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 Table of Contents  
ORIGINAL RESEARCH REPORT
Year : 2022  |  Volume : 19  |  Issue : 4  |  Page : 112-118

Breast cancer heterogeneity: Comparing pre- and postmenopausal breast cancer in an African population


1 Department of Surgery, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda
2 Department of Biostatistics, School of Public Health, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda
3 Department of Statistics and Actuarial Science, University of Waterloo, Waterloo, Canada
4 Department of Pathology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda
5 Department of Gynecology and Obstetrics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda

Date of Submission14-Jun-2022
Date of Acceptance09-Sep-2022
Date of Web Publication09-Nov-2022

Correspondence Address:
Prof. Faustin Ntirenganya
Department of Surgery, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali
Rwanda
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcls.jcls_47_22

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  Abstract 


Background: Breast cancer (BC) is the most prevalent cancer in women and the leading cause of women's cancer-related deaths and morbidity worldwide. Conventionally considered as a single disease, recent advances suggest that BC is rather a heterogeneous disease with different molecular subtypes exhibiting distinct clinical presentation, anatomo-pathological features, response to treatment and survival outcomes. The purpose of this study was to compare tumor characteristics and epidemiologic risk factors associated with premenopausal versus postmenopausal BC and to assess heterogeneity by menopausal status. Methods: This was a comparative cross-sectional study. A total of 340 patients were included in the study (170 premenopausal vs. 170 postmenopausal BC). Patients' and tumor characteristics were compared in both populations. Percentages and means have been used for descriptive statistics. For categorical variables with comparison groups not exceeding 2, Fischer's exact test was used, otherwise, Chi-square test was used. For continuous variables, Mann–Whitney U-test has been used to compare the numerical ranked variables. A value of P = 0.05 or less was considered statistically significant. Odds ratio (OR) and 95% confidence interval (CI) was estimated using logistic regression analysis. Results: The median age of patients was 49 years (range: 18–89 years), with premenopausal median age of 41 years (range 18–50 years) and postmenopausal median age of 58 years (range 48–89 years). Factors associated more with the occurrence of premenopausal BC than postmenopausal BC were obesity/overweight in adolescence/early adulthood (OR = 0.29 95% CI 0.18–0.49, P < 0.001) and history of benign breast disease (OR 0.34 95% CI 0.14–0.83, P = 0.014), while factors associated more with postmenopausal than premenopausal BC included alcohol intake (OR = 2.47 95% CI 1.54–3.98, P < 0.001), history of breastfeeding (OR = 2.75 1.12–6.78, P = 0.036). However, sports activities (OR = 0.33 95% CI 0.16–0.65, P = 0.0015) and contraceptive use (OR = 0.19 95% CI 0.12–0.32, P < 0.001) seem to be protective for postmenopausal BC. In premenopausal period, patients presented more at advanced stages (Stage III and IV) (51.2% of premenopausal vs. 44.7% for postmenopausal, P = 0.0246), reported more intermediate-to-rapid disease progression (92% in premenopausal vs. 81.1% in postmenopausal (P < 0.001), had more invasive ductal carcinoma (98% in premenopausal vs. 93.5% in postmenopausal (P = 0.053) and had more poorly differentiated tumors (72% compared to 19.4% of postmenopausal BC patients (P < 0.0001). There was no statistically difference in molecular subtypes distribution between premenopausal and postmenopausal women (P = 0.062). However, progesterone receptor (PR) positivity was more associated with postmenopausal BC (P = 0.0165). Conclusion: BC is a heterogeneous disease. Premenopausal BC seems to be more aggressive than postmenopausal BC, with a relatively high prevalence of poorly differentiated and high-grade tumors with rapid progression. However, pre- and postmenopausal BC have similar molecular subtypes with different PR expression but similar ER and human epidermal growth factor receptor 2/Neu oncogene expression.

