Sirwan M Hadad

Publications

• 4.70

  Impact points

  Evidence for biological effects of metformin in operable breast cancer: a pre-operative, window-of-opportunity, randomized trial.

  Sirwan Hadad, Takayuki Iwamoto, Lee Jordan, Colin Purdie, Susan Bray, Lee Baker, Gera Jellema, Steve Deharo, D Grahame Hardie, Lajos Pusztai, Stacy Moulder-Thompson, John A Dewar, Alastair M Thompson

  Breast cancer research and treatment. 06/2011; 128(3):783-94.

  Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer. Non-diabetic women with operable invasive breast cancer received pre-operative me... [more] Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer. Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of eight patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500-mg o.d. for 1 week increased to 1-g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin-fixed paraffin-embedded cores and serum insulin determination were performed blinded to treatment. Seven patients (7/32, 21.9%) receiving metformin withdrew because of gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the metformin arm (P = 0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly downregulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels that affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By ingenuity pathway analysis, the tumour necrosis factor receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB and MEKK were upregulated and cdc42 downregulated; mTOR and AMPK pathways were also affected. Gene set analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expression following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients. This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin.
• 2.74

  Impact points

  Histological evaluation of AMPK signalling in primary breast cancer.

  Sirwan Hadad, Lee Baker, Philip Quinlan, Katherine Robertson, Susan Bray, George Thomson, David Kellock, Lee Jordan, Colin Purdie, David Hardie, Stewart Fleming, Alastair Thompson

  BMC cancer. 09/2009; 9(1):307.

  ABSTRACT: BACKGROUND: AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, thus ensuring that energy-consuming processes proceed only if there are sufficient metabolic resources. Malfunction of the AMP... [more] ABSTRACT: BACKGROUND: AMP-activated protein kinase (AMPK) acts as a cellular fuel gauge that responds to energy stress by suppressing cell growth and biosynthetic processes, thus ensuring that energy-consuming processes proceed only if there are sufficient metabolic resources. Malfunction of the AMPK pathway may allow cancer cells to undergo uncontrolled proliferation irrespective of their molecular energy levels. The aim of this study was to examine the state of AMPK phosphorylation histologically in primary breast cancer in relation to clinical and pathological parameters. METHODS: Immunohistochemistry was performed using antibodies to phospho-AMPK (pAMPK), phospho-Acetyl Co-A Carboxylase (pACC) an established target for AMPK, HER2, ERalpha, and Ki67 on Tissue Micro-Array (TMA) slides of two cohorts of 117 and 237 primary breast cancers. The quick score method was used for scoring and patterns of protein expression were compared with clinical and pathological data, including a minimum 5 years follow up. RESULTS: Reduced signal, compared with the strong expression in normal breast epithelium, using a pAMPK antibody was demonstrated in 101/113 (89.4%) and 217/236 (91.9%) of two cohorts of patients. pACC was significantly associated with pAMPK expression (p=0.007 & p=0.014 respectively). For both cohorts, reduced pAMPK signal was significantly associated with higher histological grade (p=0.010 & p=0.021 respectively) and axillary node metastasis (p=0.061 & p=0.039 respectively). No significant association was found between pAMPK and any of HER2, ERalpha, or Ki67 expression, disease-free survival or overall survival. CONCLUSION: This study extends in vitro evidence through immunohistochemistry to confirm that AMPK is dysfunctional in primary breast cancer. Reduced signalling via the AMPK pathway, and the inverse relationship with histological grade and axillary node metastasis, suggests that AMPK re-activation could have therapeutic potential in breast cancer.
• 2.70

  Impact points

  Delay from symptom onset increases the conversion rate in laparoscopic cholecystectomy for acute cholecystitis.

  Sirwan M Hadad, Jayant S Vaidya, Lee Baker, Hoey C Koh, Timothy P Heron, Kashif Hussain, Alastair M Thompson

  World journal of surgery. 01/2009; 32(12):2747.
• 5.33

  Impact points

  A candidate molecular signature associated with tamoxifen failure in primary breast cancer.

  Julie Vendrell, Katherine Robertson, Patrice Ravel, Susan Bray, Agathe Bajard, Colin Purdie, Catherine Nguyen, Sirwan Hadad, Ivan Bieche, Sylvie Chabaud, Thomas Bachelot, Alastair Thompson, Pascale Cohen

  Breast cancer research : BCR. 11/2008; 10(5):R88.

