Middle Eastern Cancer and Oncology Journal

Breast cancer is the most prevalent form of cancer among the global female population, constituting a significant contributor to morbidity and mortality rates (Bray et al., 2018; Ferlay et al., 2021; Harbeck et al., 2019). It is widely acknowledged that a multitude of reproductive factors exert a significant influence on the risk of developing breast cancer (Akram et al., 2017; Bellanger et al., 2018; Ferlay et al., 2019; Lukong, 2017; Torre et al., 2017). These factors encompass parameters such as parity, age at first childbirth, and the duration of breastfeeding. As demonstrated in the relevant literature, breastfeeding has been shown to confer long-term protective effects through hormonal modulation, reduced lifetime oestrogen exposure, and alveolar cell differentiation (Akram et al., 2017; Skibinski & Kuperwasser, 2015).

The biological behaviour of tumours is significantly influenced by hormonal receptor status (ER and PR) and HER2/neu expression. These factors play a crucial role in determining treatment pathways and prognostic outcomes (Kamińska et al., 2015; Kolak et al., 2017; Nascimento, 2022; Tuasha & Petros, 2020). Triple-negative breast cancer (TNBC), defined by the absence of ER, PR, and HER2 receptors, is associated with higher grade, poorer prognosis, and earlier recurrence (Kotsopoulos, 2018; Melvin et al., 2016; Shiovitz & Korde, 2015). The identification of modifiable factors that influence receptor expression patterns remains a significant research priority.

Despite the findings of numerous international studies indicating a possible protective association between breastfeeding and the development of aggressive tumour subtypes, including TNBC, data from the Middle East and Iraq remain scarce (Angahar, 2017; Feng et al., 2018; Hanahan, 2022). It is imperative to comprehend these associations in order to formulate efficacious public health strategies and to raise awareness of the long-term benefits of breastfeeding.

The present study aims to explore the relationship between breastfeeding history and hormonal/HER2 receptor expression among breast cancer patients, with a view to providing insight into potential protective mechanisms associated with reproductive behaviour. Despite the consistent association between breastfeeding and a reduced overall risk of breast cancer, the relationship between breastfeeding and tumour biological characteristics, particularly hormonal and HER2/neu receptor status, remains less clearly defined. Existing studies have focused predominantly on breast cancer incidence rather than tumour subtype differentiation, and evidence from Middle Eastern populations remains limited. In view of the prognostic and therapeutic importance of receptor status, the present study aims to explore the association between breastfeeding history and hormonal and HER2/neu receptor expression among breast cancer patients.

Study Design and Setting

The present retrospective observational study was conducted among 144 breast cancer patients who were diagnosed and treated at a tertiary oncology centre. The objective of the study was to examine the association between breastfeeding history and tumour receptor status using routinely collected clinical data.

Study Population

Patients were eligible for inclusion if they had a confirmed diagnosis of breast cancer, complete clinical, reproductive, and pathological data available in their medical records, and documented estrogen receptor (ER), progesterone receptor (PR), and HER2/neu receptor status. Patients were excluded from the study if they had recurrent or metastatic disease at the time of diagnosis, incomplete receptor status information, or unavailable breastfeeding history. Cases with missing or incomplete clinical, reproductive, or pathological variables were excluded from the analysis to ensure the completeness of the data used in statistical comparisons.

Data Collection

The data were derived from medical records and encompassed demographic and reproductive characteristics, including age, parity, and marital status. The breastfeeding history of the patients was obtained from the documented clinical records and was classified dichotomously as "yes" or "no" based on whether the patient had ever breastfed. The tumor-related variables that were collected for analysis included tumor grade, cancer stage, and the presence of lymphovascular invasion. The pathological data also included ER, PR, and HER2/neu receptor status, as well as the classification of triple-negative breast cancer, defined by the absence of ER, PR, and HER2/neu expression.

