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Compared with other breast cancer subtypes, patients with triple-negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This-in return-has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti-PD-L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key-practice changing-clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.

Background::Androgen receptor (AR) upstreams complex signaling pathways that regulate cell proliferation and contribute to breast tumorignensis. Several clinical trials were initiated to investigate the clinical relevance of targeting AR especially in hormone-receptor-negative breast cancer.Methods::The search was performed in PubMed and the meeting libraries of ASCO, ESMO, SABCS, ImpakT congresses from January 2005 to July 2017. The following key words were used: Breast cancer, Androgen receptor, androgen agonist/antagonist, Flutamide, Abiraterone, Bicalutamide, Enzalutamide, Enobosarm, selective androgen receptor modulator.Results::Screening of title/abstracts yielded a total of 20 relevant results. Of those, twelve studies were found eligible: eleven clinical trials along with one case report. Response rates ranged from 0 to 12% while clinical benefit rates reached up to 35% in 2 studies (with enzalutamide and enobosarm). Progression-free survival ranged from 2.8 to 4.5 months. The most widely used cutoff for AR expression was 10%. High expression of AR was associated with more clinical benefit. Regarding safety, anti-androgens were generally well tolerated with hot flushes, elevated transaminases and fatigue being the most commonly reported across all agents.Conclusion::Androgen receptor pathway targeting in advanced breast cancer remains a valid option with reasonable clinical benefit in non-selected patients. Future studies are needed to define an AR addicted cohort with better responses and outcome.

Breast cancer (BC) is the most frequent cancer in women and the leading cause of cancer death in females worldwide. Rapid research advancements add to the complexity of treatment options for this disease. It is known that the quality of patients’ care is deeply affected by healthcare professionals following these advancements. There is a growing need for academic education to increase clinical knowledge and skills of physicians treating BC patients. The certificate of Competence in Breast Cancer Program (CCB) is a Certificate in Advanced Studies (CAS) organized by the European School of Oncology in cooperation with Ulm University (Germany), which focuses on both the clinical and scientific competence required for improving quality in the management of BC patients. This paper describes the experience of the second CCB cohort (CCB2), which brought together 24 physicians from four continents who shared the common will to improve their competence and skills in BC treatment.

Purpose Menin, encoded by the MEN1 gene, was recently reported to be involved in breast cancers, though the underlying mechanisms remain elusive. In the current study, we sought to further determine its role in mammary cells. Methods Menin expression in mammary lesions from mammary-specific Men1 mutant mice was detected using immunofluorescence staining. RT-qPCR and western blot were performed to determine the role of menin in ERα expression in human breast cancer cell lines. ChIP-qPCR and reporter gene assays were carried out to dissect the action of menin on the proximal ESR1 promoter. Menin expression in female patients with breast cancer was analyzed and its correlation with breast cancer subtypes was investigated. Results Immunofluorescence staining revealed that early mammary neoplasia in Men1 mutant mice displayed weak ERα expression. Furthermore, MEN1 silencing led to both reduced ESR1 mRNA and ERα protein expression in MCF7 and T47D cells. To further dissect the regulation of ESR1 transcription by menin, we examined whether and in which way menin could regulate the proximal ESR1 promoter, which has not been fully explored. Using ChIP analysis and reporter gene assays covering − 2500 bp to + 2000 bp of the TSS position, we showed that the activity of the proximal ESR1 promoter was markedly reduced upon menin downregulation independently of H3K4me3 status. Importantly, by analyzing the expression of menin in 354 human breast cancers, we found that a lower expression was associated with ER-negative breast cancer (P = 0.041). Moreover, among the 294 ER-positive breast cancer samples, reduced menin expression was not only associated with larger tumors (P = 0.01) and higher SBR grades (P = 0.005) but also with the luminal B-like breast cancer subtype (P = 0.006). Consistent with our clinical data, we demonstrated that GATA3 and FOXA1, co-factors in ESR1 regulation, interact physically with menin in MCF7 cells, and MEN1 knockdown led to altered protein expression of GATA3, the latter being a known marker of the luminal A subtype, in MCF7 cells. Conclusion Taken together, our data provide clues to the important role of menin in ERα regulation and the formation of breast cancer subtypes.

