PARP1, BRCA1 and androgen receptor expression in triple-negative breast cancer patients treated with neoadjuvant chemotherapy / Expresión de receptores de PARP1, BRCA1 y andrógenos en pacientes de cáncer de mama triple negativo tratados con quimioterapia neoadyuvante

Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype, where no effective therapies have been established for it. Searching for therapeutic targets for TNBC patients is the aim of the current research. Poly adenosine diphosphate ribose polymerase (PARP1) inhibitors are promising antitumor therapy that have a high potency in BRCA1-deficient breast cancers. Materials and methods: Forty TNBC patients who received neoadjuvant chemotherapy (NAC) were enrolled in this study, and evaluated for PARP1, BRCA1, and Androgen receptor (AR) immunohistochemical expression before and after receiving NAC. Data of patients' clinical and pathological responses to the chemotherapy were collected and finally analyzed. Results: The immunohistochemical results revealed 10 cases (25%) positive for AR, while 18 cases (45%) and 22 cases (55%) expressed PARP1 at low and high levels, respectively. Twelve cases (30%) and 28 cases (70%) expressed BRCA1 at low and high levels, respectively. There was a significant difference between PARP1 expression in normal and malignant tissues (P < 0.001). Higher PARP1 expression was correlated with a better overall clinical response (OAR) and pathological complete response (pCR) (P = 0.018, 0.01 respectively). Co-expression of both PARP1 & BRCA1 was correlated with OAR and pCR. Chemotherapy decreases PARP1 protein levels in matched patient samples (P = 0.015). Positive AR expression was correlated with BRCA1 overexpression. Conclusion: PARP1 is highly expressed in TNBC with a better OAR and pCR especially in cases with high BRCA1, so it might be considered as a therapeutic target for this risky group. (AU)

Introducción: El cáncer de mama triple negativo (TNBC) es un subtipo agresivo, donde no se han establecido terapias efectivas para este cáncer. La búsqueda de dianas terapéuticas para pacientes con TNBC es el objetivo de la investigación actual. Los inhibidores de la poli adenosina difosfato ribosa polimerasa (PARP1) son prometedores terapia antitumoral que tienen una alta potencia en los cánceres de mama deficientes de BRCA1. Materiales y métodos: Cuarenta pacientes de TNBC que recibieron quimioterapia neoadyuvante (NAC) se inscribieron en este estudio y se evaluaron para la expresión inmunohistoquímica de PARP1, BRCA1 y receptores de andrógenos (AR) antes y después de recibir NAC. Se recogieron y finalmente se analizaron los datos de las respuestas clínicas y patológicas de los pacientes a la quimioterapia. Resultados: Los resultados inmunohistoquímicos revelaron 10 casos (25%) positivos para AR, mientras que 18 casos (45%) y 22 casos (55%) expresaron PARP1 en niveles bajos y altos, respectivamente. Doce casos (30%) y 28 casos (70%) expresaron BRCA1 en niveles bajos y altos, respectivamente. Hubo una diferencia significativa entre la expresión de PARP1 en tejidos normales y malignos (P 0.001). Una mayor expresión de PARP1 se correlacionó con una mejor respuesta clínica global (OAR) y una respuesta patológica completa (pCR) (P = 0,018, 0,01 respectivamente). La co-expresión de ambos PARP1 y BRCA1 se correlacionó con OAR y pCR. La quimioterapia disminuye los niveles de proteína PARP1 en muestras de pacientes emparejadas (P = 0,015). La expresión positivos de AR se correlacionó con la expresión de BRCA1. Conclusión: El PARP1 está muy expresado en TNBC con una mejor OAR y pCR especialmente en casos con BRCA1 alto, por lo que podría ser considerado como una diana terapéutica para este grupo de riesgo. (AU)

Clinical significance of cytokeratin 19 and OCT4 as survival markers in non-metastatic and metastatic breast cancer patients.

