Breast cancer (referring to mammary carcinoma, not mammary sarcoma) is an extremely common malignancy, affecting one in eight women during their lifetime. In fact, in women, 32% of all cancers arise in the breast, but they only account for 18% of cancer deaths. Designating an individual as high risk for breast cancer depends primarily on a positive family history. In addition, ethnic origin is also related to cancer risk.
Breast cancer is histopathologically and almost certainly etiologically and genetically heterogeneous. The histology of breast cancers in women predisposed by reason of carrying BRCA1 and BRCA2 mutations differs from that in sporadic cases. Important genetic factors have been indicated by familial occurrence and bilateral involvement. In addition, breast cancer requires the presence of estrogens and androgens for their proliferation.
Inherited cases of breast cancer have been associated with a variety of genes such as: BRCA1, BRCA2, BRCATA, BRCA3, BWSCR1A, TP53, BRIP1, RB1CC1, PTEN, and STK11 genes. Low penetrance genes like TNFA, HSP70-2 and TNFRII may increase the susceptibility to sporadic breast cancer. However, a high percentage of hereditary breast cancers usually contain mutations in the BRCA1 and BARCA2 genes. Germline mutations in the TP53 gene usually lead to the development of distinct type of breast cancer known as Li-Fraumeni syndrome, which requires about 20 years to develop. On the other hand, other types of breast cancer include Cowden syndrome, due to mutations in the PTEN gene, and Peutz-Jegher syndrome, due to mutations in the STK11 gene. There also appears to be an increased risk of breast and ovarian cancer in ataxia-telangiectasia, and there is some evidence that heterozygotes for the ataxia-telangiectasia mutated gene (ATM) have an increased risk of breast cancer.
In a study to identify the various types of breast diseases in Bahrain, Darwish et al. (1994) studies 215 breast specimens from 207 patients with breast disease. Breast carcinoma was found to be the third most common disease in this sample, and was represented in 14% of the specimens. Invasive ductal carcinoma, not otherwise classified, was the most common form of malignancies detected (61%), followed by lobular carcinoma and medullary carcinoma (10% each), and mucinous carcimoa (3.5%). Two rare malignancies were also observed in this study. The first was a case of malignant phylloides tumor, in a 41-year old patient. The tumor recurred after six surgical attempts, and required left mastectomy. The second rare observation was a case of metaplastic carcinoma in a 55-year old patient with a painless lump. Mammogram results showed cystically dilated spaces, and evidenced a phylloides tumor. However, examination of the lump after excision showed both carcinomatous and anaplastic sarcomatous components. The cystically dilated ducts thought to be seen in the mammogram were actually found to be blood spaces.
Fakhro et al. (1999) undertook a study to identify patient characteristics, and to compute the survival rates among 93 Bahraini breast cancer patients discharged from the hospital. Majority of the patients were between 40 and 49 years of age (33.3%), and 48.4% of the women were below 50 years of age. This is in contrast to the findings from industrialized countries, where increased risk of breast cancer is associated with increase in age. The higher incidence of patients in stage II and III shows that most cancer patients in Bahrain visit the physician late in the progression of the disease. Fakhro et al. (1999) also conducted survival analyses on these patients in relation to tumor size, lymph node involvement, clinical stage, line of management, and age group. The cumulative survival rates for the Bahraini patients after 5, 7, and 10 years were 64.31%, 54.67%, and 36.44% respectively. Survivability increased with early diagnosis and aggressiveness of clinical management. Fakhro et al. (1999) stressed the urgent need for improved screening techniques for early detection and to improve women's awareness of breast cancer in Bahrain.
Al-Saweer et al. (2003) performed a prospective study on the prevalence of common risk factors associated with breast cancer in patients with the disease in Bahrain. Review of medical records of female patients showed that majority of them were between 41 and 60 years of age, were either of low or middle education, and had their menarche below the age of 13-years. Most of the patients were diagnosed with the tumor at stage two and the average size of the tumor at first presentation was around 5.5 cm. Incidentally, the size of the tumor at first presentation was found to be inversely related to the level of education of the patients. A large majority of the patients had infiltrative ductal carcinoma. The upper outer quadrant of the breast was found to be the one most affected. Additionally, most of the patients did not show any family history for the disease. Most of the patients reported breast-feeding their children, questioning the significance of lactation as a protector of breast cancer. Interestingly, almost all the cases were discovered by the patients themselves, purely by accident. Only a single case was discovered via screening, indicating that more efforts are needed in Bahrain to develop a screening program for earlier detection of breast cancer.
