BC is a multifaceted and heterogeneous disease influenced by a range of clinical, pathological, and biological factors that exhibit variability across different populations 1. These prognostic factors play a crucial role in the management of breast cancer. Therefore, to gain a deeper understanding of breast cancer and its molecular subtypes, we conducted an analysis of 9310 breast cancer cases.
Our study determined that the age at breast cancer diagnosis ranged from 22 to 85 years, with a mean of 48.93 ± 11.72 years. This finding is consistent with the results of earlier studies 3, 17. However, in Western and Asian countries, breast cancer typically occurs at a later age 18. The age at diagnosis is a crucial prognostic factor, as tumors diagnosed in younger individuals tend to be more aggressive and/or less responsive to treatment 3. Several factors may influence the variation in age at diagnosis, including population characteristics, genetic predisposition, and environmental factors 2. Our study also revealed a statistically significant difference in mean age at diagnosis among various breast cancer subtypes (P > 0.003). Patients with Invasive papillary carcinoma subtypes were generally older than those with other subtypes (57.24 ± 12.92) years. Invasive papillary carcinoma is classified as a low-grade carcinoma 19. Owing to the rarity of the disease and the complexity of its histological classification, there is no universally accepted consensus on the management of patients with invasive papillary carcinoma 20. Interestingly, invasive papillary carcinoma is relatively more prevalent among males 21 which is consistent with our observation of invasive papillary carcinoma breast cancer subtypes in male patients. Our study also reported a significantly higher female-to-male ratio (99.43%) compared to other studies 22, 23.
Our study identified invasive ductal carcinoma as the predominant histological subtype, aligning with the findings of most previous studies on breast cancer 28. Patients with invasive carcinoma with medullary features (53.0%) and invasive papillary carcinoma (57.8%) exhibited a greater tendency for right breast involvement. Conversely, patients with invasive ductal carcinoma (51.3%), invasive lobular carcinoma (55.9%), and mucinous tumor (54.4%) showed a higher prevalence of left breast involvement. A statistically significant correlation was established between the involved breast side and tumor type (P < 0.001). Numerous studies have delved into the possible reasons for the observed left-sided predominance in breast cancer 24, 25. Furthermore, a study reported that patients with left-sided breast cancer treated with radiation therapy were at an increased risk of cardiovascular complications and historically had worse outcomes 26.
Over half of all tumor sizes across subtypes fell within the 2 to 5 centimeter range, with tumor size less than 2 centimeters being more prevalent among patients with invasive papillary carcinoma (37.5%). Tumor size greater than 5 centimeters was more common among patients with mucinous tumors (11.8%). A statistically significant difference in tumor size was observed between the subgroups (P = 0.003). Moreover, tumor size at the time of diagnosis was significantly correlated with tumor subtype (P < 0.001). According to the "Size-Note" hypothesis, tumor size and the number of positive lymph nodes independently contribute to the lethality of invasive breast cancer 27. Smaller tumors (diameter less than 2 cm) exhibit a lower risk of axillary lymph node metastasis, and tumor size serves as an independent predictor of nodal positivity 28. Therefore, we propose that tumor size can predict survival by influencing regional lymph node metastasis, as larger tumors tend to invade adjacent tissues more extensively, increasing the likelihood of lymph node involvement 29. In Western countries, the majority of breast tumors are less than 2 cm in diameter, reflecting the early detection of the disease 30. However, the percentage of tumors larger than 2 cm in our study was higher compared to other studies 30, 31.
Our study revealed that 60.9% of invasive ductal carcinoma cases and 58.3% of invasive lobular carcinoma cases exhibited grade II histology. The majority of patients with mucinous (75.8%) and invasive papillary carcinoma (52.0%) tumors had grade I histology. Notably, more than half of patients with invasive carcinoma with medullary features (57.1%) had grade III histology. This finding contrasts with studies reporting a lower percentage of grade II tumors and a higher level of grade III histology 32. Histological grading serves as a powerful prognostic factor and is an integral component of several clinical decision-making tools, such as the Nottingham prognostic index and Adjuvant online 33. Interestingly, specific genetic and transcriptomic features of breast cancers were associated with distinct tumor grades 34. However, a multicenter study indicated that only lymph node status and lymphovascular invasion influenced prognosis, not tumor size or histological grade 35.
TNM stage 2 was the most frequently observed stage across all breast cancer subtypes, and a statistically significant association was established between TNM stage and breast cancer tumor g staging which was devised to classify the extent of local, regional, and distant disease involvement at the time of initial treatment, providing objective and enduring descriptions of the disease 36. Categories with similar prognostic significance can be combined to define the disease stages 37. However, our findings contrast with those of other studies, which have reported an unclear relationship between tumor stage and clinical outcome across the breast cancer patient population 38. This implies that TNM staging alone may not be an adequate predictor of therapeutic outcomes in breast cancer patients, not because of limitations in the staging system but rather due to the distinct biological characteristics of TNBC compared to other subtypes.
