Mohammad AM, Abdel HA, Abdel W, Ahmed AM, Wael T, Eiman G. Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. Indian J Cancer. 2006;43(4):163-8. Abstractn/a

BACKGROUND: A number of studies have shown over-expression of cox-2 in breast cancer. Also it has been recorded that human breast cancer expresses high level of cox-2 and 12-lipoxygenase which may be beneficial in future therapy plan for those patients.

AIMS: The present study aims to examine the level of transcripts of cox-2 and 12-lipoxygenase in Egyptian breast cancer patients and to compare between the expressions of both enzymes and TNM staging, hormone receptors status (including estrogen and progesterone) and HER2/neu expression.

MATERIALS AND METHODS: Total cellular RNA was extracted from 64 frozen tissue samples of breast carcinoma and their corresponding normal adjacent tissues. Cox-2 and 12-lipooxygenase expressions were detected using RT-PCR. Hormonal receptors as well as HER2/neu were detected immuno-histochemically for each patient.

RESULTS: About 47 and 62.5% of carcinoma samples showed over-expression of cox-2 and 12-lipooxygenase respectively as compared to their corresponding normal tissues. The results revealed that cox-2 significantly associated with TNM staging (P = 0.0047) and hormonal receptors status (P = 0.0201). The relationship between cox-2 and HER2/neu expression was close to a significant value (P = 0.0747). 12-lipooxygenase showed only significant association with TNM staging (P = 0.0076). Neither hormonal receptors nor HER2/neu showed significant association with this enzyme.

CONCLUSION: Elevated levels of cox-2 and 12-lipoxygenase expression were detected in human breast cancer. Also, the results revealed that cox-2 and 12-lipooxygenase mRNA expressions are associated with TNM staging in human breast cancer. Furthermore, there is an inverse association between cox-2 expression and hormonal receptor status. This observation may drive us to the possible role of those two enzymes in determining the plan of therapy of breast cancer patients.

Ibrahim E, Al-Gahmi AM, Zeenelin AA, Zekri JM, Elkhodary TR, Gaballa HE, et al. Basal vs. luminal A breast cancer subtypes: a matched case-control study using estrogen receptor, progesterone receptor, and HER-2 as surrogate markers. Med Oncol. 2009;26(3):372-8. Abstractn/a

Breast cancer is a heterogeneous disease that encompasses several distinct entities with different biological characteristics and clinical behavior. Basal subtype is considered as a prognostically unfavorable subset. The purpose of this study is to compare the clinico-pathological characteristics and outcome of basal vs. luminal A subtype, as approximated by ER, PR, and HER-2. Sixty-four patients with basal breast cancer were matched for age, stage, and year of diagnosis with 64 patients having luminal A disease. Basal tumors were immunohistochemically defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER-2, while luminal A cancers were ER+ or PR+, and HER-2-. As compared with luminal A, basal subtype patients had significantly larger primary tumor size, higher percentage of grade III tumor, more tumor that showed lymphovascular invasion, less presence of non-invasive disease, and higher proportion of extranodal extension. There was no statistically significant difference in metastatic sites, pathology type, or in the axillary lymph nodal status. A few patients received neoadjuvant chemotherapy--13 and 9 patients in basal and luminal A groups, respectively). The complete pathological response was 20% and 14%, respectively (not significant). At a median follow-up of approximately 2 years, there was no statistically significant difference in the overall survival rate between basal and luminal A patients. Analysis of disease-free survival (DFS) for stage I-III (53 patients in each group) showed that the median DFS for basal patients was 41.4 months (95% CI, 26.5-55.3 months), whereas the DFS for the luminal A patients was not reached (P = 0.014). After adjusting for several significant prognostics variables identified in a univariate analysis, a multivariate conditional logistic regression analysis identified the negative effect of lymphovascular invasion and the favorable influence of the use of neoadjuvant and/or adjuvant chemotherapy. This matched case-control study confirmed the poor clinical and pathological characteristics of patients with basal subtype and their unfavorable outcome compared with luminal A disease. Management of basal tumors remains a challenging task, and new therapeutic strategies are warranted.

Ibrahim EM, Zeeneldin AA, Al-Gahmi AM, Sallam YA, Fawzi EE, Bahadur YA. Safety and efficacy of cetuximab-chemotherapy combination in Saudi patients with metastatic colorectal cancer. Indian J Cancer. 2007;44(2):56-61. Abstractn/a

BACKGROUND: Cetuximab-based combination chemotherapy (CBCC) proved safe and effective as second-line strategy for metastatic colorectal cancer (mCRC). This prospective phase-II study was designed to assess the efficacy and safety of CBCC as first-, second- or third-line among Saudi patients with mCRC.