Ravichandran and Al Zahrani (2009) studied and compared the incidence of breast cancer in the GCC countries as obtained from the Gulf Centre for Cancer Registration (GCCR) and tried to determine its association with reproductive factors. Between 1998 and 2002, 337 women were diagnosed with breast cancer in Bahrain, which amounted to 35.4% of all cancer cases in the country. The ASR (age standardized incidence rate) was calculated as 46.4 per 100,000 population and is the highest among all GCC countries. Along with Kuwait and Qatar, Bahrain was classified as a country with a 'high incidence' of breast cancer. Interestingly, these countries were also characterized by lower fertility rates, a rapid decline in early childbearing age, and a lower duration of breast feeding.
[See also: Syria > Raj et al., 1991; Kuwait, Oman, Qatar, Saudi Arabia, UAE > Ravichandran and Al-Zahrani, 2009].
Ismail et al. (2011a) investigated the loss of heterozygosity incidence that target FHIT genomic structure and chromosome 3p in cancerous and pre-neoplastic lesions of Egyptian breast patients. Loss of heterozygosity was detected in 51% of breast cancer cases in at least one microsatellite marker of the four investigated markers while none of the markers showed loss of heterozygosity among the pre-neoplastic breast lesions. Ismail et al. (2011a) also observed a significant association between loss of heterozygosity and invasive ductal carcinoma histopathological type while no association observed between loss of heterozygosity and patients' age, tumor grade, or lymph node involvement. In a second study, Ismail et al. (2011b) investigated the pattern of homozygous deletion that target the FHIT gene exons 3 to 9 genomic structure in Egyptian breast cancer patients. They have found that 65% (40 out of 62) of the cases exhibited homozygous deletion in at least one FHIT exon. The incidence of homozygous deletion was not associated with patients' clinicopathological parameters including patients' age, tumor grade, tumor type, and lymph node involvement.
The Ministry of Health started the first cancer registry in 1996. During January to December 2003, 1,598 cases were diagnosed. Breast cancer was the leading cancer, and represents 28% of all female cancers. The latest Jordanian record of cancer registry was in 2000 and breast cancer is still the leading type of cancer and represents 16.5% of all cancers (Ministry of Health, 2000).
Al-Zoubi et al. (2016) studied 73 Jordanian breast cancer patients to identify an association between RAD51 and the risk of breast cancer. The patients did not have a family history of breast cancer or any BRCA mutations. Using paraffin embedded tissue blocks from these patients, genotyping and statistical analysis of the 5’ UTR variants T172T and G135C were carried out. While G135C failed to show a link with the disease, it was found that T172T showed a statistically significant association [p<0.0001, OR=3.717 (2.283-6.052)] with the risk of breast cancer. About 63% of the Jordanian cases carried the T127T genotype compared to only 15% of the controls. It was also found that on stratifying studied subjects into T127T or G135C carriers against the other variants (G172T, G172G or G135G), the T172T or G135C carriers showed a significant association with breast cancer risk (p=0.0001).
Hoogstraten et al. (1982) reported the results of the first case-control study of breast cancer conducted among Arab women. The study revealed an annual incidence of 7.67 per 100,000 Kuwaiti women, which was among the lowest globally. Hoogstraten et al. (1982) attributed this low incidence rate to several factors, including a short period of active menstruation, low family history, early age at first childbirth, and significant dietary factors. Although, due to delay in presentation, many of the patients had extensive disease at the time of diagnosis, the incidence of inflammatory breast carcinoma was low.
Nasralla et al. (1992) studied the relation between epidermal growth factor levels and estrogen and progesterone receptors in 132 primary breast cancer tissue specimens. An inverse significant correlation was observed between ER and PR levels vs. epidermal growth factor receptor levels in tumors of post-menopausal women. No such correlation could be seen in pre-menopausal patients. While EGFR positive tumors showed no significant difference in the levels of ER and PR in premenopausal and postmenopausal women, EGFR negative tumors showed a significantly higher value in the postmenopausal women.
A very rare form of breast cancer was reported by Hamid (2000) for the first time in Kuwait. The case reported had a carcinoma originating from ectopic breast tissue.
