Clinicopathologic Features of Breast Cancer in Egypt—Contemporary Profile and Future Needs: A Systematic Review and Meta-Analysis

Abstract

PURPOSE

Breast cancer (BC) is the most common cancer among Egyptian females. No current national cancer database is available in Egypt to provide reliable data on the specific clinicopathologic features of BC in this population. Herein, we investigated the clinical profile of BC among Egyptian women.

METHODS

A systematic review of studies on BC published from inception until December 2021 was performed. We explored pooled estimated proportions of different stages of BC at presentation in Egypt and other clinicopathologic features including age, menopausal status, tumor (T) and lymph node (N) stages, and biological subtypes. Data analysis was performed using meta package (R).

RESULTS

Twenty-six studies were eligible for our systematic review and meta-analysis, including 31,172 BC cases. In 12 studies, including 15,067 patients with BC, the estimated mean age was 50.46 years (95% CI, 48.7 to 52.1; I², 99%), with a pooled proportion of premenopausal/perimenopausal women of 57% (95% CI, 50 to 63; I², 98%). Among 9,738 patients with BC, pooled proportions of stage I, II, III, and IV were 6% (95% CI, 4 to 8; I², 90%), 37% (95% CI, 31 to 43; I², 93%), 45% (95% CI, 42 to 49; I², 78%), and 11% (95% CI, 9 to 15; I², 87%), respectively. The pooled proportions of patients with T3 and T4 tumors were 21% (95% CI, 14 to 31; I², 99%) and 8% (95% CI, 5 to 12; I², 96%), respectively, while those with positive lymph nodes were 70% (95% CI, 59 to 79; I², 99%).

CONCLUSION

Dominance of advanced stage and young age at diagnosis represented the two main features of BC among Egyptian women. Our data may serve to guide the policymakers in Egypt as well as other countries with lower resources to prioritize the diagnostic and therapeutic needs in this context.

INTRODUCTION

Breast cancer (BC) is the most commonly diagnosed cancer worldwide, with estimated new cases exceeding 2 million in 2020. Furthermore, it represents the leading cause of cancer death in women, with more than 680,000 deaths.¹

CONTEXT

• Key Objective

• What are the clinicopathologic features of breast cancer (BC) at presentation in Egyptian women?

• Knowledge Generated

• This systematic review and meta-analysis provided pooled estimated proportions for the stage of BC at presentation in Egypt, and other clinicopathologic features including age, menopausal status, tumor (T) and lymph node (N) stages, and biological subtypes.

• Relevance

• Egyptian patients with BC were diagnosed at a younger age, with a far more advanced stage and aggressive biological subtypes compared with developed countries. This may explain the worse prognosis of the disease in this population and highlight the need for prioritization of tailored cancer control programs for BC.

Despite the difference in incidence rates of BC between developed and developing countries,^1,2 the disease remains the most common type of female cancer in Egypt with an age-specific incidence rate of 48.8/10⁵. Approximately 46,000 incident cases are forecasted in 2050.³ Although this incidence rate in Egypt is lower than the global figures, mortality is higher at an age-standardized rate of 20.4/100,000⁴ compared with the US rate of 12.3/10⁵ and the developed countries' rate of 12.8/10⁵.¹ When comparing the mortality/incidence rate ratio for BC between Egypt and developed countries, Egypt had approximately double the ratio (41% v 23%). Moreover, it is currently the second most common cause of Egyptian cancer mortality after hepatocellular carcinoma with estimated mortality rate around 11% in 2020.⁵ Notably, this mortality rate is far higher than those of other developing countries counterparts like China, where age-standardized mortality rate is 6.3/10⁵.⁶