BackgroundBreast cancer (BC) is the 2ndmost prevalent malignancy worldwide and is the most prevalent cancer among Egyptian women. The number of newly described cancer-associated genes has grown exponentially since the emergence of next-generation sequencing (NGS) technology. We aim to identify activating mutations in liquid biopsy of Egyptian breast cancer patients using targeted NGS technology. We also demonstrate the microsatellite instability (MSI) status using BAT25, BAT26, and NR27 markers which are tested on the Bioanalyzer 2100 system.ResultsTwenty-one variants were detected in 15 genes: 7 Substitution-Missense, 12 Substitution-coding silent, and 2 Substitution-intronic. Regarding ClinVar database, out of 21 variants there were 14 benign variants, 3 variants with conflicting interpretations of pathogenicity, 3 variants not reported, and 1 drug response variant.TP53p.(Pro72Arg) missense mutations were found in 75% of patients.PIK3CAp.(Ile391Met),KDRp.(Gln472His) missense mutations were detected in 25% of patients each. Two patients revealed APC gene missense mutation with p.(Ile1307Lys) and p.(Glu1317Gln) variants. Only one patient showedATMp.(Phe858Leu) gene mutation and one showed FGFR3 p.(Ala719Thr) variant. Regarding microsatellite instability (MSI) status, 2/8 (25%) patients were MSS, 3/8 (37.5%) patients were MSI-L, and 3/8 (37.5%) patients were MSI-HI.ConclusionIt is essential to use and validate minimally invasive liquid biopsy for activating mutations detection by next-generation sequencing especially in patients with inoperable disease or bone metastasis. This work should be extended with larger patient series with comparison of genetic mutations in liquid-based versus tissue-based biopsy and longer follow up period.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). It accounts for 15%–20% of all breast cancers and is associated with an aggressive evolution and poor outcomes with the majority of recurrences and deaths occurring in the first 5 years. Chemotherapy remains the mainstay of treatment in the absence of effective targets, but the good understanding of immune tumor microenvironment, the identification of immune-related targets, and the role of tumor-infiltrating lymphocytes (TILs) in TNBC has allowed to develop promising immunotherapeutic strategies for this unique subset of breast cancer. Recently, immunotherapy is being extensively explored in TNBC and clinical trials have shown promising results. In this article, we tried to explain the rationale and mechanisms of targeting the immune system in TNBC, to report the results from recent clinical trials that put immunotherapy as a new standard of care in TNBC in addition to ongoing trials and future directions in the next decade.

Hamdy A Azim,1 Ashraf Omar,2 Hesham Atef,1,† Heba Zawahry,3 Mohamed K Shaker,4 AH Kamel Abdelmaksoud,5 Mohamed EzzElarab,6 Omar Abdel-Rahman,7 Mohamed Ismail,8 Loay Kassem,1 Imam Waked9 1Department of Clinical Oncology, Faculty of Medicine, Cairo University, Cairo, Egypt; 2Department of Gastroenterology, Faculty of Medicine, Cairo University, Cairo, Egypt; 3Department of Medical Oncology, National Cancer Institute, Cairo, Egypt; 4Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 5Department of Diagnostic and Intervention Radiology, Cairo University, Cairo, Egypt; 6National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt; 7Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 8Clinical Oncology Department, Cairo Oncology Center, Cairo, Egypt; 9Institute of Liver Disease, Menoufiya University, Menoufiya, Egypt †Dr Hesham Atef passed away on November 16, 2017, during the preparation of the manuscript Background: Phase II trials found that tegafur–uracil (UFT) is an effective drug in hepatocellular carcinoma (HCC), while preclinical data suggested that its combination with sorafenib may have a promising activity. Our Phase II randomized trial aimed to evaluate efficacy and tolerability of sorafenib plus UFT vs sorafenib in advanced HCC.Methods: Patients with advanced HCC, with no prior systemic therapy, were randomized to receive either UFT at 125 mg/m2 twice daily for 4 out of 5 weeks plus sorafenib at 400 mg twice daily (arm 1) or single agent sorafenib at 400 mg twice daily (arm 2). Primary end point was time to progression (TTP).Results: Between March 2012 and March 2014, 76 eligible patients – out of 143 preplanned – were randomized. The study was terminated early because of futility. This is the final analysis of the study, after a median follow-up of 10.2 months and death of 86% of randomized patients (n=64). Median TTP was 7.5 months and 8.2 months in arms 1 and 2 respectively (HR: 1.07; 95% CI, 0.52–2.22; P=0.855), while the median overall survival was 8.2 months and 10.5 months respectively (HR: 1.58; 95% CI: 0.90–2.76, P=0.112). Nine patients (25%) in the combination arm discontinued treatment because of toxicity vs eight patients (21.1%) in the sorafenib monotherapy arm (P=0.899).Conclusion: In patients with advanced HCC, adding UFT to sorafenib is feasible, but it did not improve efficacy outcome over sorafenib monotherapy. Keywords: advanced hepatocellular carcinoma, sorafenib, tegafur/uracil, Egypt