Temmim et al. (2001) studied male breast cancer in Kuwait in 41 cases (median age: 54 years), most of whom (51%) were in stage II. Almost all of the tumors (97%) were infiltrating ductal carcinomas, with axillary lymph node metastases observed in 69%. Lower clinical stage and grade, smaller tumor size, absence of metastases, and age below 50-years were factors associated with favorable prognoses. Immunohistochemical studies showed that a high percentage of tumors stained for markers for ER, Cathepsin D, and PR.
Luqmani et al. (2002) studied the allelic imbalance in 15 male patients with breast cancer in Kuwait. Comparison of PCR amplified products from normal and tumor DNA samples revealed microsatellite repeat number abnormalities in five patients; in three of them at multiple sites. Similarly, loss of heterozygosity was found in eight cases; in 50% of them at more than one site. Two of these patients were found to have allelic variation at more than half of the assessable sites. The results indicated that similar to breast cancer in females, male breast cancer tissues were also characterized by replication errors and allelic loss.
Anim et al. (2005) undertook immunohistochemical studies of tissue sections from 114 consecutive breast cancer cases to understand the relation between six specific markers and prognosis. Detection of both estrogen and progesterone receptors were found to be positively related to the presence of lower grades of cancer, indicating good prognosis. Of the other four markers, only c-erbB2 and Cathepsin D were found to be useful, in that they were possibly associated with poor prognosis.
Al-Shaibani et al. (2006) conducted a case-control study to assess the risk factors for breast cancer among Kuwaiti women. The one-year study included 1070 women between 30 and 65 years of age, 48% of whom were breast cancer patients, while the rest were controls. Binary logistic regression analysis was used to analyze the data obtained from questionnaires filled up by the subjects. The results revealed that in Kuwait breast cancer patients were relatively young in age. The factors that were found to increase the risk of breast cancer in this population included menopause, hormone replacament therapy, family history of the disease, and history of breast surgery or biopsy. The risk of breast cancer was significantly less among lactating women. No association was found between the risk of breast cancer and the use of oral contraception, cigarette smoking, age at menarche, nulliparity, and marital status.
Saleh and Reno (2008) investigated cases of breast carcinoma of the invasive cribriform type seen between 1996 and 2006 in Kuwait. Tissue samples from patients with grade I and stage IIA (T2, N0, M0) were immunostained to look for expressions of the CD44 antigen. The results indicated a significantly extensive expression (83.3% of the samples) of the v3 and v6 isoforms, while 83.3% lacked the expression of the v4 isoform.
Ayad et al. (2009) compared 38 breast cancer patients from Kuwait with 50 from London to study the differences between these two populations. They noted a low incidence of low grade tumors and a higher incidence of axillary lymph node metastases in the Kuwaiti population and suggested that this could be a result of differences in genetics or lifestyle, or could be due to early screening programs in the UK. Interestingly, the Kuwaiti patients showed a significantly younger age (mean age: 50.4 years) compared to the Western patients (57.7 years). This age difference persisted between the various subtypes of breast cancer, indicating a genetic difference, necessitating an earlier screening program in Kuwait. Triple-negative tumors were encountered in 13% and 16% of the Kuwaiti and UK patients, respectively. Morphologic and biological characters of the tumor appeared similar in the two populations.
Ravichandran and Al Zahrani (2009) determined the number of breast cancer cases among women in Kuwait between 1998 and 2002 to be 551. This amounted to 33.2% of all cancer cases in the country, with an ASR of 44.3 per 100,000 population. Ravichandran and Al Zahrani (2009) categorized Kuwait as a country with a 'high incidence' of breast cancer [See also: Bahrain > Ravichandran and Al-Zahrani, 2009].