These disparities in incidence and mortality between Egypt and other countries have been largely attributed to delayed presentation at diagnosis. In Egypt, most of the cases present as locally advanced or metastatic rather than early stages.^7,8 In a study⁹ to investigate this delayed presentation among Egyptian women, the average time lag was 7 months from developing the first symptom until commencing treatment, where patients contributed to 61% of the wait time (4.4 months). This could be attributed to low awareness levels of BC symptoms, risk factors, or difficult access to health care. This was also demonstrated by other studies^10,11 and by the most recent Demographic and Health Surveys report by the Egyptian Ministry of Health and Population, which revealed very low rate of mammographic breast screening among Egyptian ladies.¹² These factors eventually lead to higher rates of stages III and IV at presentation, which is a major detriment on prognosis and treatment outcomes.^13,14

In fact, the burden and demographics of BC were clearly depicted for the majority of the regions across the world, even in nations without well-established national-based registries, which aids in the direction of cancer control initiatives. However, with the lack of a current national cancer database in Egypt and paucity of documented data, it is important to comprehensively represent the estimated burden of BC and its specific clinicopathologic profile to direct future plans for BC prevention, early detection, and management and to guide future research. Albeit reluctantly, some studies (mostly hospital-based retrospective studies) had presented limited clinicopathologic data with wide variations that do not capture the national profile. For example, age at diagnosis of BC ranged from 47.8¹⁵ to 57 years,¹⁶ while percentage of T1 tumors ranged from 5%¹⁵ to 26%.¹⁷

Therefore, we conducted a systematic review of literature and meta-analysis aimed at providing a snapshot for the contemporary status of BC in Egypt, to elucidate the estimated burden of the disease and its clinicopathologic features. The primary objective was to explore the pooled estimated proportion of different stages at presentation in Egypt according to the American Joint Committee on Cancer (AJCC). The secondary objectives were to describe other clinicopathologic features including mean age, menopausal status, T and N stages, histopathologic types, and biological subtypes. Furthermore, the patterns of BC surgery were also investigated.

METHODS

We performed this systematic review in compliance with the preferred reporting items of the systematic review and meta-analysis (PRISMA) checklist.¹⁸ All steps were conducted in concordance with the Cochrane Handbook of Systematic Review and Meta-Analysis.¹⁹

Inclusion and Exclusion Criteria

All studies that met the following criteria were included: (1) observational studies (registries or retrospective or prospective studies) that represent the data for BC in a specific center or institute in Egypt; (2) studies that report the clinicopathologic characteristics of the BC cohort at presentation (age at diagnosis or stage or tumor size or pathology type or pathology grade or receptor status or type of surgery); and (3) studies published in English language. Abstracts that report the investigated outcomes were eligible.

The excluded studies included any of the following (to avoid duplicate population or any confounders for selection bias): (1) survey studies; (2) studies that represent pathologic assessment of paraffin blocks; (3) interventional studies; and (4) studies that address specific category only (ie, male BC or phyllodes tumors, etc) or specific stage (ie, inflammatory BC or metastatic BC, etc). We also excluded letters to editor, reviews, study protocols, case reports, and case series studies, in addition to any studies that had unreliable or unpublished data for extraction or duplicates.

Search Strategy

The PROSPERO database was checked for similar registered protocols, where none was detected. Then, the literature was systematically searched from inception till December 7, 2021, in the following databases: PubMed Central, PubMed National Institutes of Health, Scopus, and Cochrane library. The search terms for each database are provided in the Appendix Table 1, Data Supplement. In brief, the following keywords were used: “Breast Neoplasms” OR “Breast Cancer” OR “Breast Tumor” OR “Breast Tumors” OR “Breast Carcinoma” AND “Egypt.”

Moreover, manual search for reference lists of relevant articles was performed to find further eligible studies. The search process was independently performed by two authors (H.E. and M.A.). First, all identified citations were imported to Endnote software. Then, an independent review and screening of records by title and abstract were done by both authors. After removing the duplicates, the relevant articles were shortlisted, where the full-length papers were assessed for the eligibility criteria. Then, the articles that fulfilled all the eligibility criteria were retrieved for the final systematic review and meta-analysis. Any disagreements were discussed till reaching a consensus among all authors.

