Browsing by Author "Milovanovic, Zorka (25228841900)"

We present the case of a 69-year-old Caucasian man with a 5-year history of untreated chronic lymphocytic leukemia who presented with Merkel cell carcinoma on the right gluteal region. Six months after surgical treatment of Merkel cell carcinoma, we detected massive lymphadenopathy in the right retroperitoneum descending to the inguinum. A lymph node biopsy confirmed Merkel cell carcinoma relapse, and the patient was unsuccessfully treated with radiotherapy. As patients with chronic lymphocytic leukemia have a risk for developing a secondary malignancy, skin lesions need to be carefully examined and new lymphadenopathy must be pathohistologically evaluated. © 2015, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.

Multiple cancers represent 2.42% of all human cancers and are mainly double or triple cancers. Many possible causes of multiple malignancies have been reported such as genetic alterations, exposure to anti-cancer chemotherapy, radiotherapy, immunosuppressive therapy and reduced immunologic response. We report a female patient with multiple sclerosis and quadruple cancers of different embryological origin. Patient was diagnosed with stage III (T3, N1a, MO) medullary thyroid carcinoma (MTC), multicentric micropapillary thyroid carcinoma, scapular and lumbar melanomas (Clark II, Breslow II), and lobular invasive breast carcinoma (T1a, NO, MO). All tumors present in our patient except micropapillary thyroid carcinomas were investigated for gene alterations known to have a key role in cancer promotion and progression. Tumor samples were screened for the p16 alterations (loss of heterozygosity and homozygous deletions), loss of heterozygosity of PTEN, p53 alterations (mutational status and loss of heterozygosity) and mutational status of RET, HRAS and KRAS. Each type of tumor investigated had specific pattern of analyzed genetic alterations. The most prominent genetic changes were mutual alterations in PTEN and p53 tumor suppressors present in breast cancer and two melanomas. These co-alterations could be crucial for promoting development of multiple malignancies. Moreover the insertion in 4th codon of HRAS gene was common for all tumor types investigated. It represents frameshift mutation introducing stop codon at position 5 which prevents synthesis of a full-length protein. Since the inactivated RAS enhances sensitivity to tamoxifen and radiotherapy this genetic alteration could be considered as a good prognostic factor for this patient.

Purpose: The purpose of this study was to assess the immunohistochemistry and chromogenic in situ hybridization (CISH) inter-laboratory consensus between national pathology laboratories in Serbia. Methods: This study was conducted between 2013 and 2016. In 2013, HER2 results were evaluated using two sets of four different breast cancer specimens in five laboratories. A total of 20 immunohistochemistry and 20 CISH cases were tested. In 2014, there were 6 testing rounds, and a total of 24 specimens were analyzed, whereas in 2015 and 2016, seven testing rounds were conducted, with four additional cases (i.e. a total of 28 specimens). In 2014, 2015 and 2016, all institutions performed immunohistochemical analysis only. Results: We found discrepancies in HER2 immunohistochemical (IHC) results in all four surveys. IHC testing resulted in diagnostic discordance between participating centers in two (2/17) cases in 2013, two (2/24) in 2014, four (4/27) cases in 2015 and three cases (3/27) in 2016. The overall agreement among the centers was 79%, 85.5%, 83.5% and 89.4%, respectively. For CISH analyses, the results for 16 (84.2%) of 19 samples were consistent for all participants. Three results were found to be discordant, indicating a misdiagnosis rate of 15.8%. In all the discrepant cases, interinstitutional discordances were related to technical and evaluation issues. Conclusions: Our study highlights the difficulty encountered during HER2 testing using immunohistochemistry and CISH. This also emphasizes the need for rigorous quality control procedures for specimen preparation and analysis. © 2019 Zerbinis Publications. All rights reserved.

