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Nrh protein expression in healthy and tumoral tissues (A) Nrh protein expression in human healthy tissues. Immunohistochemistry on tissue array (B) Nrh expression assessed by western blot in cell lysate of liver cancer. (NAT) normal adjacent tissue.

Time-lapse imaging of dTAT-NDP action on CAL-51 breast cancer cell line

Fig. S8. Mechanism for irradiation-free dTAT peptide internalization Fig; S9. dTAT peptide treatment increases apoptosis of tumor cells in vivo

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.

I- Reagents and antibodies. Vectors. RNA preparation & RT-qPCR -II- Supplementary Table 1: Invasive breast carcinomas patient cohort characteristics -III- Supplementary Table 2: Correlation between Nrh protein expression and the clinicopathologic factors of breast cancer -IV- Supplementary Table 3: Multivariate analysis of clinical parameters predicting shorter DMFS -V- Legend of supplementary movie : Time-lapse imaging of dTAT-NDP action on CAL-51 breast cancer cell line

Background: The gold standard for axillary staging in node-negative early-stage breast cancer is sentinel lymph node biopsy (SLNB). Axillary lymph node dissection (ALND), SLNB, and axillary radiotherapy have all been associated with axillary problems, but at a smaller incidence with SLNB alone than with ALND. The Z0011 trial demonstrated that there is no benefit from axillary dissection in the context of positive SLN. Aim: Compare locoregional recurrence, disease free survival (DFS), and overall survival (OS) between SLNB and observation in patients with early stage clinically node negative breast cancer by palpation and preoperative ultrasonography. Methodology: Candidates for Breast Conservative Surgery include 60 patients with clinically and radiologically node-negative early breast cancer, randomized to one of two groups: Study group (group A): 30 patients underwent BCS with no further axillary surgery. Control group (group B): 30 patients underwent BCS and SLNB. Follow up was done to detect the two years locoregional recurrence, DFS and OS. Results: After a two-year follow-up, there was no discernible difference between the two arms in terms of axillary, local, or metastatic recurrence. Regarding post-operative arm edema, both arms significantly differ from one another. Conclusion: Omission of axillary surgery in T1 and some cases of T2 N0 breast cancer patients appears safe and applicable without affecting locoregional recurrence and axillary/nodal recurrence. Longer term follow-up is needed

Background: In patients with metastatic triple-negative breast cancer (TNBC), PD-L1 expression has been demonstrated to predict response to immunotherapy. It is unclear whether PD-L1 expression measured with currently available validated assays can predict chemotherapy response in patients with non-metastatic TNBC. Methods: We conducted a systematic review and meta-analysis of clinical studies to assess the PD-L1 expression as a predictor of response to chemotherapy in non-metastatic TNBC using validated assays. The primary endpoint was pathological complete response (pCR) rate to neoadjuvant chemotherapy. Secondary endpoints included the prevalence of PD-L1 expression in non-metastatic TNBC and its impact on disease-free survival (DFS) and overall survival (OS). Moreover, RNA sequence data from the TCGA breast cancer cohort was used to define the relationship between PDCD1 and response to chemotherapy and prognosis. Results: Nineteen studies were eligible for the meta-analysis with a total of 2403 patients with non-metastatic TNBC disease. The PD-L1-positive cohort had a significantly higher likelihood of achieving pCR with neoadjuvant chemotherapy (pooled odds ratio =1.95; 95% CI= 1.39-2.73, p Conclusion: This analysis clearly shows that patients with PD-L1 positive TNBC respond better to neoadjuvant chemotherapy and are associated with better survival outcomes compared to patients with PD-L1 negative tumors. The newly distinct quadruple negative breast cancer (QNBC) subtype should be defined as the BC subtype with the poorest outcome in the non-metastatic setting, highlighting the need for more aggressive therapy approaches.

