Predictors and effectiveness of different biopsy techniques in spotting invasion in the clinically diagnosed breast ductal carcinoma in situ / Factores predictivos y efectividad de diferentes técnicas de biopsia en la detección de focos infiltrantes en carcinomas in situ diagnosticados clínicamente

Objectives: To study the management of patients with ductal carcinoma in situ (DCIS) and detect the predictors of recurrence and of missing an invasive component in the preoperative biopsy, aiming at guiding tailored treatment of these cases.Materials and methods: A total of 123 cases of DCIS, pure/with invasion, were retrieved from the database of a tertiary cancer hospital in the period from February 2007 to February 2018. Clinical, radiologic & pathologic characteristics and its impact on the surgical management were analyzed.Results: The mean age of the patients was 50.5±12.4 years. The commonest presentation was a palpable mass in 82.9% of the cases. Conservative breast surgery was successfully performed in 15 cases and mastectomy in 108 cases. Recurrence was reported in 11 cases. The underestimation rate in core needle biopsy was 48.9% missing invasive component within diagnosed malignant lesions and 19.6% missing the diagnosis of malignancy. On the other hand, overtreatment was noted as regard surgical procedure and adjuvant therapies.Conclusions: Mastectomy still the most common surgical treatment of DCIS and unfortunately sentinel lymph node biopsy is still underused. Underestimation of invasive component can occur in at least 1/4 of the patients, complexing the treatment plan. Overtreatment with axillary surgery, chemotherapy or radiotherapy needs governance. (AU)

Objetivos: Estudiar el manejo de pacientes con carcinoma ductal in situ (CDIS) y detectar los predictores de recaída y de ausencia de un componente invasivo en la biopsia preoperatoria, con el objetivo de orientar el tratamiento a medida de estos casos.Materiales y métodos: Se recuperó un total de 123 casos de CDIS, puro/con invasión de la base de datos de un hospital de cáncer terciario en el período de febrero de 2007 a febrero de 2018. Se analizaron las características clínicas, radiológicas y patológicas, así como su impacto en el manejo quirúrgico.Resultados: La edad media fue de 50,5 ± 12,4 años. La presentación más común fue masa palpable en el 82,9% de los casos. Se realizó cirugía de mama conservadora con éxito en 15 casos y mastectomía en 108 casos. Se informó de recaída en 11 casos. La tasa de subestimación en la biopsia con aguja fue de 48,9% sin componente invasivo en lesiones malignas diagnosticadas y 19,6% sin diagnóstico de malignidad. Por otra parte, se observó un exceso de tratamiento con relación al procedimiento quirúrgico y las terapias adyuvantes.Conclusiones: La mastectomía sigue siendo el tratamiento quirúrgico más común del CDIS y desafortunadamente no se utiliza aún la biopsia de ganglio linfático centinela. La subestimación del componente invasivo puede ocurrir en al menos el 25% de los pacientes, complejizando el plan de tratamiento. Debe gestionarse el sobretratamiento con cirugía axilar, quimioterapia o radioterapia. (AU)

Incidence of trastuzumab-induced cardiotoxicity and impact of body mass index in patients with breast cancer: Results from a Saudi tertiary cancer center.

The effect of BMI as a risk factor in trastuzumab-induced cardiotoxicity in Saudi patients with HER2-neu positive breast cancer treated with trastuzumab and anthracyclines is not fully understood. The present study retrospectively evaluated the overall incidence of cardiotoxicity and the effect of BMI as a risk factor for cardiotoxicity. A retrospective study performed between 2011 and 2015 of patients with Her2-neu positive early breast cancer who were treated with either a combination of trastuzumab and anthracycline or a combination of trastuzumab with non-anthracycline or hormonal treatment in the adjuvant settings was carried out. The incidence of cardiotoxicity and the effect of BMI, hypertension and diabetes mellitus as risk factors for cardiotoxicity were assessed. Cardiotoxicity was measured using a drop in the ejection fraction of >10 percentage points to a left ventricular ejection fraction of <50%. The present cohort included 105 patients diagnosed with stage I and II breast cancer. The mean age of the present cohort was 47.5±1.0 years (range, 25-76 years), the mean height was 153.9±14.1 cm (range, 126-170 cm), the mean body weight was 75.7±15.6 kg (range, 40-143 kg) and the mean BMI was 31.3±5.8 (range, 18-49). Cardiotoxicity was detected in 21.9% of the cohort. The BMI was calculated for 81 patients who were treated with a combination of trastuzumab and anthracycline. Cardiotoxicity was detected in 3 out of 9 patients with a BMI <25, in 9 out of 23 patients with a BMI between 25 and 29, and in 6 patients with a BMI >30. There was a significant association between cardiotoxicity and BMI (P=0.03). No significant association between age, hypertension and diabetes and cardiotoxicity was identified. In conclusion, compared with global cohorts, the present results revealed a higher incidence of cardiotoxicity among Saudi patients with HER2-neu positive early breast cancer treated with trastuzumab combinations in adjuvant settings. Increased BMI was significantly associated with cardiotoxicity.