Brain metastasis (BM) is a life-threatening event in breast cancer patients. Identifying patients at a high risk for BM can help to adopt screening programs and test preventive interventions. We tried to identify the incidence of BM in different stages and subtypes of breast cancer.We reviewed the clinical records of 2193 consecutive breast cancer patients who presented between January 1999 and December 2010. We explored the incidence of BM in relation to standard clinicopathological factors, and determined the cumulative risk of BM according to the disease stage and phenotype.Of the 2193 included women, 160 (7.3%) developed BM at a median follow-up of 5.8 years. Age younger than 60 years (P = .015), larger tumors (P = .004), lymph node (LN) positivity (P .001), high tumor grade (P = .012), and HER2 positivity (P .001) were associated with higher incidence of BM in the whole population. In patients who presented with locoregional disease, 3 factors independently predicted BM: large tumors (hazard ratio [HR], 3.60; 95% confidence interval [CI], 1.54-8.38; P = .003), axillary LN metastasis (HR, 4.03; 95% CI, 1.91-8.52; P .001), and HER2 positivity (HR, 1.89; 95% CI, 1.0-3.41; P = .049). A Brain Relapse Index was formulated using those 3 factors, with 5-year cumulative incidence of BM of 19.2% in those having the 2 or 3 risk factors versus 2.5% in those with no or 1 risk factor (P .001). In metastatic patients, 3 factors were associated with higher risk of BM: HER2 positivity (P = .007), shorter relapse-free interval (P .001), and lung metastasis (P .001).Disease stage and biological subtypes predict the risk for BM and subsequent treatment outcome.

A major, yet precisely studied, shift has occurred in the treatment of advanced hormone-sensitive prostate cancer (HSPC) by the addition of docetaxel to androgen deprivation therapy (ADT) in the first line. Recently, two landmark trials showed that abiraterone acetate (AA) can be an effective alternative along with ADT in the same setting. We implemented a network meta-analysis to compare the safety and efficacy of the two combinations.PubMed database, ASCO and ESMO meeting library databases of all results published until June 2017 were searched using the keywords: "prostate cancer" AND "docetaxel" OR "abiraterone acetate". Efficacy endpoints including progression-free survival (PFS) and overall survival (OS), and safety endpoints (including treatment related deaths and selected adverse events) were assessed.Twenty relevant studies were retrieved and assessed for eligibility. Of those trials, eight were found potentially eligible. Inconsistent reporting of efficacy outcomes limited our analysis to M1 HSPC. The pooled hazard ratios (HRs) of OS and PFS of the direct comparison of abiraterone acetate plus ADT versus ADT were 0.63 (95% CI: 0.545-0.717) and 0.38 (95% CI: 0.34-0.43), respectively. Meanwhile, in the trials of docetaxel plus ADT the pooled HRs of OS and PFS were 0.75 (95% CI: 0.65-0.86) and 0.634 (95% CI: 0.57-0.70), respectively. The indirect comparison showed that the HRs of OS and PFS in DOC + ADT in comparison to AA + ADT were 1.2 (95% CI: 0.98-1.46) and 1.65 (1.40-1.94), respectively. The pooled RR of treatment-related mortality in docetaxel + ADT versus AA + ADT was 1.438 (95% CI: 0.508-4.075).Patients with metastatic HSPC (mHSPC) who received abiraterone acetate with ADT had better PFS and less toxicity compared to those receiving docetaxel with ADT. A trend towards superior OS and fewer treatment-related deaths was also observed, but was statistically non-significant. In view of lacking clear OS advantage, the choice between docetaxel and AA should include a discussion with the patient about the potential toxicities and impact on quality of life of each regimen.

The introduction of specific cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly improved progression-free survival in hormone receptor-positive metastatic breast cancer. CDK 4/6 inhibitors induce cell cycle arrest via liberating the tumor suppressor retinoblastoma protein from CDK4/6 inhibitory effect. Preliminary studies suggested an increase in the hematological toxicities which might affect the quality of life in such palliative setting. We searched PubMed, ASCO, ESMO and San Antonio meeting databases for randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors with safety data provided on the incidence of hematological adverse effects. Our search identified 1012 citations that were screened for relevance. Thirty-six studies were found to be potentially eligible. After excluding the ineligible studies, six studies were deemed to be eligible for meta-analysis. The risk ratio (RR) was 11.31 [95% confidence interval (CI) 8.06–15.87; p