Devi et al. (2000) evaluated histopathological reports on breast cancer to check for their completeness in recording the pathological prognostic factors. All patients diagnosed with primary breast carcinoma in an Omani Hospital during the period of four years (1994 to 1997) were analyzed, and cases of excision biopsies (lumpectomy) and mastectomy were selected for further analysis. The pathology reports of these patients were analyzed for the tumor size, histological type and grade, presence or absence of tumor emboli in the vascular channels, and the proximity of the tumor to the surgical resection margin. Reports on axillary lymph nodes were reviewed for the recording of the number of the lymph nodes sampled and the number of those involved, and the reason behind not mentioning it. It was found that a total of 102 cases were analyzed during the four year period, 95% of which had their tumor size mentioned in the reports and one case from each year of 1994, 1995, and 1996, and two cases from 1997 had no information about their tumor sizes. The histological types were mentioned in 97%, which were 100% in 1995 and 1997, but in 1994, in one case it was difficult to give a histological type and in one of three cases in the year 1996, it was labeled as invasive carcinoma of uncertain type, and the pathologist had difficulty deciding between atypical medullary carcinoma and infiltrating duct carcinoma NOS (not otherwise specified) in the other two. Grading of the tumor was carried out in 82 reports (80%) and it was found that grading was not done in eight cases which included in situ carcinomas and carcinomas of special types, while 12 cases were overlooked by the pathologist. In only 50% of the cases, was the tumor emboli mentioned, with no emboli seen in six cases. Of the remaining 45 cases, it was reported that 20 cases had vascular and 18 cases had lymphatic emboli. The reporting of tumor proximity to the resection margin was low in 1994 (90%), increasing to 95% in 1995 and 100% in 1996, but decreasing to 96% in 1997. In 1994, only half the cases (50%) had axillary clearance with either lumpectomy or mastectomy, which improved to 83% and 88% in the year 1995 and 1996, respectively, and had a decline to 78% in 1997. The total number of lymph nodes was recorded in 64 out of 77 (83%) specimens with axillary clearance. Metastasis was recorded in 71%, 19% had no evidence of metastasis, in 7% the number was not recorded due to matting, and in another 7%, it was not recorded for no obvious reasons. This study had shown that there was an improvement after introducing the new concept of prognostic factors in histopathology reporting in 1994, with further improvement in 1995, but slight deterioration was noticed in 1996 which Devi and colleagues (2000) explained as due to the possibility that the increased work load on the pathologist resulted in them overlooking the factors, or that new appointees were not made aware of the guidelines. Devi et al. (2000) concluded that the high standard of reporting could be maintained by providing written protocols and repeating such audit processes.
Faris et al. (2002) conducted a study to estimate the incidence of Her2/neu expression in 15 cases (mean age of 47.5 SD 13.9 years) of breast cancer in Oman and to evaluate its effect on prognosis. Hercep test was used for detection of the Her2/neu oncogene receptors via immunohistochemical staining, and then prognostic factors (TNM staging, oestrogen and progesterone receptors, tumor grade and vascular invasion), disease free period (DFP- date of surgery to date of relapse), and overall survival (OS- date of presentation to date of death) were compared between those with positive expression and those with negative receptors. Out of the 15 patients with breast cancer (2 males and 13 females, 46% were in pre-menopausal status), eight had Her2/neu over-expression while seven did not express this oncogene. There was no significant difference between the two groups as regarding the prognostic factors, but patients with positive receptors had shortened DFP and OS (42 and 69 months, respectively), when compared to those with negative Her2/neu receptors (10 months and 15 months, respectively).
Al-Moundhri et al. (2004) conducted a retrospective study to determine the outcome of breast cancer treatment in Oman through analyzing the clinical and pathological features as well as the treatment modalities used, prognostic factors and survival, and comparing these with other developing and developed countries. Data (medical and pathological) were collected from the hospital records of patients diagnosed with invasive breast cancer from two main teaching hospitals in Oman, during the period of seven years (1996-2002). A total of 152 patients (150 females, 2 males) were included in the study. The variables studied included the age and date of presentation, sex, menstrual status, right or left breast involvement, histopathological type, clinical and pathological size and stage at presentation, involvement of the skin, nipple, axillary lymph nodes, presence of estrogen and progesterone receptors, and the use of surgery, chemotherapy, and radiotherapy. The overall survival (OS) was calculated from the date of diagnosis till death, and the relapse free survival (RFS) was measured from diagnosis to relapse. Statistical methods used were the Kaplan-Meier test for presenting the survival and relapse estimates, the log rank test for comparison, Cox univariate analysis for estimating the relative risk of the above mentioned variables, and Cox multivariate analysis for measuring the significance. Of the female patients, 48% were premenstrual. The mean age of the patients was found to