Purpose: The purpose of this study was to assess the immunohistochemistry and chromogenic in situ hybridization (CISH) inter-laboratory consensus between national pathology laboratories in Serbia. Methods: This study was conducted between 2013 and 2016. In 2013, HER2 results were evaluated using two sets of four different breast cancer specimens in five laboratories. A total of 20 immunohistochemistry and 20 CISH cases were tested. In 2014, there were 6 testing rounds, and a total of 24 specimens were analyzed, whereas in 2015 and 2016, seven testing rounds were conducted, with four additional cases (i.e. a total of 28 specimens). In 2014, 2015 and 2016, all institutions performed immunohistochemical analysis only. Results: We found discrepancies in HER2 immunohistochemical (IHC) results in all four surveys. IHC testing resulted in diagnostic discordance between participating centers in two (2/17) cases in 2013, two (2/24) in 2014, four (4/27) cases in 2015 and three cases (3/27) in 2016. The overall agreement among the centers was 79%, 85.5%, 83.5% and 89.4%, respectively. For CISH analyses, the results for 16 (84.2%) of 19 samples were consistent for all participants. Three results were found to be discordant, indicating a misdiagnosis rate of 15.8%. In all the discrepant cases, interinstitutional discordances were related to technical and evaluation issues. Conclusions: Our study highlights the difficulty encountered during HER2 testing using immunohistochemistry and CISH. This also emphasizes the need for rigorous quality control procedures for specimen preparation and analysis. © 2019 Zerbinis Publications. All rights reserved.

We present a patient who first developed a distant metastatic site in the cerebellum during treatment for Her2 3+ locally advanced breast cancer (LABC). LABC was in complete remission at that time and isolated cerebellar metastasis was resected. The patient is still alive more than 135 months after LABC diagnosis, and more than 99 months after neurosurgery, and is still receiving trastuzumab without further progression or any toxicity. To the best of our knowledge, this is first report of such exceptional disease course for a patient with a predicted grave prognosis according to all prognostic parameters.

Purpose: The purpose of this study was to present the Screening Registry and the results of organized cervical cancer screening program (OCCSP) in the Republic of Serbia using a database made as an output model, linked with the Screening Registry. Methods: Data were respectively collected over a one-month period from 3 state primary health care centers (and related hospitals/clinical center) in central Serbia in which OCCSP was conducted. The sample consisted of women of the target population (25 to 64 years old) who responded the call for Pap test. Results: The most frequent abnormal cytological diagnosis was in the 38-50 years age group, and consisted of atypical squamous cells of undetermined significance - ASCUS (7.5%) and low grade squamous intraepithelial lesions - L-SIL (7.3%). The most frequent abnormal colposcopie finding in the youngest age group of women (25-37 years) was iodine negative epithelium (35.7%) and in the group of women aged 38-50 and 51-64 years acid-white epithelium. The most common histopathological diagnosis was L-SIL. Positive predictive value of colposcopy in relation to the Pap test was 0.64 (95% CI=0.56-0.70). Interrater agreement (between cytotechnicians and supervisors) measured by the Cohen's coefficient was 0.94 (95% Ci=0.91 to 0.97), but between cytology (supervisors) and pathology findings it was 0.83 (95% CI = 0.67 to 0.99). Conclusion: The existence of a screening registry contributes to a better epidemiological surveillance of a screening program, and to a possibility for development of various epidemiological researches.

Purpose: The purpose of this study was to present the Screening Registry and the results of organized cervical cancer screening program (OCCSP) in the Republic of Serbia using a database made as an output model, linked with the Screening Registry. Methods: Data were respectively collected over a one-month period from 3 state primary health care centers (and related hospitals/clinical center) in central Serbia in which OCCSP was conducted. The sample consisted of women of the target population (25 to 64 years old) who responded the call for Pap test. Results: The most frequent abnormal cytological diagnosis was in the 38-50 years age group, and consisted of atypical squamous cells of undetermined significance - ASCUS (7.5%) and low grade squamous intraepithelial lesions - L-SIL (7.3%). The most frequent abnormal colposcopie finding in the youngest age group of women (25-37 years) was iodine negative epithelium (35.7%) and in the group of women aged 38-50 and 51-64 years acid-white epithelium. The most common histopathological diagnosis was L-SIL. Positive predictive value of colposcopy in relation to the Pap test was 0.64 (95% CI=0.56-0.70). Interrater agreement (between cytotechnicians and supervisors) measured by the Cohen's coefficient was 0.94 (95% Ci=0.91 to 0.97), but between cytology (supervisors) and pathology findings it was 0.83 (95% CI = 0.67 to 0.99). Conclusion: The existence of a screening registry contributes to a better epidemiological surveillance of a screening program, and to a possibility for development of various epidemiological researches.

