Publications by authors named "Dahish Ajarim"

42 Publications

Trastuzumab, Pertuzumab, and Docetaxel as the First Line for HER-2-Positive Metastatic Breast Cancer among Arabs.

Breast Care (Basel) 2021 Feb 6;16(1):59-65. Epub 2020 Apr 6.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Introduction: Human epidermal growth factor receptor 2 (HER-2) targeted therapy regimens can improve tumor response in HER-2-positive metastatic breast cancer (MBC), with overall survival benefits.

Objective: We evaluated the efficacy of dual HER-2 blockade combined with chemotherapy for HER-2-positive MBC patients as a first-line therapy in our patient population.

Patients And Methods: We identified 75 patients at King Faisal Specialist Hospital and Research Center that received trastuzumab, pertuzumab, and docetaxel as a first-line therapy in HER-2 positive MBC in 2013-2016.

Results: Median age at diagnosis was 45 years; 54.7% were estrogen receptor (ER)-positive. 10% of patients presented with only bone metastasis. The median follow-up time was 36 months with an objective response rate of 74.7% (complete response [CR] 18.7%; partial response [PR] 56%). The 5-year progression-free survival (PFS) and overall survival (OS) were 21% and 71.9% respectively, with a median PFS of 36 months (95% confidence interval [CI] 23.6-48.4). The 5-year OS for ER-negative and ER-positive patients was 93.9% and 59.4% respectively ( = 0.189); 23 patients experienced grade 1/2 toxicity and 2 patients had grade 3/4 toxicity. In terms of OS and PFS, the site of metastasis did not make any significant difference.

Conclusions: First line pertuzumab, trastuzumab, and docetaxel for HER-2-positive MBC patients was found to be an effective and safe therapy in the Saudi population. This finding was consistent with the results seen in the CLEOPATRA trials.
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http://dx.doi.org/10.1159/000506824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923938PMC
February 2021

Impact of Pathologic Complete Response following Neoadjuvant Chemotherapy ± Trastuzumab in Locally Advanced Breast Cancer.

J Oncol 2021 12;2021:6639763. Epub 2021 Feb 12.

Medical Oncology Section, Oncology Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11564, Saudi Arabia.

Purpose: This study was designed to examine the relationship between breast cancer molecular subtypes and pathological response to neoadjuvant chemotherapy (NAC) ± trastuzumab, in locally advanced breast cancer (LABC).

Methods: Female patients with LABC (T2-T4, N0-N2, and M0) who received neoadjuvant chemotherapy + trastuzumab if HER2+ subtype, followed by surgery and radiotherapy ± hormonal therapy, were identified. The primary endpoint was pathologic complete response (pCR) in the breast and axilla (ypT0/ypN0), with final analysis on disease-free survival (DFS) and overall survival (OS).

Results: Six hundred eighty-one patients with a median age of 44 years, premenopausal: 70%, median tumour size: 7.0 cm (range 4-11 cm), stage II B: 27% and III A/III B: 73%, ER+/HER2-: 40.8%, ER-/HER2-: 23%, ER+/HER2+: 17.7%, and ER-/HER2+: 18.5%. Overall pCR (ypT0/ypN0) was 23%. The pCR rates based on molecular subtypes were ER+/HER2-: 9%; ER+/HER2+: 29%; ER-/HER2-: 31%; and ER-/HER2+: 37%. At median follow-up of 61 months, ER+/HER2+ and ER+/HER2- subtypes had the best 5-year DFS and OS; meanwhile, ER-/HER2+ and ER-/HER2- subtypes had the worst.

Conclusion: Women with ER+/HER2- disease are the least likely to achieve pCR, with the highest rates in HER2+ and triple-negative subgroups. Degree of response is associated with OS; despite the comparatively higher likelihood of achieving pCR in ER-/HER2+ and triple-negative, these subgroups experience a survival detriment. We are consistent with the published data that patients who attain the pathological complete response defined as ypT0/ypN0 have improved outcomes.
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http://dx.doi.org/10.1155/2021/6639763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895557PMC
February 2021

Single-Institute Review of HER-2/Neu-Positive Invasive Lobular Breast Carcinoma in an Arab Population.

Am J Case Rep 2021 Feb 5;22:e928012. Epub 2021 Feb 5.

Section Medical Oncology, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

BACKGROUND Invasive lobular carcinoma is special subtype of breast cancer that has clinical behavior and morphology distinct from other breast cancer subtypes. It accounts for 5-15% of breast cancer. Overall, HER-2 gene amplification occurs at a significantly lower rate in ILC, but also has been linked to adverse outcomes. Most cases of ILCs with HER-2 overexpression and or amplification generally have the pleomorphic variant. We report the first series of cases from Saudi Arabia for this rare cancer in an Arab population. CASE REPORT Nine patients retrospectively were evaluated with HER-2/neu-positive ILC of the breast that were diagnosed and managed from 2003 to 2020. Four patients were diagnosed as early breast cancer, 3 had metastatic disease and 2 were locally advanced at their initial presentation. The mean age was 58 years; 30% were classic ILC and another 60% were of mixed non-classic variants (histologic pattern represented by nuclear pleomorphism). Management of patients with HER-2-positive ILC was performed according to standard multimodality breast cancer guidelines, consisting of surgery, chemotherapy with anti-HER-2/neu blockade, radiation, and endocrine therapy, based on stage and hormone status. CONCLUSIONS In conclusion, HER-2-positive invasive lobular carcinoma of the breast is uncommon in the Arab population, which has not been previously reported in the literature. Further studies are warranted to explore the biology, molecular characteristics, and clinical course in this group of patients.
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http://dx.doi.org/10.12659/AJCR.928012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872945PMC
February 2021

PD-L1 Protein Expression in Middle Eastern Breast Cancer Predicts Favorable Outcome in Triple-Negative Breast Cancer.