Keywords: Breast cancer, heterogeneity, menopausal status, molecular subtypes, risk factors


How to cite this article:
Ntirenganya F, Twagirumukiza JD, Bucyibaruta G, Rugwizangoga B, Rulisa S. Breast cancer heterogeneity: Comparing pre- and postmenopausal breast cancer in an African population. J Clin Sci 2022;19:112-8

How to cite this URL:
Ntirenganya F, Twagirumukiza JD, Bucyibaruta G, Rugwizangoga B, Rulisa S. Breast cancer heterogeneity: Comparing pre- and postmenopausal breast cancer in an African population. J Clin Sci [serial online] 2022 [cited 2022 Nov 29];19:112-8. Available from: https://www.jcsjournal.org/text.asp?2022/19/4/112/360622




  Introduction Top


Breast cancer (BC) continues to be a neglected killer disease in Africa. Every year, around 150,000 new cases are diagnosed with 63,000 deaths, which is expected to double in the next 30 years.[1]

The majority of cases are found in young and productive women hindering seriously the continent development.[2],[3]

BC heterogeneity has been documented not only among different patients (inter-tumor heterogeneity) but also within each individual tumor (intra-tumor heterogeneity). The existence of different molecular subtypes of BC, indicating intra-tumor heterogeneity, create diagnostic and therapeutic challenges but have improved the classification of BC patients into low-, intermediate- and high-risk groups for personalized treatments.[4],[5],[6]

It is important to understand BC etiologic and biologic heterogeneity. Early studies on etiologic heterogeneity of BC linking environmental exposures to somatic mutations caused by smoking, exposures to infectious agents or exposure to other known carcinogens, supported the existence of distinct epigenetic profiles of BC in general.[7],[8],[9]

However, compared to postmenopausal BC, there are not yet enough evidence to conclude that premenopausal BC is totally different to justify specific treatment guidelines, screening, and early detection strategies.[10],[11],[12]

A better understanding of molecular subtypes drivers may have invaluable clinical and public health importance. In fact, molecular markers profiling constitutes a cornerstone and the basis for all therapeutic decisions in modern BC management, playing a big role in prognostication and monitoring of disease progression. Indeed, BC molecular subtyping permits to adapt of treatment guidelines and to tailor therapies to individual patients for better outcomes.[13],[14],[15],[16]

The purpose of this study was to compare breast tumor characteristics and epidemiologic risk factors associated with premenopausal versus postmenopausal BC and to assess heterogeneity by menopausal status.


  Methods Top


Study design and setting

This was a comparative cross-sectional study conducted at the University Teaching Hospital of Kigali (CHUK) and Butaro Cancer Center of Excellence (BCCOE) in Rwanda from September 2019 to September 2020.

Population

Women attending breast clinics at CHUK and BCCOE have been recruited for the study after histological confirmation of BC. For the purpose of the study, the premenopausal period was defined based on self-rated menopausal status:

  1. Any woman who reported having seen her menses within the last month was considered premenopausal, as well as those who were pregnant or breastfeeding during the study period. In addition, women who reported not having seen menses in the previous 6 months for identifiable medical reasons (medications, diseases) were also considered premenopausal if aged ≤50 years
  2. Any women who reported not having seen menses in the previous 6 months without any identifiable medical reasons (medications, diseases) were considered postmenopausal if aged ≥50 years. However, if aged ≤50 years, hormonal tests to determine menopausal status were conducted. High follicle-stimulating hormone levels (over 40 mIU/ml) and low estradiol levels (below 30 pg/ml) were diagnostic for premature menopause. Furthermore, regardless of their age, women who underwent bilateral surgical removal of ovaries were considered postmenopausal.


Data collection

A preestablished questionnaire was used to collect sociodemographic, clinical, and pathological characteristics of BC. A data capture sheet was developed based on different questionnaires used in previous studies, and information on established or probable BC risk factors (lifestyle, reproductive, hormonal, genetic, and medical history) was collected for both pre- and postmenopausal women. Clinical, histopathological, and immunohistochemistry findings were collected using direct patients' interviews, pathology registries, reports, and patients' files.

Sample size calculation

The sample size was calculated using G*Power 3.1.9.7 for windows, online software for sample size calculation. Assuming 95% power, the effect size of 0.25, alpha error of 0.05. Therefore, the total sample size was found to be 316.

Statistical analysis

Data analysis was performed using SPSS version 25.0 (IBM Corporation, Armonk, New York, 10504-1722, USA). Percentages and means have been used for descriptive statistics. The Chi-square test was used for categorical variables. However, while for ladder-assessed values (e.g. slow, intermediate, and rapid) Chi-square for trend test was used, Fisher's exact test was used for categorical variables with comparison groups not exceeding 2. Mann–Whitney U-test was used for ranked continuous variables. Logistic regression analysis was performed for associations, and risk factors of BC was estimated by odds ratio (OR). For all ORs, 95% confidence interval (CI) was considered. A P < 0.05 was considered statistically significant.