Background:Globally, triple-negative breast cancer (TNBC) is responsible for approximately 15% of all invasive Breast cancer and has been typically associated with poor prognosis. Some retrospective studies have suggested a relatively higher incidence of TNBC in the Middle East and North African Arab countries. Nevertheless, there is complete lack of prospective data, on TNBC in the region, including clinico-pathologic characteristics, treatment patterns and disease outcomes. The TRIPOLI study aims to bridge this information gap.Methods:TRIPOLI is an ongoing prospective multinational, disease registry, designed to recruit 700 newly diagnosed TNBC patients, from 15 institutions within 9 Arab countries: Egypt, Jordon, Morocco, Kingdom of Saudi Arabia, Lebanon, Oman, Kuwait, Qatar and Iraq. This interim analysis includes the patients’ characteristics and treatment approaches of the first 449 cases included in the study from December 2017 to September 2019.Results:All the 449 TNBC patients were females, with a median age of 49 years (range 23.8 - 93.6 years). Premenopausal status was reported in 54.7%, while a positive family history of BC was stated in 25.2% of these cases. 0.2% of patients were below normal (BMI 40 years, patients ≤ 40 years were less likely to be obese (39.4% versus 60.6%; p=0.002), more likely to have grade III tumours (62.3% versus 53.5%; p=0.116), more likely to have T3 or T4 tumours (41.4% versus 32.7%; p=0.038).Conclusion:In this interim analysis, Arab women with TNBC had high parity (≥ 3) and high BMI, compared to existing literature based on western population. High tumor grade, younger age and advanced stages at presentation are in line with similar world-wide reports. Younger women in the Arab region (≤40 years) presented with poor prognostic features, which will be further elucidated in subsequent reports. Citation Format: Hamdy A. Azim, Alaa Kandil, Heba El Zawahry, Hikmat Abdel-Razeq, Hesham Elghazaly, Suad Al Kharusi, Manal M. Abdelwahab, Salah Fayaz, Ahmed Saadeddin, Huda A. Alabdulkarim, Rasha Aboelhassan, Hassan Errihani, Tahseen Al Rubai, Salha Bujassoum Al Bader, Nashwa Mohamed Abdel Aziz, Nagi El Saghir, Giulia Attinà, Ahmed Yosry, Mohamed El Leithy, Loay Kassem, Marwan Ghosn. Triple negative breast cancer prospective registry in middle East and Africa (TRIPOLI) study: Interim analysis of the patients’ characteristics [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-65.

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.

Cancer in young women is a major health problem in the Middle Eastern and North African population. We explored the awareness, barriers and practice of Arab oncologists towards oncofertility.Oncologists from Arab countries treating female cancer patients were invited to complete a 30-item web-based questionnaire that explores oncologists' demographics, available techniques and barriers to oncofertility.170 oncologists working in 9 different Arab countries responded to the questionnaire. Among the responders, 89 (52.4%) were from Egypt and the central region, 60 (35.3%) were from North Africa and 21 (12.4%) were from the Gulf region.While most participants considered a dedicated training 'necessary', only 43 oncologists (25.3%) received a formal training. Only 17 participants (10%) had a fertility clinic in their centre, 44 (25.9%) and 13 (7.6%) had to refer patients to other centres or other cities, respectively. A total of 96 oncologists (56.5%) did not have access to a fertility preservation service.Out of 147 responders, 79 (53.7%) offered fertility preservation only in patients presenting with early disease and 38 (25.9%) did not offer fertility preservation. In terms of proposed strategies, 50 responders (29.4%) offered embryo cryopreservation, 79 (46.5%) oocyte cryopreservation and 48 (28.2%) ovarian tissue cryopreservation.A large gap exists between international clinical practice guidelines and current practices of fertility preservation in Arab countries. Barriers to optimum service delivery include the lack of physician awareness/training, unavailability of some advanced techniques and a lack of dedicated fertility clinics within the cancer centres.