Introduction: Cytokeratin 19 (CK19) is highly expressed in epithelial tumours such as breast cancer (BC). Octamer-binding transcription factor 4 (OCT4), a transcription factor of the POU (Pit-Oct-UNC) family, plays a criti-cal role in the self-renewal and maintenance of pluripotency of embryonic stem cells; therefore, it has been used as a promising CSC marker. Material and methods: CK19 was assessed in peripheral blood using flow-cytometric analysis while OCT4 was evaluated in breast tissue samples by immunohistochemistry from 70 patients (non-metastatic BC, meta-static BC, and non-malignant breast tumours). Results: CK19 and OCT4 were significantly associated with BC patients compared to control (p < 0.001). CK19 was detected in 38 patients with BC (62.2%); meanwhile, OCT4 was positive in 37 BC patients (60.6%). CK19 was positively associated with grade (p = 0.002), HER2 (p = 0.009), metastasis (p = 0.026), molecular subtypes and LN (p < 0.001), and stage (p = 0.001) while OCT4 expression was positively associated with BMI (p < 0.023), aggressive molecular subtype (p < 0.019), ER expression (p = 0.025), presence of LN metastases (p < 0.017), and distant metastasis (p < 0.018). A non-significant relation was found between the expression of CK19 and OCT (p = 0.291). The positive expression of CK19 and OCT4 was significantly and inversely associated with both 3-year OS and 3-year PFS. Conclusions: CK19 and OCT4 are associated with BC, so they can be considered as prognostic and predictive markers for poor OS and PFS in non-metastatic as well as metastatic BC patients.

Prognostic impact of immunohistochemical expression of claudin-4 and epithelial mesenchymal-related markers (Snail-1) in breast invasive duct carcinoma / Impacto pronóstico de la expresión inmunohistoquímica de Claudin-4 y marcadores epiteliales-mesenquimales relacionados (Snail-1) en el carcinoma ductal infiltrante de la mama

Introduction: Although the molecular profile of the breast provides prognostic indicators, risk stratification in breast cancer continues to be a challenge. Therefore, it is mandatory to seek new prognostic markers that could aid the early diagnosis of potential metastases in biopsy samples from breast cancer; among these are increased Snail-1 and Claudin-4 expression.Objectives: The aim of this study was to analyze the correlation between Snail-1 and Claudin-4 with other clinical-pathological parameters and distinct molecular subtypes.Methods: This study included 110 patients with invasive ductal carcinoma from 2009 to January 2015. Snail-1 and Claudin-4 were assessed by immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks and the data were correlated with clinical-pathological data and survival.Results: A total of 65 patients (68.2%) were positive for Snail-1 and 85 patients (77.3%) were positive for Claudin-4. High Snail-1 and high Claudin-4 were detected in high-grade tumors and were associated with lymphovascular infiltration and lymph node metastases (p<0.001 for each). There was a highly significant correlation between Snail-1, Claudin-4 expression and the molecular subtype of breast cancer (p<0.001), with higher Snail-1 expression in TNBC and Her 2/neu cases (p=0.001). Claudina-4 expression in the Her2/neu enriched subtype, Snail-1-positivity and high Claudin-4 expression were associated with recurrence (p=0.001; 0.004 respectively) among the cases studied. Snail-1 and Claudin-4 were inversely related with overall survival (p=0.001) and disease-free survival (p=0.001).Conclusion: High Snail-1 and Claudin-4 levels were associated with adverse outcomes in patients with breast cancer. (AU)

Introducción: Aunque el perfil molecular de la mama proporciona indicadores de pronóstico, la estratificación del riesgo de cáncer de mama sigue siendo un desafío y es obligatoria para buscar nuevos marcadores de pronóstico que puedan facilitar el diagnóstico temprano de metástasis potenciales en las muestras de biopsia de cáncer de mama; entre estos se encuentra la expresión creciente de Snail-1 y Claudin-4.Objetivos: El objetivo de este trabajo es estudiar la correlación de Snail-1 y Claudin-4 con otros parámetros clínico-patológicos y diferentes subtipos moleculares.Métodos: Se inscribieron 110 pacientes con carcinoma de conducto invasivo en este estudio durante el período de enero de 2009 a enero de 2015. Snail-1 y Claudin-4 fueron evaluados por inmunohistoquímica (IHC) en bloques de parafina y los datos se correlacionaron con características clínico-patológicas y de supervivencia.Resultados: Fueron positivos 75 casos (68,2%) para Snail-1 y 85 (77,3%) positivos para Claudin-4. High Snail-1 y High Claudin-4 se detectaron en tumores de alto grado y se asociaron con invasión linfovascular y metástasis en los ganglios linfáticos (p < 0,001 para cada uno). Se detectó una correlación altamente significativa entre Snail-1, la expresión de Claudin-4 y el subtipo molecular de cáncer de mama (p < 0,001), con la mayor expresión de Snail-1 en los casos de cáncer de mama triple negativo (TNBC) y Her 2/neu (p = 0,001). La expresión de Claudina-4 en subtipo Her2/neu enriched, Snail-1 positivo y alta expresión de Claudin-4 se asoció con recaída (p = 0,001; 0,004, respectivamente) entre los casos estudiados. La expresión de Snail-1 y Claudin-4 se relacionó inversamente con la SG (p = 0,001) y la SSE (p = 0,001).Conclusión: Los niveles altos de proteínas Snail-1 y Claudin-4 se asocian con resultados adversos en pacientes con cáncer de mama. (AU)