Ethical considerations

The study was approved by IRB of the College of Medicine and Health Sciences, University of Rwanda and by ethical committees of the CHUK and BCCOE. Written informed consent was obtained before prospective data collection.


  Results Top


Three hundred and forty patients were included in the study (170 premenopausal vs. 170 postmenopausal BC). The median age of patients was 49 years (range: 18–89 years), with premenopausal median age of 41 years (range 18–50 years) and postmenopausal median age of 58 years (range 48–89 years). Factors more associated with the occurrence of premenopausal BC than postmenopausal BC were obesity/overweight in adolescence/early adulthood (OR = 0.29 95% CI 0.18–0.49 P < 0.001) and history of benign breast disease (OR 0.34 95% CI 0.14–0.83 P = 0.014), while factors associated more with postmenopausal than premenopausal BC included alcohol intake (OR = 2.47 95% CI 1.54–3.98, P < 0.001), history of breastfeeding (OR = 2.75 1.12–6.78, P = 0.036). However, sports activities (OR = 0.33 95% CI 0.16–0.65, P = 0.0015) and contraceptive use (OR = 0.19 95% CI 0.12–0.32 P < 0.001) seem to be protective for postmenopausal BC [Table 1].
Table 1: Exposure to breast cancer risk factors among premenopausal and postmenopausal cases

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In premenopausal period, patients presented more at advanced stages (Stage III and IV) (51.2% of premenopausal vs. 44.7% for postmenopausal, P = 0.0246), reported more intermediate to rapid disease progression (92% in premenopausal vs. 81.1% in postmenopausal, P < 0.001). However, postmenopausal BC was more associated with the presence of chronic diseases 10% in premenopausal versus 22.4%, P = 0.002) [Table 2].
Table 2: Clinical characteristics

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Premenopausal women had more invasive ductal carcinoma (98% in premenopausal versus 93.5% in postmenopausal (P = 0.053), had more poorly differentiated tumors (72% compared to 19.4% of postmenopausal BC patients (P < 0.0001) and had high-grade tumors (48.8% with Nottingham grade 3 in premenopausal versus 43.5% in postmenopausal (P = 0.036). There was no statistically difference in molecular subtypes distribution between premenopausal and postmenopausal women (P = 0.062) [Table 3].
Table 3: Histological and molecular characteristics

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Estrogen receptors (ER) and human epidermal growth factor receptor 2 (HER2)/Neu oncogene expression was similar in both groups. However, progesterone receptor (PR) expression was statistically different (P = 0.016) [Table 4].
Table 4: Comparison of cell biology receptors expression among premenopausal and postmenopausal breast cases

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  Discussion Top


Classically, BC is described as a disease of older women. However, contrasting with what is seen in developed countries, BC may be presenting at a younger age in developing countries, progressing rapidly to advanced disease and have a poor prognosis.[17],[18],[19] In general, in Africa, and particularly in Rwanda, many young premenopausal women are suffering from unexplained aggressive forms of BC with an unacceptably high mortality rate.[20],[21],[22],[23] This study confirmed the younger age and the aggressive nature of BC in Rwanda, with a median age of 49 years, a vast majority of patients reporting a rapid disease progression and many high grade and poorly differentiated tumors.

Studies on etiologic heterogeneity of BC linking environmental exposures to somatic mutations caused by smoking, exposures to infectious agents, hormones or exposure to other known carcinogens supported the existence of distinct epigenetic profiles of BC.[24],[25],[26] Few studies which compared probable or established BC risk factors distribution per menopausal status found many differences.[27],[28],[29] Comparing pre- and postmenopausal BC, our study findings are in line with the literature by highlighting the existence of BC etiologic heterogeneity among the above-mentioned populations. In fact, factors more associated with the occurrence of premenopausal BC than postmenopausal BC were obesity/overweight in adolescence/early adulthood and history of benign breast disease, while factors associated more with postmenopausal than premenopausal BC included alcohol intake and history of breastfeeding. Indeed, the role of alcohol consumption in premenopausal BC cannot be ignored despite the causal relation being less clear. Inconsistent results were published regarding the menopausal status and different BC risk factors. Due to small sample sizes and methodological issues, results from those studies were probably underpowered to detect consistent differences.[30],[31],[32],[33],[34]