Background:Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors show promising results in metastatic breast cancer. However, an increased incidence of adverse events is remarkable. Among others, gastrointestinal (GI) involvement is of momentous impact on patients and their quality of life.Methods:Our search included PubMed, ASCO, ESMO and SABCS databases. Randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors were identified and considered relevant based on providing a sufficient safety profile on the incidence of adverse GI effects.Results:Of the 999 records initially screened for relevance, 33 articles were found relevant and 4 studies were finally eligible for meta-analysis with a total of 2007 patients. The relative risk (RR) for all-grade nausea was 1.48 [95% confidence interval (CI): 1.12–1.93, p = 0.005], vomiting was 1.74 (95% CI: 1.09–2.76, p = 0.02), decreased appetite was 1.42 (95% CI: 1.07–1.88, p = 0.02), and for diarrhea it was 1.44 (95% CI: 1.19–1.74, p = 0.0002). Meanwhile, the RR for high-grade nausea was 1.10 (95% CI: 0.29–4.13, p = 0.89), vomiting was 1.38 (95% CI: 0.25–7.75, p = 0.72), decreased appetite was 4.00 (95% CI: 0.87–18.37, p = 0.07), and high-grade diarrhea was 1.19 (95% CI: 0.44–3.21, p = 0.73).Conclusion:Selective CDK4/6 inhibitors were not associated with higher-grade GI toxicities reflecting a well-tolerated safety profile. Regarding the increase in all-grade GI toxicities, it needs further caution with addition of cytotoxic chemotherapy.

Cyclin-dependent kinase (CDK) inhibitors emerge as efficacious agents in hormone positive metastatic breast cancer with more acceptable toxicity profiles than cytotoxic chemotherapy. However, some adverse effects such as fatigue, alopecia and stomatitis, vastly concern patients.The search was conducted in PubMed, American Society of Clinical Oncology meeting library, European Society for Medical Oncology meeting abstract, and the San Antonio meeting abstract databases. We identified phase 2 or 3 trials recruiting patients with breast cancer, randomized to receive hormonal treatment plus either CDK4/6 inhibitors or placebo. We considered studies providing incidence of fatigue, alopecia and stomatitis relevant.One thousand records were screened. 34 studies were considered relevant. Four studies were found to be eligible for meta-analysis with a total of 2007 patients. The relative risk for all grade fatigue was 1.34 [95% CI: 1.17-1.54, p 0.0001], for all grade alopecia was 2.14 [95% CI: 1.23-3.73, p = 0.007], and for all grade stomatitis 4.87 [95% CI: 2.11-11.24, p = 0.0002]. In addition, the relative risk for high grade fatigue was 2.40 [95% CI: 1.10-5.26, p = 0.03].CDK4/6 inhibitors were associated with an increased risk of fatigue, alopecia and stomatitis. Further studies with self-reported questionnaires may elucidate the impact of the increased risk of these selected adverse effects on the patients' quality of life.

During the last 2 decades, extensive research has focused on the molecular functions of BRCA1 and BRCA2 genes. This has led to the development of Poly(ADP-ribose) polymerase inhibitors (PARPi), as effective target therapies, based on their preferential cytotoxicity in tumor cells harboring germline BRCA1 and BRCA2 mutations. At the present time, 2 PARPi (Olaparib and Talazoparib) are approved as single agent for the treatment of patients with metastatic HER2-ve breast cancer, who have BRCA germline mutations. The clinical benefit of these agents might be also anticipated in patients harboring germline mutations in some additional genes involved in the process of homologous recombination repair (HRR) other than BRCA1/BRCA2. In this review, we summarize the molecular rational for the therapeutic development of PARPi and the clinical evidence supporting their use as anticancer drugs in breast cancer patients with BRCA1/BRCA2 germline mutations. We also discuss the role of platinum-based chemotherapy and how it compares with PARPi in the management of these patients. We will go through some relevant clinical trials of various combinations of PARPi with cytotoxic or immunotherapeutic agents, which may potentially provide better treatment results, compared to what is already achieved with their use as monotherapy.

Endocrine therapy (ET) has been regarded for many years as the standard treatment for patients with hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC) without visceral crisis. However, the efficacy of single-agent ET is constrained by the development of resistance, attributed to alterations in several intracellular signaling pathways, including those related to cell cycle dysregulation. The cyclin-dependent kinases 4 and 6 (CDK4/6) are principal regulators of cell cycle progression from the G1-phase into the DNA synthesis (S)-phase. In vitro inhibition of CDK4/6 activity has potent antiproliferative properties against luminal breast cancer cell lines, which are enhanced when combined with traditional ET. This has led to a substantial interest in targeting this pathway to overcome endocrine resistance in the clinic. Three selective CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved as first-line therapy in combination with an aromatase inhibitor, or fulvestrant in the case of ribociclib in patients with ER+/HER2- ABC. To date, there is no clue as to which subgroup of patients might benefit most from these combinations. Here, we outline some of the established approaches to overcome endocrine resistance, with special emphasis on the unique mechanism of action of CDK4/6 inhibitors.

