Klinikopatológiai szemléletű emlőrákkutatások

In the second half of the 20th century research focusing to breast carcinomas at the Semmelweis University had been mostly linked to the 2nd Department of Pathology. Nowadays, following the rapidly improving treatment modalities in breast cancer there is an increasing need for defining new predictive and prognostic markers. The modern molecular pathological approach helps tremendously in mapping the biological behavior of individual cases of breast cancers and meanwhile, it is one of the prerequisites of a more efficient treatment both in neoadjuvant and adjuvant settings, as well as in metastatic disease. We provide a brief review of the relevant results we have obtained in breast cancer research between 2000 and 2015

Clinicopathological Features and Prognosis of Pregnancy Associated Breast Cancer – A Matched Case Control Study

Pregnancy Associated Breast Cancer (PABC) manifests during pregnancy or within a year following delivery. We sought to investigate differences in management, outcome, clinical, histopathology and immunohistochemistry (IHC) characteristics of PABC and matched controls in a retrospective case control study. PABC and control patients were selected from breast cancer cases of women </=45 years, diagnosed in the 2nd Department of Pathology, Semmelweis University, Budapest, Hungary between 1998 and 2012. Histopathology information on tumor type, grade, size, T, N, lympho-vascular invasion (LVI), Nottingham Prognostic Index (NPI), associated in situ lesions and IHC charcteristics: ER, PgR, HER2, Ki67, p53 were recorded, IHC-based subtype was assessed, clinical, management and outcome data were analysed. Thirty-one breast cancer cases were pregnancy related. Clinical management data did not differ in cases and controls. Histopathology of disease at presentation was not significantly different, but NPI assessed the PABC group as having poor, whereas controls as having intermediate prognosis. Associated in situ lesion was more often high grade Extensive Intraductal Carcinoma Component (EIC) in PABC. Triple negative and LuminalB prol tumors predominated in PABC. Disease-free and overall survival was inferior compared to controls. PABC patients with LuminalB prol and Triple negative tumors had inferior outcomes. On multivariate analysis inferior prognosis of PABC was associated with pregnancy. Our study has demonstrated inferior outcome of PABC. Difference in tumor biology is reflected by the predominance of triple negative and LuminalB tumors in PABC. The strength of the study is the analysis of complete pathology and IHC data

Molaterhesség postmenopausában

A molaterhesség a terhességi trophoblastbetegségek közé sorolt, rendkívül ritka kórkép. A kórkép patogenezise egye- dülálló, hiszen az anyai daganat eredete maga a terhességi szövet. Előfordulását tekintve főleg a reproduktív korú nőket érinti. Esetbemutatásunkban egy 53 éves nőbeteg postmenopausalis vérzési rendellenességet okozó panaszai- nak hátterében igazolódott molaterhesség. A molaterhesség fokozott kockázattal járó veszélyállapot, mely esetén a mihamarabbi befejezés alapját a megfelelő diagnosztika adja. Kezdeti tünetei megtévesztőek lehetnek, ectopiás ter- hességet vagy inkomplett abortuszt, anovulációs vérzési rendellenességet utánozhatnak. Esetismertetésünk célja, hogy felhívja a figyelmet a molaterhesség atipikus megjelenésére; postmenopausalis nőbetegünk kapcsán áttekintjük a molaterhesség kezelésének alapelveit, és bemutatjuk egy sikeresen kezelt eset diagnosztikus és terápiás lépéseit

Ki-67 as a controversial predictive and prognostic marker in breast cancer patients treated with neoadjuvant chemotherapy

BACKGROUND: Studies have partly demonstrated the clinical validity of Ki-67 as a predictive marker in the neoadjuvant setting, but the question of the best cut-off points as well as the importance of this marker as a prognostic factor in partial responder/non-responder groups remains uncertain. METHODS: One hundred twenty patients diagnosed with invasive breast cancer and treated with neoadjuvant chemotherapy (NAC) between 2002 and 2013 were retrospectively recruited to this study. The optimal cut-off value for Ki-67 labeling index (LI) to discriminate response to treatment was assessed by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier curve estimation, log-rank test and cox regression analysis were carried out to reveal the association between Ki-67 categories and survival (DMFS = Distant metastases-free survival, OS = Overall survival). RESULTS: Twenty three out of 120 patients (19.2%) achieved pathologic complete remission (pCR), whereas partial remission (pPR) and no response (pNR) to neoadjuvant chemotherapy (NAC) was detected in 60.8% and 20.0%, respectively. The distribution of subtypes showed a significant difference in pathological response groups (p < 0.001). Most of the TNBC cases were represented in pCR group. The most relevant cut-off value for the Ki-67 distinguishing pCR from pNR cases was 20% (p = 0.002). No significant threshold for Ki-67 was found regarding DMFS (p = 0.208). Considering OS, the optimal cut-off point occurred at 15% Ki-67 (p = 0.006). The pPR group represented a significant Ki-67 threshold at 30% regarding OS (p = 0.001). Ki-67 and pPR subgroups were not significantly associated (p = 0.653). For prognosis prediction, Ki-67 at 30% cut-off value (p = 0.040) furthermore subtype (p = 0.037) as well as pathological response (p = 0.044) were suitable to separate patients into good and unfavorable prognosis cohorts regarding OS. However, in multivariate analyses, only Ki-67 at 30% threshold (p = 0.029), and subtype (p = 0.008) were independently linked to OS. CONCLUSIONS: NAC is more efficient in tumors with at least 20% Ki-67 LI. Both Ki-67 LI and subtype showed a significant association with pathological response. Ki-67 LI represented independent prognostic potential to OS in our neoadjuvant patient cohort, while pathological response did not. Additionally, our data also suggest that if a tumor is non-responder to NAC, increased Ki-67 is a poor prognostic marker