Predictive value of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in breast cancer patients treated with neoadjuvant chemotherapy / Valor predictivo de los linfocitos infiltrantes de tumor, y de la expresión del ligando del factor de muerte celular programada 1 en las pacientes de cáncer de mama tratadas con quimioterapia neoadyuvante

Introduction Immune system plays an important role in behavior of cancer. Breast cancer and its stroma display high levels of immune-cell infiltrates (tumor-infiltrating lymphocytes TILs). Programmed cell death-ligand 1 (PD-L1) is one key inhibitor mechanism for TILs. Potential of TILs and PD-L1 as predictive factors for chemotherapy response in breast cancer is a promising field of study. The aim of this work is to investigate the correlation of PD-L1, TILs and pathologic response following neoadjuvant chemotherapy (NAC) in breast cancer patients and effect of NAC on PD-L1 expression and TILs in residual tumor mass.MethodsThirty patients with invasive duct carcinoma diagnosed by core biopsy and received NAC were enrolled in this prospective study from November 2018 to October 2020. PD-L1 expression was evaluated by immunohistochemistry and relates this to TILs, clinical characteristics, and response to neoadjuvant chemotherapy and then re-evaluated in residual masses after surgery.ResultsPD-L1 expression was observed in 40% of cases in the tumor cells. High stromal TILs were detected in 46.7%. Also, 64.3% and 58.3% of patients expressed TILs and PD-L1 (respectively) in their core biopsies gained complete clinical and pathologic responses with significant difference (p value<0.001; 0.013). High PD-L1 expression and high TILs were observed in triple negative breast cancer (TNBC) and Her2 enriched cases but without significant difference.ConclusionHigh TILs and PD-L1 are associated with complete clinical and pathologic responses in breast cancer patients who receiving NAC.(AU)

Introducción El sistema inmune juega un papel importante en el comportamiento del cáncer. El cáncer de mama y su estroma exhiben altos niveles de infiltrados de las células inmunitarias (linfocitos infiltrantes de tumor [TIL]). El ligando del factor de muerte programada 1 (PD-L1) es un mecanismo inhibidor clave para los TIL. El potencial de TIL y PDL-1 como factores predictivos para la respuesta a la quimioterapia en el cáncer de mama es un campo de estudio prometedor. El objetivo de este estudio es estudiar la correlación de PD-L1, TIL y la respuesta patológica tras la quimioterapia coadyuvante (NAC) en pacientes con cáncer de mama, así como el efecto de NAC en la expresión de PDL-1 y TIL en la masa tumoral residual.MétodosSe incluyó en este estudio prospectivo a 30 pacientes con carcinoma ductal invasivo diagnosticadas mediante biopsia central, que recibieron NAC de noviembre de 2018 a octubre de 2020. La expresión de PD-L1 fue evaluada mediante inmunohistoquímica, y fue relacionada con TIL, características clínicas y respuesta a la quimioterapia neoadyuvante, reevaluándose en masas residuales tras la cirugía.ResultadosLa expresión de PD-L1 se observó en el 40% de los casos en las células tumorales. Se detectaron altos niveles de TIL estromales en el 46,7% de los casos. De igual modo, el 64,3 y el 58,3% de las pacientes con expresión de TIL y PDL-1, respectivamente, en sus biopsias centrales logró respuestas clínicas y patológicas completas con diferencia significativa (p<0,001; 0,013). La alta expresión de PDL1 y los altos niveles de TIL fueron observados en el cáncer de mama triple negativo (TNBC) y en los casos de Her2 enriquecido, aunque sin diferencia significativa.ConclusiónLa alta expresión de TIL y PDL1 se asocia a respuestas clínicas y patológicas completas en las pacientes de cáncer de mama que reciben NAC.(AU)

Clinicopathological Features and Treatment Challenges in Triple Negative Breast Cancer Patients: A Retrospective Cohort Study.

