Introduction

Breast cancer (BC) is a heterogeneous non-gynaecological cancer of females worldwide, with different characteristics, types/subtypes, stages at diagnosis, and grades1. It mainly affects women aged 50 years and older, but younger age groups can also be affected by BC. About 1 in 8 women are diagnosed with BC during their lifetime, although the incidence is highly affected by race, ethnicity, and age. However, there is a high likelihood of achieving a complete remission if the disease is diagnosed and treated at an early stage2. Physiological, behavioural, and genetic risk factors might be attributed to premenopausal (52.7%) and postmenopausal (54.7%) BC cases3. Risk factors that increase the risk of BC include fibrocystic breast disease, a first child after the age of 35 years, and chest irradiation. However, improper lifestyle, including obesity, alcoholism, smoking, low physical activity, and unhealthy diets, are among the other risk factors that enhance this cancer4.

Generally, there is a lack of awareness and knowledge of BC symptoms among women, especially in low-income and developing countries, including Iraq. BC can exhibit various symptoms, but the initial, obvious sign is usually a lump and a small mass or region of solidified breast tissue5. Thus, it’s recommended that women perform breast self-examination manually and regularly for any alterations, and mammography is recommended for general breast health above age 45 years (menopause age)6,7. BC comprises three main tumour subtypes, including luminal (A and B), human epidermal growth factor 2 (HER2)- overexpressing, and triple-negative breast cancer (TNBC), which are characterised based on estrogen receptor (ER)/progesterone receptor (PR) expression and erb-b2 receptor tyrosine kinase 2 (ERBB2) gene amplification. These subtypes have diverse risk profiles and treatment modalities. The ideal treatment for the patients depends on the tumour subtype, cancer stage, tumour biology, and patient preferences8.

The survival rates for young women with BC are lower than for older women9. Thus, progress to counteract BC death could be enhanced by modifying racial differences through improved access to high-quality screening and treatment via nationwide Medicaid expansion and partnerships between community stakeholders, advocacy organisations, and healthcare systems9. There are different modalities of BC management. Chemotherapy, hormonal therapy, and ovarian function suppression can be started before or after the operation based on the molecular subtype and stage of the disease. On the other hand, BCS or lumpectomy is more accepted by patients cosmetically. Previously, only the size of the tumour, its site and the grade of the cancer were considered in deciding to do BCS or mastectomy10. Thus, we aimed to study the clinicopathological and molecular landscape of premenopausal BC among patients.

Methodology

Patients and study setting

This prospective study was done on 300 primary BC patients aged 25 to 50 at Hiwa Hematology and Oncology Hospital, Sulaimaniyah, Iraq, from January 2016 to May 2022. Patients underwent definitive management either before chemotherapy or after receiving neo-adjuvant (n = 13, 9.1%) and on regular follow-up.

Inclusion criteria

Female patients aged 25 to 50 years with primary BC who underwent surgical operations regardless of ethnicity or nationality were included in this study.

Exclusion criteria

BC patients with metastases, stage IV disease, and menopause were excluded from the study BC.

Questionnaire

A well-designed questionnaire, validated by four local experts in the field, was used to collect patients’ sociodemographic data, including marital status, age at diagnosis, age at menarche, history of breastfeeding, past surgery, and parity, through face-to-face interviews (Supplementary 1).

Study protocol

Post-operative patients’ samples were obtained for histopathological examination (HPE) after a surgical operation (mass excision/lumpectomy or mastectomy) by an expert surgical team, excluding the author. Consequently, BC patients were divided into six groups (luminal A, luminal B, luminal B-HER2+, HER2 (low and high), and TNBC, depending on the expression of ER, PR, HER2, Ki-67, and TNM (tumour size, spread, and metastases) staging11. If the axillary lymph node (LN) was positive by Fine Needle Aspiration Cytology (FNAC) test or sentinel biopsy by frozen section, then LN dissection levels I & II were done. Then, information on tumour stage, size, grade, and margin involvement was abstracted from pathology reports.

Ethics approval

The proposal for the current study was revised and accepted by the Scientific and Ethical Committees of the College of Medicine, University of Sulaimani (No. 85/15/01/2023-COM-UOS). All procedures and tests were conducted by the principles outlined in the Declaration of Helsinki.

Statistical analysis

Statistical Package for the Social Sciences (SPSS, IBM, Chicago, USA, version 25) was used for data analysis. Variables were presented as numbers and percentages. Fisher’s exact test was used to compare the data between different variables. A p < 0.05 was considered significant.