Data Extraction

Two authors (M.A. and A.E.) had independently extracted the data, using a standard data extraction form. Then, a third author (H.E.) had reviewed it and agreed the data before proceeding to the statistical analysis. Data were extracted for females with BC; however, studies including men with BC as well in the cohort were not excluded as they typically represent <2% of total BC cases.²⁰ For different publications representing dependent analyses for data extracted from the same cancer database, we used the article that reported the outcome of interest once in our analysis to avoid duplicate population. Missed data were excluded from the total counts in the analysis. The study settings and data related to the patient and tumor characteristics were extracted (author, year of publication, study setting, type of study/registry, sample size, mean age, and number of the patients presented with following: premenopausal/perimenopausal status, different AJCC stages, different tumor T stages, different lymph node N stages, different pathologic types, estrogen receptor [ER+], progesterone receptor [PR+], human epidermal growth factor receptor 2 [HER2+], triple-negative breast cancer [TNBC], and lastly treated with breast-conservative surgery [BCS] and modified radical mastectomy [MRM]). Any disagreements were resolved by mutual discussion with all authors.

Assessment of Publication Bias and Quality

We carried out an assessment of publication bias through a visual inspection of the funnel plot. The quality of the included studies was assessed independently by two reviewers (H.E. and A.E.), using the Newcastle-Ottawa Scale criteria scale,²¹ to assess the potential for selection and information bias. A quality score ranging from 0 to 10 was given to each study, accounting for very good (9-10 points), good (7-8 points), satisfactory (5-6 points), and unsatisfactory (0-4 points).

Data Analysis

The data analysis was done using the meta package in R. The effect size was reported as pooled proportion and 95% CI level. Heterogeneity was assessed by the chi-square test (χ²) and measured by the I² test. In the case of evident heterogeneity, DerSimonian and Laird random-effects models were applied to pool the outcomes. To investigate the causes of heterogeneity, subgroup and sensitivity (leaving-one-out study) analyses were done. If heterogeneity was not explained, we recalculated the results of our meta-analysis using remove outlier function.

RESULTS

Included Studies

In total, 662 studies were retrieved by our search, where 42 full-text papers were assessed for eligibility. Of them, 26 studies^15-17,22-44 were eligible for the current review and meta-analysis, including 31,172 BC cases. Figure 1 depicts the PRISMA flow chart for the search strategy. Three studies^30,32,37 presented data extracted from population-based cancer registries, while other three studies^22,28,42 were based on hospital-based cancer registries. Furthermore, 16 studies^{16,17,24-26,31,33-36,38-41,43,44} had collected data retrospectively and three studies^23,27,29 were cross-sectional studies. The data represent BC cases presented during approximately 2 decades, from 1997 till 2015. Eight studies^{16,17,22,24,33,36,41,43} represented the capital (Cairo), while 11^{15,23,27,30-32,35,37-39,42} and six studies^{25,26,28,34,40,44} represented North and South Egypt, respectively; however, one study²⁹ presented patients with BC in the capital and North Egypt simultaneously. It is worth noting that different editions of the AJCC staging manual (4^th-7^th) were used by most of the studies. Table 1 illustrates the characteristics of included studies.

FIG 1.

The PRISMA search strategy flow chart. BC, breast cancer; NIH, National Institutes of Health; PRISMA, Preferred Reporting Items of the Systematic review and Meta-Analysis.

TABLE 1.

Characteristics of Included Studies

Overall, the studies were of acceptable methodological quality, where 18 studies^{15,17,23,24,27-29,31-36,39-41,43,44} were scored good, four studies scored very good,^22,30,37,42 and four studies scored satisfactory.^16,25,26,38 Funnel plots were generated for the included studies in the analysis for the AJCC stages, where the visual assessment showed relatively symmetrical plots with no evidence of publication bias (Data Supplement [Appendix Figure 1]).