Cells 2021 Jan 25;10(2). Epub 2021 Jan 25.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211, Saudi Arabia.

Programmed cell-death ligand 1 (PD-L1) has been shown to induce potent T-cell mediated anti-tumoral immunity. The significance of PD-L1 expression in the prognosis of breast cancer (BC) remains controversial and its prevalence and prognostic value in breast cancer from Middle Eastern ethnicity is lacking. A total of 1003 unselected Middle Eastern breast cancers were analyzed for PD-L1 expression using immunohistochemistry. PD-L1 expression, seen in 32.8% (329/1003) of cases, was significantly associated with poor prognostic indicators such as younger patients, high-grade tumors, estrogen-receptor (ER)-negative, progesterone-receptor (PR)-negative, and triple-negative breast cancers (TNBC) as well as high Ki-67 index. We also found a significant association between PD-L1 expression and deficient mismatch repair protein expression. No association was found between PD-L1 expression and clinical outcome. However, on further subgroup analysis, PD-L1 expression was found to be an independent marker for favorable overall survival and recurrence-free survival in TNBC. In conclusion, we demonstrated strong association between PD-L1 and mismatch repair deficiency in Middle Eastern BC patients and that PD-L1 overexpression in tumor cells was an independent prognostic marker in TNBCs from Middle Eastern ethnicity. Overall, these findings might help in the development of more appropriate treatment strategies for BC in Middle Eastern population.
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http://dx.doi.org/10.3390/cells10020229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910988PMC
January 2021

Does the Timing of Surgery after Neoadjuvant Therapy in Breast Cancer Patients Affect the Outcome?

Oncology 2020 9;98(3):168-173. Epub 2020 Jan 9.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background: There is a paucity of literature examining the impact of timing of surgery after neoadjuvant chemotherapy.

Objective: This study aimed to analyze the impact of the time taken to initiate surgical treatment following completion of neoadjuvant chemotherapy on patients' outcomes by evaluating their pathological response, overall survival (OS), and disease-free survival (DFS).

Methods: This is a retrospective review of 611 patients diagnosed with stage II and III breast cancer that received neoadjuvant chemotherapy and surgery between January 2004 and December 2014. The data was collected from a prospectively gathered registry. The patients were stratified into three cohorts according to the time of surgery after neoadjuvant chemotherapy: <4 weeks, 4-7 weeks, or ≥8 weeks. Outcomes were assessed using Kaplan-Meier curves, and the variables were compared using log-rank statistics.

Results: The 5-year OS rate was 89.6% and the 5-year DFS rate was 74%. OS and DFS were not significantly different when stratified according to timing of surgery; however, the trends of OS and DFS were poor when surgery was delayed for ≥8 weeks. Median OS and median DFS have not yet been reached. Of the 17% of patients that had surgery after ≥8 weeks, 12.9% had pathological complete response (pCR), while among those that received surgery 4-7 weeks and <4 weeks after neoadjuvant chemotherapy, 26% and 21% had pCR, respectively (p = 0.02). ER+/HER-2+ patients had a statistically significant decrease in pCR if surgery was performed after ≥8 weeks.

Conclusion: Our patients showed improved pCR if surgery was performed within 8 weeks, especially for ER+/HER-2+ patients. All patients had better OS and DFS trends if surgery was performed between 4 and 7 weeks after neoadjuvant chemotherapy.
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http://dx.doi.org/10.1159/000504964DOI Listing
March 2020

Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population.

Genomics 2020 03 31;112(2):1746-1753. Epub 2019 Oct 31.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia. Electronic address:

Sanger Sequencing and immunohistochemistry was employed to investigate the TERT promoter mutations and TERT protein expression with their association to clinicopathological characteristics in over 2200 samples of Middle Eastern origin from 13 different types of cancers. The TERT promoter mutations were most frequently present in bladder cancer (68.6%), followed by central nervous system tumors (28.7%), thyroid cancer (15.4%), prostate cancer (9.3%), endometrial carcinoma (3.7%), rhabdomyosarcoma (1.4%), colorectal cancer (1%), epithelial ovarian carcinoma (0.7%) and breast cancer (0.7%). No mutations were observed in other types of cancers. In bladder cancer, we found significant inverse association with metastasis and a trend to good survival in patients with TERT mutations. In gliomas, TERT promoter mutations predicted poor prognosis. In thyroid cancer, high frequency of TERT mutation was observed in poorly differentiated carcinoma. In addition, TERT promoter mutations were associated with aggressive markers and poor outcome in follicular thyroid carcinomas.
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http://dx.doi.org/10.1016/j.ygeno.2019.09.017DOI Listing
March 2020

Behavior and Outcomes of Pregnancy Associated Breast Cancer

Asian Pac J Cancer Prev 2019 Jan 25;20(1):135-138. Epub 2019 Jan 25.