MATERIALS AND METHODS: Patients with mCRC were offered CBCC to assess time-to-disease progression (TTP), response rate and duration, overall survival (OS) and safety.

RESULTS: Nineteen patients were eligible and their median age was 51 years. Seven patients received CBCC as first-line and 12 as second- or third-line. Responses: 11 (58%) partial responses, 5 (26%) stable disease and 3 (16%) disease progressions. The median response duration was 4.3 months [95% confidence interval (CI): 3.4-5.2 months]. The median TTP was 6.8 months (95% CI: 2-13.9 months) for all 19 patients compared to 9.3 months (95% CI: 3.9-14.6 months) for the seven patients who received CBCC as first-line. The median OS for the entire population was 12.3 months (95% CI could not be determined). On the other hand, while the median OS for those who received CBCC as first-line have not been reached, the median OS for those who received CBCC after failure of other salvage therapies was 12.3 months (95% CI: 3.2-21.4 months). CBCC was generally tolerable. One patient had a severe hypersensitivity reaction and another fatal cardiac arrest.

CONCLUSION: CBCC is active with an acceptable safety profile. Until results from phase-III clinical trials are available, using CBCC as first-line is probably justified.

Ibrahim EM, Zeeneldin AA, Sadiq BB, Ezzat AA. The present and the future of breast cancer burden in the Kingdom of Saudi Arabia. Med Oncol. 2008;25(4):387-93. Abstractn/a

BACKGROUND: Despite the low cancer incidence in the Kingdom of Saudi Arabia (KSA), the country must be ready to face the challenge of foreseeable increase in cancer burden attributed to growth and aging of population. This work was designed to study female breast cancer as a model to assess future cancer burden and the impact on healthcare resources.

METHODS: Cancer statistics for the KSA were compared with that for the USA. The Joinpoint regression program was used to identify changes in secular trends, while the GLOBOCAN 2002 software projected future incidence and mortality.

RESULTS: In the KSA, the age-standardized cancer rate (ASR) is 61 per 100,000 population, while the median age at diagnosis is 54 and 49 years for men and women, respectively. Fitting the ASR for breast cancer did not show any significant trend over a 10-year calendar period (16.2-18.2 per 100,000), a pattern that was similar to that for the USA in the prescreening mammography era. Considering the growth and aging of population and using conservative estimates for the annual percent change in incidence (increase) and mortality (decrease) by 2025, incidence and mortality cases are expected to increase by about 350% and 160%, respectively.

CONCLUSION: In developing countries, future cancer rates could demonstrate a considerable increase and enormous demands on healthcare resources. The present work may provide an impetus to study other prevalent cancer types particularly in developing countries.

El-Zawahry HE, Zeeneldin AA, Samra MO, Mattar MM, El-Gammal MM, Abd El-Samee A, et al. Cost and outcome of treatment of adults with acute myeloid leukemia at the National Cancer Institute-Egypt. J Egypt Natl Canc Inst. 2007;19(2):106-13. Abstractn/a

BACKGROUND: Despite important advances in the therapy of acute myeloid leukemia (AML), the majority of patients die of their disease, unless bone marrow transplantation (BMT) is done. Infection and hemorrhage are still the major causes of mortality in AML patients. Progress in therapy and supportive care has led to gradual improvement in the overall results, but further improvements are still needed.

PATIENTS AND METHODS: The aim of this study is to identify the outcome and costs of adult AML patients treated with conventional chemotherapy (CCT) at the National Cancer Institute (NCI), Cairo University during the time period from April 1999 to January 2002. Clinical, laboratory characteristics were all recorded. Data regarding different types of therapies given for these patients including response, outcome and costs were also collected.

RESULTS: The median age of 82 identified AML patients was 34 years. The complete remission (CR) rate after induction with CCT was 52% (42/82 patients) with a median CR duration of 9 months. Twenty-eight percent of patients who achieved CR subsequently relapsed. By January 2003, fifty-eight patients were dead (70.7%). Infections were the major mortality cause, followed by disease progression then bleeding (65% , 28% and 7% respectively). The median treatment cost per patient was 33158 Egyptian Pounds (LE). It was higher for patients who achieved CR compared to those who relapsed and/or died. Drugs contributed by 78 % to the total treatment cost, while hospitalization, investigations and blood-component therapy contributed by 6%, 7% and 8% respectively.