Our study determined that luminal A molecular subtype was widespread across all breast cancer histological subtypes, and luminal B was more prevalent among invasive ductal carcinoma than other subtypes (18.7%), consistent with the results of another study 39. However, our findings differ from those of other studies, which reported luminal B tumors as the most common subtype 40. Genetic, racial, and environmental factors may explain these inconsistencies, and variations in diagnostic facilities may also contribute. Our findings corroborate those of other studies 41, in demonstrating a higher frequency of triple negativity among invasive carcinoma with medullary features than other subtypes (35.4%). A statistically significant difference was observed in the distribution of molecular subtypes among breast cancer histological subtypes (P < 0.001).
Breast cancer is characterized by a distinct recurrence pattern. Sopik et al. demonstrated that the majority of recurrences and deaths occur within the first five years after diagnosis, with a particularly high risk in the first three years 42. The risk of recurrence steeply declines after this initial period. Conversely, in another group of patients, the risk of recurrence is low within the first five years after diagnosis, but distant recurrences continue to accumulate for up to 17 years 43. This study revealed that the majority of patients (more than 70% in all cancer subtypes) remained recurrence-free during the investigated time interval. Visceral organs and the brain are the most common sites of recurrence in breast cancer 44.
Chemotherapy has been demonstrated to improve survival outcomes for breast cancer patients, while the role of radiotherapy remains a subject of debate. In our study, postoperative chemotherapy was more frequently administered to patients with invasive ductal carcinoma (81.5%) and invasive carcinoma with medullary features (85.4%) subtypes. While multiple studies have confirmed the beneficial effects of radiotherapy on overall survival (OS) in breast cancer patients 45, others have suggested that its benefits may be limited. For instance, Chua et al. found that radiotherapy effectively reduced local-regional recurrences but not distant recurrences 46. Haque et al. proposed that mastectomy combined with radiotherapy was associated with improved OS only in high-risk patients (T3–4 or node-positive), whereas lumpectomy with radiotherapy was beneficial in both high- and low-risk cohorts (T1–2N0) 47. Chest and axillary radiotherapy was performed in most breast cancer subtypes in our study. The majority of study participants received hormonal therapy, except for women with invasive carcinoma with medullary features (61.7% not treated with hormonal therapy). A 2011 meta-analysis revealed that 5-year adjuvant hormonal therapy (HT) effectively reduces the risk of breast cancer recurrence and mortality 48. Non-compliance with and early cessation of HT are linked to elevated relapse and mortality rates 49. BCS was the most prevalent surgical procedure across all breast cancer subtypes (P < 0.001). Mastectomy was the second most common treatment approach. Studies have documented an increase in the utilization of BCS following neoadjuvant treatment and the gradual expansion of treatment options to less toxic targeted therapies 50. The conversion rate from mastectomy to BCS exceeded 50% after neoadjuvant chemotherapy (NACT) plus dual-target therapy in the Asian population 51.
This study revealed that invasive lobular carcinoma and invasive papillary carcinoma and mucinous tumors displayed exceptional 1, 3, and 5-year OS rates (100%), compared to other subtypes at stage 1. In stage 2, invasive lobular carcinoma and mucinous, and invasive papillary carcinoma demonstrated improved 1, 3, and 5-year OS. At stage 3, invasive lobular carcinoma tumor exhibited higher 1-year OS rates, and invasive carcinoma with medullary features displayed higher 1, 3, and 5-year OS rates. Statistically significant differences in OS were observed among breast cancer subtypes within TNM stages 2 and 3 (P value = 0.03 and 0.02, respectively). The current literature suggests an OS of 92% in target patients, implying higher OS rates in our study compared to the findings reported by Carey et al. 15.
Invasive carcinoma with medullary features achieved the highest 1-year, 3-year, and 5-year DFS rates (100%). Mucinous and invasive papillary carcinoma demonstrated the highest 1-year, 3-year, and 5-year DFS rates in TNM stage 1. Mucinous tumors exhibited the highest 1-year, 3-year, and 5-year DFS rates in TNM stage 2, followed by invasive carcinoma with medullary features.
There is a paucity of studies investigating OS and DFS of breast tumors classified by histological subtypes according to TNM stages. However, some studies have explored OS and DFS of breast cancers categorized by molecular subtypes. One such study 52 examined the death rate among molecular subgroups in 24 breast cancer patients following a follow-up period of up to 92 months. Moreover, Zanguri et al. reported the 5-year OS and DFS rates in the Invasive papillary carcinoma group were better than those in the Invasive ductal carcinoma group 19.