Purpose: In order to investigate if aberrant promoter methylation of p16, BRCA1 and RASSF1A genes contributes to biological behavior of triple-negative breast cancer (TNBC), marked as the most aggressive phenotype of breast cancer, we compared the hypermethylation pattern between TNBC and ER+PR+Her2- breast cancer. Methods: 131 patients with histologically confirmed breast cancers were included - 61 TNBC and 70 ER+PR+Her2- cases. The patients were followed up for 1-87 months (median 78). DNA from tumor tissues was isolated by the salting out procedure. The methylation status was assessed by nested methylation-specific PCR after bisulfite modification of DNA. Results: The frequency of p16 hypermethylated breast cancer cases was significantly higher in TNBC than in ER+PR+Her2- group (33; 54.1% vs. 20; 28.6%, p=0.00298). Co-methylated p16 and RASSF1A genes were more frequent in the TNBC than in ER+PR+Her2- group (20; 32.8% vs. 10; 14.3%, p=0.0225). The same result was observed when hypermethylated BRCA1 gene was added in the analysis: 12; 19.7% vs. 3; 4.3%, p=0.00791. Although there was significant difference in disease-free survival (DFS) and overall survival (OS) between TNBC and ER+PR+Her2- group, further analysis of co-methylation of p16 and RASSF1A (p16+RASSF1A+) showed that DFS was significantly shorter in the patients with both genes co-methylated in TNBC than in ER+PR+Her-2- group (8/20; 40% vs. 2/10; 20%, p=0.03272). Conclusions: The obtained data indicate that hypermethylated p16 and RASSF1A cell-cycle inhibitor genes might be considered as biomarkers for bad prognosis in breast cancer. Hypermethylation of these genes may influence the clinical disease course, distinguishing a particular group of TNBC patients with even more aggressive phenotype. © 2018 Zerbinis Publications. All rights reserved.

Purpose: In order to investigate if aberrant promoter methylation of p16, BRCA1 and RASSF1A genes contributes to biological behavior of triple-negative breast cancer (TNBC), marked as the most aggressive phenotype of breast cancer, we compared the hypermethylation pattern between TNBC and ER+PR+Her2- breast cancer. Methods: 131 patients with histologically confirmed breast cancers were included - 61 TNBC and 70 ER+PR+Her2- cases. The patients were followed up for 1-87 months (median 78). DNA from tumor tissues was isolated by the salting out procedure. The methylation status was assessed by nested methylation-specific PCR after bisulfite modification of DNA. Results: The frequency of p16 hypermethylated breast cancer cases was significantly higher in TNBC than in ER+PR+Her2- group (33; 54.1% vs. 20; 28.6%, p=0.00298). Co-methylated p16 and RASSF1A genes were more frequent in the TNBC than in ER+PR+Her2- group (20; 32.8% vs. 10; 14.3%, p=0.0225). The same result was observed when hypermethylated BRCA1 gene was added in the analysis: 12; 19.7% vs. 3; 4.3%, p=0.00791. Although there was significant difference in disease-free survival (DFS) and overall survival (OS) between TNBC and ER+PR+Her2- group, further analysis of co-methylation of p16 and RASSF1A (p16+RASSF1A+) showed that DFS was significantly shorter in the patients with both genes co-methylated in TNBC than in ER+PR+Her-2- group (8/20; 40% vs. 2/10; 20%, p=0.03272). Conclusions: The obtained data indicate that hypermethylated p16 and RASSF1A cell-cycle inhibitor genes might be considered as biomarkers for bad prognosis in breast cancer. Hypermethylation of these genes may influence the clinical disease course, distinguishing a particular group of TNBC patients with even more aggressive phenotype. © 2018 Zerbinis Publications. All rights reserved.

Purpose: Since one of possible causes of resistance to antiestrogen therapy in steroid receptor positive (SR+) breast cancer (BC) patients is an alteration of PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopausal patients with steroid SR+ BC treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) statuses and disease outcome. Methods: This was a retrospective analysis of 78 postmenopausal stage I/II SR+ BC patients treated with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry. Results: The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62.8%) patients with ductal and in 26/35 (74.3%) patients with lobular carcinomas; and PTEN- status in 16/43 (37.2%) patients with ductal and in 9/35 (25.7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 patients: 14/53 (26.4%) of PTEN+ BC subgroup and 24/25 (96%) of PTEN- subgroup (x2,=0.018). There were no significant associations between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression. Patients with PTEN- had significantly shorter disease-free interval (DFI) and overall survival (OS) (for both, log rank test, p <0.01) compared to PTEN+ BC patients. Conclusion: Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR+ BC patients treated with adjuvant tamoxifen. © 2011 Zerbinis Medical Publications.