Screening for Lynch syndrome in young Saudi colorectal cancer patients using microsatellite instability testing and next generation sequencing.

Individuals with Lynch syndrome (LS) have germline variants in DNA mismatch repair (MMR) genes that confer a greatly increased risk of colorectal cancer (CRC), often at a young age. Identification of these individuals has been shown to increase their survival through improved surveillance. We previously identified 33 high risk cases for LS in the Saudi population by screening for microsatellite instability (MSI) in the tumor DNA of 284 young CRC patients. The aim of the present study was to identify MMR gene variants in this cohort of patients. Peripheral blood DNA was obtained from 13 individuals who were at high risk of LS due to positive MSI status and young age (<60 years at diagnosis). Next generation sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification were used to screen for germline variants in the MLH1, MSH2, MSH6 and PMS2 MMR genes. These were cross-referenced against several variant databases, including the International Society for Gastrointestinal Hereditary Tumors Incorporated database. Variants with pathogenic or likely pathogenic significance were identified in 8 of the 13 high risk cases (62%), comprising 4 in MLH1 and 4 in MSH2. All carriers had a positive family history for CRC or endometrial cancer. Next generation sequencing is an effective strategy for identifying young CRC patients who are at high risk of LS because of positive MSI status. We estimate that 7% of CRC patients aged <60 years in Saudi Arabia are due to LS, potentially involving around 50 new cases per year.

Predictive and prognostic significance of CD8+ tumor-infiltrating lymphocytes in patients with luminal B/HER 2 negative breast cancer treated with neoadjuvant chemotherapy.

The immunobiology of breast cancer (BC) subtypes, including luminal cancer, remains unclear. Cluster of differentiation (CD)8+ tumor-infiltrating lymphocytes (TIL) are essential components of tumor-specific cellular adaptive immunity. However, only few studies have addressed the significance of cluster of differentiation 8+(CD8+) TIL in patients with luminal BC. The present study aimed to evaluate the predictive and prognostic significance of CD8+ TIL in patients with luminal B/human epidermal growth factor receptor 2 (HER 2)-negative BC treated with anthracycline-based neoadjuvant chemotherapy (NC). A total of 31 patients who underwent breast-conserving surgery or mastectomy post-NC were enrolled. Immunostaining for CD8+ TIL was performed using rabbit monoclonal antibodies against human CD8+. Intra- and peritumoral CD8+ TIL expression levels were classified into high and low, based on the median value of each. CD8+ TIL expression data were demonstrated to be correlated with disease-free survival (DFS) and overall survival (OS), using Kaplan-Meier and Cox's proportional hazards regression tests. The results revealed that, among all clinicopathological characteristics, only pathological complete response (pCR) was significantly correlated with intratumoral CD8+ TIL expression (P=0.016). A total of 9/16 patients (56%) with high intratumoral CD8+ TIL expression achieved pCR, in contrast with 2 out of 15 patients (13.3%) with low expression (P=0.016). High expression of intratumoral CD8+ TIL was significantly associated with OS (log-rank test, P=0.023). Multivariate Cox regression analysis revealed that intratumoral expression of CD8+ TIL was an independent prognostic factor for OS [hazard ratio (HR)=2.82; 95% confidence interval (CI)=0.911-4.833, P=0.007], but not for DFS (HR=1.11; 95% CI=0.282-2.078; P=0.508). In conclusion, the results of the present study suggested that high intratumoral CD8+ TIL expression was significantly predictive of pCR post-NC, and represented an independent prognostic factor for improved OS. In contrast, low intratumoral CD8+ TIL expression was a strong predictor of lack of pCR to NC, as well as an independent prognostic factor for poor OS. Assessment of the immune response in conjunction with the usual parameters may aid in the further stratification of patients with luminal B/HER 2-negative BC regarding the prediction of pCR post-NC and overall prognosis.

Triple Negative Breast Cancer: A Tale of Two Decades.

Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% of breast cancer cases worldwide. TNBC is associated with poor prognosis and lack of sustained response to conventional chemotherapeutic agents. Tumoral heterogeneity and the presence of several subtypes of TNBC such as Basal like (BL)-1, BL-2, immune-modulatory, luminal androgen receptor, mesenchymal, and mesenchymal/stem like subtype and claudin low subtype, may explain some of the difficulties faced in managing this challenging disease subgroups. Although no approved targeted therapy is available for TNBCs, molecular-profiling efforts have revealed promising molecular targets such as the vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), polyadenosine ribose polymerase inhibitors (PARPi) and DNA repair pathway, androgen pathway, and NOTCH pathway. TNBC is subject to intense research activities aiming at dissecting potential pathways, identifying potential molecular signatures and biomarkers in order to properly develop new targeted biologic modifiers. Despite this, there is a lack of approved predictive and prognostic biomarkers, and keeping in view the complexity of TNBC biology, research should be targeted towards identifying multi-factorial signatures rather than single markers. This review aims to summarize the current evidence, ongoing research and discuss future strategies for the treatment of patients with TNBC. In addition we have reviewed the recent advances in detecting predictive and prognostic biomarkers and identifying surrogate markers for early identification of potential responders to the new therapies.

Breast cancer characteristics in very young Egyptian women ≤35 years.

BACKGROUND: Breast cancer in very young patients represents a unique issue that needs more attention as the number of cases is increasing and it has special characteristics at presentation, diagnosis, and biologic behaviors which reflect on both treatment strategies and survival. The aim of the current study was to analyze and report the clinico-pathological characteristics and treatment procedures used for breast cancer in very young patients over the last decade in a single Egyptian cancer center. PATIENTS AND METHODS: A retrospective study was conducted in the Oncology Center - Mansoura University, where the data of all breast cancer patients, between September 2006 and August 2015, were reviewed. Among 4,628 patients who were diagnosed with breast cancer during this period, only 300 patients aged ≤35 years had complete registry data. Clinico-pathological characteristics, therapeutic procedures, and survival outcome were reported. RESULTS: Three hundred and seventy-nine patients (8.19%) were aged ≤35 years at the time of presentation. The age ranged between 21 and 35 years, and the mean age was 31 years (±3 standard deviation). Positive family history of breast cancer was found in 12.3%, and metastatic presentation was seen in 4.7%. The rate of axillary lymph nodes involvement was 75.7%. The estrogen receptor-negative disease was found in 51%, and among 217 patients who did HER2 test, 82 patients (37.8%) were HER2 positive, while triple-negative subtype was found in 57 patients (26.4%). Ki 67 percentage ranged between 3% and 66% (median was 35%). The median disease-free survival was 61 months (95% confidence interval 44-78 months); the 3-year and 5-year disease-free survival were 58% and 50%, respectively. The 3-year and 5-year overall survival were 88% and 68%, respectively. CONCLUSION: Very young Egyptian patients with breast cancer should be given focus and specially studied as the presentation has more aggressive biologic behavior at advanced stages, so the treatment strategies have to be tailored in a very precise manner.

Predictive Value of IHC4 Score for Pathological Response to Neoadjuvant Chemotherapy in Hormone Receptor-Positive Breast Cancer.

PURPOSE: This study aimed to explore the value of IHC4 in predicting pathological response after neoadjuvant chemotherapy in patients with hormonal receptor (HR)-positive breast cancer (BC). MATERIALS AND METHODS: In this retrospective exploratory study, data for 68 HR-positive BC patients who received neoadjuvant chemotherapy were recorded. IHC4 scores were calculated based on estrogen receptors/progesterone receptors, Ki-67 and HER2 status. Logistic and ordinal regression analyses in addition to likelihood ratio test were used to explore associations of IHC4 scores and other clinico-pathological parameters with pathological complete response (pCR) and pathological stage. RESULTS: Taking the 25th percentile as the cut-off, a lower IHC4 score was associated with an increased probability of pCR (low; 52.9% vs. High; 21.6%, OR=4.1, 95% CI= 1.28-13.16, p=0.018) and a lower pathological stage (OR =3.9, 95% CI=1.34-11.33, p=0.012). When the IHC4 score was treated as a continuous variable, a lower score was again associated with an increased probability of pCR (OR=1.010, 95% CI=1.001-1.018, p=0.025) and lower pathological stage (OR=1.009, 95% CI= 1.002-1.017, P=0.008). Lower clinical stage was associated with a better pCR rate that was of borderline significance (P=0.056). When clinical stage and IHC4 score were incorporated together in a logistic model, the likelihood ratio test gave a P-value of 0.004 after removal of the IHC4 score and 0.011 after removal of the stage, indicating a more significant predictive value of the IHC4 score for pCR. CONCLUSIONS: This study suggests that the IHC4 score can predict pathological response to neoadjuvant chemotherapy in HR-positive BC patients. This finding now needs to be validated in a larger cohort of patients.