Noha Rashad,1 Mohamed Abdulla,2 Mohamed Farouk,3 Yasser Elkerm,4 Salem Eid Salem,5 Maha Yahia,5 Amr S Saad,6 Ahmed Hassan Abdel Aziz,6 Ghada Refaat,6 Ibrahim Awad,7 Maha ElNaggar,8 Khaled Kamal,6 Basel Refky,9 Mohamed Abdelkhalek,9 Ahmed Touny,10 Loay Kassem,2 Emad Shash,5 Abdelhay A Abdelhay,11 Bahaa Eldin Mahmoud,11 Karima Oualla,12 Nesrine Chraiet,13 Hussein AwadElkarim H Maki,14 Yasser Abdel Kader2 1Medical Oncology Department, Faculty of Medicine, Suez University, Suez, Egypt; 2Clinical Oncology and Nuclear Medicine Department, Kasr Al-Aini Medical School, Cairo University, Cairo, Egypt; 3Department of Clinical Oncology, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 4Department of Cancer Management and Research, Medical Research Institute Hospital, University of Alexandria, Alexandria, Egypt; 5Department of Medical Oncology, National Cancer Institute (NCI), Cairo University, Cairo, Egypt; 6Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 7Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 8Clinical Oncology Department, Assiut University Hospital, Assiut, Egypt; 9Department of Surgical Oncology, Oncology Center Mansoura University, Mansoura, Egypt; 10Department of Surgical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt; 11Department of Diagnostic Radiology, Cairo University, Giza, Egypt; 12Medical Oncology Department, Hassan II University Hospital Sidi Mohamed Ben Abdellah University, Fes, Morocco; 13Medical Oncology Department, Salah Azaiez National Cancer Institute, Tunis, Tunisia; 14Clinical Oncology Department, Ahfad University for Women, Khartoum, SudanCorrespondence: Noha Rashad, Medical Oncology Department, Faculty of Medicine, Suez University, Faisal, Suez Governorate, Egypt, Tel +20 1225157339, Email Noha16880@gmail.comPurpose: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the second cause of cancer related mortality. Treatment options for patients with metastatic CRC (mCRC) expanded during the last two decades, with introduction of new chemotherapeutic and targeted agents. Egypt is a lower middle-income country; Egyptian health care system is fragmented with wide diversity in drug availability and reimbursement policies across different health care providing facilities. We report the results of consensus recommendations for treatment of patients with metastatic colorectal cancer developed by Egyptian Foundation of Medical Sciences (EFMS), aiming to harmonize clinical practice through structured expert consensus-based recommendations consistent with the national status. EFMS recommendations could be utilized in other countries with similar economic status.Methods: EFMS recommendations were developed using a modified Delphi process, with three rounds of voting till the final recommendations were approved. A non-systematic review of literature was conducted before generating the provisional statements. Content experts were asked to vote on some recommendations in two different resource groups (restricted resources and non-restricted resources). External review board of experts from a low income and lower-middle countries voted on the applicability of EFMS recommendations in their countries.Results: The current recommendations highlighted the discrepancy in health care between restricted and non-restricted resources with expected survival loss and quality of life deterioration. Access to targeted agents in first line is very limited in governmental institutions, and no access to agents approved for third line in patients who failed oxaliplatin and irinotecan containing regimens for patients treated in restricted resource settings.Conclusion: Management of mCRC in developing countries is a challenge. The currently available resource-stratified guidelines developed by international cancer societies represent a valuable decision-making tool, adaptation to national status in each country based on healthcare system status is required.Keywords: colorectal cancer CRC, consensus recommendations, metastatic CRC, management in a lower-middle income country

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.

Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ERα-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylERα/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. Methods The interaction of ERα/Src and ERα/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ERα+ and 3 ERα− PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ERα/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ERα/Src and ERα/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ERα+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ERα/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ERα signaling, since genomic degradation of ERα was unaltered in these tumors, whereas the treatment did not diminish the level of ERα/PI3K interaction. Interestingly, in 2 ERα− models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ERα/PI3K interaction. Conclusions Our results demonstrate that ERα/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ERα+ tumors was associated with a lack of impairment of ERα/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ERα/PI3K in ERα− tumors could constitute a promising therapeutic option.