The benefit of adding ovarian function suppression (OFS) to tamoxifen in the adjuvant treatment of premenopausal women with breast cancer is uncertain. We conducted a meta-analysis of randomized controlled trials that addressed this question.Systematic search of PubMed, the web of science, and the meeting library of ASCO, ESMO, and SABCS was conducted using the following keywords: tamoxifen, ovarian suppression, and breast cancer. Eligible studies were those recruiting patients with breast cancer randomized to receive adjuvant tamoxifen and OFS versus tamoxifen alone. Pooled hazard ratio [HR]) for disease-free (DFS) and overall survival (OS) with 95% confidence interval (CI) were calculated using the fixed effect model.We searched a total of 845 records, of which 5 clinical trials, including 7557 patients, were eligible for our analysis. Adding OFS to tamoxifen improved DFS with pooled HR: 0.88 (95% CI: 0.80-0.96, P= 0.004) and OS (pooled HR: 0.87 {95% CI: 0.77-0.98, P= 0.02}) compared to tamoxifen alone. The benefit of the addition of OFS to tamoxifen was mostly observed in patients younger than 40 years where the pooled HRs of DFS was 0.76 (95% CI: 0.63-0.91; P= 0.004), and in those who received adjuvant chemotherapy with pooled HRs of DFS 0.80 (95% CI: 0.65-0.99, P= 0.042). There was an increase in the incidence of all grade musculoskeletal symptoms and high-grade hot flushes with the addition of OFS with risk ratios of 1.12 (95% CI: 1.07-1.17, P0.001) and 2.14 (95% CI: 1.01-4.51, P= 0.047) respectively.Our analysis indicates that the addition of OFS to tamoxifen improves DFS and OS. This strategy could be considered in patients in which tamoxifen alone is not deemed sufficient or in case of poor tolerance to OFS with aromatase inhibitors.

BACKGROUND: The PI3K/AKT/mTOR pathway alterations have been shown to play significant roles in the development, progression, and metastatic spread of breast cancer. Furthermore, they have been implicated in the process of drug resistance, especially endocrinal therapies. In this study, we aimed to define the correlation between the PI3K mutations and the expression of the phosphorylated forms of different downstream molecules in women with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2–negative (luminal) early breast cancer treated at Cairo university hospitals. METHODS: Next-generation sequencing was used to detect mutations in the PIK3CA hotspots (in exons 9 and 20). Immunohistochemistry was performed on tissue microarray blocks prepared from samples of 35 Egyptian luminal breast cancer patients in the pathology department of Centre Léon Bérard (CLB). The intensity and the percentage of stained tumor cells were integrated to define high versus low biomarker expression. The cytoplasmic and nuclear stainings were graded separately. Patients were followed for a median of 4.7 years (2.1 to 6.9 years). Correlation was done between PI3K mutations and the immunohistochemistry expression of pAKT, LKB1, p4EBP1, and pS6 ribosomal protein (pS6RP) with the clinicopathologic features and disease free survival (DFS) of the patients. RESULTS: Median age at diagnosis was 51.3 years (range, 25 to 82 years). Tumors were larger than 20 mm in 79.2% of the cases, whereas 57.9% had axillary lymph node deposits. Only 12.3% of the patients had SBR grade I tumors, 50.8% had grade II, and 36.8% had grade III. ERs were negative in 6 patients (17%) after pathology review. Thirty-two cases were assessable for LKB1 and pAKT, 33 for p4EBP1 and pS6RP, and 24 for PI3K mutations. Nuclear LKB1, cytoplasmic LKB1, nuclear pAKT, cytoplasmic pAKT, nuclear p4EBP1, and cytoplasmic pS6RP expression was high in 65.6%, 62.5%, 62.5%, 68.8%, 42.4%, and 57.6%, respectively. PIK3CA mutations were found in 7 patients (29.2%). PI3K mutations were correlated with nuclear localization of pAKT (i.e., decreased cytoplasmic pAKT, P = .04; and increased nuclear pAKT, P = .10). There was a tendency toward an inverse correlation between PI3K mutations and the expression of pS6RP (P = .10) and p4EBP1 (P = .19). Nuclear LKB1 expression was a marker of good prognosis. It was associated with smaller tumors (P = .05), more ER (P = .08) and progesteron receptor (PgR) positivity (P = .002). In the Kaplan Meier (KM) model, patients with high nuclear LKB1 had longer DFS (hazard ratio = 0.36; 95% confidence interval, 0.15-1.10; P = .08). Nuclear pAKT high expression also carried a tendency toward longer DFS (hazard ratio = 0.51; 95% confidence interval, 0.11-1.16; P = .13). The expression of p4EBP1, pS6RP, and the PI3K mutational status did not show any prognostic significance in our cohort. CONCLUSION: Among the studied biomarkers, only nuclear expression of LKB1 and pAKT tended to predict better survival in breast cancer patients. PI3K mutation was correlated with the expression of nuclear pAKT but not pS6RP or p4EBP1.

