Frequency of chromosome 17 polysomy in relation to CEP17 copy number in a large breast cancer cohort.

Eligibility to anti-HER2 therapy for breast tumors strictly depends on demonstrating HER2 overexpression (by immunohistochemistry) or HER2 gene amplification by in situ hybridization (ISH), usually defined by the ratio of HER2 gene to chromosome 17 centromere (CEP17) copies. However, the CEP17 copy number increase (CNI) has been proven responsible for misleading HER2 FISH results and recent small cohort studies suggest that chromosome 17 polysomy is actually very rare. Here we investigated by FISH the frequency of true chromosome 17 polysomy in a consecutive cohort of 5,477 invasive breast cancer patients. We evaluated and selected the LSI 17p11.2 probe for chromosome 17 enumeration on a training cohort of 67 breast cancer samples (CEP17 ≥ 2.5). LSI 17p11.2 was used in the 297/5,477 patients from the validation cohort displaying CEP17 CNI (CEP17 ≥ 3.0). Using HER2/17p11.2 scoring criteria, 37.3%/1.5% patients initially classified as equivocal/non-amplified were reclassified as amplified. For a more accurate assessment of chromosome 17 and ploidy in the samples, we tested six markers located on chromosome 17 and centromeric regions of chromosome 8 (CEP8) and 11 (CEP11) in 67 patients with CEP17 and LSI 17p11.2 CNI. True polysomy (hyperdiploidy) according to these markers was found in 0.48% of cases (24/5,020). CEP8 and CEP11 CNI (≥3.0) was more frequent in the hyperdiploid than CEP17 non-polysomic group (55.6% vs. 6.1% and 25% vs. 2.3%, respectively). Our results suggest that chromosome 17 polysomy is a rare event found in <1% breast cancer cases and that polysomy of other chromosomes frequently occurs with chromosome 17 polysomy.

BCL2 is an independent predictor of outcome in basal-like triple-negative breast cancers treated with adjuvant anthracycline-based chemotherapy.

Neither targeted therapies nor predictors for chemotherapy sensitivity are available for triple-negative breast cancer (TNBC). Our study included 187 patients with TNBC, 164 of whom were treated with anthracycline-based adjuvant chemotherapy. Eleven molecular biomarkers were analyzed. BCL2, epidermal growth factor receptor (EGFR), MYC, TOP2A, and Ki-67 protein expression was evaluated by immunohistochemistry. The status of the EGFR, MYC, and TOP2A genes and chromosomes 7, 8, and 17 was assessed using fluorescence in situ hybridization. High BCL2 expression predicted poor relapse-free survival (RFS) in patients treated with anthracycline-based adjuvant chemotherapy (p = 0.035), poor breast cancer-specific survival (BCSS) (p = 0.048), and a trend to poor overall survival (OS) (p = 0.085). High levels of BCL2 expression predicted poor OS in basal-like (BL) TNBC patients treated with adjuvant anthracycline-based regimens (log-rank p = 0.033, hazard ratio (HR) 3.04, 95 % confidence interval (CI) 1.04-8.91) and a trend to poor RFS (log-rank p = 0.079) and poor BCSS (log-rank p = 0.056). Multivariate analysis showed that BCL2 status, tumor size, and nodal status all had independent predictive significance for RFS (p = 0.005, p = 0.091, p = 0.003, respectively; likelihood ratio test for the whole model, p = 0.003), BCSS (p = 0.012, p = 0.077, p = 0.01, respectively; likelihood ratio test for the whole model, p = 0.016), and OS (p = 0.008, p = 0.004, p = 0.004, respectively; likelihood ratio test for the whole model, p = 0.0006). Similarly, multivariate analysis for BL TNBC showed BCL2, tumor size, and nodal status all had independent predictive significance for RFS (likelihood ratio test for the whole model, p = 0.00125), BCSS (p = 0.00035), and OS (p = 0.00063). High EGFR expression was associated with poor BCSS (p = 0.039) in patients treated with anthracycline-based adjuvant chemotherapy. Patients who underwent anthracycline-based adjuvant chemotherapy and exhibited CMYC amplification had a trend to worse BCSS (p = 0.066). In conclusion, high BCL2 expression is a significant independent predictor of poor outcome in TNBC patients treated with anthracycline-based adjuvant chemotherapy, and this is the first study showing the BCL2 prediction in BL TNBC. BCL2 expression analysis could facilitate decision making on adjuvant treatment in TNBC patients.