Section Medical Oncology, Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Email:

Introduction: Pregnancy Associated Breast cancer (PABC) is associated with poor prognosis and a decreased overall survival. A retrospective review was conducted to review the experience and outcome in a tertiary care hospital, and to compare those seen in a matched group for year of diagnosis. Materials and Methods: This is a retrospective review of a prospectively collected breast cancer registry. The study was conducted in a tertiary care hospital in Riyadh, Saudi Arabia from January to Decamber 2014 . Female patients with PABC were identified and matched with similar cohort of non-pregnant breast cancer patients that were diagnosed between 2001-2010. Clinical data including age, tumor biology, clinical stage, follow up and outcomes (disease free survival, DFS) were analyzed and compared between the two groups using SAS 9.3 and R-2.14.1 Results: A total of 110 patients in Group 1 and 114 patients in Group II were analyzed. In both groups, the patient age ranged was between 20 to 45 years; the median follow up was 34 months in PABC and 54 months in non-pregnant cohort. PABC were statistically more likely to be triple negative (p value-0.05) and diagnosed at advanced stage (stage 3 and 4) (p value-0.02). There was no difference in the occurrence of Her-2 positive disease. In pregnant patients there was a 5-year survival rate of 65% compared to non-pregnant cohort of 82% with p value of 0.002 and DFS was also 47.5% versus 65.4% with a p value .002 which is statistically significant. Conclusion: Pregnancy associated breast cancer (PABC) is diagnosed at a more advanced stage and tends to be triple negative and they are associated with a worse DFS and overall survival. Early detection during pregnancy may improve outcome.
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http://dx.doi.org/10.31557/APJCP.2019.20.1.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485574PMC
January 2019

Overexpression of PARP is an independent prognostic marker for poor survival in Middle Eastern breast cancer and its inhibition can be enhanced with embelin co-treatment.

Oncotarget 2018 Dec 18;9(99):37319-37332. Epub 2018 Dec 18.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Patients with aggressive breast cancer (BC) subtypes usually don't have favorable prognosis despite the improvement in treatment modalities. These cancers still remain a major cause of morbidity and mortality in females. This has fostered a major effort to discover actionable molecular targets to treat these patients. Poly ADP ribose polymerase (PARP) is one of these molecular targets that are under comprehensive investigation for treatment of such tumors. However, its role in the pathogenesis of BC from Middle Eastern ethnicity has not yet been explored. Therefore, we examined the expression of PARP protein in a large cohort of over 1000 Middle Eastern BC cases by immunohistochemistry. Correlation with clinico-pathological parameters were performed. Nuclear PARP overexpression was observed in 44.7% of all BC cases and was significantly associated with aggressive clinico-pathological markers. Interestingly, nuclear PARP overexpression was an independent predictor of poor prognosis. PARP overexpression was also directly associated with XIAP overexpression, with PARP and XIAP co-expression in 15.8% (159/1008) of our cases. We showed that combined inhibition of PARP by olaparib and XIAP by embelin significantly and synergistically inhibited cell growth and induced apoptosis in BC cell lines. Finally, co-treatment of olaparib and embelin regressed BC xenograft tumor growth in nude mice. Our results revealed the role of PARP in Middle Eastern BC pathogenesis and prognosis. Furthermore, our data support the potential clinical development of combined inhibition of PARP and XIAP, which eventually could extend the utility of olaparib beyond BRCA deficient cancer.
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http://dx.doi.org/10.18632/oncotarget.26470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324669PMC
December 2018

FoxM1 is an independent poor prognostic marker and therapeutic target for advanced Middle Eastern breast cancer.

Oncotarget 2018 Apr 3;9(25):17466-17482. Epub 2018 Apr 3.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Breast cancer (BC) is the most common cause of cancer-related death in females in Saudi Arabia. BC in Saudi women tend to behave more aggressively than breast cancer in the West. Therefore, identification of new molecular targets and treatment strategies are highly warranted to improve patient outcome. FoxM1 has been shown to play a critical role in pathogenesis of various malignancies. In this study, we explored the prevalence and clinical implication of FoxM1 overexpression in Saudi breast cancer. FoxM1 protein overexpression was seen in 79% (770/975) of BC tissues and was associated with aggressive clinical parameters such as younger age (< 30 yrs) ( = 0.0172), high grade ( < 0.0001), mucinous histology ( < 0.0001) and triple negative phenotype ( < 0.0001). Overexpression of FoxM1 was significantly associated with activated AKT ( < 0.0001), Ki67 expression ( < 0.0001), VEGF ( < 0.0001), MMP-9 ( < 0.0001), XIAP ( < 0.0001) and Bcl-xL ( = 0.0300). Importantly, FoxM1 overexpression is found to be an independent prognostic marker in multivariate analysis in advanced stage (Stage III and IV) breast cancer ( = 0.0298). data using BC cell lines showed that down-regulation of FoxM1 using specific inhibitor, thiostrepton or siRNA inhibited cell migration, invasion and angiogenesis. In addition, treatment of BC cell lines with thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. , thiostrepton treatment regressed MDA-MB-231 cells generated xenografts via down-regulation of FoxM1 and its downstream targets. Our results suggest that FoxM1 may be a potential therapeutic target for the treatment of aggressive breast cancers.
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http://dx.doi.org/10.18632/oncotarget.24739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915129PMC
April 2018

Expanding the spectrum of germline variants in cancer.

