Breast cancer is a frequent type of cancer and the first cause of cancer mortality in women, with an expected incidence of 2.3 million cases globally in 2020. Breast cancer incidence and mortality rates varied greatly among communities and nations due to variances in lifestyles, living, environments, and races [1, 2]. In Asia, the breast cancer incidence rate is lower compared to that of Western countries, however, it has been rising faster in the last decades [3, 4]. Furthermore, recent investigations revealed that there are disparities between these two women groups with breast cancer regarding the clinical features and the biological profiles [5, 6].

In Vietnam, a developing country in Southeast Asia, breast cancer happens most frequently, with 21,555 new cases and 9345 cancer deaths in women in 2020 [1]. It is likewise the most prevalent type of cancer in Italy, a Southern Europe nation, with 55,133 new cases and 12,633 deaths in 2020 [1, 7, 8]. Breast cancer (BC) is the primary cause of mortality for women both in Vietnam and Italy. The majority of BC patients in Italy occurred in women aged 50 to 69, with a low proportion of metastases at first diagnosis [9].

In general, when compared to Western countries, Vietnam has younger breast cancer onset ages [6]. Vietnam has a greater mortality rate than Italy while having a significantly lower incidence rate of BC. Most Vietnamese BC patients present to the hospital at a young age having aggressive tumors at the late stages of diagnosis [10]. Furthermore, Vietnamese tumors have a high rate of human epidermal growth factor receptor (HER2)-positive and some modern techniques to evaluate the amplification of HER2 gene, such as fluorescence in situ hybridization (FISH), have not been commonly used yet. As a result, many patients are not properly diagnosed, classified, and treated [6, 10, 11]. To identify BC patients who might be beneficial from targeted HER2 therapy, it is essential to accurately assess HER2 status [12].

This study aimed to make a comparison of the clinical and pathological features of BC between Vietnamese and Italian women as well as to correlate HER2 with prognostic factors to find out whether there are significant disparities in the biological profiles of tumors in both countries. The findings of this research will also contribute to improving the Vietnamese breast cancer screening program.

Our research revealed that clinical profile and tumor characteristics varied significantly between breast cancer patients in Italy and Vietnam. The variations in presentation, clinicopathological profiles, biomarkers, and molecular subtypes might be attributed to the differences in race, lifestyle, living environment, and late diagnosis expression [3, 17, 18]. Our findings from this study are roughly in accord with those reported in Vietnam and Italy, respectively [6, 9, 18, 19, 20, 21].

Vietnam is advantageously exposed to more light and sunshine because of its southern location compared to Italy. Exposure to light and sunshine promotes cellular glucose absorption while upregulating all hormonal processes, increasing estrogen and thyroxin signals and vitamin D production. In southern populations, all of these characteristics contribute to lower cancer incidence, including lower breast cancer incidence [22].

Compared to Italian women, Vietnamese ones had an earlier onset of breast cancer, in our study. While the average age at diagnosis of Italian women was 62, that figure for Vietnamese was just 52.5. The highest-proportion group of Vietnamese patients in the study was the 50 to 60-year-old group, while breast cancer in Italy increased with age and peaked at the age above 70. Our result was consistent with studies carried out by other Vietnamese and Asian authors. For example, Thanh Huong Tran [23] and Dung X. Pham [4] reported a mean age at diagnosis of approximately 50. The mean age of our findings was comparable to earlier reports from Asian nations [5]. A similar result was also seen in studies on the Italian population as Cossu and Tagliabue [9, 24] documented a figure of 60.4 and 61 years old, respectively. The consistency in results so far ultimately proved that Asian women tend to have breast cancer at a younger age than Western ones [4, 6]. This suggests that the Vietnamese screening program should be frequently implemented in women 45 to 60 years of age and widely applied in the general population.