An adult multifocal medulloblastoma with diffuse acute postoperative cerebellar swelling: immunohistochemical and molecular genetics analysis.

Medulloblastoma (MB), the most common malignant tumor typically affecting children, occurs only exceptionally in adults. Multifocal presentation of this malignancy in adulthood is even much rarer­only four cases with favorable postoperative course have been reported, so far. The study illustrates a very rare rapid postoperative clinical deterioration due to diffuse cerebellar swelling (DCS) in an adult multifocal MB (MMB). To the best of their knowledge, authors for the first time performed genetic analysis of MMB and demonstrated expression patterns of selected markers that put the patient within the sonic hedgehog (SHH) molecular subgroup and at least partially explain her unsatisfactory clinical course. Herein, authors summarized the relevant literature concerning this issue with the aim to determine features that would facilitate diagnosis and therapy of such a scarce clinical entity.

Isocitrate dehydrogenase 1 and 2 mutations in gliomas.

Over the past few years, new biomarkers have allowed a deeper insight into gliomagenesis and facilitated the identification of possible targets for glioma therapy. Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations have been shown to be promising biomarkers for monitoring disease prognosis and predicting the response to treatment. This review summarizes recent findings in this field. Web of Science, Science Direct, and PubMed online databases were used to search for publications investigating the role of IDH in glioma. References were identified by searching for the keywords "IDH1 or IDH2 and glioma and diagnostic or predictive or prognostic" in papers published from January, 2008, to April, 2014. Only papers in English were reviewed. Publications available only as an abstract were not included. IDH1/2 mutations are tightly associated with grade II and III gliomas and secondary glioblastomas, with better prognosis and production of a recently described oncometabolite, 2-hydroxyglutarate (2HG). Although the contradictory positive effect of IDH mutation on prognosis and negative role of 2HG in tumor transformation remain unresolved, the future direction of personalized treatment strategies targeted to glioma development is likely to focus on IDH1/2 mutations.

Primitive neuroectodermal tumor (PNET) of the lung in an adult woman.

Primary primitive neuroectodermal tumors (PNETs) are extremely rare in the lung and especially in adult women. We describe a case of PNET of the lung with aggressive behavior in 31-year-old woman. Diagnosis was based on histopathological and immunohistochemical studies, and confirmed by molecular genetic analysis of chromosome rearrangements in the EWSR1 gene region. Clinical follow-up, post-mortem findings, and differential diagnosis are also discussed.

Clinical and prognostic significance of detecting CEA, EGFR, LunX, c-met and EpCAM mRNA-positive cells in the peripheral blood, tumor-draining blood and bone marrow of non-small cell lung cancer patients.

Background: Surgical treatment of early-stage non-small cell lung cancer (NSCLC) yields highest expectations for recovery. However, the frequency of further disease progression remains high since micro-metastatic disease may be undetected by conventional diagnostic methods. We test the presence and prognostic impact of circulating tumor cells (CTCs) in peripheral blood (PB), tumor-draining pulmonary blood (TDB) and bone marrow (BM) samples from NSCLC patients. Methods: The presence of circulating/disseminated tumor cells (CTCs/DTCs) was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis in PB, TDB and BM samples before surgery in 119 stage IA-IIIA NSCLC patients (Clinical Trial NS10285). Results: NSCLC patients with the presence of carcinoembryonic antigen (CEA) mRNA-positive CTCs/DTCs in TDB and BM had significantly shorter cancer-specific survival (CSS) (P<0.013, resp. P<0.038). Patients with the presence of epithelial cellular adhesion molecule (EpCAM) mRNA-positive CTCs in TDB samples had significantly shorter CSS and disease-free survival (DFS) (P<0.031, resp. P<0.045). A multivariate analysis identified the presence of CEA mRNA-positive CTCs in the PB as an independent negative prognostic factor for DFS (P<0.005). No significant correlation of CTCs/DTCs presence and other prognostic factors was found. Conclusions: In NSCLC patients undergoing radical surgery, the presence of CEA and EpCAM mRNA-positive CTCs/DTCs is associated with poorer survival.