Hum Genet 2017 11 3;136(11-12):1431-1444. Epub 2017 Oct 3.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.
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http://dx.doi.org/10.1007/s00439-017-1845-0DOI Listing
November 2017

XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis.

BMC Cancer 2017 Sep 11;17(1):640. Epub 2017 Sep 11.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Cancer, MBC#98-16, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Background: Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored.

Methods: We examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors.

Results: XIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo.

Conclusion: These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.
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http://dx.doi.org/10.1186/s12885-017-3627-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594504PMC
September 2017

Reply to "letter to the editor concerning the article-Impact of surgery on survival in stage IV breast cancer".

Breast J 2017 11 8;23(6):775. Epub 2017 May 8.

Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1111/tbj.12826DOI Listing
November 2017

Reply to "Letter to the Editor Concerning the Article-Impact of Surgery on Survival in Stage IV Breast Cancer".

Breast J 2017 01 31;23(1):119. Epub 2016 Oct 31.

Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1111/tbj.12701DOI Listing
January 2017

Impact of Surgery on Survival in Stage IV Breast Cancer.

Breast J 2016 Nov 26;22(6):678-682. Epub 2016 Aug 26.

Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

We aimed to assess retrospectively the survival outcome in patients with stage IV breast cancer who underwent surgery. In a retrospective, nonrandomized study of stage IV breast cancer patients diagnosed in a single institution between 2000 and 2012, we assessed patient's survival in the context of baseline characteristics. A total 678 patients with metastatic breast cancer were included; 412 (60.77%) underwent surgery for the primary tumor (Surgery group), and 266 (39%) did not underwent surgery for the primary tumor (Nonsurgery group), with a median follow-up of 41 months. Patients in the Surgery group had longer survival (41 versus 27 months, p < 0.0029). The 5-year survival rate for Surgery group was 34% compared with 14% for the Nonsurgery group. A multivariate analysis revealed surgery (p = 0.0003), large tumor size (p = 0.0195), ER-positive (p < 0.0001), and metastasis at presentation (p = 0.0032) were prognostic variables. Loco-regional surgery does confer a survival advantage in stage IV breast cancer, however, selection bias cannot be excluded, a well-designed and powerful randomized, controlled trial would be valuable to answer whether surgery can improve survival.
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http://dx.doi.org/10.1111/tbj.12662DOI Listing
November 2016

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

Int J Cancer 2016 09 3;139(5):1091-7. Epub 2016 May 3.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.
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http://dx.doi.org/10.1002/ijc.30143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111783PMC
September 2016

A multicenter prospective phase II trial of neoadjuvant epirubicin, cyclophosphamide, and 5-fluorouracil (FEC100) followed by cisplatin-docetaxel with or without trastuzumab in locally advanced breast cancer.

Cancer Chemother Pharmacol 2016 Jan 12;77(1):147-53. Epub 2015 Nov 12.

Oncology Centre, King Faisal Specialist Hospital and Research Centre, MBC 64, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Purpose: To evaluate the efficacy and safety profile of the (FEC100) followed by cisplatin/docetaxel with and without trastuzumab as primary chemotherapy for patients with locally advanced breast cancer (LABC).

Methods: Eighty patients with LABC (T2-T4, N0-N2, M0) were enrolled to receive 24 weeks of neoadjuvant chemotherapy using epirubicin, cyclophosphamide, and 5-fluorouracil (FEC100) followed by cisplatin and docetaxel, plus trastuzumab if HER2 positive. The primary endpoint was pathologic complete response (pCR) in breast and axilla in separate HER2-negative and HER2-positive cohort.

Results: Eighty patients were evaluable for analysis of which 51 were HER2 negative and 29 HER2 positive: median age: 43 years, premenopausal: 82%, median tumor size: 7.0 cm (4-10), stage IIB: 25% and IIIA/IIIB: 75%, both ER/PR positive: 56%, HER2 positive (3+) by IHC staining: 36%. Clinical complete response was seen in 48%, and clinical partial response was seen in 52%. Overall the pathologic complete response (pCR) was 36% in breast, 64 % in axilla, and 32% in both breast and axilla. Analysis of pCR in breast and axilla, as a function of the hormonal receptor (HR) and HER2, was as follows: HR(+)/HER2(-): 11%; HR(+)/HER(+): 56 %; HR(-)/HER2(-): 36%; HR(-)/HER2(+): 62%.