be 48.5 years, which was consistent with that in other developing countries but less than that of developed countries (60 -65 years). About 20% of the patients were aged 40- years or younger, and the patients showed almost equal involvement of the right and left breast (50% and 48.7%, respectively). As regarding the treatment modalities, 65.8% had modified radical mastectomy, only 13.2% (constituted 37.7% of the 53 patients with locally advanced disease- stage III) received neoadjuvant chemotherapy (anthracycline (AC/FEC/FAC) regimens) and 60.2% of the non metastatic group received chemotherapy. These reflected the underutilization of chemotherapy. Adjuvant external beam radiotherapy to the breast area was given to 63.1% of the patients, and as such a facility was not present on Oman, it was received it in other countries, while hormonal therapy (Tamoxifen and Goserelin) was given to 75.7% of the patients. The average tumor size clinically and pathologically was found to be 5.4cm and 4.6 cm, respectively. In clinical staging, T3 and T4 lesions were found in 25% and 17% of the patients, respectively and T1 in only 14.5%. Advanced breast cancer predominated with stages III and IV was found in 34.9% and 15.8%, respectively, while stage III predominated in pathological staging being present in 41.7% of the patients who underwent surgery. Axillary lymph node dissection in 120 patients revealed that 33.3% had 1-3 positive nodes, 24.2% had 4-9 positive nodes, and 11.7% had 10 or more positive nodes. Five histopathological subtypes of the tumor (which was poorly, moderatly and highly differentiated in 48.1%, 16.4% and in 35.5%, respectively), were identified; ductal (88%), lobular (6.5%), medullary (five), mucinious (two patients). and the tubular subtype (one patient). In 107 patients whom the receptor status was available, 68% had estrogen and 58% had progesterone receptors. In the 128 patients with the non metastatic disease, there were 23 deaths (13 deaths were in the metastatic group), 42 had relapsed, 13 were alive with persistant disease, and 86 were alive and free of disease. The overall five year RFS rate and OS rate were 62% and 64% (consistent with that of developing countries but lower than that reported from the west), respectively. The predictors of RFS according to the Cox univariate regression analysis were found to be tumor size of more than five cm, axillary lymph node status and poor differentiation, while only the tumor size and differentiation grade were predictors of OS. According to the Cox's multivariate analysis, tumor differentiation was predictor of disease free survival and involvement of 4 9 lymph nodes was predictor of OS. In view of these results, Al-Moundhri et al. (2004) advised increasing the breast cancer awareness, providing breast cancer screening programs and easy accessibility for patients to tertiary hospitals for proper management, and they concluded that more research is required to explore the genetic, environmental and cultural influences on the breast cancer to provide more explanation of its clinical and pathological features.
Al Bahrani et al. (2004) conducted a study to evaluate the pattern of relapse and the management experience of metastatic and relapsed breast cancer in Oman. All patients who initially presented with metastatic disease or developed metastatic disease between 1999 and 2001 were enrolled in the study, and data analyzed included demographic information, tumor characteristics, previous treatment, period of follow up, and pattern of relapse and hence the disease free period (DFP- day of surgery to confirmation of metastasis) and progression free survival (PFS- from first chemotherapy to disease progression) were calculated. Out of 49 studied patients (48 females and one male with mean age of 52.7 years), 31 had relapsed/progressive disease with a mean DFP of 32.2 months while that of the treated relapsed patients was 10.4 months. Out of the 31 patients, 19 received chemotherapy which was anthracycline-based chemotherapy if they had received the standard CMF as first line adjuvant chemotherapy (12 patients) and seven received second line Taxanes based chemotherapy as their first line was anthracycline-based chemotherapy. In the second group the PFS was significantly longer (11.2 months) than of those treated with anthracyclines (PFS of 8.3 months). Complete response was detected in two patients and one patient who received anthracyclines and Taxanes, respectively, while partial response was seen in four patients and one patient, respectively, while disease progressed in six patients and in one patient, who received anthracyclines and Taxanes, respectively. Out of the 18 patients (mean PFS of 14.4 months) who initially presented with metastatic disease, 72% had one site involved, with a mean PFS of 15.5 months, while the rest (28%) had more than two sites and their mean PFS was 11.5 months. Anthracycline-based chemotherapy was given to 11 patients with metastatic disease (mean PFS was 16 months) and of them two had complete response, three had partial response, in three the disease was stable, and the disease progressed in another three. One patient from the metastatic group received CMF with a mean PFS of 10 months, and the rest received hormonal therapy. During the study period, there were no treatment mortalities nor was there discontinuation of treatment for toxicity, which was tolerable and managed successfully. Al Bahrani et al. (2004) highlighted that the majority of their patients presented in advanced disease and therefore advised on increasing the awareness of both the patients and health providers by health education so as to diagnose the disease at an early stage.