Genomic Landscape of Normal and Breast Cancer Tissues in a Hungarian Pilot Cohort

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM. Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN, RAD51C, BRIP1, and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations

Prognostic impact of progesterone receptor expression in HER2-negative luminal B breast cancer

Aim: The new classification of breast cancer is based on microarray studies. Within the estrogen receptor (ER) positive breast carcinoma subtype further subgroups could be identified. In the present study, we analyzed the Her2 negative, highly proliferative subgroup (Luminal B1-like, LUMB1) with emphasis on their clinicopathological characteristics and progesterone receptor (PR) expression. Patients and methods: Our retrospective study concerned the period between 2000 and 2010. 158 patients were selected with ER positive, Her2 negative, Ki67>15% breast cancer. The pathological and clinical data were collected and analyzed. Age, tumor grade and stage, ER, PR, Her2 and Ki67 expression were recorded. The clinicopathological variables were correlated to PR expression. Results: The mean age of the patients was 57.5 (28-75) years. The ratio of patients younger than 40, was 8.86%. Shorter metastasis-free survival was observed in this young age group (P=0.044). The majority of our cases belonged to the pT1-pT2 stages (41.28% and 44.95%, respectively) whereas pT3 and T4 stage was detected in 5.50% and 8.25% of the cases, respectively. Almost half of the cases had no axillary lymph node metastasis (pN0: 48.91%), 1-3 lymph node metastases were detected in 38.04% (pN1), 4-10 metastatic lymph nodes were identified in 9.78% (pN2) and pN3 stage was found in 3.26% of the cases. Most commonly the tumors were either grade 2 or 3 (44.16% and 45%, respectively). The median value of Ki67 labeling index was 30%. Disease progression was detected in 36.19% of the patients. According to PR expression, a tendency to better prognosis (i.e. longer disease free- and overall survival) was detected in cases showing >10% PR positivity. However, no difference was found regarding tumor size, axillary stage, grade and age when comparing lower and higher PR expressing tumors. Conclusions: LUMB1 breast carcinomas are typically grade 2 and grade 3, the Ki67 labeling index is often 30% or higher. Distant metastases occur in more than one third of the cases. Within this subgroup, those cases with low PR expression represent a poor prognostic cohort. These findings require further investigations in larger number of LUMB1 breast cancer cases

Expression of tight junction protein claudin-4 in basal-like breast carcinomas

Claudins (CLDN) are tight junction proteins which contribute to the paracellular transport and ionic permeability of various epithelia. In recent years they came into focus for their suggested role in carcinogenesis and possible role in cancer therapy. According to our previous studies, in breast tissue CLDN4 is also related to the level of cellular differentiation. Thirty-eight estrogen (ER) and progesterone receptor (PgR) negative, HER2/neu negative, but cytokeratin 5/6 positive basal-like—mainly grade 3— breast carcinomas were compared with twenty-one grade 1, twenty-five grade 2 and twenty grade 3 non-basal-like invasive breast carcinomas, in respect to their CLDN4 expression. The immunohistochemical reactions were evaluated both semiquantitatively and by morphometrical analysis. Statistically significant difference (p=0.001) was observable regarding CLDN4 expression in the basal-like group as compared to grade 1 and 2 cancers. Further, CLDN4 expression was significantly higher (p=0.017) in the basal-like compared with the non-basal-like grade 3 carcinomas. Our results suggest that basal-like carcinomas are a subset of breast cancer with high level of CLDN4 protein expression. The finding is in accordance with our former observation that CLDN4 is indeed related to cellular differentiation. This observation may be seen as a further proof that basal-like carcinomas represent a separable group amongst grade 3 breast carcinomas