When it comes to tumor size, while most Vietnamese patients had larger-than-2 cm tumors (72.2%), in Italy, the highest percentage belonged to small tumors which were less than 2 cm in size (65.5%). Similarly, compared to Italian patients, a much lower percentage of Vietnamese ones with breast cancer had been diagnosed early (15.1% vs 48.1%). Most Vietnamese patients were diagnosed with an advanced diagnosis, with about 85% in stages II and III. Our study showed that Vietnamese patients hospitalized with big tumors had been developing diseases for a long time and had metastasis. Moreover, most of them were in high grade. Specifically, the percentage of tumors in grade III was significantly higher than that in Italian patients (47.6% vs 17.1%).

Similar characteristics of Vietnamese breast cancer patients were also reported in other recent studies [18, 25]. For instance, a study by Vu Hong Thang also compared those features among Vietnamese and Swedish patients with breast cancer [19, 26]. Furthermore, similar to our findings, a study by Giovanna Tagliabue showed that Italian patients had smaller tumors and were diagnosed at an early stage with low grades [9]. The differences in tumor characteristics between Vietnamese and Italian groups may be mainly due to delays in diagnosis and treatment in Vietnam. Lack of knowledge, being too busy, staying far from treatment facilities, bearing high treatment costs, and not receiving good quality healthcare service, … might be some reasons leading to the delay in the treatment [10]. In addition, the participation rate in breast cancer screening programs in Vietnam and other Asian countries was lower compared to Western countries [3, 18]. There is not enough information provided about screening processes and how screening services are integrated with other areas of the health system. Thus, several patients arrived at the hospital when their tumor had already become large in size and their disease stage was late with high grade and accompanying metastasis [18]. Delay in cancer diagnosis is also a major contributor to an increased risk of premature mortality, lower cancer survival rate, and a higher cancer burden. Therefore, it is necessary to launch a more positive screening strategy for the early diagnosis of cancer patients.

Regarding ER/PR status, our result recognized a lower percentage of ER- and PR-positive in Vietnamese tumors than that in Italian ones. Similar to our findings, ER-positive rates of breast cancer in Vietnamese patients were statistically significantly lower than in Swedish ones, as reported in another study [26]. Our results reconfirmed previous findings of a lower percentage of ER/PR positive in Asian women than in Western ones in the advanced publication [27].

Moving to cell proliferation index (Ki-67), this is a crucial biomarker that has been used in routine clinicopathological practice. This prognostic marker predicts whether endocrine therapy and chemotherapy will be effective or ineffective. Most Vietnamese patients with breast cancer were diagnosed at a late stage when their tumor had been developing for a long time. Thus, the percentage of the Ki-67 high ($\ge$14%) in the Vietnamese patients was undoubtedly higher than that in the Italian ones (81.8% vs 45.1%). The mean Ki-67 of the Vietnamese group was substantially greater than that of the Italian ones (28.9% vs 18.2%). Based on Elston-Ellis, tumor grading includes an analysis of mitotic numbers. It is not surprising to know that tumors of Vietnamese patients had high Ki-67 values, which were corresponding to grade III. Similar results have also been reported in another study on Vietnamese women in 2015 [19].

In terms of HER2 results, our study revealed that Vietnamese patients had a considerably greater prevalence of HER2 positive that Italian patients did (32.9% vs 8.1%). Our findings in HER2-positive Italian patients matched those of a previous study by K.D. Awadelkarim [20] and a study by Pathmanathan were conducted in Southern Vietnam [6]. The prevalence of HER2-positive breast cancer diagnosed in Vietnam matched that in other Asian nations (Malaysia and Hong Kong), but it was generally higher than that in Western nations [6, 20, 28]. A study comparing Vietnamese and Swedish breast cancer patients has also discovered these differences [26]. These disparities could result from variations in population characteristics including biological profiles, ethnicities, geographical location, and environment [29]. Recent studies found a correlation between the HER2 status and clinicopathological features, as well as between the HER2 status and biomarkers in breast cancer [30, 31]. We got similar findings in our study, showing that the status of HER2 in Vietnamese women was substantially correlated with histological grade and cell proliferation index Ki-67, but not with any other clinicopathological characteristics such as tumor size, axillary lymph node metastasis or stage of disease. On the other hand, tumors with big size, metastasis and advanced stage were more likely to have HER2-positive breast cancer. The prevalence of HER2 positive and high Ki-67 index was considerably higher in Vietnamese patients than in Italian ones. Therefore, Vietnamese breast cancer had a worse prognosis and higher mortality rate. In addition, most of the Vietnamese breast cancer were premenopausal cases that were associated with worse prognostic indicators such as low ER/PR positive, higher Ki-67, and HER2 enrichment. This leads to a high breast cancer mortality rate in Vietnam.

