Current understanding and distinct features of multifocal and multicentric breast cancers

Abstract Background Multifocal (MF) and multicentric (MC) breast cancers are referred to as synchronous, multiple ipsilateral breast cancers; however, the definitions vary among the literature, which has made understanding and analyzing these diseases challenging. Recent findings The incidence ranges from 1% to 60%, with a higher prevalence in pre‐menopausal women. MF and MC breast cancers, compared with unifocal breast cancers, tend to be more aggressive and are associated with lower survival rates, higher recurrence, and lymph node metastasis. Typically, patients with MF/MC breast cancers are treated with radical surgery, while breast conservation therapy may also be considered. Investigations have focused on elucidating the distinct biological features of MF/MC breast cancers, including the clonality of the cancers, the genetic alterations, and the impact of these features on disease aggressiveness and patient prognosis. Conclusion These findings will broaden the understanding of these breast cancer subtypes and aid in the development of more tailored treatment plans for patients.


| INTRODUCTION
Breast cancer can be categorized into different subtypes based on the number of carcinoma foci present within the same breast tissue. Unifocal (UF) breast cancer is defined by a singular breast carcinoma, while multifocal (MF) and multicentric (MC) breast cancers are referred to as multiple synchronous ipsilateral breast carcinomas. However, there is substantial variation in the definitions of MF and MC subtypes in the literature, most notably in the use of breast quadrants, the distance between foci, and the inclusion of in situ lesions. These varying definitions of MF/MC cancers can be attributed to the wide range of incidence, from 1% to 60%. [1][2][3][4][5][6][7][8][9] The incidence rate of MF/MC breast cancers has increased in recent years partly due to the improvement of imaging techniques. 3,10 While it is still somewhat debated, MF/MC breast cancers, compared with UF breast cancers, tend to be more aggressive and have worse prognosis, including lower survival rates, higher recurrence rates, and increased lymph node metastasis. 1,2,[4][5][6][7]9,[11][12][13][14] MF/MC breast cancers are more common in pre-menopausal women than UF breast cancers. 2,3 Typically, MF/MC breast cancers are treated with radical surgical options; however, recent studies have explored the viability of breast conservation therapy (BCT) as a treatment option for patients with these breast cancer subtypes. 10,[15][16][17][18][19] In addition, recent investigations have focused on understanding the distinct biological differences between MF/MC and UF breast cancers that could elucidate the underlying causes of the increased aggressiveness and poorer prognosis associated with MF/MC cancers to aid in the selection of better treatment plans for these patients. Some studies have focused on studying the clonality of multiple MF/MC lesions via the homogeneity and heterogeneity of their grades, histological types, molecular subtypes, and genetic profiles and the impact of these features on the tumors' aggressiveness and patient prognosis. [20][21][22][23][24][25][26][27][28] Other studies have investigated the effects of MF/MC subtypes on the expression of molecular biomarkers, genes of canonical cancer pathways, and cancer stem cell biomarkers. 8,25,27,[29][30][31][32][33][34] In this paper, we aim to review and update the current understanding of MF/MC breast cancers in terms of definitions, incidence, prognosis, and treatment options available for these diseases.
Furthermore, we highlight findings on biological features, namely the clonality and the distinct biomarkers found in MF/MC breast cancers.
We only select original research publications (most are retrospective studies) and one systematic review in English. Google Scholar and PubMed are the two main electronic databases for searching relevant articles. The following keywords are used to narrow the aspects of MF/MC breast cancers: "multifocal and multicentric," "breast cancer," "MMBC," "multiple tumors," "biomarkers," "prognosis," and "treatment." The selected studies are found to be published between 1995 and 2022 and conduct experiments with a sample size of at least 11 patients.

| DISCREPANCIES IN THE DEFINITION OF MULTIFOCAL AND MULTICENTRIC BREAST CANCERS
The definitions of MF and MC breast cancers are inconsistent in the literature, especially regarding the location of foci in breast quadrants, the distance between foci, and the invasiveness of the foci (Table 1).
Most authors accept that MF and MC breast cancers involve multiple distinct tumors in the same and different breast quadrants, respectively. 3,[5][6][7]12,21,28 Some studies combine MF and MC cases (typically referred to as MMBC) and define the diseases as two or more invasive carcinomas that are separated by benign tissue, regardless of whether they are in the same or different breast quadrants. 1,4,9,11,20,35 Some authors additionally consider the distance between tumors in their definitions. For example, MF breast cancer was defined as two or more lesions in the same breast quadrant or separated by less than 4 cm, while MC breast cancer was defined as lesions separated by more than 4 cm or in different breast quadrants. 36 However, a wide range of distances between tumors has been reported, ranging from 1 to 5 cm. 8,35,37 Furthermore, most MF/MC cancers are defined as exclusively invasive carcinomas, including ductal and/or lobular breast cancers; however, some studies also included in situ lesions. 5,7,8,12,16,20,28,35,37,38 In addition to the non-standardized criteria for MF/MC breast cancers, conventional mammogram and gross pathological examination seem to be unable to detect all MF/MC cancers. 10,36 Therefore, if two or more tumors cannot be distinguished, it can lead to the classification of a UF tumor rather than multiple tumors. 11 This lack of consensus on the definitions of MF and MC breast cancers has challenged the treatment and management of MF/MC cancers 16 ; moreover, it makes studying and comparing the biological behavior of these diseases difficult.

| VARYING INCIDENCE RATES AND POTENTIAL POOR PROGNOSIS OF MULTIFOCAL/MULTICENTRIC BREAST CANCERS
Many studies determined that roughly 10%-20% of breast cancer cases were MF or MC, although a wide range of MF/MC incidence was found, from 1% to 60%, partially because of the discrepancies in T A B L E 1 Discrepancies in definition criteria of multifocal and multicentric breast cancers.

Author
Year  36 The use of magnetic resonance imaging increased the sensitivity of the detection of invasive foci, especially in dense breast tissue, despite the persistence of high levels of false positives. 38 MF/MC breast cancers are more aggressive than UF cancers. They tend to have worse prognosis, including lower survival rate, increased rate of recurrence, and increased lymph node metastasis. [1][2][3][4][5][6][7]9,[11][12][13][14] Several studies determined that MC cases were even more aggressive than MF cases, with lower overall survival and more advanced TNM staging. 3 status, another study determined that MF/MC cancers were associated with lower 5-and 10-year survival rates than UF tumors; however, multivariate analysis did not support multifocality as a significant independent prognostic factor. 40 Coombs et al. compared the two tumor staging methods and their association with axillary node metastasis. 7 The conventional method clearly indicated that multifocality was a significant independent predictor of node positivity, while the method using aggregated diameters of all foci did not. 7  Although non-heterogeneous tumors were prevalent, these studies highlighted the heterogeneity existing between MF/MC foci.
Some authors agree that multiple foci mainly exhibit intramammary spread and are thus monoclonal; however, they may also arise independently. 20,25,29 Most other studies do not make clear conclusions about the clonality or origins of the foci. 21,23,24,[26][27][28]42 In addition, changes that result in heterogeneity could occur during tumor progression and dissemination. 22 The heterogeneity data presented in these studies could be beneficial for the prediction of metastasis and prognosis and the recommendation of different postoperative treatments. 22

ACKNOWLEDGMENTS
We would like to thank Sarah Lamb and Khadija Fatima for significantly helping with the literature search and with organizing the research contents. We are also grateful for the support from the AAUW Research Publication Grant in Engineering, Medicine, and Science that made this work and publication possible.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

ETHICS STATEMENT
Not applicable.