The Influence of Gene Aberrations on Survival in Resected IDH Wildtype Glioblastoma Patients: A Single-Institution Study.

This prospective population-based study on a group of 132 resected IDH-wildtype (IDH-wt) glioblastoma (GBM) patients assesses the prognostic and predictive value of selected genetic biomarkers and clinical factors for GBM as well as the dependence of these values on the applied therapeutic modalities. The patients were treated in our hospital between June 2006 and June 2015. Clinical data and tumor samples were analyzed to determine the frequencies of TP53, MDM2, EGFR, RB1, BCR, and CCND1 gene aberrations and the duplication/deletion statuses of the 9p21.3, 1p36.3, 19q13.32, and 10p11.1 chromosome regions. Cut-off values distinguishing low (LCN) and high (HCN) copy number status for each marker were defined. Additionally, MGMT promoter methylation and IDH1/2 mutation status were investigated retrospectively. Young age, female gender, Karnofsky scores (KS) above 80, chemoradiotherapy, TP53 HCN, and CCND1 HCN were identified as positive prognostic factors, and smoking was identified as a negative prognostic factor. Cox proportional regression models of the chemoradiotherapy patient group revealed TP53 HCN and CCND1 HCN to be positive prognostic factors for both progression-free survival and overall survival. These results confirmed the influence of key clinical factors (age, KS, adjuvant oncotherapy, and smoking) on survival in GBM IDH-wt patients and demonstrated the prognostic and/or predictive importance of CCND1, MDM2, and 22q12.2 aberrations.

Merkel cell carcinoma of the gluteal region with ipsilateral metastasis into the pancreatic graft of a patient after combined kidney-pancreas transplantation.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare tumour of the skin that predominantly affects elderly or immunocompromised patients. The malignant transformation of Merkel cells is currently considered to be related to an infection with Merkel cell polyomavirus. CASE REPORT: We present the case of a 62-year-old man who developed a Merkel cell polyomavirus-positive MCC in a non-UV-exposed part of the right gluteal region 8 years after combined kidney-pancreas transplantation. Following excision and radical re-excision of the tumour, no adjuvant radiotherapy was indicated because of the risk of adjacent pancreatic graft failure. Despite adjustment of the immunosuppressive therapy with conversion to sirolimus, the tumour generalised and metastasised into the pancreatic graft, leading to its failure. Subsequent chemotherapy did not affect the course of the disease, and the patient died 9 months after diagnosis. CONCLUSIONS: To our knowledge, we present the first case of MCC associated with metastatic involvement of the transplanted pancreas followed by its subsequent failure. Given the highly aggressive course of the disease in patients after organ transplantation, MCC therapy should be sufficiently aggressive from the time of diagnosis and should not be influenced by attempts to preserve graft function.

Dumbbell-shaped peripheral primitive neuroectodermal tumor of the spine--case report and review of the literature.

Primary spinal peripheral primitive neuroectodermal tumors (pPNETs) are extremely rare. Here, we present a case study of a 29-year-old male with a dumbbell-shaped pPNET at the T9-10 spine level, including details of his examination, surgical procedures applied, histological and genetic findings, and his subsequent treatment. We discuss the clinical course, the pathology and treatment for this disease, the surgical approach to thoracic dumbbell tumors and we review the literature. To our knowledge, this is the first report of a case of a dumbbell-shaped intradural and spinal peripheral PNET.

Tumor-Infiltrating Lymphocytes/Plasmocytes in Chemotherapeutically Non-Influenced Triple-Negative Breast Cancers - Correlation with Morphological and Clinico-Pathological Parameters.