OBJECTIVE: As the genetic and molecular profiles of triple negative breast carcinoma (TNBC) are elucidated, multiple therapeutic targets have been produced. TNBC with less than 1% androgen receptor (AR) expression may respond to enzalutamide with greater response association in higher levels. A metronomic dose of capecitabine and docetaxel are effective developed drugs for angiogenic process inhibition. We aimed to demonstrate the treatment outcome of triple-negative breast cancer patients in correlation to their clinicopathological features. MATERIALS AND METHODS: A retrospective cohort study of 80 TNBC patients was conducted. The patients underwent proper observation with the reporting of their treatment and follow-up data. Patients with a metastatic disease, neoadjuvant chemotherapy, follow-up drop or data shortage were excluded from the survival analysis. RESULTS: The study results revealed a significant association between negative androgen expression and younger age ≤35 years, premenopausal status, higher grade, extracapsular extension, lymphovascular invasion, Ki 67, and CA15-3 (p=0.003, 0.02, < 0.001, 0.001, 0.027, 0.005, 0.009 respectively). The three-year overall survival (OS) in patients who received bicalutamide was better than those patients who received capecitabine or docetaxel but of no significance (p=0.46). The three-year disease free survival (DFS) was significantly better in the bicalutamide arm versus the other two groups (p=0.012). CONCLUSIONS: We concluded that extended adjuvant antiandrogen such as bicalutamide and metronomic capecitabine are well tolerated with accepted compliance and affordability compared to docetaxel and are warranted for problem-solving and better DFS and OS in some TNBC patients.

Prognostic impact of Apaf-1, Cyclin D1, and AQP-5 in serous ovarian carcinoma treated with the first-line chemotherapy.

Chemoresistance is the major obstacle to effective treatment in patients with serous ovarian carcinoma (SOC), which frequently related to the failure of chemotherapeutic agents to induce apoptosis. In this study, the immunohistochemical expression of Apaf-1, Cyclin D1, and Aquaporin-5 (AQP-5) was studied in 50 paraffin blocks of SOC. Data on overall survival (OS), disease-free survival (DFS) and response to the first-line chemotherapy were collected and then statistically analyzed. Apaf-1 expression was observed in 84% of the SOC cases with a significant down-regulation with higher tumor grade, lymph node metastasis, and advanced FIGO stage. Cyclin D1 expression was found in 70% of the cases with a significant up-regulation with higher tumor grade, lymph node metastasis, and advanced FIGO stage. Positive AQP-5 expression was noted in 84% of the cases with a significant positive association with higher tumor grade, lymph node metastasis, and advanced FIGO stage. During the follow-up period, the Apaf-1 expression had a significant negative association with OS and DFS (p < 0.001 for each), while both Cyclin D1 and AQP-5 expression had a significant positive association with unfavorable OS and DFS. The cases of SOC treated with suboptimal surgery revealed a significant association of low Apaf-1, high Cyclin D1, and strong AQPs with the poor response to the first-line chemotherapy (p = 0.047, p < 0.001, and 0.006 respectively). CONCLUSIONS: Down-regulation of Apaf-1 protein and the overexpression of Cyclin D1 and AQP-5 proteins possibly contribute to an aggressive SOC with a high risk of recurrence and poor response to the first-line chemotherapy.

Control of type 2 diabetes in King Abdulaziz Housing City (Iskan) population, Saudi Arabia.

OBJECTIVE: To assess the level of control and prevalence of type 2 diabetes in King Abdulaziz Housing City (Iskan) population of Saudi Arabia. MATERIALS AND METHODS: Retrospective cross-sectional study conducted in a primary-care setting. All Type 2 diabetics referred to our diabetes center between January 2011 and January 2015 were identified, and their computerized records reviewed. Glycated hemoglobin levels (HbA1c), low-density lipoprotein (LDL), blood pressure (BP), and the albumin-creatinine ratio (ACR) were noted and the patients categorized accordingly. Demographic data (age and gender) were also documented. Inactive patients (not seen for more than 2 years) were excluded. RESULTS: The overall prevalence of type 2 diabetes for all age groups in ISKAN population was 3.25%. About 56% of the diabetics were female and 70% were aged between 18 and 59 years. The rate of uncontrolled diabetes was 59.3%. Males were more likely to have uncontrolled diabetes (odds ratio: 1.44, CI: 1.17-1.76, P = 0.0004). Forty percent of the diabetics had an LDL above target (≥2.6 mmol/l) while 25.9% had uncontrolled hypertension (BP ≥ 140/90). Of those who had an ACR test done within the last year (59.3%), the rate of micro- and macro-albuminuria was 8.8% and 2.5%, respectively. CONCLUSIONS: The overall prevalence of type 2 diabetes in our community seems lower than the previously reported national figures. An alarming number of diabetics in our population have an uncontrolled disease. More stringent diabetes annual review and recall program is needed to control diabetes and reduce complications.