The Proportion of Breast Cancer From the Total Cancer Cases in Females

Among registered female patients in two large oncology institutions (Cairo National Cancer Institution and Mansoura University Hospital),^22,42 BC was the most common cancer representing 42% (95% CI, 12 to 80; I², 98%) of all cancer cases in females (Data Supplement [Appendix Figure 2]).

The AJCC Stage at Presentation

Eight studies^{15,16,31,32,34,35,40,41} had presented the AJCC stage including 9,738 patients with BC, where the pooled estimated proportions of stage I, II, III, and IV were 6% (95% CI, 4 to 8; I², 90%), 37% (95% CI, 31 to 43; I², 93%), 45% (95% CI, 42 to 49; I², 78%), and 11% (95% CI, 9 to 15; I², 87%) respectively (Figure 2). No trend for downstaging was observed over time.

FIG 2.

The pooled proportion of AJCC stages at presentation: (A) stage I, (B) stage II, (C) stage III, and (D) stage IV. AJCC, American Joint Committee on Cancer.

Subgroup analysis was done according to the geographical region (Capital, North, and South of Egypt), period of the study, and age category, where none had explained the evident heterogeneity in the pooled estimates for the AJCC stage. Moreover, for stage I and II, leave-one-out sensitivity analysis was done to explain the heterogeneity, where I² had dropped to 83% and 89% after omitting Ibrahim et al³⁴ (proportion of stage I = 5%; 95% CI, 4 to 7) and Abdelfattah et al¹⁵ (proportion of stage II = 35%; 95% CI, 31 to 39), respectively. However, remove outlier function was done for stage III, where omitting Abdelfattah et al¹⁵ and Ibrahim et al³⁴ had resolved the heterogeneity (I², 17%) with resultant estimated proportion of stage III of 45% (95% CI, 44 to 46). Furthermore, remove outlier function for stage IV (omitting Abdelfattah et al¹⁵ and Gabr et al⁴⁰) had improved the heterogeneity (I², 61%) with resultant estimated proportion of stage IV of 12% (95% CI, 11 to 13).

Furthermore, three studies^34,37,41 had reported the AJCC stage for young patients (≤35 or ≤40 years), including 1,078 patients, where the pooled estimated proportions of stage I, II, III, and IV were 4% (95% CI, 2 to 8; I², 0), 39% (95% CI, 33 to 45; I², 15%), 48% (95% CI, 37 to 59; I², 69%), and 9% (95% CI, 3 to 21; I², 73%), respectively. Interestingly, there was low to moderate heterogeneity between these studies. The forest plots are presented in Data Supplement, (Appendix Figure 3).

The Clinicopathologic Criteria of Breast Cancer at Presentation

Among 15,067 patients with BC in 12 studies,^{15-17,24,27,29,31,32,36,38,40,44} the estimated mean age was 50.46 years (95% CI, 48.7 to 52.1; I², 99%; Figure 3). Moreover, patients who are older than 40 years at presentation comprised 80% among 11,208 patients (95% CI, 73 to 85; I², 95%; Data Supplement [Appendix Figure 4]). The pooled estimate for the proportion of premenopausal/perimenopausal females was 57% (95% CI, 50 to 63; I², 98%) of the total BC cases at presentation, representing 5,376 premenopausal/perimenopausal patients out of 9,833 patients in 10 studies (Data Supplement [Appendix Figure 5]).^{15-17,24,26,34-36,40,44}

FIG 3.

The estimated pooled mean age at presentation among the breast cancer cases. MRAW, raw mean; SD, standard deviation.