CONCLUSIONS: Outcome of patients with AML treated at NCI- Cairo University can be enhanced by improvement of supportive therapy; mainly infection control and expanding BMT programs to accommodate all eligible patients.

Ibrahim EM, Al-Gahmi AM, Zekri JM, Awadalla SS, Elkhodary TR, Fawzy EE, et al. Pre-operative systemic therapy in locally advanced breast cancer: a single institution experience. Ecancermedicalscience. 2009;3:161. Abstractn/a

BACKGROUND: Locally advanced breast cancer (LABC) is common in developing countries and it frequently affects younger women. Patients do very poorly when treated by locoregional therapy alone; therefore, pre-operative systemic therapy (PST) is commonly used.

MATERIALS AND METHODS: Medical records of 64 Saudi patients with LABC treated with PST in a single institution were retrospectively reviewed.

RESULTS: At diagnosis, most patients were young (median age 41 years), and had poor clinicopathological characteristics. Following surgery, complete pathologic response (pCR) in the breast was achieved in 13 patients (20%). Of 62 patients with known nodal status, 22 (34%) had negative axillary nodes. Presence of oestrogen receptor (ER) negative tumour was the only dependent variable that predicted pCR in the breast (p = 0.03). At a median follow-up of 42 months, the median progression-free survival (PFS) was 48 months (95% CI, 20-76 months) and the projected five-year overall survival (OS) was 68%. The recently published scoring system (Jeruss et al (2008) J Clin Oncol26 2 246-52), was the only variable that independently influenced PFS, while ER negative tumours and presence of lymphovascular space invasion were the only factors that adversely affected OS.

CONCLUSIONS: despite the use of standard multi-modality approach in the management of patients with LABC, prognosis remains guarded.

Zeeneldin AA, Mohamed AM, Abdel HA, Taha FM, Goda IA, Abodeef WT. Survival effects of cyclooxygenase-2 and 12-lipooxygenase in Egyptian women with operable breast cancer. Indian J Cancer. 2009;46(1):54-60. Abstractn/a

BACKGROUND: Breast cancer (BC) is the commonest among women in Egypt as well as in many other countries. Cyclo-oxygenase-2 (COX-2) and 12-lipo-oxygenase (12-LOX) are over-expressed in 30-40% of patients and carry a poor prognosis. The objectives of this study were to correlate COX-2 and 12-LOX expression with various clinico-pathologic patients' characteristics and their impact on overall survival (OS) and disease free survival (DFS) in Egyptian women with operable BC.

MATERIALS AND METHODS: This prospective study included 57 consecutive BC cases presenting to the Egyptian National Cancer Institute. Sections from BC and nearby normal tissues were examined for expression of COX-2 and 12-LOX using reverse transcriptase polymerase chain reaction.

RESULTS: The patients' median age was 45 years. Fifty-three percent were premenopausal. Stage II and III disease represented 25 and 75% respectively. Adjuvant chemotherapy, radiotherapy and tamoxifen were used in 90, 75 and 60% respectively. Sixty percent had hormone-receptor positive tumors and 28% over-expressed HER2/neu. Forty-nine and sixty-five percent showed over-expression of COX-2 and 12-LOX respectively. Patients with higher TNM stage or who developed visceral metastases had significantly higher COX-2 expression. For the whole group of patients, the median DFS was 37 months, while the median OS was not reached. OS or DFS did not differ significantly between patients with normal and over-expression of COX-2. DFS but not OS was significantly higher in 12-LOX over-expression compared to normal expression.

CONCLUSION: COX-2 over-expression was associated with poor prognostic criteria in BC, but did not affect DFS or OS. 12-LOX over-expression was associated with better DFS, but not OS.

Ibrahim EM, Zeeneldin AA, El-Khodary TR, Al-Gahmi AM, Bin Sadiq BM. Past, present and future of colorectal cancer in the Kingdom of Saudi Arabia. Saudi J Gastroenterol. 2008;14(4):178-82. Abstractn/a

BACKGROUND/AIMS: The crude frequency of colorectal cancer (CRC) is second to breast cancer in the Kingdom of Saudi Arabia (KSA). To assess the future burden of CRC in the country, we designed a model that takes into consideration the recent lifestyle pattern and the growth and aging of the population.