Background: Social support (SS) has been proven to be associated with improved outcome of early breast cancer. Little is known about the magnitude of social support available for Egyptian breast cancer patient and much less is known about the changes that occur in such support after the diagnosis of breast cancer and starting treatment. Methods: We designed a longitudinal questionnaire based prospective cohort study using the six item form of the Medical Outcomes Study- Social Support Survey (MOS-SSS) questionnaire and included patients with pathologically proven non-metastatic breast cancer 18-70 years of age. Patients completed the self administered questionnaire at 2 time points: at first diagnosis of breast cancer and after 3-6 months of starting treatment. Comparison of the pre and post treatment questionnaires was done using paired sample T test. Results: A total of 48 patients completed the 2 questionnaires. Median age was 48 years (range: 24-65 years). Seventy percent of our patients were married, 67% had more than 2 children and 77.8% were housewives. Around half of the patients (45.2%) had monthly income below 1200 EGP. Patients who had higher education level (p=0.002) and those who were living in Cairo (p=0.033) reported higher SS at baseline. Mean MOS-SSS score at baseline was 64.4 (±24.8) while after treatment was 76.4 (±22.3); pConclusion: The majority of Egyptian breast cancer patients had a supportive environment after the diagnosis of breast cancer. A special attention should be paid to the at-risk groups with no sufficient SS during that period.

Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain–dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh. Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404–17. ©2018 AACR.

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients.

Background The Transforming growth factorβ (TGFβ) signaling has a paradoxical role in cancer development and outcome. It protects against tumorigenesis by inhibiting cell growth and promoting apoptosis, but at advanced stages, it promotes tumor progression. Besides, the prognostic significance of the TGFβ1, SMAD4 in breast cancer patients is also an area of many contradictions. Transcriptional intermediary factor 1γ (TIF1γ) is thought to interact with the TGFβ/SMAD signaling through different mechanisms. Our study aimed at defining the prognostic significance of TGFβ1, SMAD4 and TIF1γ expression in breast cancer patients in addition to detection of possible interactions among those markers that might affect the outcome and explain the contradictory results. Methods Immunohistochemistry was performed on TMA blocks prepared from samples of 248 operable breast cancer patients who presented at CLB between 1998 and 2001 using. The intensity and the percentage of stained tumor cells were integrated into a single score (0-6) and a cutoff was defined for high or low expression for each marker. Correlation was done between the TGFβ1, SMAD4 and TIF1γ expression with the clinico-pathologic parameters using Pearson’s chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test. Results 223 cases were assessable for TIF1γ, 204 for TGFβ1 and 173 for SMAD4. Median age at diagnosis was 55.8 years (range: 27 to 89 years). Tumors were larger than 20 mm in 49.2% and 45.2% had axillary lymph node (LN) metastasis (N1a to N3). 19.4% of the patients had SBR grade I tumors, 46.8% grade II tumors and 33.9% grade III tumors. ER was positive in 85.4%, PR in 75.5% and Her2-neu was over-expressed in 10% of the cases. Nuclear TIF1γ, cytoplasmic TGFβ1, nuclear and cytoplasmic SMAD4 staining was high in 35.9%, 30.4%, 27.7% and 52.6% respectively. TIF1γ expression was associated with younger age (p=0.006), higher SBR grade (p TGFβ1 expression in tumor cells was a marker of poor prognosis regarding DMFS (HR=2.28; 95%CI: 1.4 to 3.8; p=0.002), DFS (HR=2.00; 95% CI: 1.25 to 3.5; p=0.005) and OS (HR=1.89; 95%CI: 1.04 to 3.43; p=0.037). TIF1γ expression carried a tendency towards poorer DMFS (p=0.091), DFS (p=0.143) and OS (p=0.091). In the multivariate analysis TGFβ1 remained an independent predictor of shorter DMFS, DFS and OS after adjustment for age, tumor size, SBR grade and LN invasion. Moreover, the prognostic significance of TGFβ1 was more obvious in the TIF1γ high patient subgroup than in the patients with TIF1γ low expression. The subgroup expressing both markers had the worst DMFS (HR=3.2; 95%CI: 1.7 to 5.9; p Conclusion There is a crosstalk between the TIF1γ and the TGFβ1/SMAD4 signaling that deteriorate the outcome of operable breast cancer patients and when combined together they can serve as an effective prognostic tool for those patients. Citation Format: Loay Kassem, Laurent Fattet, Jonathan Lopez, Goulvent Thibault, Emilie Lavergne, Sylvie Chabaud, Nicolas Carrabin, Nicolas Chopin, Thomas Bachelot, Germain Gillet, Isabelle Treilleux, Ruth Rimohk. TIF1[gamma] interacts with the TGFβ1/SMAD4 signaling leading to poorer outcome in operable breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-24.