Purpose: Since one of possible causes of resistance to antiestrogen therapy in steroid receptor positive (SR+) breast cancer (BC) patients is an alteration of PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopausal patients with steroid SR+ BC treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) statuses and disease outcome. Methods: This was a retrospective analysis of 78 postmenopausal stage I/II SR+ BC patients treated with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry. Results: The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62.8%) patients with ductal and in 26/35 (74.3%) patients with lobular carcinomas; and PTEN- status in 16/43 (37.2%) patients with ductal and in 9/35 (25.7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 patients: 14/53 (26.4%) of PTEN+ BC subgroup and 24/25 (96%) of PTEN- subgroup (x2,=0.018). There were no significant associations between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression. Patients with PTEN- had significantly shorter disease-free interval (DFI) and overall survival (OS) (for both, log rank test, p <0.01) compared to PTEN+ BC patients. Conclusion: Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR+ BC patients treated with adjuvant tamoxifen. © 2011 Zerbinis Medical Publications.

Quadruple primary malignancies occur with an incidence of less than 0.1%. Only less than hundred cases have been published until today. The number of multiple malignancies reported is gradually increasing. Here, we present a female patient with a multiple sclerosis and quadruple cancers from different embryological origin. The patient had medullary thyroid carcinoma (stage III-T3, N1a, M0) and multicentric micropapillary carcinomas, two melanomatous lesions, 1.24 and 0.85 mm thick (Clark II, Breslow II) and breast cancer (T1a, N0, M0). There were no signs of disease recurrence during the 5 years including the exam performed last month. Further genomic studies and closer clinical attention are needed to clarify the relation between secondary malignancies, applied treatments and endogenous and exogenous carcinogens in the process of carcinogenesis in quadruple malignancies.

Purpose: The incidence of histologically proven lymph node metastases (LNM) in papillary thyroid carcinoma (PTC) reaches 80%. According to different guidelines surgical management in clinically N0 (cN0) patients with PTC remains controversial. The purpose of this study was to investigate if sentinel lymph node biopsy (SLNb) using methylene blue dye is accurate in the detection of LNM in the lateral neck compartment in cN0 patients with PTC. Methods: Enrolled were 153 cN0 patients with PTC. All underwent total thyroidectomy with central neck dissection and SLNb in the lateral neck compartment, using methylene blue dye as marker. Selective modified radical neck dissection was performed in cases of metastatic SLNs. Results: Neck LNMs were histologically verified in 40.9% of the cases. Predictive factors for LNM were: males, younger than 45 years, tumors greater than 1cm, capsular and vascular invasion. The central neck compartment of LNM was predictive for lateral LNM in 80.5% of the cases. LNM were confirmed in 24% of SLNs in the lateral neck compartment, which were over 56% predictive of LNM to other dissected lateral LN. SLN identification rate (IR) was 91.8%. Sensitivity, specificity, positive value (PPV) and negative predictive value (NPV) were 85.7, 96.7, 88.3 and 95.9%, respectively. The overall accuracy of the method was 94.3%, with probability of 91.2% (ROC AUC, 95% CI; 84.2-98.3). Conclusion: The proposed method of SLN biopsy using methylene blue dye is feasible, safe and accurate in the detection of LNM in the lateral neck compartment and may help in the decision to perform selective modified radical neck dissection in cN0 patients with PTC. © This work by JBUON is licensed under a Creative Commons Attribution 4.0 International License.

Purpose: The incidence of histologically proven lymph node metastases (LNM) in papillary thyroid carcinoma (PTC) reaches 80%. According to different guidelines surgical management in clinically N0 (cN0) patients with PTC remains controversial. The purpose of this study was to investigate if sentinel lymph node biopsy (SLNb) using methylene blue dye is accurate in the detection of LNM in the lateral neck compartment in cN0 patients with PTC. Methods: Enrolled were 153 cN0 patients with PTC. All underwent total thyroidectomy with central neck dissection and SLNb in the lateral neck compartment, using methylene blue dye as marker. Selective modified radical neck dissection was performed in cases of metastatic SLNs. Results: Neck LNMs were histologically verified in 40.9% of the cases. Predictive factors for LNM were: males, younger than 45 years, tumors greater than 1cm, capsular and vascular invasion. The central neck compartment of LNM was predictive for lateral LNM in 80.5% of the cases. LNM were confirmed in 24% of SLNs in the lateral neck compartment, which were over 56% predictive of LNM to other dissected lateral LN. SLN identification rate (IR) was 91.8%. Sensitivity, specificity, positive value (PPV) and negative predictive value (NPV) were 85.7, 96.7, 88.3 and 95.9%, respectively. The overall accuracy of the method was 94.3%, with probability of 91.2% (ROC AUC, 95% CI; 84.2-98.3). Conclusion: The proposed method of SLN biopsy using methylene blue dye is feasible, safe and accurate in the detection of LNM in the lateral neck compartment and may help in the decision to perform selective modified radical neck dissection in cN0 patients with PTC. © This work by JBUON is licensed under a Creative Commons Attribution 4.0 International License.