BACKGROUND: Triple-negative breast cancers (TNBCs) are considered a morphologically heterogeneous group of breast carcinomas characterized by the absence or low protein expression of hormone receptors and HER2/neu/ERBB2 with a specific biological behavior and therapeutic response. This study aimed to evaluate correlations of the density of tumor-infiltrating lymphocytes/plasmocytes (TILs) in the tumor parenchyma, stroma, and invasive margins with tumor morphology, the proliferation rate, Bcl-2 expression, and selected clinical and pathological parameters in early breast cancer patients prior to mastectomy who had not received initial chemotherapy. MATERIALS AND METHODS: Samples of 3,544 breast cancer patients investigated in our department between 2007 and 2017 were re-examined. In total, 413 (11.65%) patients were diagnosed with TNBC. Only 61 cases did not undergo neoadjuvant therapy prior to mastectomy. Correlations between the density of TILs and tumor morphology, Bcl-2 expression, proliferative activity measured by Ki-67, patient age at diagnosis, tumor grade, and metastases were investigated. RESULTS: The samples were predominantly relatively well-localized invasive carcinomas of no special type with medullary features (80.32%) that measured on average 13.4mm (range 5-20mm, median 15mm) and exhibited central necrosis or fibrosis, a tendency to undergo spindle cell and/or apocrine-like differentiation, and intensive infiltration of TILs. There were significant positive correlations between TILs and premenopausal status (p=0.003), Ki-67 expression (p=0.015), and tumor grade (p=0.002), a marginal positive correlation between TILs and tumor size (p=0.065), and a significant negative correlation between TILs and Bcl-2 expression (p=0.035). In younger patients (< 50 years) with tumor size less than or equal to 20 mm (pT1a-pT1c) we recorded a lower number of women with metastatic lymph node involvement (p=0.001). CONCLUSION: The density and location of TILs in non-therapeutically influenced TNBCs, evaluated in the context of morphological changes and other clinicopathological parameters, may have prognostic significance and assist effective therapy planning.

[A retrospective analysis of trastuzumab-based therapy in metastatic breast cancer patients at Masaryk Memorial Cancer Institute. Identification of predictive factors]. / Výsledky retrospektivní analýzy cílené lécby metastatického karcinomu prsu trastuzumabem v MOU. Identifikace prediktivních faktoru.

INTRODUCTION: Trastuzumab is a humanized monoclonal antibody directed against the HER-2 receptor. Trastuzumab-based therapy significantly improves response rate (RR), time to progression (TTP) and overall survival (OS) for women with HER-2 positive metastatic breast cancer. Despite its initial efficacy, acquired resistance to trastuzumab develops in a majority of patients with MBC, and a large subset never responds, demonstrating primary resistance. The purpose of this retrospective study was to determine prognostic factors applicable to clinical practice. METHODS: We enrolled 112 women with metastatic breast cancer, who started the trastuzumab-based therapy at Masaryk Memorial Cancer Institute until January 2007. Clinical and laboratory factors, such as: patients conditions, character ofmetastatic spread, histology, estrogen, progesterone and Her-2 receptor status, Her-2/neu gene amplification, and serum tumor markers CEA, CA 15-3 and extracellular domain of Her-2 receptor (S-HER-2 ECD) were monitored. The association of all factors to response to therapy, time to progression (TTP) and overall survival (OS) was assessed. RESULTS: In 95% patients, the trastuzumab was combined with cytostatics (83% taxanes), 88,4% of patients started the trastuzumab as the first or second-line anticancer treatment. The median TTP was 284 days (9,3 months) and the median OS was 612 days (20,1 months) for all patients, RR was 54,5%. The highest RR was associated with the first-line treatment (p<0.0001) and with HER-2 gene/Chromosome 17 ratio > 2,2 (p=0,0092). Eleven patients (9,8%) discontinued the treatment because of toxicity, 7 patients did it as a result of cardiotoxicity (6,2%). CNS metastases occurred in 31 patients (27,7%). The S-HER-2 ECD was the most frequently elevated serum marker at the time of the treatment initialization (72,5%) and at the time of the progression (55,9%). Cox regression analysis identified S-HER-2 ECD levels at the beginning and between day 90 and 130 of the trastuzumab therapy as the best predictors of TTP. On the other hand the best predictor of OS was level of CEA before the treatment started and level of S-HER-2 ECD between day 90 and 130 of the trastuzumab therapy. CONCLUSIONS: We confirmed that the only one predictive marker for response to trastuzumab therapy is a proof of HER-2 tumor positivity.The highest prevalence of S-HER-2 ECD positivity among serum tumor markers and the strong association between initial and subsequent S-HER-2 ECD serum concentrations and time to progression and overall survival make the S-HER-2 ECD the most significant prognostic marker.