Conclusion: In this series of locally advanced breast cancer, the combination of (FEC100) followed by cisplatin/docetaxel with and without trastuzumab was very active obtaining an impressive rate of pCR, particularly in HER2-positive and triple negative disease, which merits further investigation.
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http://dx.doi.org/10.1007/s00280-015-2906-5DOI Listing
January 2016

ALK alteration is a frequent event in aggressive breast cancers.

Breast Cancer Res 2015 Sep 17;17:127. Epub 2015 Sep 17.

Department of Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Makkah Al Mukarramah Branch Road, Riyadh, 12713, Saudi Arabia.

Introduction: Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Anaplastic lymphoma kinase (ALK) gene has been found to be altered in several solid and hematologic tumors. We aimed to comprehensively study the prevalence of ALK expression, and changes in copy number and translocation in a large cohort of breast cancer cases in a Middle Eastern population.

Methods: ALK protein expression was investigated by immunohistochemistry and numerical and structural variations of the ALK gene were analyzed by fluorescence in situ hybridization (FISH) in a tissue microarray format in a cohort of more than 1000 Middle Eastern breast cancers. The data were correlated with clinicopathologic parameters and other important molecular biomarkers.

Results: Immunohistochemical analysis showed ALK overexpression in 36.0 % of the breast cancer patients and gene amplification was present in 13.3 % of cases, seen by FISH analyses. ALK overexpression was significantly associated with ALK gene amplification (p = 0.0031). ALK-overexpressing tumors showed significant association with high-grade tumors (p = 0.0039), ductal histologic subtype (p = 0.0076), triple-negative phenotype (p = 0.0034), and high Ki-67 (p = 0.0001) and p-AKT (p <0.0001).

Conclusions: Immunohistochemical analysis showed ALK is overexpressed in a substantial proportion of breast cancers and possibly plays a significant role in the aggressive behavior of this cancer. Gene amplification is hypothesized to be a possible cause for a significant proportion of this overexpression. Based on these findings, a potential role for an ALK inhibitor, as a therapeutic agent targeting aggressive subtypes of breast cancer, merits further investigation.
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http://dx.doi.org/10.1186/s13058-015-0610-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588266PMC
September 2015

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

Breast Cancer Res Treat 2015 Jun 16;151(3):541-53. Epub 2015 May 16.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211, Saudi Arabia,

PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.
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http://dx.doi.org/10.1007/s10549-015-3430-3DOI Listing
June 2015

Obesity is a significant risk factor for breast cancer in Arab women.

BMC Cancer 2014 Oct 29;14:788. Epub 2014 Oct 29.

Division of Clinical Epidemiology, Sidra Medical and Research Centre, Doha, Qatar.

Background: Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death amongst women worldwide. The risk factors of this disease are numerous, and their prevalence varies between racial and ethnic groups as well as geographical regions. Therefore, we sought to delineate the association of socio-demographic, reproductive and life-style related risk factors with breast cancer in the Arab population.

Methods: Unmatched case-control study was conducted in the kingdom of Saudi Arabia using 534 cases of histologically confirmed breast cancer and 638 controls. Controls were randomly selected from primary health care visits and were free of breast cancer. Unconditional logistic regression analysis was performed to estimate odds ratios (ORs) and to examine the predictive effect of each factor on risk for BC. All study participants were interviewed by trained interviewers at hospital (cases) or at primary health care centers (controls).

Results: A total of 1172 women were eligible for this study, of which 281 (24.0%) were aged ≤35 years, 22.9% illiterate, 43.6% employed, 89.5% married, and 38.1% were obese. Grade III tumors constituted 38.4% of cases. Tumor stage I was 7.5%; II, 50.7%; II, 30.9%; IV, 11.1%. We have shown strong association between breast cancer among Arab females and obesity (OR =2.29, 95% CI 1.68-3.13), positive family history of breast cancer (OR =2.31, 95% CI 1.60 - 3.32), the use of hormonal replacement therapy (OR =2.25, 95% CI 1.65 - 3.08), post-menopause (OR =1.72, 95% CI 1.25 - 2.38), lack of education (OR =9.09, 95% CI 5.88 - 14.29), and never breastfeed (OR =1.89, 95% CI 1.19 - 2.94).

Conclusion: These results indicate the presence of classical risk factors established in the western countries, and also some specific ones, which may result from genetic and/or environmental factors. Thereby, these findings will be of great value to establish adequate evidence-based awareness and preventative measures in the Arab world.
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http://dx.doi.org/10.1186/1471-2407-14-788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532295PMC
October 2014

Age-specific gene expression signatures for breast tumors and cross-species conserved potential cancer progression markers in young women.

PLoS One 2013 21;8(5):e63204. Epub 2013 May 21.

Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross-species analysis may provide robust biomarkers for the detection of disease progression in young women, and lead to more effective treatment strategies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063204PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660335PMC
December 2013

Role of nuclear factor-κB regulators TNFAIP3 and CARD11 in Middle Eastern diffuse large B-cell lymphoma.