Ravichandran and Al Zahrani (2009) determined the number of breast cancer cases among women in Oman between 1998 and 2002 to be 333. This amounted to 16.1% of all cancer cases in the country, with an ASR of 14.4 per 100,000 population. Ravichandran and Al Zahrani (2009) categorized Oman as country with a 'low incidence' of breast cancer [See also: Bahrain > Ravichandran and Al-Zahrani, 2009].
Using the national cancer registry, Bujassoum and Gehani (2004) undertook a retrospective study of breast cancer in Qatar during the period between 1999 and 2002. Breast cancer was found to be the most common malignancy in the country, with a total of 214 patients diagnosed with this condition during this period (incidence: 5 in every 10,000 each year). Of the female patients, 23% were Qatari. Males constituted 3.2% of the total group. The condition was also found to be most common in patients between 45 and 55 years of age (64%), followed by in those below 45 years (22.5%). Most cases were diagnosed at stage II (50%), and were of the invasive ductal carcinoma type. Only 27% cases were detected in stage I, probably due to lack of screening programs. Interestingly, there was a significant decrease in cases of stage III and IV over the last couple of years of the study. In addition, compared to the previous data taken between the period 1990 and 1998, in this study period, there was an earlier detection of breast cancer. Mortality was recorded in 4.3% of the cases, and the rate of mortality was found to decrease over the study period. The study showed a clear trend towards improved survival, which Bujassoum and Gehani (2004) attributed to early diagnosis.
Bener et al. (2008) retrospectively studied the Qatar National Cancer Registry to assess the trend in various cancer incidences in Qatar. Breast cancer was diagnosed in 68 Qatari patients between 1991 and 1996, 91 Qataris between 1997 and 2001, and in 126 Qataris between 2002 and 2006.
Ravichandran and Al Zahrani (2009) determined the number of breast cancer cases among women in Qatar between 1998 and 2002 to be 90. This amounted to 23.5% of all cancer cases in the country, with an ASR of 35.5 per 100,000 population. Ravichandran and Al Zahrani (2009) categorized Qatar as a country with a 'high incidence' of breast cancer [See also: Bahrain > Ravichandran and Al-Zahrani, 2009].
Bin Amer et al. (2008) screened the expression profiles of 1176 genes to establish consensus gene expression profiles of invasive breast tumors from Saudi females. The study looked at 38 invasive breast tumors and eight tumor adjacent tissues and identified 48 differentially expressed genes in tumors. The results from this study were not very different from comparable studies on samples from Caucasians. However, five genes were significantly differentially expressed in tumor tissue and not in tumor adjacent tissues. The latter genes are IGHG3, Cdk6, Catenin, RPS9, and VEGF1. The study indicates that the genes IGHG3, CDK6, and RPS9 may have a novel role in breast cancer.
Ravichandran and Al Zahrani (2009) determined the number of breast cancer cases among women in Saudi Arabia between 1998 and 2002 to be 2,987. This amounted to 20.3% of all cancer cases in the country, with an ASR of 12.9 per 100,000 population. Ravichandran and Al Zahrani (2009) categorized Saudi Arabia as a country with a ‘high incidence’ of breast cancer [See also: Bahrain > Ravichandran and Al-Zahrani, 2009].
Alshatwi et al (2012) studied a cohort of 200 subjects that included 100 women with breast cancer who were clinically and histopathologically diagnosed at King Khalid University Hospital from January 2009 to October 2010 and 100 healthy women of similar age (50 ± 5 years), who were voluntarily enrolled as controls. Both study groups were from Riyadh, Saudi Arabia. The demographic details revealed early onset and late diagnosis of breast cancer in these patients. The average age of the randomly selected group of 100 invasive ductal carcinoma cases with stage I (24%), stage II (39%), stage III (33%), and stage IV (2%) disease was about 51.5 years. Metastatic disease was seen in 58% of the cases, with 42% of them showing nodal invasion. Fifty-eight percent of the patients were premenopausal cases, with an average age of 37.5 years. The average age of postmenopausal patients was 61.2 years. The presence of one MDM2 GG genotype, but not one TP53 Pro/Pro genotype, was associated with an increased risk of breast cancer. The presence of both MDM2 GG and TP53 Pro/Pro genotypes was associated with an even higher risk for breast cancer compared with those who lacked both genotypes. TP53 and MDM2 polymorphisms were also found to be possible influences on the development of breast cancer in the Saudi population. In conclusion, the study showed for the first time in this ethnic population of the Arab world, a significant association between the MDM2 309T > G and TP53 72Arg/Pro polymorphisms and the risk of developing breast cancer. The association of MDM2 polymorphism with the risk of breast cancer displayed a multiplicative gene–gene interaction with the TP53 72Arg/Pro polymorphism. These molecular epidemiological findings were consistent with the results obtained from functional analyses.