Genetic Markers in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancer cases and is characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Though TNBC is a highly heterogenic and aggressive disease, TNBC patients have better response to neoadjuvant therapy compared to other breast cancer subtypes. Nevertheless, patients with residual disease have a very poor prognosis, with higher probability of relapse and lower overall survival in the first years after diagnosis. TNBC has 6 subtypes with distinct molecular signatures with different prognoses and probably different responses to therapy. The precise stratification of TNBC is therefore crucial for the development of potent standardized and targeted therapies. In spite of intensive research into finding new molecular biomarkers and designing personalized therapeutic approaches, BRCA mutational status is the only clinically validated biomarker for personalized therapy in TNBC. Recent studies have reported several promising biomarkers that are currently being validated through clinical trials. The objective of this review was to summarize the clinically relevant genetic markers for TNBC that could serve as diagnostic, prognostic, or predictive or could improve personalized therapeutic strategies.

Age-associated prognostic and predictive biomarkers in patients with breast cancer.

To date, no comprehensive prognostic or predictive marker profiling analysis has been performed in association with the age of patients with breast cancer. In the present study, 632 breast cancer tissue samples were analyzed for expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), B-cell lymphoma (Bcl)-2 protein, HER2 gene amplification, proliferation [as evaluated by proliferating cell nuclear antigen (PCNA) and Ki-67 index], tumor grade, histological type and molecular subtype. The data revealed correlations with the age of patients. A statistically significant positive correlation was identified between patient age and expression of ER (P<0.0001). There was no significant association between patient age and PR, HER2 protein expression, HER2 gene amplification or PCNA. A significant negative correlation between age and Ki-67 expression (P<0.0001) as well as grade of tumor (P=0.007) was identified. The spectrum of molecular subtypes differed according to age (P=0.0003). The highest incidence of aggressive triple-negative and HER2-positive breast cancer was present in patients aged between 20 and 39 years. Luminal A subtype was the most frequent cancer subtype in patients from age 40 onwards, where proliferation activity declined with age and expression of hormone receptors increased along with Bcl-2 expression. Aggressive forms of breast cancer were more common in younger patients. Prognostic and predictive markers have a complex age-specific distribution. The findings of less aggressive luminal A and B subtypes in older patients, and the positive correlation with ER, PR and Bcl-2 expression reveal the potential efficacy of Bcl-2 as a marker of hormone responsiveness in these patients.

A duplication dup(4)(q28q35.2) de novo in a newborn.

We report here a case of a newborn with hypotrophy and somatic stigmatization: microcephaly, facial dysmorphism, heart defect and immunodeficiency syndrome. The proband's karyotype was 46,XY,dup(4)(q28q35.2) de novo with chromosomal breaks in 4% of metaphases. We demonstrate the usefulness of a combination of physical examination, classical cytogenetics, FISH and PCR techniques in order to establish correct diagnosis because of overlap of some clinical and cytogenetic features of Nijmegen breakage syndrome (NBS) and duplication 4q in our patient. Although FISH technique detected translocation t(14q;21q) in 4 metaphases, deletion 657del5 in exon 6 of the NBS1 gene associated with NBS in Slavic population was not confirmed. We compare in this report similarity of the clinical picture of our patient, NBS cases and other patients carrying a duplication of the distal part of 4q as described in the literature.

Evaluation of HER2 Gene Status in Breast Cancer Samples with Indeterminate Fluorescence in Situ Hybridization by Quantitative Real-Time PCR.