Thyroglossal duct cyst (TDC) carcinoma is a comparable rare entity and treatment strategies have not been standardized. Here, we report a favorable outcome of TDC carcinoma patients based on our therapeutic strategy. Twelve patients with TDC carcinoma treated in our department from 1986 to 2012 were enrolled. Ten patients underwent Sistrunk's procedure in other institutions and referred to our institution for re-operation after the diagnosis of TDC carcinoma and the remaining two underwent initial surgery in our institution. Eleven patients were diagnosed as papillary and one as follicular carcinoma originating from TDC. We performed total thyroidectomy for 11, and limited thyroidectomy for one patient. Three patients (25%) had carcinoma lesions in the thyroid. We routinely dissected level I bilaterally and 6 of 11 patients (55%) with papillary carcinoma-type TDC carcinoma had metastasis. Level II/III nodes were biopsied and if positive, we performed level II-IV dissection. Of the 5 patients positive for level II/III, 2 were also positive for level IV. For the 3 patients with synchronous carcinoma in the thyroid, we performed level VI dissection and two had metastasis in this level. To date, 1 patient showed a recurrence to the lung, but none of the patients in our series died of carcinoma. For surgery of TDC carcinoma, Sistrunk's procedure, total thyroidectomy with level I dissection is mandatory. Whether level II-IV dissection is performed depends on pathology of biopsied level II/III nodes. Level VI dissection is also recommended especially when carcinoma lesions are pre/intra operatively detected in the thyroid. ©The Japan Endocrine Society.

Thyroglossal duct cyst (TDC) carcinoma is a comparable rare entity and treatment strategies have not been standardized. Here, we report a favorable outcome of TDC carcinoma patients based on our therapeutic strategy. Twelve patients with TDC carcinoma treated in our department from 1986 to 2012 were enrolled. Ten patients underwent Sistrunk's procedure in other institutions and referred to our institution for re-operation after the diagnosis of TDC carcinoma and the remaining two underwent initial surgery in our institution. Eleven patients were diagnosed as papillary and one as follicular carcinoma originating from TDC. We performed total thyroidectomy for 11, and limited thyroidectomy for one patient. Three patients (25%) had carcinoma lesions in the thyroid. We routinely dissected level I bilaterally and 6 of 11 patients (55%) with papillary carcinoma-type TDC carcinoma had metastasis. Level II/III nodes were biopsied and if positive, we performed level II-IV dissection. Of the 5 patients positive for level II/III, 2 were also positive for level IV. For the 3 patients with synchronous carcinoma in the thyroid, we performed level VI dissection and two had metastasis in this level. To date, 1 patient showed a recurrence to the lung, but none of the patients in our series died of carcinoma. For surgery of TDC carcinoma, Sistrunk's procedure, total thyroidectomy with level I dissection is mandatory. Whether level II-IV dissection is performed depends on pathology of biopsied level II/III nodes. Level VI dissection is also recommended especially when carcinoma lesions are pre/intra operatively detected in the thyroid. ©The Japan Endocrine Society.

Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive and chemoresistant tumor with dismal prognosis. Most ATCs harbor mutations that activate RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. Therefore, we investigated and correlated the expression of phosphatase and tensin homolog, pERK, and pAKT proteins as well as mutations of BRAF, RAS, and p53 genes in samples of patients with ATC. Furthermore, we evaluated the potential of inhibition of these pathways on chemosensitization of ATC using 2 thyroid carcinoma cell lines (FRO and SW1736). Our results revealed a negative correlation between the activity of RAS-MAPK-ERK and PI3K-AKT-mTOR pathways in samples of patients. To be specific, the PI3K-AKT-mTOR pathway was suppressed in patients with activated NRAS or high pERK expression. In vitro results suggest that the inhibition of either RAS-MAPK-ERK or PI3K-AKT-mTOR components may confer sensitivity of thyroid cancer cells to classic chemotherapeutics. This may form a basis for the development of novel genetic-based therapeutic approach for this cancer type. © 2014 Elsevier Inc.