Statistical Analysis

The associations between breastfeeding history and tumour receptor status were assessed using the chi-square test or Fisher's exact test, as appropriate. Statistical significance was defined as a two-sided p value of less than 0.05. All analyses were conducted using standard statistical software.

The subsequent section presents the demographic profile, tumour characteristics, and the association between breastfeeding history and receptor status, as demonstrated in Tables 1-4.

Demographic and Reproductive Characteristics

The following subsection delineates the age distribution, parity, breastfeeding history, contraceptive use, and family history of breast cancer. The mean age of the patients was 52.5 years (± 22.5), with 88% of patients having given birth. A breastfeeding history was documented in 70.6% of patients, while 21.3% had used oral contraceptives. A family history of breast cancer was documented in 37.3% of patients. The findings outlined in this section delineate the reproductive and familial profile of the cohort, as demonstrated in Table 1.

Tumor Characteristics

This subsection offers a synopsis of the salient pathological characteristics of the tumours. The majority of patients (98.6%) were diagnosed with invasive ductal carcinoma, with grade 2 tumours accounting for 80% of cases. Lymphovascular invasion was observed in 65.3% of cases, and the majority of these cases presented with T2 tumours (65.3%) and N1 nodal status (69.3%). The characteristics outlined reflect the overall disease burden, as demonstrated in Table 2.

Association Between Breastfeeding and Receptor Status

This subsection presents a comparative analysis between patients with and without a history of breastfeeding. No significant differences were identified for ER, PR, or HER2/neu positivity. However, the data revealed a significant association between breastfeeding and a reduced proportion of triple-negative breast cancer (TNBC), with a p-value of 0.014. The findings presented herein suggest a potential protective relationship between breastfeeding and certain aggressive tumour subtypes, as illustrated in Tables 3 and 4.

The present study examined the association between breastfeeding history and receptor status (ER, PR, HER2/neu) in breast cancer patients, revealing a key finding: breastfeeding was significantly associated with a lower frequency of triple-negative breast cancer (TNBC) (p = 0.014). Although breastfeeding did not have a significant effect on the expression of ER, PR, or HER2/neu, the protective association of breastfeeding against TNBC is consistent with global data indicating that lactation may modulate tumour biology in a way that favours less aggressive phenotypes (Akram et al., 2017; Kolak et al., 2017; Kotsopoulos, 2018; Lukong, 2017).

This phenomenon can be attributed to several biological mechanisms. It has been demonstrated that breastfeeding induces terminal differentiation of mammary epithelial cells, which has the effect of reducing the pool of vulnerable progenitor cells implicated in the development of basal-like and TNBC tumours (Akram et al., 2017; Melvin et al., 2016). This differentiation reduces the susceptibility of primitive stem-like cells to carcinogenic transformation, consistent with molecular studies showing that TNBC often arises from undifferentiated basal compartments (Kotsopoulos, 2018; Melvin et al., 2016; Shiovitz & Korde, 2015).

Moreover, breastfeeding has been demonstrated to induce a suppression of ovulation, thereby reducing cumulative lifetime estrogen exposure. Although TNBC is hormone-independent, a reduction in oestrogen cycling has been demonstrated to decrease mammary epithelial proliferation, thereby decreasing the accumulation of DNA replication errors and genomic instability (Akram et al., 2017; Bellanger et al., 2018; Lukong, 2017; Torre et al., 2017). This hormonal modulation is consistent with the findings of studies demonstrating a decreased risk of breast cancer with extended breastfeeding durations (Akram et al., 2017; Lukong, 2017).

It is evident that a further protective mechanism is the physiological shedding and apoptosis of damaged epithelial cells during lactation and post-lactational involution. This process eliminates genetically unstable or premalignant cells, thereby functioning as a natural "clearance" mechanism that lowers the likelihood of aggressive tumour subtypes forming (Akram et al., 2017; Kotsopoulos, 2018).