  ABSTRACT: INTRODUCTION: Few markers are available to predict response to tamoxifen treatment in estrogen receptor positive (ER+) breast cancers. The identification of such markers would be clinically useful. The aim of this work was to identify molecular markers associated with tamoxifen failure in ... [more] ABSTRACT: INTRODUCTION: Few markers are available to predict response to tamoxifen treatment in estrogen receptor positive (ER+) breast cancers. The identification of such markers would be clinically useful. The aim of this work was to identify molecular markers associated with tamoxifen failure in breast cancer. METHODS: Eighteen initially ER+ patients treated with tamoxifen requiring salvage surgery (Tamoxifen Failures; TF) were compared with 17 patients disease free 5 years after surgery plus tamoxifen adjuvant therapy (Controls; C). cDNA microarray, RTQ-PCR and immunohistochemistry on tissue microarrays (TMA) were used to generate and confirm a gene signature associated with tamoxifen failure. An independent cohort of 33 breast tumor samples from patients who relapsed (R group; n=14) or not (NR group; n=19) under tamoxifen treatment from a different geographical location was subsequently used to explore the gene-expression signature identified. RESULTS: Using a screening set of 18 tumor samples (8 C and 10 TF), a 47-gene signature discriminating the TF and C samples was identified by cDNA-arrays. In addition to ESR1/ERa, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4 and BCL2 subsequently validated in a larger set of tumor samples (17 C and 18 TF). Confirmation at the protein level by TMA immunohistochemistry was observed for estrogen receptor alpha, gamma synuclein and IGFBP4 proteins on the 35 original samples. In an independent cohort of breast tumor samples (19 NR and 14 R), reduced expression of ESR1/ERa, IGFBP4, SNCG, BCL2 and FOS was observed in the R group, and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERa, BCL2 and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have a more accurate prognostic value for RFS than ESR1/ERa alone (likelihood ratio test). CONCLUSIONS: This study has identified molecular markers including a BCL2/FOS signature associated with the tamoxifen failure, and points to their clinical potential in the management of ER+ breast cancer.
• 5.27

  Impact points

  Targeting AMPK: A new therapeutic opportunity in breast cancer.

  Sirwan M Hadad, Stewart Fleming, Alastair M Thompson

  Critical reviews in oncology/hematology. 08/2008; 67(1):1-7.

  BACKGROUND: This paper reviews the mammalian Target Of Rapamycin (mTOR) pathway dysregulation in breast cancer, and the current evidence targeting this pathway directly or through activation of AMP-activated protein kinase (AMPK) as an additional therapeutic opportunity for intervention in breast ca... [more] BACKGROUND: This paper reviews the mammalian Target Of Rapamycin (mTOR) pathway dysregulation in breast cancer, and the current evidence targeting this pathway directly or through activation of AMP-activated protein kinase (AMPK) as an additional therapeutic opportunity for intervention in breast cancer. METHODS: Relevant articles were identified through computerised searches of Medline and Pubmed. Secondary articles were identified from the reference lists of key papers and by hand searching. RESULTS AND CONCLUSION: The current consensus to target the AMPK/mTOR pathway in breast cancer is based on in vitro and epidemiological evidences. A low incidence of cancer in diabetic patients on metformin has been explained in vitro by the drug's anti-proliferative effect through activation of AMPK. There is a need to explore the anticancer effects of metformin and the potential to develop the therapeutic avenues offered by targeting the AMPK/mTOR pathway.
• 4.70

  Impact points

  Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model.

  Sirwan Hadad, Virginia Appleyard, Alastair Thompson

  Breast cancer research and treatment. 05/2008;
• 2.70

  Impact points

  Delay from symptom onset increases the conversion rate in laparoscopic cholecystectomy for acute cholecystitis.

  Sirwan M Hadad, Jayant S Vaidya, Lee Baker, Hoey C Koh, Timothy P Heron, Alastair M Thompson

  World journal of surgery. 07/2007; 31(6):1298-01; discussion 1302-3.

  BACKGROUND: Randomized trials suggest that laparoscopic cholecystectomy should be performed on first admission for acute cholecystitis. However, this is not widely practiced, possibly because of a perceived high conversion rate. We hypothesized that delay from onset of symptoms may increase the conv... [more] BACKGROUND: Randomized trials suggest that laparoscopic cholecystectomy should be performed on first admission for acute cholecystitis. However, this is not widely practiced, possibly because of a perceived high conversion rate. We hypothesized that delay from onset of symptoms may increase the conversion rate. METHODS: We performed a retrospective case note review of patients undergoing emergency cholecystectomy in a single institution between January 2002 and December 2005. We analyzed whether delay from onset of symptoms was related to the conversion rate in patients with a histopathological diagnosis of acute cholecystitis. RESULTS: Of patients who underwent emergency laparoscopic cholecystectomy in our institution, 32.4% (197/608) had acute cholecystitis on histopathology. The conversion rate of those with acute cholecystitis was considerably higher (24.4%) than for those with other pathologies (6.3%). For patients with acute cholecystitis, the conversion rates increased with duration of symptoms: 9.5%, 16.1%, 38.9%, and 38.6% for delays of 0-2 days, 3-4 days, 5-6 days, and > 6 days from symptom onset, respectively (chi-square for trend = 14.27, DF = 1, p = 0.00016). Most conversions were due to the presence of acute inflammatory adhesions. CONCLUSIONS: Early intervention for acute cholecystitis (preferably within 2 days of onset of symptoms) is most likely to result in successful laparoscopic cholecystectomy; increasing delay is associated with conversion to open surgery.

• A candidate molecular signature associated with tamoxifen failure in primary breast cancer

  Julie A Vendrell, Katherine E Robertson, Patrice Ravel, Susan E Bray, Agathe Bajard, Colin A Purdie, Catherine Nguyen, Sirwan M Hadad, Ivan Bieche, Sylvie Chabaud, Thomas Bachelot, Alastair M Thompson, Pascale A Cohen

• Histological evaluation of AMPK signalling in primary breast cancer

  Sirwan M Hadad, Lee Baker, Philip R Quinlan, Katherine E Robertson, Susan E Bray, George Thomson, David Kellock, Lee B Jordan, Colin A Purdie, David G Hardie, Stewart Fleming, Alastair M Thompson