Leuk Lymphoma 2012 Oct 18;53(10):1971-7. Epub 2012 Apr 18.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Aberrant nuclear factor-κB (NF-κB) regulation has been observed in many hematopoietic malignancies including diffuse large B-cell lymphoma (DLBCL). Considering the potential therapeutic utility of targeting NF-κB and its key modulators, we studied genetic alterations (mutations and amplifications) in TNFAIP3 and CARD11 genes in DLBCL samples. The incidence of CARD11 and TNFAIP3 mutations was 10.7% and 4.6%, respectively. Interestingly, CARD11 amplification was seen in a significant proportion of cases of DLBCL (23%) and was linked to NF-κB activation (p = 0.0142). Immunohistochemical analysis of DLBCL samples showed CARD11 overexpression and loss of TNFAIP3 in 17.7% (32/181) and 13.5% (24/178), respectively. Poor overall survival was noted in DLBCL harboring CARD11 gene amplification (p = 0.0491). Our study reports the incidence of TNFAIP3 and CARD11 alterations in Saudi DLBCL, a potentially unique ethnic group, and highlights for the first time the role of CARD11 gene amplification as a novel mechanism for NF-κB activation in Middle Eastern DLBCL.
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http://dx.doi.org/10.3109/10428194.2012.668286DOI Listing
October 2012

Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules.

PLoS One 2011 4;6(11):e27339. Epub 2011 Nov 4.

Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined. We have used variety of immunological and functional assays to study whether fascin regulates breast cancer metastasis-associated molecules. In this report we found a direct relationship between fascin expression in breast cancer patients and; metastasis and shorter disease-free survival. Most importantly, in vitro interference with fascin expression by loss or gain of function demonstrates a central role for this protein in regulating the cell morphology, migration and invasion potential. Our results show that fascin regulation of invasion is mediated via modulating several metastasis-associated genes. We show for the first time that fascin down-regulates the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). In addition, fascin up-regulates NF-kappa B activity, which is essential for metastasis. Importantly, fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9. This study demonstrates that fascin expression in breast cancer cells establishes a gene expression profile consistent with metastatic tumors and offers a potential therapeutic intervention in metastatic breast cancer treatment through fascin targeting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0027339PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208623PMC
March 2012

The biological and clinical impact of inhibition of NF-κB-initiated apoptosis in diffuse large B cell lymphoma (DLBCL).

J Pathol 2011 Jul 19;224(3):355-66. Epub 2011 Apr 19.

Human Cancer Genomic Research, Research Center, King Fahad National Center for Children's Cancer, Riyadh, Saudi Arabia.

NF-κB is frequently over-expressed in a variety of non-Hodgkin's lymphomas (NHLs) and has been implicated in lymphomagenesis; however, its role in diffuse large B cell lymphoma (DLBCL) as a prognostic biomarker has not been fully elucidated. Therefore, we investigated the role of NF-κB and its association with clinicopathological features in a tissue microarray cohort of 230 DLBCL patient samples. We then elucidated the role of NF-κB inhibition on cell viability and apoptosis in vitro, using DLBCL cell lines. Using immunohistochemistry, NF-κB was detected in 25.6% (52/203) DLBCL tumours, was associated with activated B cell (ABC) phenotype (p = 0.0054), Epstein-Barr virus (EBV; p = 0.0080) and over-expression of the anti-apoptotic marker XIAP (p = 0.0013). DLBCL cases with nuclear expression of NF-κB showed a significantly poorer overall survival as compared to those without NF-κB expression (p = 0.0236). In a multivariate analysis using a Cox proportional hazard model for IPI and NF-κB expression, the relative risk was 2.97 for high NF-κB expression (95% CI 1.27-6.94; p = 0.0113) and 7.55 for the high-IPI group (95% CI 3.34-18.35; p < 0.0001). In vitro, Bay 11-7085 inhibited constitutively active NF-κB expression in a dose-dependent manner and inhibition of NF-κB also down-regulated expression of the downstream target gene products Bcl-2, Bcl-XL (BCL2L1), XIAP and Survivin, leading to apoptosis via activation of the mitochondrial apoptotic pathway. NF-κB over-expression was found to be an independent prognostic marker for poor survival in DLBCL. Altogether, these results suggest that NF-κB may be a useful prognostic biomarker and a potential target for therapeutic intervention in DLBCL.
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http://dx.doi.org/10.1002/path.2864DOI Listing
July 2011

Survey of utilization of multidisciplinary management tumor boards in Arab countries.

Breast 2011 Apr 12;20 Suppl 2:S70-4. Epub 2011 Feb 12.

Breast Center of Excellence, NK Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon.

Multidisciplinary management (MDM) of cancer patients provides better care and is recommended by all authorities and published guidelines. There is very little documentation of MDM practices in low and middle income countries. A survey of 338 practicing oncology specialists from various Arab countries was conducted at four major pan-Arab oncology conferences in the first half of 2010. While 72% of respondents reported having an MDM tumor board, only 49% reported that their tumor boards met on a weekly basis. Of those who do not have a tumor board, 57% attend a tumor board meeting at another hospital within their country. 60% of respondents attend tumor board meetings to seek group opinion and help in the management of their patients. 93% of physicians surveyed agreed that tumor boards should be mandatory. The vast majority of physicians agreed that in the absence of all specialties, "mini tumor boards" should be organized between available specialists at all hospitals that treat cancer patients.
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http://dx.doi.org/10.1016/j.breast.2011.01.011DOI Listing
April 2011

Clinico-pathological pattern of extranodal non-Hodgkin's lymphoma in Saudi Arabia.