METHODS: We compared CRC statistics for KSA (using data from the National Cancer Registry) with that from the Surveillance, Epidemiology and End Results (SEER) databases of the United States of America (USA). We used the Joinpoint regression program to identify changes in secular trends, while the GLOBOCAN 2002 software was used to project future incidence and mortality.

RESULTS: Between 1994 and 2003, age-standardized rates (ASRs) for CRC in KSA almost doubled, as compared to a nonsignificant decline in USA. Between 2001 and 2003, while the annual percent change (APC) of CRC incidence in the USA showed a nonsignificant decrease in females, APC in Saudi females showed a nonsignificant rise of six percent. On the other hand, the rising incidence among Saudi males, during the years 1999 to 2003, was significant, with an APC of 20.5%. The projection model suggested that the incidence of CRC in KSA could increase fourfold in both genders by the year 2030.

CONCLUSIONS: In KSA, the present and expected increase in CRC rates is alarming. Pragmatic recommendations to face that challenge are discussed. The present work could serve as a model to study other prevalent types of cancer, particularly in developing countries.

Taha FM, Zeeneldin AA, Helal AM, Gaber AA, Sallam YA, Ramadan H, et al. Prognostic value of serum vascular endothelial growth factor in Egyptian females with metastatic triple negative breast cancer. Clin Biochem. 2009;42(13-14):1420-6. Abstractn/a

OBJECTIVES: The aim of this work was to explore the value of serum vascular endothelial growth factor-A (VEGF-A) in patients with metastatic triple negative breast cancer (TNBC) treated with chemotherapy. The primary end point was overall survival (OS). Secondary end points were response rate (RR), progression-free survival (PFS) and VEGF-A level at baseline, mid-therapy and at the end of therapy.

DESIGN AND METHODS: Female patients aged 18 years or above with histologically proven metastatic TNBC were included. Serum VEFG-A levels were measured at baseline, after the 3rd and 6th cycles of FAC chemotherapy regimen (Fluorourcil, Adriamycin, and Cyclophamide).

RESULTS: The overall RR was 57%. The median PFS and OS were 7 and 11.2 months, respectively (95% CI: 4.3-9.7 and 3.8-18.5 months, respectively). Patients whose disease progressed despite therapy had a significantly higher baseline VEGF-A level than those who did not progress. VEGF-A level did not drop with continuation of therapy. Patients with high VEGF-A level had a significantly lower PFS but not OS than patients with low levels.

CONCLUSION: The outcome of metastatic TNBC is poor with FAC chemotherapy regimen. Alternative chemotherapeutic regimens and novel therapeutic approaches including targeting of VEGF and/or its receptors are warranted.

Zekri JM, Ibrahim E, Ben Sadiq B, Al-Gahmi AM, Zeeneldin AA, Elkhodary TR, et al. A matched group study of triple negative versus HER-2 positive (irrespective of hormonal status) breast cancer: two subtypes with high-risk features and poor outcome. Ecancermedicalscience. 2010;4:167. Abstractn/a

INTRODUCTION: Genetic profile studies of breast cancer identified a number of biologically different subtypes. These genetic subtypes are often surrogated by oestrogen receptors (ERs), progesterone receptors (PR) and HER2 status as measured by immunohistochemistry (IHC). Triple negative (TN) subtype is recognized to have high-risk features and poor outcome. Over-expression of the HER2 is also recognized as poor outcome marker. The characteristics and outcome of HER2 positive tumours (irrespective of hormonal status) (HER2 HR+/-) identified by IHC have not addressed in the era of surrogate genetic subtyping. Therefore, we retrospectively compared the risk features and clinical outcome of patients with TN against these with HER2 HR+/- tumours.

PATIENTS AND METHODS: Forty patients with HER2 HR+/- tumours were matched for age and stage to 40 patients with TN tumours. Clinical and pathological data were collected retrospectively. All patients were managed in a single institution.

RESULTS: Tumour grade and stage and rate of pathologically involved lymph nodes were similar in both groups. There was a trend of more lymphovascular invasion in HER2 HR+/- than TN patients (40% vs. 27.5%. p=0.07). Relapse and death rates were not statistically different (p=0.469 and p=1.0, respectively). Median relapse free survival was 38 months for TN and not reached for HER2 HR+/- patients (Log rank; p=0.757). Median overall survival was not reached in both groups. Multivariate analysis did not identify TN or HER2 HR+/- status to have any differential impact on RFS.

CONCLUSION: HER2 HR+/- tumours exhibit high risk, presenting features and relatively poor clinical outcome possibly not very different from the increasingly recognized TN tumour.