In a meta-analysis of case–control studies that addressed whether prior oral contraceptive use is associated with premenopausal BC, Kahlenborn et al. found that the use of oral contraceptives is associated with an increased risk of premenopausal BC, especially with use before the first full-term pregnancy.[35] In the same line, we found that contraceptive use is more associated with premenopausal BC, while it seems to be protective for postmenopausal BC. Indeed, most of the early research on this topic found no association between oral contraceptive use and BC, reassuring many in the research and clinical communities that there was little or no increased risk.[35],[36] Although several studies reported elevated risk estimates for particular aspects of oral contraceptive use, there was no consistency among these elevated risk estimates. The picture seems to have changed since the late 80s.[35],[37],[38] There are a number of studies during this period that do not support an increased risk related to oral contraceptive use.[39] However, an increasing number of studies have appeared that suggest an elevated risk in relation to some aspects of oral contractive use[12],[30],[40] These studies, especially those with positive findings, have received much publicity and generated renewed concern over the safety of oral contraceptives.

In our study, premenopausal women had more invasive ductal carcinoma, more poorly differentiated tumors, higher grade tumors compared to postmenopausal women. As reported in most of the previous studies, infiltrating duct carcinoma was the prominent histopathological type; other types included lobular carcinoma, Paget disease, and carcinoma in situ. Indeed, BC in young women is associated with adverse pathological factors, including high-grade tumors and are much more aggressive.[41],[42]

The consensus seems to be achieved in the current literature that the existence of different molecular subtypes of BC indicates intra-tumor heterogeneity, creating diagnostic and therapeutic challenges.[12],[13] However, it had improved the classification of BC patients into low-, intermediate-, and high-risk groups for personalized treatments.[43],[44],[45] By stratifying BC by menopausal status, our study found no difference in molecular subtypes distribution, O ERs, and HER2/Neu oncogene expression. Contrary to our findings, few authors had found that the expression of key biomarkers ER, PR, HER2/Neu, and proliferation markers like Ki67 appear to be different in young patients compared to older women.[46],[47] Furthermore, it seems that premenopausal ER-positive BC may respond poorly to endocrine therapy compared to postmenopausal BCs, suggesting the existence of heterogeneity as far as therapeutic outcomes are concerned.[20],[48] However, this was beyond the scope of this study.

Indeed, growing evidence suggest that estrogen positive premenopausal BC has distinct molecular characteristics compared to postmenopausal cancers. They have distinct integrin/laminin and estimated glomerular filtration rate signaling pathways, which may explain their different behavior vis-à -vis some therapeutic agents.[49],[50],[51] High incidence of estrogen-receptor positive tumors found in our postmenopausal patients may have a better prognosis. As it has been recorded in several studies, it sounds like good news for BC patients because these are more treatable tumors.[52],[53]

The results of the study should be interpreted, bearing in mind a number of limitations. In fact, despite its cross-sectional design, this study attempted to find associations between the past event (risk factors) and current status (BC). There may have been room for potential recall bias, which may make it difficult to demonstrate the relationship between exposure and outcome. Furthermore, we may have failed to identify all confounding variables, as there is no exhaustive list of probable risk factors for premenopausal and postmenopausal BC. Finally, the information about genetic risk factors was missing as well FISH analysis for equivocal HER2/Neu oncogene.


  Conclusion Top


BC is heterogeneous disease. Premenopausal BC seems to be more aggressive than postmenopausal BC, with a relatively high prevalence of poorly differentiated and high-grade tumors with rapid progression. However, pre- and postmenopausal BC in Rwanda have similar molecular subtypes with different PR expressions but similar ER and HER2/Neu oncogene expressions.

Disclosure

This study was sponsored by the Consortium for Advanced Research Training in Africa (CARTA). CARTA is jointly led by the African Population and Health Research Center and the University of the Witwatersrand and funded by the Carnegie Corporation of New York (Grant No--B 8606.R02), Sida (Grant No: 54100113), the DELTAS Africa Initiative (Grant No: 107768/Z/15/Z) and Deutscher Akademischer Austauschdienst (DAAD). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)'s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (UK) and the UK government. The statements made and views expressed are solely the responsibility of the Fellow.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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