2.10; p < 0.001)., Conclusions: Clinicopathological features, geographical distribution of sTILs and TAPC are similar between pure and non-pure IMPCs. Despite a high proportion of grade 3 tumors and lymph node involvement, we observed a low rate of distant recurrences and breast cancer-related death in this cohort of stage I-III IMPCs treated with primary surgery. Caution in interpretation of the observed prognostic correlations is required given the very low number of events, warranting validation in other cohorts.

Purpose: To explore the impact of breast cancer subtype on metastatic behavior and long-term outcome defined as breast cancer specific survival (BCSS)., Methods: Retrospective single centre cross-sectional study of 5972 patients with newly diagnosed, unilateral first diagnosis of breast cancer, diagnosed 2000-2010. Patients had either early breast cancer (EBC) treated primarily by surgery (SURG n = 5072), neoadjuvant systemic therapy (NEO n = 592), or upfront metastatic disease (META n = 308). Surrogate breast cancer subtypes were defined according to classical pathological criteria. Analysis was performed using Kaplan-Meier method and logistic/Cox regression., Results: After median follow-up time of 103.6 months (IQR 73.4-139.2 months), 817 patients with EBC at diagnosis (14.4%) developed distant metastases of which 621 (12.2%) SURG and 196 (33.1%) NEO. Metastasis rate after EBC was: LuminalA 8.1%, LuminalB1(HER2-) 20.4%, LuminalB2(HER2+) without (neo)adjuvant trastuzumab 21.7%, LuminalB2(HER2+) with trastuzumab 9.0%, HER2Positive(ER-) without trastuzumab 30.0%, HER2Positive(ER-) with trastuzumab 19.9% and TripleNegative 25.3%. There were major differences in site of first metastases according to subtype. For single site first metastases, median BCSS assessed from time of metastases was worst for brain localization (13.9 months) and best for bone (48.4 months). Multiple sites of first metastases had worse BCSS from date of metastases than single site first metastases (median BCSS for 1 site 40.0, 2 sites 27.1, ≥ 3 sites 20.5 months). Median BCSS from date of metastases is longer in upfront metastases compared to secondary metastases after EBC (43.4 vs. 27.9 months)., Conclusions: Tumor subtype influences the metastatic behavior and survival after development of distant metastases.

Purpose: Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients., Methods: We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution's ethical research committee., Results: A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2)., Conclusions: The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

Introduction: Prognostic subgroup classification of operable breast cancers using cDNA clustering of breast cancer-related genes resembles the classification based on the combined immunohistochemical (IHC) expression of the hormone and HER-2 receptors. We here report the short-term disease-free interval (DFI) of operable breast cancers by their joint hormone receptor/HER-2 phenotype., Patients and Methods: Short-term follow-up (FU) of a prospective cohort of 1,958 breast-cancer patients primary operated at our institution between 2000 and 2005. Receptors were evaluated using IHC. Steroid receptors were considered positive for any nuclear staining; HER-2 for strong (3+) membrane staining or positive fluorescence in situ hybridization (FISH). Kaplan-Meier (KM) DFI curves were calculated for any relapse defined as a local, regional, contralateral, or distant breast cancer event for the six predefined breast cancer subgroups: ER + PR + HER-2 - (PPN), ER + PR - HER-2 - (PNN), ER + PR + HER-2 + (PPP), ER - PR - HER-2 - (NNN), ER - PR - HER-2 + (NNP), and ER + PR - HER-2 + (PNP). P-values were calculated for comparison of the six different survival curves using two possible adaptations for multiple testing. A multivariate model for the receptors predicting DFI did incorporate local and systemic adjuvant therapy., Results: Median patient age was 57 years (ranges 26-96) and median FU was 3.35 years. Overall, DFI at median FU was 91%; 94% for PPN, 89% for PNN, 86% for NNN, 81% for PPP, 80% for PNP, and 76% for NNP cases. Some receptor subgroups had a significantly better DFI than others based on multiple testing, especially when the PPN group was compared against the four most frequent subtypes. The multivariate model with local and systemic adjuvant therapy confirmed the prognostic value of ER, PR, and HER-2 for short-term DFI., Conclusion: It is possible to distinguish short-term prognostic breast cancer subgroups only on the basis of ER, PR, and HER-2 even when stratified for local and systemic adjuvant therapy. While gene expression profiles based on microarray data of over hundreds of genes will probably teach us much about breast cancer biology, heterogeneity, and prognosis, we emphasize the important short-term prognostic value of currently used IHC markers for ER, PR, and HER-2.