Background ERα-36 is a splice variant of ER-α with molecular weight of 36-kDa that lacks transactivation domains, and is expressed in the cytoplasm and cell membrane of ER (ERα66) negative as well as ERα66 positive breast cancer cells. It is also thought to predict resistance to tamoxifen therapy. Here we investigate its prognostic significance, its association with other clinico-pathologic factors and correlation with other biomarkers of the PI3K/AKT/mTOR pathway. Methods We studied ERα-36 expression on TMA blocks prepared from samples of 160 consecutive operable breast cancer patients who presented at CLB between 1998 and 2001. The intensity of the staining and the percentage of tumor cells stained for each biomarker (ERα-36, PI3K, pAKT, p4EBP1, pS6RP and LKB1) were integrated into a single score and a cutoff was defined for high versus low expression. Correlations were done between ERα-36 expression and the clinico-pathological parameters and other biomarkers using Pearson’s chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test. Cox regression model was used to adjust for other prognostic parameters in the multivariate analysis. Results Median age at diagnosis was 56.9 years (range: 30 to 87 years). The maximum tumor size was larger than 2 cm in 57.5% of cases and axillary lymph nodes (LN) were positive (N1a to N3) in 52.5% of cases. 16.3% of the patients had SBR grade I, 44.4% had grade II and 39.4% had grade III tumors. ERα66 was positive in 91.2%, PgR in 74.7% and HER2 was over-expressed in 15% of the cases. High ER-α36 expression in the cell membrane was observed in 65 patients (40.6%). ERα-36 expression was independent of the ERα66, PgR or HER2 expression and was not associated with age, tumor size, SBR grade or axillary LN invasion. There was no correlation between ERα-36 expression and PI3K, pAKT, p4EBP1, pS6RP or LKB1 expression. ERα-36 expression in tumor cells was a predictor of poor prognosis regarding DMFS (HR=2.02; 95% CI: 1.2 to 3.4; p=0.008), DFS (HR=1.7; 95% CI: 1.05 to 2.7; p=0.031) and OS (HR=1.8; 95% CI: 1.02 to 3.2; p=0.043). In the multivariate analysis and after adjustment for age, tumor size, SBR grade and LN invasion, ERα-36 remained an independent predictor of shorter DMFS (p=0.016) and DFS (p=0.052) in addition to SBR grade and axillary LN metastasis. The ERα-36 expression predicted shorter DMFS for patients who received tamoxifen as the only adjuvant systemic treatment (p=0.022) and also for those who received other hormonal therapy and adjuvant chemotherapy (p=0.039). Conclusion Immunohistochemically detected membranous ERα-36 expression can be a poor prognostic factor for patients with operable breast cancer that is independent from the traditional clinico-pathologic parameters and from PI3K/AKT/mTOR pathway activation status. Citation Format: Loay Kassem, Soleilmane Omarjee, Sylvie Chabaud, Emilie Lavergne, Christelle Faure, Frédéric Beurrier, Olivier Tredan, Laura Corbo, Isabelle Treilleux, Muriel Le Romancer. Membranous ERα-36 expression is an independent predictor of poor prognosis in operable breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-23.