Administration of drugs targeting HER2 (official symbol ERBB2) is an important component of therapy for breast cancer patients with HER2 amplification/overexpression as determined by in situ hybridization (ISH) and immunohistochemistry (IHC). In approximately 5% of breast cancers, ISH assays fail. In these cases, HER2 protein expression is evaluated by IHC alone that may yield false negatives/positives for poor-quality samples. Therefore, we developed a method that was based on quantitative real-time PCR applicable for DNA from formalin-fixed, paraffin-embedded tissue samples. Its limit of detection was determined with breast cancer cell lines and validated with 223 breast cancer patient samples. On the basis of comparisons with fluorescent ISH (FISH) and IHC data, the sensitivity of the new method was 94.2% and 95.1%, its specificity was 100% and 99.1%, and overall concordance between results obtained with the quantitative real-time PCR method and FISH/IHC was 97.6% for both methods. The quantitative real-time PCR method was then used to evaluate the HER2 status of 198 of 3696 breast cancer tissues that yielded indeterminate FISH results. The HER2 copy number was successfully determined in 69.2% of these indeterminate samples. Thus, the DNA-based technique appears to be a specific, sensitive method for determining HER2 copy numbers when the FISH assay fails, which may complement IHC tests.

Non-small cell lung cancer--genetic predictors.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer that is the leading cause of cancer-related mortality worldwide. Several predictive markers have been found in NSCLC patients to date but only a few are currently used for tailored therapy. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search review and original articles on the most important predictive markers in NSCLC. CONCLUSION: EGFR activating mutations (exons 18 to 21) and EML4-ALK rearrangement are clinically important markers able to select NSCLC patients which benefit from EGFR or ALK tyrosine kinase inhibitors (gefitinib, erlotinib, crizotinib). Other markers, such as KRAS mutation, EGFR T790M mutation and C-MET amplification, are responsible for resistance to these inhibitors. Overcoming of this resistance as well as discovery of new potential markers and inhibitors is the main goal of ongoing research and clinical trials in NSCLC.

High lapatinib plasma levels in breast cancer patients: risk or benefit?

AIMS AND BACKGROUND: Lapatinib is a tyrosine kinase inhibitor targeting epidermal growth factor receptors 1 (EGFR/HER1) and 2 (HER2) used in the treatment of patients with HER2-positive breast cancer. The aim of the present study was to determine lapatinib plasma levels in breast cancer patients treated with lapatinib plus capecitabine. PATIENTS AND METHODS: We assessed lapatinib plasma levels in blood samples from 21 breast cancer patients treated with lapatinib plus capecitabine using the standard regimen in an expanded access program. Liquid chromatography tandem mass spectrometry was used for measuring lapatinib plasma concentrations. The validated method was applied for measurement of 55 plasma samples. RESULTS: The median lapatinib plasma level was 5.09 µg/mL, with large interindividual differences. Patients of lower weight tended to have higher lapatinib plasma levels (Spearman correlation coefficient R = -0.435, P = 0.055). One patient's lapatinib plasma levels were markedly higher than those of the others, with a median level of 11.25 µg/mL and repeatedly exceeding 7.80 µg/mL. The treatment was terminated after 8 months when hyperbilirubinemia occurred. CONCLUSIONS: The lapatinib plasma levels reported here are twice as high as the clinically effective steady-state geometric mean maximum concentration. We conclude that increased lapatinib body levels occur when patients are in a nonfasting state at the time of drug intake and when lapatinib doses are not adjusted to low body weight or weight loss during treatment. In Europe, dose adjustments are not recommended in the case of hepatic function impairment. Thus, attention should be paid to changes in liver function test results in clinical practice, especially in patients of small stature and weight, given the risk of high plasma concentrations. Prospective lapatinib plasma level assessment in treated patients might be useful to confirm or refute the possible correlation of high lapatinib plasma levels with hepatic and/or other toxicities.

Lapatinib in breast cancer - the predictive significance of HER1 (EGFR), HER2, PTEN and PIK3CA genes and lapatinib plasma level assessment.