The Ki-67 index was added as a criterion by the 12th St. Gallen International Breast Cancer Conference to identify luminal A from luminal B [32]. In our study, 14% was chosen as an optimal cut-off point for Ki-67. This cut-off point has also been utilized by several authors in their research [15, 33]. Breast cancer subtypes in Italian and Vietnamese people differed in some aspects. Luminal A cancers were less prevalent (18.2%), whereas Luminal B, triple-negative, and HER2 enrichment tumors were commonly found. In contrast, Italian women were more likely to have luminal A than Vietnamese women (54.1% vs 18.2%). Italian women, on the other hand, had less HER2 enrichment than Vietnamese women (0.9% vs 22.7%). Our findings for subtypes matched those of another study on Italian women [9, 21]. This study showed that the luminal A subtype had the highest percentage (66.2%), while the triple-negative occupied 8.5% [9]. Another study comparing the luminal A of Vietnamese and Swedish patients found that the luminal A of Sweden was higher than that of the Vietnamese. In contrast, HER2 enrichment in Vietnam was lower than in Sweden [19]. These differences among studies existed because of the heterogeneous nature of the breast cancer [34]. Furthermore, in this study, an increase in the percentage of high Ki-67 contributed to a decrease in the prevalence of luminal A. In addition, the variances in biological properties of tumors among countries may be explained by our baseline data being different from other studies. The environment, ethnicity and geographic location all also affect molecular subtypes’ distribution [21, 29].

In conclusion, Vietnamese patients demonstrated more severe tumor features and worse prognostic biomarkers than Italian patients. Most Vietnamese patients presented to the hospital with large tumor size at the advanced stage of disease with high histologic grade and metastasis. The HER2 positive, high-level Ki-67 and luminal B prevalence in Vietnamese women were considerably higher than in Italian ones. Histological grade and the cell proliferation index Ki-67 were significantly correlated with HER2 positivity in both groups. The remarkable differences in clinicopathological characteristics between two populations might be explained by the diversities in biological profiles, ethnicities, geographical location, living environment, and the effectiveness of the screening program as well. We recommend a screening program be implemented in the younger population, particularly in women with a family having a history of BC to detect breast cancer at an earlier stage.

The dataset used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Conceptualization, methodology, and supervision—FT, VM, and TDC; data collection, formal analysis, statistical analysis—TTNP, FT, VM, TNT, HTA, TLV, and HTVT; the original draft, manuscript revision, review, and editing—TTNP, TNT, and TDC. All authors contributed to the interpretation of the data and approved the final manuscript.

All subjects gave their informed consent for inclusion before they participated in the study. The privacy of all patients enrolled in this study was protected. The study was approved by the Institutional ethics committee of Hue University of Medicine and Pharmacy (approval number: H2020/034).

The authors acknowledge the partial support of Hue University under the Core Research Program (NCM.DHH.2022.02). The authors would like to thank Bui Manh Hung, a master’s student in the Department of Ophthalmology, College of Medicine, Seoul National University, Korea for his English editing.

This study was supported by the Hue University-level research projects in science and technology (DHH 2020-04-123).

The authors declare no conflict of interest.