Results

Patients’ sociodemographic data

In this study, 300 patients with BC were studied. Regarding their sociodemographic data, most of them (90.3%) were married, aged 45–50 years (36%) when diagnosed, aged 13–14 years at menarche (70.3%), had a history of breastfeeding (76.7%), given childbirth (85%), and without past surgical history (92%) (Table 1). Additionally, the mean age of patients at diagnosis was 41.2 ± 5.8 years, while the mean age at menarche was 13.3 ± 1.3 years.

Table 1 Socio-demographic characteristics of the studied patients.
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A molecular subtype of breast cancer

Most patients (39%) had luminal B subtype, while the fewest (0.34%) had HER2 overexpression. A significant correlation was found between the molecular subtype and type of surgery (p = 0.041). The overall rate of BCS was 66.7%, with the highest rate observed in patients with TNBC molecular subtypes (87%). The overall rate of mastectomy was 33.3%, with the highest rate (44.9%) found in patients with the luminal B-HER2 + subtype (Table 2).

Table 2 Type of surgery by molecular subtype in studied patients.
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Tumour margin

Most (83.79%) of the tumour margin was free (mostly in TNBC type), while 9.03% was involved (mostly in luminal A type), and only 5.7% was close (mostly in luminal B-HER2+). Concerning the involvement of the tumour margin, 12.33% with luminal A molecular subtype had involvement, followed by luminal B subtype (10.3%), then luminal B-HER2+ (5.8%), and TNBC (4.3%). There was a significant difference between the molecular subtype and tumour margin involvement (p = 0.043) (Table 3).

Table 3 Tumour margin status by molecular subtype in studied patients (n = 295).
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Tumour focality

Upon histopathological examination of the tumour mass, most patients (63.7%) had unifocal BC. Therefore, they were the most suitable for BCS, and only 4.7% ended up with involved margins and needed revision surgery. The tumour margin involved 20.3% and 15.6% of cases diagnosed with multifocal and multicentric tumour masses, respectively. However, 84.7% had a free tumour margin for all tumour mass types, while a close tumour margin was only found in 5.7% of excised masses. There was a significant association between the focality of the tumour and the margin postoperatively (p < 0.001) (Table 4).

Table 4 Tumour focality by histopathological examination of the mass in studied patients.
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Breast cancer stage

Most patients (n = 91) had stage II-A; the fewest (n = 47) had stage III-C. The highest rate of luminal A type (40.6%) was observed in stage III-A, but it was significantly lower in stage III-C (19.1%). Regarding luminal B-HER2+, the rate was 61.5% among those with no lesion, 16.9% in stage I-A, 19.8% in stage II-A, 25% in stage II-B, and then decreased to 6.3% in stage III-A, with a sharp increase to 36.2% in stage III-C. The HER2 overexpression had the lowest level (3.3%) in all stages. A significant association was found between molecular subtypes and the stage of the disease (p < 0.001) (Table 5). Most tumour masses (52%) were sized > 2 - <5 cm (T2) with the highest involved margin (48.3%), followed by T1 mass (37.9%), then T3 mass (10.3%), while DCIS had no involved margin. No significant association was detected between the margin involvement by tumour cells and the tumour size (p = 0.606) (Table 6).

Table 5 Molecular subtype by stage of the disease in the studied patients.
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Table 6 Pathological tumour size after treatment by margin involvement in studied patients.
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Discussion

Generally, incidence, response to therapy, management, mortality, and survival rates of BC vary considerably in age, stage of cancer, cancer type (primary or secondary), cancer subtype, detection and diagnosis time, and therapy used12. Therefore, in this study, the sociodemographic characteristics of the enrolled patients were studied thoroughly using a well-designed questionnaire. It was realised that the incidence of BC was positively correlated with those aged 45–50 years (premenopausal), married, aged 13–14 years at menarche, practised breastfeeding, given birth, with no surgical history, and had a tumour mass of < 5 cm.