Aims: To examine the frequency of axillary lymph node (ALN) invasion of operable breast cancers by their combined oestrogen receptor (ER), progesterone receptor (PR) and HER-2 status., Methods: 2227 recently operated cases in one centre were retrieved from the Multidisciplinary Breast Centre database and stratified according to their combined immunohistochemical (IHC) expression of ER/PR/HER-2 status. An equivocal HER-2 status was further analysed by Fluorescence in situ Hybridisation (FISH). The following 6 groups were considered: ER(-)PR(-)HER-2(-) (NNN; triple negative), ER(-)PR(-)HER-2(+) (NNP), ER(+)PR(-)HER-2(-) (PNN), ER(+)PR(-)HER-2(+) (PNP), ER(+)PR(+)HER-2(- )(PPN), ER(+)PR(+)HER-2(+) (PPP; triple positive). For ALN, the following variables were tested in uni- and multivariate models: age at diagnosis (years), tumour size (mm), tumour grade, ER, PR, HER-2 and the combined steroid receptor and HER-2 status. Likelihood ratio chi(2)-tests were used for univariate analysis and logistic regression for multivariate analysis., Results: Triple positive tumours had a higher likelihood of being ALN positive than others (56.2% versus 35.7%; P<0.0001). Univariate logistic regression also withheld age, size, grade and HER-2 as predictors of ALN involvement. Final multivariate logistic regression revealed age, size, grade and PPP versus non-PPP to be independent predictors of ALN involvement; the odds ratio (OR) and 95% CI for PPP versus non-PPP tumours was 2.169 (1.490-3.156)., Conclusion: Our data provide insight into the natural history of triple positive breast carcinomas. Such tumours are more likely ALN positive than those with another steroid receptor and HER-2 status. How these findings correlate with breast cancer prognosis remains to be investigated.

Objective: Arthralgia, skeletal and muscle pain have been reported in postmenopausal women under treatment with third generation aromatase inhibitors (AIs). However, the pathogenesis and anatomic correlate of musculoskeletal pains have not been thoroughly evaluated. Moreover, the impact of AI-induced musculoskeletal symptoms on normal daily functioning needs to be further explored., Patients and Methods: We examined 12 consecutive non-metastatic breast cancer patients who reported severe musculoskeletal pain under a third generation AI; 11 were on letrozole and 1 on exemestane. Clinical rheumatological examination and serum biochemistry were performed. Radiological evaluation of the hand/wrist joints were performed using ultrasound (US) and/or magnetic resonance imaging (MRI)., Results: The most common reported symptom was severe early morning stiffness and hand/wrist pain causing impaired ability to completely close/stretch the hand/fingers and to perform daily activities and work-related skills. Six patients had to discontinue treatment due to severe symptoms. Trigger finger and carpal tunnel syndrome were the most frequently reported clinical signs. US showed fluid in the tendon sheath surrounding the digital flexor tendons. On MRI, an enhancement and thickening of the tendon sheath was a constant finding in all 12 patients., Conclusions: Musculoskeletal pains in breast cancer patients under third generation AIs can be severe, debilitating, and can limit compliance. Characteristic tenosynovial, and in some patients joint changes on US and MRI were observed in this series and have not been reported before.