Ali et al. (2016) investigated the association between XRCC3 polymorphisms and the risk of breast cancer in Saudi women. A total of 143 breast cancer affected females and 145 healthy controls were recruited to the study. Genotyping and statistical analysis found a significant association between the SNP rs1799794 and breast cancer [p<0.0001, OR=28.1 (3.76-21.12)] where the mutant G allele was protective against the disease. A similar association was found between this SNP and triple negative cancer. The SNPs; rs1799796 and rs861539 were also tested but were not found to be significantly associated with the disease. However, when patients were categorized based on their age of onset, tumor grade and hormone receptor status, it was found that the SNP rs1799796 showed several significant associations. Specifically, the A allele of the rs1799796 was found to be more frequent in patients with an early age of onset (<48 years), in patients with a grade III tumor compared to grade II and in patients that were ER- and HER2- compared to ER+ and HER2+. The SNP rs1799796 can thus be considered a marker of disease severity.
Tulbah et al. (2016) analyzed the association between three RAD51 polymorphisms (rs1801320, rs1801321 and rs2619681) and the risk of breast cancer in the Saudi population. A total of 96 breast cancer affected females were recruited to the study along with 96 age- and sex- matched healthy controls. Genotyping and statistical analysis was carried out. No association was seen between the SNP rs1801320 (G>C) and breast cancer. The SNP rs1801321(G>T) however, showed a statistically significant association with breast cancer risk. The GG genotype and the G allele were related to an increased risk of cancer (p<0.0001) while the T allele was found to be protective against the disease (p<0.0001). The SNP rs2619681 (C>T) also showed a strong association with breast cancer risk, with the CC genotype and the C allele being more frequent in cancer patients (p=0.012) and the T allele conferring protection against the disease. Patients were then grouped according to their tumor grade, epidermal growth factor receptor, estrogen receptor (ER), and progesterone receptor (PR) status to determine if the SNPs were associated with these parameters. It was found that the CC genotype of the SNP rs1801321 was more frequent in patients that were ER- than in ER+ patients. Also, the C allele of rs2619681 was more frequent in ER+ and PR+ patients than those that were ER- and PR-.
Semlali et al. (2017) attempted to identify an association between 3 TLR2 SNPs (rs3804100, rs4696480, and rs3804099) and the development of Breast Cancer (BC) in the Saudi population. 126 BC affected women were recruited to the study along with 146 healthy controls. Genotyping and statistical analysis found that there was no correlation between these TLR2 polymorphisms and an increased risk of BC in Saudi Arabian females. The cohort was then further stratified by age as well as Estrogen Receptor (ER) status. The SNPs did not show an association with BC in the different age groups or in the ER+ group. However, in the ER- cases, the T allele of SNP rs3804099 showed a significant correlation with BC compared to controls (OR, 1.61, p=0.005). The authors noted that this finding could possibly be attributed to a small sample size.
Raj et al. (1991) described a 16-year-old Syrian woman with lactating adenoma. A 10 cm mobile lump was detected in her right breast on the third postnatal day, however, she had noticed the lump two years earlier and it enlarged during pregnancy. Lumpectomy was performed and a large lobulated mass was found during surgery. On histopathological examinations, the lump was found to be a solid tumor mass surrounded by thick rim of fibro-fatty tissue. On section, it was a well demarcated, multinodular, pseudoencapsulated homogenous white tumor, yellow in hue with wide focal microcytic areas. Microscopic examination of the specimen showed closely packed alveoli of varying sizes. The lumens were filled with foamy eosinophilic secretory material and foamy vacuolated macrophages. Periductal stoma showed significant collections of chronic inflammatory cells with disruption of glandular walls.