BACKGROUND: Breast cancer treatment trends are currently based on tailored therapies using tumor and patient biomarkers. Lapatinib is the first dual inhibitor of HER1 (EGFR, ErbB1) and HER2 (ErbB2, Neu) tyrosine kinases to be used in clinical practice. However, only HER2 is currently used for therapy indications and new predictors for the treatment with lapatinib are sought. METHODS AND RESULTS: This minireview focuses on lapatinib and its role in breast cancer treatment. Preclinical and clinical studies as well as pharmacological characteristics are briefly reviewed while the focus is on efficacy assessment including predictive factors for therapy outcome. CONCLUSION: Lapatinib (Tykerb/Tyverb) was Food and Drug Administration (FDA) approved in 2007 for use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who had received previous treatment (including anthracycline, taxane and trastuzumab containing regimens) and in 2010 for use in combination with letrozole for postmenopausal women with hormonal receptor positive and HER2- positive metastatic breast cancer. In contrast to trastuzumab (Herceptin), lapatinib is orally administered and it targets both HER2 and HER1 receptors. As a synthetic and oral tyrosine kinase inhibitor (TKI), it is convenient, cheaper and easier to produce than monoclonal antibodies. The recommended dosage is not dependent on body weight either. Lapatinib plasma level measurement could be an approach to tailored therapy for further optimizing the dose and prolonging this efficient therapy. New lapatinib response predictors are being evaluated. At this time, only HER2 amplification/overexpression is used to choose lapatinib therapy candidates. Further studies on concurrent HER1 fluorescent in situ hybridization (FISH)/immunohistochemistry (IHC) assessment and/or microarray analyses may produce new data on the predictive role of the HER1 (EGFR) gene/protein. PTEN loss and PIK3CA gene mutations are other markers that may predict lapatinib poor response.

Intramedullary spinal cord and cauda equina metastasis of breast carcinoma: case report.

AIM: We present a case report of a female patient with metastasis of breast carcinoma to the medullary conus and cauda equina. METHODS: A 48-year-old woman with a history of breast tumor, suddenly felt severe weakness and numbness of the lower extremities. MRI of the spine disclosed a mass lesion within the medullary conus, with leptomeningeal involvement of cauda equina at the spinal level L1. Laminectomy was performed and partial resection of the medullary conus tumor and especially release of nerve roots of cauda equina was achieved using microsurgical techniques. RESULTS: Her clinical status, especially right leg weakness and sensory loss in the lower extremities have immediately improved but bladder dysfunction remained and she was unable to walk. The histological picture and immunophenotype indicates the presence of metastatic ductal adenocarcinoma of the mammary gland. Patient died 4 months after the spinal cord and cauda equina surgery. CONCLUSION: To our knowledge, this is the first report of successful surgical treatment of metastatic leptomeningeal infiltration of breast carcinoma.

Fetal colon cell line FHC exhibits tumorigenic phenotype, complex karyotype, and TP53 gene mutation.

Stable cell lines obtained by spontaneous immortalization might represent early stages of malignant transformation and be useful experimental models for studies of mechanisms of cancer development. The FHC (fetal human cells) cell line has been established from normal fetal colonic mucosa. Detailed characterization of this cell line and mechanism of spontaneously acquired immortality have not been described yet. Therefore, we characterized the FHC cell line in terms of its tumorigenicity, cytogenetics, and TP53 gene mutation analysis. FHC cells displayed capability for anchorage-independent growth in semisolid media in vitro and formed solid tumors after transplantation into SCID (severe combined immunodeficiency) mice. This tumorigenic phenotype was associated with hypotriploidy and chromosome number ranging from 66 to 69. Results of comparative genetic hybridization arrays showed that most chromosomes included regions of copy number gains or losses. Region 8q23 approximately 8q24.3 (containing, e.g., MYC proto-oncogene) was present in more than 20 copies per nucleus. Moreover, we identified mutation of TP53 gene in codon 273; triplet CGT coding Arg was changed to CAG coding His. Expression of Pro codon 72 polymorphic variant of p53 was also detected. Mutation of TP53 gene was associated with abolished induction of p21(Waf1/Cip1) and MDM-2 proteins and resistance to apoptosis after genotoxic treatment. Because of their origin from normal fetal colon and their relative resistance to the induction of apoptosis, FHC cells can be considered a valuable experimental model for various studies.