In the present study, breastfeeding was not found to be significantly associated with individual ER, PR, or HER2/neu status. This finding is supported by prior research demonstrating that breastfeeding does not uniformly influence receptor expression patterns, but has a more selective effect on reducing the emergence of receptor-negative, high-proliferation tumours (Feng et al., 2018; Kolak et al., 2017; Kotsopoulos, 2018). The present study found no significant association between HER2/neu expression and breastfeeding, which is consistent with reports that HER2-positive disease is driven more by molecular amplification pathways than reproductive factors (Kotsopoulos, 2018; Melvin et al., 2016; Zhao et al., 2018).

The protective association observed between breastfeeding and triple-negative breast cancer (TNBC) is clinically meaningful. TNBC is characterised by high grade, rapid progression, early recurrence, and limited targeted therapy options, making it one of the most challenging breast cancer subtypes to manage (Kotsopoulos, 2018; Melvin et al., 2016; Shiovitz & Korde, 2015). Consequently, public health strategies promoting breastfeeding may contribute to a reduction in the incidence of biologically aggressive tumours, particularly TNBC, in Middle Eastern populations.

In the present study, an investigation was conducted into the correlation between receptor status and a range of additional demographic factors. These additional demographic factors included age, parity, oral contraceptive use, and family history. However, the investigation revealed that no significant correlation was observed between receptor status and the aforementioned demographic factors. This finding is consistent with the broader literature, which demonstrates that reproductive history exerts a stronger influence on tumour subtype development than basic demographic characteristics (Akram et al., 2017; Bellanger et al., 2018; Ferlay et al., 2019; Lukong, 2017; Torre et al., 2017; Tuasha & Petros, 2020).

While these findings offer valuable insights into the regional context, it is important to acknowledge the limitations of the study. The retrospective design and single-centre setting of the study may limit its generalisability. It is evident that certain subgroup analyses (for instance, HER2-positive or PR-negative groups) encompassed relatively modest numbers, and the incorporation of larger multicentre cohorts would serve to enhance the statistical potency. Notwithstanding, this analysis provides valuable evidence from Iraq regarding the relationship between reproductive behaviour and tumour biology.

It is important to acknowledge the limitations of the study. The retrospective design imposes limitations on causal inference and may be susceptible to selection bias and unmeasured confounding. Furthermore, the reliance on existing medical records resulted in the restriction of available reproductive and lifestyle variables that may have influenced tumour biology. These limitations must be considered when interpreting the findings.

The present study demonstrates that breastfeeding is associated with a significantly lower incidence of triple-negative breast cancer, thus reinforcing its role as a protective reproductive factor. These findings align with international evidence, underscoring the significance of breastfeeding promotion as a component of breast cancer prevention strategies, particularly in regions experiencing an increase in TNBC rates.

The analysis revealed that breastfeeding history was associated with a reduced frequency of triple-negative breast cancer, suggesting a potential protective role against more aggressive tumour subtypes. No significant associations were observed with individual hormonal or HER2/neu receptor expression. These findings underscore the significance of reproductive factors in tumour biology and underscore the importance of breastfeeding awareness in the prevention of breast cancer.

Ethics Approval and Consent to Participate

Ethical approval for this study was obtained from the Iraqi Board for Medical Specializations. Prior to analysis, all patient data were anonymised and handled confidentially in accordance with institutional guidelines and the principles outlined in the Declaration of Helsinki.

Consent for Publication

Not applicable.

Availability of Data and Material

The data that supports the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest / Competing Interests

The authors declare that there are no conflicts of interest.

Funding

The authors declare that this research received no external funding.

Authors' Contributions

K.K.H.: Methodology, Formal analysis, Data curation, Writing of the original draft.

M.F.H.: Conceptualization, Resources, Writing – review & editing, Supervision.

Acknowledgment

Not applicable

Use of Generative AI and AI-Assisted Technologies

The authors declare that no generative AI or AI-assisted technologies were used in the preparation of this work.