The prognostic significance of p53, p63 and her2 expression in non-muscle-invasive bladder cancer in relation to treatment with bacille Calmette-Guerin.

OBJECTIVE: To investigate whether the immunohistochemical expression of p53, p63 and her2/neu is correlated with the prognosis of tumour recurrence and progression in patients with non-muscle invasive (NMI) bladder cancer. PATIENTS AND METHODS: In all, 88 patients diagnosed with NMI transitional cell carcinoma of the bladder in a Urology Department from May 2009 to April 2014 were included in the study. Paraffin-embedded specimens were obtained by transurethral resection of the bladder tumours. Sections on haematoxylin and eosin-stained slides were examined histologically and tumour grade was classified according to the World Health Organisation system (2004) Mostofi classification. The sections were evaluated using p63, p53 and her2/neu immunohistochemical staining before and after immunotherapy with bacille Calmette-Guerin (BCG), and patients were followed up for 36 months in the Urology Department. RESULTS: For tumour grade there was a significant relationship with the overexpression of p53 (P = 0.010), her2 (P = 0.025) and negativity of p63 (P = 0.025). There was no significant relationship between p53 or her2/neu overexpression and tumour stage. However, there was a significant correlation (P = 0.005) between p63 negativity and tumour stage. There was a significant relationship between p53 (P = 0.01), her2/neu (P = 0.025) overexpression and p63 negativity (P = 0.005) and tumour recurrence and progression. CONCLUSION: Patients with transitional cell carcinoma who are selected for BCG treatment should preferably be positively immunoreactive for p63, but negative for both p53 and her2/neu. These patients were less susceptible to recurrence and/or progression after BCG adjuvant therapy. Further studies are needed to investigate the relationship between these three markers and treatment with anti-her2/neu therapies.

Bladder preservation multimodality therapy as an alternative to radical cystectomy for treatment of muscle invasive bladder cancer.

OBJECTIVE: • To evaluate the efficacy of a bladder preservation multimodality protocol for patients with operable carcinoma invading bladder muscle. MATERIALS AND METHODS: • In this prospective study, we included 33 patients with transitional cell carcinoma (TCC) (T2 and T3, Nx, M0) who were amenable to complete transurethral resection. • These patients refused radical cystectomy as their first treatment option. After maximum transurethral resection of bladder tumour (TURBT), all patients received three cycles of adjuvant chemotherapy in the form of methotrexate, vinblastin, adriamycin and cisplatin (MVAC) followed by radical radiotherapy. • Four weeks later, all cases had radiological and cystoscopical re-evaluation. • Complete responders were considered to be those patients who had no evidence of residual tumour. All patients were subjected to a regular follow-up by cystoscopy and tumour site biopsy conducted every 3 months. Abdomino-pelvic computed tomography and chest X-ray were conducted every 6 months. • The study endpoint was the response to treatment after completion of the first year of follow-up after therapy. RESULTS: • Out of 33 eligible patients, a total of 28 patients completed the study treatment protocol. Their mean ± SD age was 56.7 ± 6 years. Trimodal therapy was well tolerated in most of cases, with no severe acute toxicities. After 12 months of follow-up, a complete response was achieved in 39.3% and a partial response in 7.1%, with an overall response rate of 46.4%. • By the end of the first year, disease-free survival was reported in 39.3%, whereas 25% were still alive with their disease, giving an overall survival of 64.3% for all patients who maintained their intact, well functioning bladders. • Tumour stage and completeness of transurethral resection of bladder tumour were the most important predictors of response and survival. T2 lesions had complete and partial response rates of 69.2% and 23%, respectively, whereas T3 lesions had rates of 40% and 13.3%, respectively (P = 0.001). • The response rate in patients who had complete TURBT was 82.6% vs 20% in those with cystoscopic biopsy only (P = 0.001). In addition, disease-free survival was 72.7% in T2 patients and 27.3% in T3 patients (P = 0.001). CONCLUSION: • In the present study, bladder preservation protocol with MVAC and radical radiotherapy achieved suboptimal response rates at 1 year in patients with localized TCC invading bladder muscle. Patients with solitary T2 lesions that are amenable to complete TURBT achieved the best response rates. Longer follow-up is needed to verify these results. Patients with localized disease should be encouraged for radical cystectomy, which achieved better results.