Thyroid transcription factor-1 expression in advanced non- small cell lung cancer: impact on survival outcome.

BACKGROUND: The prognostic role of thyroid transcription factor-1 (TTF-1) expression in lung cancer has been assessed but with inconsistent results. The present study aimed to evaluate the prognostic value of TTF1 expression in advanced non-squamous non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this retrospective study, patients with stage IIIB-IV non-squamous NSCLC were enrolled. Progression free survival (PFS) and overall survival (OS) were assessed according to TTF1 expression status, age categories (≤60 vs >60 years), gender, performance status (PS) (0-2 vs 3-4), type of 1st line chemotherapy (pemetrexed containing vs others) and EGFR status. RESULTS: A total of 120 patients were included. In univariate analysis, PFS was improved in patients with PS 0-2 (7.0 vs 2.0 months, p=0.002) and those who received pemetrexed-containing chemotherapy (9.2 vs 5.8 months, p=0.004). OS was improved in female patients (23.0 vs 8.7 months, p<0.0001), PS 0-2 (14.4 vs 2.0 months, p<0.0001), those with pemetrexed-containing chemotherapy (17.0 vs 11.0 months, p=0.019), TTF1-positive (12.8 vs 5.8 months, p=0.011) and EGFR- mutant patients (23.0 vs 11.7 months, p=0.006). In multivariate analysis, male gender (HR=2.34, p=0.025) and non-pemetrexed containing therapy (HR=2.24, p=0.022) were independent predictors of worse PFS. Wild EGFR status (HR=2.49, p=0.015) and male gender (HR=2.78, p=0.008) were predictors of worse OS. CONCLUSIONS: Pemetrexed-containing therapy significantly improved PFS while OS was improved in EGFR mutant patients. Female patients had better PFS and OS. TTF1 expression was not a prognostic marker in advanced non-squamous NSCLC.

Methylation of SFRPs and APC genes in ovarian cancer infected with high risk human papillomavirus.

BACKGROUND: Secreted frizzled-related protein (SFRP) genes, new tumor suppressor genes, are negative regulators of the Wnt pathway whose alteration is associated with various tumors. In ovarian cancer, SFRPs genes promoter methylation can lead to gene inactivation. This study investigated mechanisms of SFRP and adenomatous polyposis coli (APC) genes silencing in ovarian cancer infected with high risk human papillomavirus. MATERIALS AND METHODS: DNA was extracted from 200 formalin-fixed paraffin-embedded ovarian cancer and their normal adjacent tissues (NAT) and DNA methylation was detected by methylation specific PCR (MSP). High risk human papillomavirus (HPV) was detected by nested PCR with consensus primers to amplify a broad spectrum of HPV genotypes. RESULTS: The percentages of SFRP and APC genes with methylation were significantly higher in ovarian cancer tissues infected with high risk HPV compared to NAT. The methylated studied genes were associated with suppression in their gene expression. CONCLUSION: This finding highlights the possible role of the high risk HPV virus in ovarian carcinogenesis or in facilitating cancer progression by suppression of SFRP and APC genes via DNA methylation.

Human papillomavirus genotyping and integration in ovarian cancer Saudi patients.

BACKGROUND: Human papillomavirus (HPV) is associated with different malignancies but its role in the pathogenesis of ovarian cancer is controversial. This study investigated the prevalence, genotyping and physical state of HPV in ovarian cancer Saudi patients. METHODS: Hundred formalin fixed paraffin embedded (FFPE) ovarian carcinoma tissues and their normal adjacent tissues (NAT) were included in the study. HPV was detected by nested polymerase chain reaction (PCR) using degenerated HPVL1 consensus primer pairs MY09/MY11 and GP5+/GP6 + to amplify a broad spectrum of HPV genotypes in a single reaction. The HPV positive samples were further genotyped using DNA sequencing. The physical state of the virus was identified using Amplification of Papillomavirus Oncogene Transcripts (APOT) assay in the samples positive for HPV16 and/or HPV18. RESULTS: High percentage of HPV (42%) was observed in ovarian carcinoma compared to 8% in the NAT. The high-risk HPV types 16, 18 and 45 were highly associated with the advanced stages of tumor, while low-risk types 6 and 11 were present in NAT. In malignant tissues, HPV-16 was the most predominant genotype followed by HPV-18 and -45. The percentage of viral integration into the host genome was significantly high (61.1%) compared to 38.9% episomal in HPV positive tumors tissues. In HPV18 genotype the percentage of viral integration was 54.5% compared to 45.5% episomal. CONCLUSION: The high risk HPV genotypes in ovarian cancer may indicate its role in ovarian carcinogenesis. The HPV vaccination is highly recommended to reduce this type of cancer.