Asian Pac J Cancer Prev 2011 ;12(12):3277-82

The Department of Medicine, King Saud University, Saudi Arabia.

Objectives: The incidence of primary extranodal non-Hodgkin's lymphoma (NHL) is variable in different regions of world but there is a paucity of literature on various demographic aspects of extranodal NHL as a group. This study was conducted to evaluate the clinico-pathological pattern of extranodal NHL in Saudi patients.

Methods: We retrospectively studied a cohort of 855 NHL patients in four tertiary care centres in Riyadh, Saudi Arabia over a period of 5 years.

Results: Extranodal NHL constituted 41.4% of the total. The mean age of affected patients was 55∓18 years and a male to female ratio of 1.5:1.0. Most presented in the age range of 41-60 years. NHL of gastro-intestinal (GI) tract was the most common extranodal variety, followed by head and neck NHL (18%), primary cutaneous lymphoma (14.4%), primary CNS lymphoma (5.6%), and primary bone, thyroid and soft tissue lymphoma (4.5% each). In the GI tract, stomach was the most common site involved, accounting for more than 81% of GI NHL. Diffuse large B-cell lymphoma was the most common histologic type, comprising around 72% of all extranodal lymphomas.

Conclusions: Extranodal NHL is common in Saudi Arabia and diffuse large B cell lymphoma is the most common histologic subtype. We found significant differences in the pattern of extranodal NHL in Saudi patients compared to those reported from other parts of the world. Further studies focused on the risk factors and treatment outcome are needed to better understand the biology of a disease common in this population.
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August 2012

Prognostic significance of XIAP expression in DLBCL and effect of its inhibition on AKT signalling.

J Pathol 2010 Oct;222(2):180-90

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

The inhibitor of apoptosis protein (IAP) family member X-linked inhibitor of apoptosis protein (XIAP) is essential for cell survival in lymphoma. However, the role of XIAP overexpression in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Therefore, we analysed the expression of XIAP protein and its clinicopathological correlation in a large cohort of DLBCLs by immunohistochemistry in a tissue micro-array format. XIAP was found to be overexpressed in 55% of DLBCLs and significantly associated with poor clinical outcome (p = 0.0421). To further elucidate the role of XIAP in DLBCL and the inter-relationship with PI3-kinase/AKT signalling, we conducted several in vitro studies using a panel of DLBCL cell lines. We found that pharmacological inhibition of XIAP led to caspase-dependent apoptosis in DLBCL cells. We also detected an inter-relationship between XIAP expression and activated AKT in DLBCL cells that may explain cellular resistance to PI3-kinase/AKT inhibition-mediated apoptosis. Finally, this anti-apoptotic effect was overcome by simultaneous pharmacological inhibition of XIAP and PI3-kinase/AKT signalling leading to a more potent synergistically induced apoptosis. In summary, our data suggest that XIAP expression is a poor prognostic factor in DLBCL and the XIAP-AKT relationship should be explored further as a potential therapeutic target in DLBCL.
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http://dx.doi.org/10.1002/path.2747DOI Listing
October 2010

Leptin receptor expression and its association with PI3K/AKT signaling pathway in diffuse large B-cell lymphoma.

Leuk Lymphoma 2010 Jul;51(7):1305-14

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

We investigated the role of the leptin receptor (Ob-R) and its relationship with PI3K/AKT activation in diffuse large B-cell lymphoma (DLBCL) clinical samples followed by in vitro studies using a panel of CRC cell lines. Leptin exerts its physiological action through its receptor Ob-R. Overexpression of Ob-R has been implicated in the pathogenesis of a variety of malignancies; however, its role in DLBCL has not been investigated. Using immunohistochemistry on a large cohort of DLBCL samples in a tissue microarray format, Ob-R immunostaining was detected in 86/216 (39.8%). Ob-R overexpression was associated with the catalytic subunit p110 of PI3K (p = 0.0283), activated AKT (p = 0.0003), and antiapoptotic marker XIAP (p = 0.0008) expression. In in vitro analysis using DLBCL cell lines, our data showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of the PI3K/AKT signaling pathway. Pretreatment of DLBCL cells with Ob-R specific small interference RNA or inactivation of PI3K/AKT activity by LY294002 abolished these responses. Altogether, these data suggest that leptin plays a critical role in DLBCL pathogesis through the P13K/AKT pathway via Ob-R.
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http://dx.doi.org/10.3109/10428191003802365DOI Listing
July 2010

Inhibition of fatty acid synthase suppresses c-Met receptor kinase and induces apoptosis in diffuse large B-cell lymphoma.

Mol Cancer Ther 2010 May 27;9(5):1244-55. Epub 2010 Apr 27.

Human Cancer Genomic Research, King Fahad National Center for Children's Cancer & Research, Research Center, Riyadh, Saudi Arabia.

Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we investigated the role of FASN in a large series of DLBCL tissues in a tissue microarray (TMA) format followed by in vitro studies using DLBCL cell lines. FASN was found to be expressed in 62.6% DLBCL samples and was seen in highly proliferative tumors, manifested by high Ki67 (P < 0.0001). Significant association was found between tumors expressing high FASN and c-Met tyrosine kinase (P < 0.0002), as well as p-AKT (P = 0.0309). In vitro, pharmacological FASN inhibition and small interference RNA (siRNA) targeted against FASN triggered caspase-dependent apoptosis and suppressed expression of c-Met kinase in DLBCL cell lines, which further highlighted the molecular link between FASN and c-Met kinase. Finally, simultaneous targeting of FASN and c-Met with specific chemical inhibitors induced a synergistically stimulated apoptotic response in DLBCL cell lines. These findings provide evidence that FASN, via c-Met tyrosine kinase, plays a critical role in the carcinogenesis of DLBCL and strongly suggest that targeting FASN may have therapeutic value in treatment of DLBCL.
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http://dx.doi.org/10.1158/1535-7163.MCT-09-1061DOI Listing
May 2010

Prospective phase II study of neoadjuvant doxorubicin followed by cisplatin/docetaxel in locally advanced breast cancer.

Med Oncol 2010 Sep 13;27(3):571-7. Epub 2009 Jun 13.

Department of Medical Oncology, King Faisal Specialist Hospital and Research Centre, Oncology Centre, MBC 64, P.O. Box 3354, Riyadh, 11211, Kingdom of Saudi Arabia.

The objective of this study is to evaluate the efficacy and safety profile of the doxorubicin followed by cisplatin/docetaxel as primary chemotherapy for patients with locally advanced breast cancer (LABC). For this evaluation, 59 patients with LABC (T2-T4, N0-N2, M0) received three cycles of doxorubicin, followed by three cycles of cisplatin/docetaxel and followed by definitive surgery and locoregional radiotherapy with or without tamoxifen. The primary end point was pathologic complete response (pCR) in breast and axilla. Fifty-nine patients were evaluable for analysis: median age: 41 years, premenopausal: 68%, median tumor size: 6.0 cm (4-10), Stage IIB: 32% and IIIA/IIIB: 68%, both ER/PR positive: 53%, Her2/neu (3+) by IHC staining: 29%. Clinical complete response was seen in 44%, and clinical partial response was seen in 56%. Breast conserving surgery was performed in 44%, and MRM in 56%. pCR in the breast was 30.5%, in axilla was 37%, and pCR in both breast and axilla was 24%. Overall at follow-up of 60 months, the disease-free (DFS) and overall survival (OS) were 70 and 82%, respectively. The DFS and OS of patients who achieved complete pathologic response in breast and axilla were 78 and 100%, respectively, while 14 patients relapsed of which 46% were Her2 positive. Sequential combination of doxorubicin followed by docetaxel/cisplatin is a safe, feasible, and active combination, which offers the possibility of conservative surgery and is associated with high clinical and pathologic response rates, with promising and encouraging survival outcomes.
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http://dx.doi.org/10.1007/s12032-009-9251-7DOI Listing
September 2010

Defective gammadelta T-cell function and granzyme B gene polymorphism in a cohort of newly diagnosed breast cancer patients.

Exp Hematol 2009 Jul 14;37(7):838-48. Epub 2009 May 14.

Histocompatibility and Immunogenetics, Riyadh, Saudi Arabia.

Objective: The purpose of this study was to examine the antitumor immune function of gammadelta T cells and to scan the granzyme B gene for the known single nucleotide polymorphism in breast cancer patients and normal controls.

Materials And Methods: Levels, cytotoxicity, and functional capacity of gammadelta T cells in peripheral blood mononuclear cells were assessed by flow cytometry, (51)Cr release, and ELISpot assays, respectively. Furthermore, sequence based typing was adopted to screen for granzyme B gene polymorphism.

Results: We have found that the frequency and function of gammadelta T cells are reduced both in peripheral blood mononuclear cells of 30 newly diagnosed breast cancer patients (2 [1.2, 3]), compared with 38 normal controls (3.2 [2.5, 5.7]) (p=0.02). In addition, resting gammadelta T cells from breast cancer patients produced significantly more interleukin-6 and tumor necrosis factor-alpha than normal controls. Moreover, ex vivo stimulation of gammadelta T cells with zoledronic acid and interleukin-2 compensated in part for this deficiency, as it stimulated the proliferation, cytokine production, and enhanced the expression of messenger RNA of granzyme B. Interestingly, when the known granzyme B gene polymorphism was screened, we found the prevalence of the mutated genotype RAH/RAH to be significantly (p<0.017) associated with breast cancer patients (14.30%) compared with normal donors (1.40%). Cytotoxicity exerted by gammadelta T cells on Daudi and MCF-7 was significantly higher in donors with the wild-type QPY/QPY (50%) compared with donors with RAH/RAH (21%).

Conclusions: Our data suggest that reduction in the proportion of gammadelta T cells and granzyme B gene polymorphism leads to defective immune function in breast cancer patients. Treatment with zoledronic acid amend partially this fault. Further studies of gammadelta T cells function and granzyme B gene polymorphism in cancers, as well as the potential therapeutic use of zoledronic acid are warranted.
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http://dx.doi.org/10.1016/j.exphem.2009.04.003DOI Listing
July 2009