Background mTOR inhibitors are widely used in different malignancies with several trials testing their efficacy and safety in gynecological malignancies. We aimed to review the current evidence that support the expansion of using such drugs in the treatment of advanced gynecological cancers. Methods A comprehensive systematic review of literature has been conducted to include prospective trials that used everolimus, temsirolimus or ridaforolimus in the management of gynecological cancers and have available efficacy and toxicity results. Results A total of 23 studies including 980 patients were considered eligible for our review. Our review included 16 phase II and 7 phase I studies with the majority of patients having uterine cancers. Regarding Endometrial cancer, the CBR ranged from 21% to 60% and median PFS from 2.8 months to 7.3 months. In Ovarian cancers, CBR ranged from 24% to 50% and median PFS from 3.2 months to 5.9 months. In the single phase II study in cervical cancer the CBR was 61% and median PFS was 3.5 months. The toxicity profile was consistent with what was observed previously in other malignancies with fatigue, mucositis, and hematological toxicities being the most common adverse events observed. Conclusion mTOR inhibitors seem to be a promising option in the second line management of advanced gynecological cancers with best safety and efficacy outcomes when given as a single agent or in combination with hormonal treatment. More research is needed for better patient selection.

Background The Transforming growth factor β (TGFβ) signaling has a paradoxical role in cancer development and outcome. Besides, the prognostic significance of the TGFβ1, SMAD4 in breast cancer patients is an area of many contradictions. The transcriptional intermediary factor 1γ (TIF1γ) is thought to interact with the TGFβ/SMAD signaling through different mechanisms. Our study aims to define the prognostic significance of TGFβ1, SMAD4 and TIF1γ expression in breast cancer patients and to detect possible interactions among those markers that might affect the outcome. Methods Immunohistochemistry was performed on tissue microarray (TMA) blocks prepared from samples of 248 operable breast cancer patients who presented at Centre Léon Bérard (CLB) between 1998 and 2001. The intensity and the percentage of stained tumor cells were integrated into a single score (0–6) and a cutoff was defined for high or low expression for each marker. Correlation was done between TGFβ1, SMAD4 and TIF1γ expression with the clinico-pathologic parameters using Pearson’s chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test. Results 223 cases were assessable for TIF1γ, 204 for TGFβ1 and 173 for SMAD4. Median age at diagnosis was 55.8 years (range: 27 to 89 years). Tumors were larger than 20 mm in 49.2 % and 45.2 % had axillary lymph node (LN) metastasis (N1a to N3). 19.4 % of the patients had SBR grade I tumors, 46.8 % grade II tumors and 33.9 % grade III tumors. ER was positive in 85.4 %, PR in 75.5 % and Her2-neu was over-expressed in 10 % of the cases. Nuclear TIF1γ, cytoplasmic TGFβ1, nuclear and cytoplasmic SMAD4 stainings were high in 35.9 %, 30.4 %, 27.7 % and 52.6 % respectively. TIF1γ expression was associated with younger age (p = 0.006), higher SBR grade (p

Purpose: Mammographic screening of the contralateral breast is often advocated during follow-up of women previously treated for primary operable breast cancer; however most guidelines state the yearly contralateral mammogram as a universal recommendation without stratifying for the risk status of the breast primary, we are trying to challenge this concept through this retrospective analysis. Methods: Breast cancer patients treated at Cairo Oncology Centre (Cairo, Egypt) in the period between 2000-2008 were reviewed. Eligible patients were those who had no evidence of metastasis at diagnosis, and complete information on date of diagnosis, treatment, estrogen receptor (ER), progesterone receptor (PR) and HER2 status. We compared the difference in systemic adjuvant therapy and pathological parameters between cases that later developed contralateral relapse and cases that did not. We investigated the impact of different clinico-pathological parameters on contralateral disease-free survival in a Cox regression model adjusted for tumor size (pT), nodal status (pN), grade, ER, PR, HER2 and treatment. Results: 2068 patients were included in the analysis. Contralateral breast cancer was diagnosed in 92patients. At a median follow up period of 11.8 months, the median contralateral DFS for the whole group was 96 months. The median CDFS for the different subgroups was 54.,71,145., 14 Months for HR + /Her2-, HR + /Her2 + , HR-/ Her2 + , Triple –ve subgroup, respectively. Factors associated with higher risk of developing contralateral breast cancer were ER -ve/PR –ve phenotype (8.4%vs. 3.3%; p = 0.001) and development of local recurrence (10.1%vs. 4.2%; p = 0.002); while adjuvant radiotherapy to the ipsilateral side seems protective against contralateral relapse (5.7% vs. 3.1%; p = 0.012), no particular chemotherapy regimen seems particularly protective against contralateral relapse. Based on univariate analysis, the only variable associated with shorter time to develop contralateral recurrence (shorter contralateral DFS) is nodal involvement (p = 0.03, HR = 1.77). Conclusion: Our data suggests that high risk breast cancer, particularly node positive and ER/PR –VE disease, warrants more frequent screening of the contralateral breast. However, this hypothesis needs to be further explored in prospective randomized studies.