However, in the 10 studies^{15-17,23,24,32,34,35,39,41} that reported the T stage, with a total of 10,619 BC cases, the overall pooled estimated proportions of stage T1, T2, T3, and T4 were 12% (95% CI, 8 to 16; I², 97%), 55% (95% CI, 48 to 61; I², 97%), 21% (95% CI, 14 to 31; I², 99%), and 8% (95% CI, 5 to 12; I², 96%), respectively, with marked heterogeneity between studies (Figure 4). It is worth noting that no trend for downsizing was observed over time.

FIG 4.

The pooled proportion of T stages at presentation: (A) T1, (B) T2, (C) T3, and (D) T4.

Three studies^34,39,41 had enclosed the T stage in young patients (≤35 or ≤40 years) including 721 patients. The pooled estimated proportions of stage T1, T2, T3, and T4 were 11% (95% CI, 5 to 23; I², 69%), 49% (95% CI, 26 to 73; I², 91%), 27% (95% CI, 6 to 66; I², 96%), and 10% (95% CI, 4 to 24; I², 77%), respectively (Data Supplement [Appendix Figure 6]).

In 13 studies^{15-17,24,28,30,34-36,38,39,41,43} with a total of 14,796 BC cases, the pooled estimated proportion of patients with positive lymph node involvement was 70% (95% CI, 59 to 79; I², 99%; Data Supplement [Appendix Figure 7]).

Among patients with positive lymph nodes, eight studies^{16,17,24,32,34,35,38,39} had presented the detailed N stage, with a total of 10,612 BC cases, where the overall pooled estimated proportions of stage N1, N2, and N3 were 29% (95% CI, 25 to 32; I², 91%), 22% (95% CI, 18 to 28; I², 93%), and 18% (95% CI, 13 to 24; I², 93%), respectively (Data Supplement [Appendix Figure 8]).

The estimated proportion of invasive duct carcinoma was 87% (95% CI, 81 to 92; I², 99%) among 15,171 patients with BC in 12 studies,^{16,17,24,32,34-36,38-41,43} while invasive lobular carcinoma represented 7% (95% CI, 5 to 10; I², 97%; Data Supplement [Appendix Figure 9]).

Among 5787 patients with BC in 10 studies,^{16,17,31,32,35,36,38,39,41,43} the estimated proportion of HER2+ subtype was 21% (95% CI, 15 to 30; I², 94%). However, among 5591 patients with BC in seven studies,^{16,17,31,38-41} the estimated proportion of TNBC subtype was 10% (95% CI, 5 to 21; I², 96%). Moreover, in 11 studies with more than 11,000 patients, the proportions of ER+ and PR + patients were 70% (95% CI, 61 to 77; I², 97%) and 61% (95% CI, 57 to 66; I², 92%), respectively (Data Supplement [Appendix Figure 10]).

Surgery Type for Breast Cancer

Among 11,382 patients with BC in 13 studies,^{15,24-26,28,32-34,36,39-41,43} the estimated proportions of BCS and MRM were 15% (95% CI, 11 to 21; I², 98%) and 85% (95% CI, 79 to 89; I², 98%) from the total BC surgeries, respectively (Data Supplement [Appendix Figure 11]). There was a trend for increase in BCS rate since 2014.

DISCUSSION

To our knowledge, this is the first report to comprehensively describe the clinical and pathologic profile of BC in Egypt during the past 2 decades. Our study included a quite large sample size of more than 31,000 Egyptian BC cases, which could provide a reliable information on demography, stage, histology, and biology of the disease, as well as the type of BC surgery.