In this regard, Abousahmeen et al. (2023) reported that BC patients had a mean age of 47.3 ± 10.7 years, with most of them being premenopausal (59.2%)13. Sauder et al. 2021 mentioned that women aged 40–64 years covered the most significant proportion of BC patients14, while Al-Thoubaity et al. 2020 found that the average age of the BC patients was 49 years with an average tumour size of 3.2 cm15. Shahid et al. (2018) reported that the age of BC patients ranged between 46 and 50 years16, and de Bonifac et al. (2021) found that women aged 50–64 reported the highest incidence of BC17. Concerning the correlation between marital status and the incidence of BC in patients, the outcomes of this study were inconsistent with the results of some studies that mentioned higher rates of BC in unmarried women18,19,20. In contrast, some studies claim that marital status does not influence this malignant disease3,21. Moreover, the age at menarche (13–15 years) was directly correlated with the possibility of mammary carcinoma in this study, which disagreed with Goldberg et al. (2020)22 but agreed with Chollet-Hinton et al. (2016)23. Breastfeeding has become a well-documented protective factor for BC24. Still, the current study realised the opposite result, which disagrees with Chollet-Hinton et al. 201623 but is consistent with that of Zhou et al. 201525, which mentioned that breastfeeding was inversely related to BC. Regarding the parity status in this study, the result was in line with another study23. However, Lima et al. (2020) stated that breastfeeding could not be attributed to alterations in parity over time26.

Based on the data studied in the literature, luminal A tumours have the highest incidence but the lowest mortality rate. However, basal-like and HER2-type tumours occur less often but are associated with poorer survival12. Consequently, the luminal B subtype reported the highest rate in this study, while HER2 overexpression reported the lowest rate. In this respect, some studies23,27 have mentioned that the luminal type is more common, while the HER2 type is less common. Similarly, luminal B was noted to be the more common type among BC patients in Indonesia28. Similarly, in Libya, luminal B reported the highest (63.66%), followed by TNBC (20.04%), then HER2+ (11.6%), and luminal A (4.7%)13; however, in Saudi Arabia, it was found that luminal A was the most prevalent (58.5%), followed by triple negative (16%), luminal B (14%), then HER2-positive (11.5%)15. Whereas in Iran, it was shown that 42% were luminal A, 19.2% luminal B, 23% triple negative and 15% HER2+16, while in Egypt, it was displayed that the most commonly detected molecular subtype was luminal B (34.9%), followed by triple negative (31.4%), HER2 (19.2%), then luminal A (14. 5%)29.

Furthermore, most of the studied patients underwent BCS, while the rest underwent mastectomy as a treatment modality for this malignant disease. The same outcomes were observed in another study, and they also mentioned higher survival rates for patients with BCS than patients assigned to mastectomy27,30,31. On the contrary, Onitilo et al.32 stated that two-thirds of patients had BCS and one-third had a mastectomy, with the same survival rates. Moreover, the number of foci should be considered an independent prognostic factor, which is currently not reflected in the TNM classification. In this regard, Multicentric and multifocal BC is an independent risk factor and should be included in the risk estimation by re-evaluating the existing TNM classification of the UICC33. In the current study, the focality of the tumour mass after surgery was primarily unifocal, multifocal, and multicentric. These findings agreed with other study results, which also mentioned that most patients with BCS had unifocal tumour mass27 and higher survival rates in patients with unifocal mass34.

Regarding BC staging, the higher the number, the more the cancer has spread, and it is usually stated upon the first diagnosis. In this study, most patients had stage II-A, followed by stage II-B, while the fewest had stage III-C. The highest rate of luminal A was found in stage III-A. Other studies have mentioned stage II as the highest, followed by stage III23,27. On the other hand, stage I and II cases that had BCS alone were low in all age groups except in most older women. Also, they stated higher survival in BCS plus radiotherapy than in mastectomy in stages I and II35. Another study in Libya mentioned that 66.1% of patients were LN-positive. Most patients were in grades II and III, while 47.0% of cases were at stage II and 39.5% were at stage III13. In Egypt, it was reported that 54.4% were in grade III and 22.4% were in stage IB29. In this study, most tumour masses were sized > 2 cm and > 5 cm (T2), followed by T1 masses, and then T3 masses. Additionally, most of the tumour margin was free, the least involved portion was minimal, and only a small portion was close. Hence, a tumour mass of > 2 cm was found to be most common in patients of another study, but the relationship between tumours with invasive BC was not linear23,36,37.

The study’s limitations include the lack of consideration for potential confounders, such as smoking and body mass index, and the possible underestimation of unlisted comorbid conditions. Additionally, this study was limited by a lack of tumour biology information, such as lymphovascular and extracapsular invasions, and the size of nodal metastases. Another limitation was that the survival and death rates in BC patients were not reported; also, the information about the types of chemotherapy used was lacking.

Conclusions

Marital status, age, breastfeeding, and parity condition of women significantly correlated with the high incidence of BC. The luminal B cancer subtype was most common among patients with the highest level of BCS. Additionally, a unifocal tumour mass with stage II-A BC was more profound in the studied case.