Mestiri et al. (2001) investigated the significance of polymorphisms of TNF-alpha and hsp70-2 genes in the risk and outcome of breast cancer. Samples were collected from 243 Tunisian patients with primary breast carcinoma and unilateral breast tumors and 174 control subjects and polymerase chain reaction and restriction enzyme digestion were used for analysis. The age mean of the patients was of 48 ± 11 years. Polymorphisms in the promoter region of the TNF-alpha gene and in the hsp70-2 gene were found to be related to an increased risk for breast cancer. The prognosis of breast cancer is influenced differently by these two agents, for the TNF-alpha polymorphism is linked to a reduced disease-free and/or overall survival whereas hsp70-2 polymorphism are responsible for an increased overall survival.
Snoussi et al. (2005) established an association, by means of polymerase chain reaction and restriction enzyme digestion, between risk and prognosis for breast cancer and the cytokines Interleukin-1beta, interleukin-1alpha and interleukin-6 in 305 unrelated Tunisian patients with a control group of 200 subjects. All patients, 301 females and 4 males, presented primary breast carcinoma with unilateral breast tumors and were between 26 and 74 years old and 27.7% died of breast carcinoma. The (+3954) T allele of the IL-1 beta gene is linked to an aggressive phenotype of breast cancer with a higher histological grade, axillary lymph node metastasis and a larger tumor size whereas the IL-1 beta (+3954) TT genotype is associated with a reduced disease-free survival. The same conclusion was made for the IL-1 alpha (-889) TT homozygous genotype adding to it a reduced overall survival hence a poor prognosis in breast cancer. In the case of the IL-6, Snoussi et al. (2005) identified the possibility of polymorphisms in the promoter region representing markers for an increased risk of breast cancer. One year later, Snoussi et al. (2006) examined the implications of polymorphisms of the LEP and LEPR genes in the prognosis and susceptibility of breast cancer in 308 breast carcinoma patients and 222 control subjects, both groups being Tunisian and included unrelated individuals. All patients had primary breast carcinoma with unilateral breast tumors and no family history for the disease. In 39% of the cases, the patients were primarily treated with chemotherapy. The study showed that LEP gene and LEPR gene polymorphism were associated with an increased risk of breast carcinoma. Furthermore, the LEP (-2548) A allele is linked to the decrease of disease-free survival and the LEPR 223R allele is connected to the decrease of overall survival.
As in many other Arab countries, breast cancer is the most common cancer in females in the United Arab Emirates (Holt, 1985). The true incidence is difficult to report as the majority of the population is migratory. However, it is well known that Arab nationals including those from the United Arab Emirates tend to develop breast cancer at least a decade earlier than their counterparts in Western countries. Due to social customs, many Arab women do not present themselves for regular medical examination and this usually results in late presentations, scanty epidemiological data, and insufficient clinico-pathological studies (Anim, 1990). Pain has been reported by some workers to be a significant presenting feature of the disease among Arab women.
In year 1985, a retrospective study comprising 153 breast cancer patients treated in various hospitals in the United Arab Emirates from year 1983 to 1985 indicated that the majority of the patients were non-UAE Arab nationals as this group constituted the largest group of female expatriates in the country at the time (Gautam and Siddiqui, 1988). Among the 153 patients, there was only one male with breast cancer. Eighty six per cent of parous patients breast-fed their babies and only 4% of the patients gave positive family history of breast cancer. All patients had delayed presentation for treatment, the majority presenting beyond six months of noticing the lump. Probably, this indicates a lack of personal perceptions of susceptibility to breast cancer, since a correct perception usually has a positive impact on the women's screening behaviors (Bener et al., 2002). However, this situation seems to have changed. At the beginning of 1998, a breast cancer screening program was introduced in the city of Al-Ain. The age-standardized incidence of breast cancer for 1998 for the population was 15.5 per 1000 (Denic and Bener, 2001). This is far lower than the incidence rates in neighboring countries such as Kuwait and Saudi Arabia. Many features of women perceptions, knowledge, and attitudes toward breast cancer are encouraging (Bener et al., 2002).
Ravichandran and Al Zahrani (2009) determined the number of breast cancer cases among women in the UAE between 1998 and 2002 to be 182. This amounted to 23.1% of all cancer cases in the country, with an ASR of 19.2 per 100,000 population. Ravichandran and Al Zahrani (2009) categorized UAE as a country with a 'high incidence' of breast cancer [See also: Bahrain > Ravichandran and Al-Zahrani, 2009].
Literature on genetic predisposition of breast cancer is limited in Arab women. Generally, it is believed that the incidence of breast cancer in Arab women is low compared with other populations (Denic and Al-Gazali, 2003). Very few studies on risk factors for breast cancer in Arab women have been reported.
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