Two main striking findings could be observed in our meta-analysis. First, the Egyptian BC population was significantly younger compared with the Western counterparts with a mean age of 50.4 years at diagnosis and 57% being premenopausal/perimenopausal. Of note, in the US-based SEER data⁴⁵ and the Japanese Breast Cancer Society registry,⁴⁶ the median age at diagnosis was 63 years and 59.7 years, respectively. This age pattern in Egypt could be explained by the population pyramid distribution, with only a minority of the female population (8%-9%) older than 60 years.⁴⁷ By contrast, a similar age pattern is seen in other developing countries, such as China, where mean age at presentation is 53 years.⁴⁸ It is worth noting that 20% of the Egyptian patients with BC was younger than 40 years, compared with 5% in the SEER database.⁴⁹ Meanwhile, the proportion of premenopausal females has declined over time in developed countries such as Korea, accounting for 59.4% in 2002 and reached 46.5% in 2015.⁵⁰

This different age pattern has various diagnostic, prognostic, and therapeutic implications. The main screening/diagnostic tool for detection of BC remains the soft tissue mammography. The American Cancer Society recommends annual mammography for moderate-risk women after the age of 45 years.⁵¹ In younger population, the sensitivity of screening mammography is much lower because of higher glandular breast density.^52,53 This means that up to half of the Egyptian patients diagnosed with BC could be missed in a mammography screening program.

Regarding disease outcome, several studies have shown that younger patients with BC carry poorer prognosis. A study by Azim et al⁵⁴ found that patients with BC younger than 40 years had poorer relapse-free survival even after adjustment for BC subtype, tumor size, nodal status, histologic grade, and treatment modality (hazard ratio, 1.34; 95% CI, 1.10 to 1.63; P = .004). This highlights age as an independent surrogate of biological aggressiveness that could contribute (in addition to advanced stage) to the poorer outcome observed in Egyptian patients with BC.

The second striking finding in our study is that Egyptian patients were more frequently presented with advanced stages (stage III disease: 45%, stages T2 and T3: 55% and 21%, respectively, and positive lymph nodes: 70%). Interestingly, young females with BC had presented with even more advanced stages, in whom the proportion of stage III was 48%, while stages T2 and T3 were 49% and 27%, respectively. Of note, in the California Cancer Registry⁵⁵ and the Chinese population,⁴⁸ the combined incidence of stages III and IV were 13% and 20%, respectively. However, younger patients were also presented with more advanced stages in a recent (2022) SEER report.⁴⁹ This higher incidence of advanced stages contributes to poorer survival irrespective of the therapeutic advances. This underlines the importance of early detection as a tool to improve the disease outcome in Egypt and other developing countries.

Moreover, our study had pointed to another factor that may contribute to the poorer prognosis in the Egyptian population, which is the higher prevalence of more aggressive biological subtypes. This was evident for the HER2+ subtype, where it represented 21% of BC in Egyptian females, compared with 14% in SEER reports.^56,57

Furthermore, there was a low rate of BCS utilization in our study, representing only 15% of total BC cases; however, a clear trend to increased BCS rates and decreased MRM rates were observed over time. Of note, in the Korean study, 67.4% were treated with BCS among 22,395 invasive cancer cases diagnosed in 2017.⁵⁰

The limitations of this study include the retrospective nature for most of the studies and the dependence on multiple AJCC manual editions for staging. Furthermore, there was a moderate to marked statistical heterogeneity between the included studies. However, this was partially resolved by sensitivity analysis for the pooled estimates for stage III.

In conclusion, our analysis shows that Egyptian patients with BC are diagnosed at a younger age, with a far more advanced stage and aggressive biological subtypes compared with Western and other developed countries. This suggests the need for a tailored screening/early detection program aiming at downstaging of the disease at the time of presentation in a younger age population, rather than the internationally recommended standard programs. Moreover, this should affect the offered modalities for diagnosis and treatment, and the burden on the health care system, according to the current population structure, which will lead to improving the survival outcomes consequently.

AUTHOR CONTRIBUTIONS

Conception and design: Hamdy A. Azim, Hagar Elghazawy, Ahmed H. Abdelaziz, Loay Kassem

Provision of study materials or patients: All authors

Collection and assembly of data: All authors

Data analysis and interpretation: Hamdy A. Azim, Hagar Elghazawy, Ramy M. Ghazy, Ahmed H. Abdelaziz, Loay Kassem

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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