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.

Additional file 10: Figure S7. Proximity ligation assay (PLA) was performed on treated BC1111 tumors embedded in paraffin to study the interactions between ERα and PI3K. IHC staining was performed on the same PDX tumors using anti-ERα, P-AKT (S473) and anti-P-S6 riboprotein (S235/6) antibodies.

Additional file 4: Figure S1. Effect of PI3kinase inhibitors on ERα/PI3K dimer formation. A. Oestrogen-deprived MCF-7 cells treated or not with PI3K inhibitors LY294002, BYL219, GDC-0032 and GDC-0941 (5 μM) 15 min before E2 treatment were incubated with E2 (10-8 M) for 5 min (see Additional supplementary methods). After fixation, in situ PLA for ERα/PI3K was performed. The detected dimers are represented by red dots. The nuclei were counterstained with DAPI (blue) (Obj:X63). B. Quantification of the number of dots per cell was performed using image J software and an automated analysis (see Additional supplementary methods). P value: ***

Additional file 8: Figure S5. Proximity ligation assay (PLA) was performed on treated HBCx-86 tumours embedded in paraffin to study the interactions between ERα and PI3K. IHC staining was performed on the same PDX tumours using anti-ERα, P-AKT (S473) and anti-P-S6 riboprotein (S235/6) antibodies.

Additional file 7: Figure S4. Proximity ligation assay (PLA) was performed on treated HBCx-3 tumours embedded in paraffin to study the interactions between ERα and PI3K. IHC staining was performed on the same PDX tumours using anti-ERα, P-AKT (S473) and anti-P-S6 riboprotein (S235/6) antibodies.

Additional file 5: Figure S2. IHC staining was performed on formalin-fixed paraffin-embedded BC1111 PDX tumor using anti-PTEN antibody.

Additional file 2: Table S1. Baseline characteristics for the patients included in the TMA study.

Additional file 9: Figure S6. Proximity ligation assay (PLA) was performed on treated HBCx-22 TamR tumours embedded in paraffin to study the interactions between ERα and PI3K. IHC staining was performed on the same PDX tumours using anti-ERα, P-AKT (S473) and anti-P-S6 riboprotein (S235/6) antibodies.

Additional file 6: Figure S3. Proximity ligation assay (PLA) was performed on treated HBCx-34 tumors embedded in paraffin to study the interactions between ERα and PI3K. IHC staining was performed on the same tumors using anti-ERα, P-AKT (S473) and anti-P-S6 riboprotein (S235/6) antibodies.

Background Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer (BC) patient survival, although 40% of ERα-positive BCs do not respond to those therapies. Aside from genomic signalling, oestrogen triggers non-genomic pathways by forming a complex containing methylERα/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumour response in vivo.Methods The interaction of ERα/Src and ERα/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analysed their anti-proliferative effects on 6 ERα + and 3 ERα- PDX models. Genomic and non-genomic oestrogen signalling were assessed by measuring ERα/PI3K interaction by PLA or the expression of key oestrogen target genes by RT-QPCR, respectively.Results We confirmed that ERα/Src and especially ERα/PI3K interaction were associated with a trend to poorer survival. In ERα + tumours, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status or ERα/PI3K targeting. Interestingly, in some ERα- models, fulvestrant alone impacted tumour growth and this was associated with a decrease in ERα/PI3K interaction.Conclusions Our results demonstrate that ERα/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant was clearly associated with a lack of ERα/PI3K targeting in the cytoplasm.

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.

Additional file 3. : Study of ERα binding to PR regulatory sequences.

Additional file 2. : List of the primers used for Chip-qPCR.

Additional file 1. : List of the primers used for RT-PCR experiments.

Additional file 4. : Effect of ERK inhibitor on PR phosphorylation.

Additional file 5. : ERα-36 regulates PR transcriptional activity.

Additional file 7. : Study of PR/ERα interaction.

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.