Tamoxifen is a standard therapeutical treatment in patients with estrogen receptor positive breast carcinoma. However, less than 50% of estrogen receptor positive breast cancers do not respond to tamoxifen treatment whereas 40% of tumors that initially respond to treatment develop resistance over time. The underlying mechanisms for tamoxifen resistance are probably multifactorial but remain largely unknown. The primary aim of this study was to investigate the impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen by analyzing loss of heterozygosity (LOH) and immunohystochemical expression of PTEN in 49 primary breast carcinomas of patients treated with tamoxifen as the only adjuvant therapy. The effect of PTEN inactivation on breast cancer progression and disease outcome was also analyzed. Reduced or completely lost PTEN expression was observed in 55.1% of samples, while 63.3% of samples displayed LOH of PTEN gene. Inactivation of PTEN immunoexpression significantly correlated with the PTEN loss of heterozygosity, suggesting LOH as the most important genetic mechanism for the reduction or complete loss of PTEN expression in primary breast carcinoma. Most importantly, LOH of PTEN and consequential reduction of its immunoexpression showed significant correlation with the recurrence of the disease. Besides, our study revealed that LOH of PTEN tumor suppressor was significantly associated with shorter disease free survival, breast cancer specific survival and overall survival. In summary, our results imply that LOH of PTEN could be used as a good prognostic characteristic for the outcome of breast cancer patients treated with tamoxifen. © 2012 Landes Bioscience.

Tamoxifen is a standard therapeutical treatment in patients with estrogen receptor positive breast carcinoma. However, less than 50% of estrogen receptor positive breast cancers do not respond to tamoxifen treatment whereas 40% of tumors that initially respond to treatment develop resistance over time. The underlying mechanisms for tamoxifen resistance are probably multifactorial but remain largely unknown. The primary aim of this study was to investigate the impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen by analyzing loss of heterozygosity (LOH) and immunohystochemical expression of PTEN in 49 primary breast carcinomas of patients treated with tamoxifen as the only adjuvant therapy. The effect of PTEN inactivation on breast cancer progression and disease outcome was also analyzed. Reduced or completely lost PTEN expression was observed in 55.1% of samples, while 63.3% of samples displayed LOH of PTEN gene. Inactivation of PTEN immunoexpression significantly correlated with the PTEN loss of heterozygosity, suggesting LOH as the most important genetic mechanism for the reduction or complete loss of PTEN expression in primary breast carcinoma. Most importantly, LOH of PTEN and consequential reduction of its immunoexpression showed significant correlation with the recurrence of the disease. Besides, our study revealed that LOH of PTEN tumor suppressor was significantly associated with shorter disease free survival, breast cancer specific survival and overall survival. In summary, our results imply that LOH of PTEN could be used as a good prognostic characteristic for the outcome of breast cancer patients treated with tamoxifen. © 2012 Landes Bioscience.

Purpose: All breast cancer (BC) patients with detectable hormone receptors (HR) expression should be offered endocrine therapy (ET). In premenopausal patients, tamoxifen and/or ovarian suppression (OvS)/ablation (OA) may improve disease outcome. Alteration of phosphatase and tensin homolog (PTEN) signaling pathways could be one of the possible mechanisms of resistance to antiestrogen therapy. The purpose of this study was to investigate the association of PTEN protein expression with prognostic factors such as tumor histology and grade, estrogen receptor (ER) and progesterone receptor (PgR) status, human epidermal growth factor receptor 2 (HER2) and disease outcome in premenopausal patients with HR-positive early BCs treated with adjuvant OA. Methods: We analyzed a group of premenopausal early stages I/II HR-positive BC patients who had undergone radical mastectomy followed only with adjuvant OA by irradiation. ER and PgR contents were determined by classical biochemical dextran-coated charcoal (DCC) method, HER2 status by chromogen in situ hybridization (CISH) analysis and PTEN status by immunohistochemistry (IHC). Results: Sixty-six premenopausal patients included into this analysis were followed for a median of 17 years (range 1-29). Compared to PTEN-positive BCs, PTEN-negative BCs were significantly more frequently associated with lobular tumor histology (p<0.05), higher ER content (p<0.05), and had significantly decreased disease-free survival (DFS) and overall survival (OS) (p<0.01 for both) compared to patients with PTEN-positive BCs. Conclusions: It seems that PTEN status determined by protein expression may discriminate between subgroups with poor and good prognosis in premenopausal HR-positive BC patients receiving adjuvant OA. © 2018 Zerbinis Publications. All Rights Reserved.