10.7910/DVN/AFTWMDCosar, RusenRusenCosarTrakya University Faculty of MedicineHarvard Dataverse2023Medicine, Health and Life Sciencesinvazive lobular breast carcinomabreast carcinomaspecial type berast carcinomaCosar, RusenRusenCosarTrakya University Faculty of Medicine2023-02-022023-02-0879498833521126601183043114230560129886614729113103913491472147349378image/tiffimage/tiffimage/tiffimage/tiffimage/tiffimage/tiffapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/vnd.openxmlformats-officedocument.wordprocessingml.documenttext/htmlapplication/octet-streamapplication/octet-streamtext/tab-separated-values2.1CC0 1.0ORIGINAL RESEARCH Cosar et al Classifying Invasive Lobular Carcinoma as Special Type Breast Cancer May Be Reducing Its Treatment Success: A comparison of Survival Among Invasive Lobular Carcinoma Rusen Cosar1, Necdet Sut2 , Sernaz Topaloglu3 , Ebru Tastekin4 , Dilek Nurlu1 , Talar Ozler1 , Eylül Şenödeyici5 , Melisa Dedeli1 , Mert Chousein1, Irfan Cicin3 1Trakya University Faculty of Medicine Department of Radiation Oncology, Edirne, Turkey 2 Trakya University Faculty of Medicine Department of Biostatistics, Edirne, Turkey 3Trakya University Faculty of Medicine Department of Medical Oncology, Edirne, Turkey 4Trakya University Faculty of Medicine Department of Pathology, Edirne, Turkey 5Trakya University Faculty of Medicine, Edirne, Turkey Correspondence: Ruşen Coşar Trakya University School of Medicine, Department of Radiation Oncology, Edirne, Turkey Tel: +902842361074 Email: rusencosar@trakya.edu.tr Disclosure The authors have declared that no competing interests exist. The authors alone are responsible for the content and writing of the paper. The authors declared that this study has received no financial support. “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” Voluntary consent form was given to patients or official guardians of deceased patients to use file information. File information was used after the forms were signed by the patient or official guardians of deceased patients. Abstract: Purpose: The literature contains differentiating information regarding the prognosis of invasive lobular carcinoma. We aimed to address the inconsistency by comparatively examining the clinical features and prognosis of invasive lobular carcinoma patients in our university and to report our experience by dividing our patients into various subgroups. Patients and methods: Records of patients with breast cancer admitted to Trakya University School of Medicine Department of Oncology between July 1999 and December 2021 were reviewed. The patients were divided into three groups (No-Special Type Breast Cancer, Invasive Lobular Special Type BC, No-Lobular Special BC). Patient characteristics, treatment methods and oncological results are presented. Survival curves were generated using the Kaplan–Meier method. Statistical significance of survival among the selected variables was compared by using the log-rank test. Results: The patients in our study consisted of 2142 female and 15 male breast cancer patients. There were 1814 patients with Non-Special Type Breast Carcinoma, 193 patients with Lobular Special Type Breast Carcinoma, and 150 patients with Non-Lobular Special Type Breast Carcinoma. The duration of disease free survival (DFS) was 226.5 months for the No-Special Type group, 216.7 months for the No-Lobular Special Type group, and 197.2 months for the Lobular Special Type group, whereas the duration of overall survival (OS) was 233.2 months for the Non-Special Type group, 227.9 for the No-Lobular Special Type group, and 209.8 for the Lobular Special Type group. The duration of both DFS and OS was the lowest in the Lobular Special Type group. Multivariate factors that were significant risk factors for OS were Lobular Special Type histopathology (p=.045), T stage, N stage, stage, skin infiltration, positive surgical margins, high histological grade and mitotic index. Modified radical mastectomy, chemotherapy, radiotherapy and use of Tamoxifen and aromatase inhibitors for more than 5 years were significant protective factors for overall survival. Conclusion: The histopathological subgroup with the worst prognosis in our study was Lobular Special Type. Duration of DFS and OS were significantly shorter in Lobular Special Type than No-Lobular Special Type group. Whether Lobular Special Type should be classified as a Special Type Breast Tumor should be reconsidered, and a more accurate treatment and follow-up process may be required. Keywords: No-Special Type Breast Cancer, Special Type Breast Cancer, Invasive Lobular Cancer, Non-Lobular Special Type Breast Cancer, Invasive Ductal Breast Cancer Introduction Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). While ILC accounts for 5% of invasive carcinomas, its incidence has increased up to 10-14% with the developments in diagnostic methods and novel discoveries. However, ILC remains less common in Asian populations (2–6%)1-6. As the incidence of ILC is significantly less than invasive ductal carcinoma (IDC), the most common histopathological subtype of breast cancer, its clinical and prognostic features and biological behavior become clearer as more studies are published7-15. ILC is within the Special Type BC group, along with tubular, mucinous, papillary, micropapillary, medullary, metaplastic, and apocrine histopathological subtypes, whereas IDC is among the No-Special Type BC group composed of highly heterogeneous subtypes10. ILC stands out among the other histopathological subtypes in the Special Type BC group with its distinct clinical course, prognosis and biological features. While the survival rate of ILC was better than or similar to that of IDC in series with less than 6 years of follow-up, the prognosis of ILC was found to be worse than IDC in series with longer follow-up. However, the St Gallen International Expert Consensus guidelines and the National Comprehensive Cancer Network (NCCN) recommend that ILC should be treated with the same treatment paradigms as IDC, despite their many different features. Therefore, systemic treatment decisions for ILC and IDC are often similar (10). Highlighting ILC as the subgroup with better prognosis in the series published in the past years may have prevented the treatment decision from being more aggressive, resulting in worse survival than IDC in the long term6-9, 11-14. Treating the “Special” ILC similarly to the “No-Special” IDC may cause the clinicians to overlook important details regarding this patient group13. However, larger tumor diameter, more lymph node metastases, high hormone receptor positivity, loss of E-cadherin and the potential of atypical metastasis are among the currently known distinct features of ILC3, 4. Unlike IDC, ILC shows different growth patterns and biological features, rather than masses that can easily be diagnosed with palpation or mammography. Additionally, an increased rate of multiple metastases, low rates of pathological complete response to neoadjuvant chemotherapy, and frequent positive surgical margins are among the features that make ILC more remarkable14,15. Different information in the literature regarding prognosis has led us to comparatively examine the clinical features and prognosis of ILC patients in our series. We aimed to determine our own patient characteristics and report our treatment experience of ILC by dividing our patient series into various subgroups. Material and methods Patient characteristics Patients with breast cancer who applied to Trakya University School of Medicine Departments of Radiation Oncology and Medical Oncology between July 1999 and December 2021 were retrospectively analyzed. Approval was obtained from the Human Research Ethics Committee of Trakya University Medical Faculty Hospital (TUTF-BAEK 2022/170) for the use of patient information in the study. The consent form was submitted to the local ethics committee (Trakya University Faculty of Medicine Dean's Non-Invasive Scientific Research Ethics Committee, Edirne, Turkey). Informed consent forms were prepared in accordance with the Declaration of Helsinki. In the study, permission was obtained from the patients, and if the patient died, from the legal guardians of the patients, by signing a written consent form, to use the information in the registry files containing the patient information. Medical records and pathological reports were retrospectively converted into SPSS data to evaluate the clinicopathological features. After excluding 190 patients with ductal carcinoma in situ and lobular carcinoma in situ from a total of 2347 breast cancer patients, the remaining 2157 patients with invasive carcinoma were included in the study. The patients in our series consisted of 2142 female and 15 male breast cancer patients. No-Special Type BC (Completely invasive ductal carcinoma, IDC) and Special Type BC were divided as invasive lobular carcinoma (ILC), mixed type (IDC+ILC), epidermoid carcinoma, mucinous carcinoma, medullary carcinoma, papillary carcinoma, tubular carcinoma, adenoid cystic carcinoma, secretory carcinoma, apocrine carcinoma, and metaplastic carcinoma. Later, the patients were divided into three groups: Non-Special Type BC (IDC) (n=1814), Lobular Special Type (ILC, ILC+IDC mixed type) (n=193), and Non-Lobular Special Type BC (n=150). Disease-free survival (DFS) and overall survival (OS) analyzes of the patient groups were performed. Patient characteristics were tabulated as ratios and numbers, and comparisons were made between groups. Finally, univariate and multivariate analyzes of factors affecting DFS and OS were performed. Clinicopathological Features Pathological and clinical staging in our series was performed according to the seventh edition of the American Joint Committee on Cancer Staging Manual16. IDC, Non-Lobular Special Type, ILC, and histopathological diagnoses were evaluated using hematoxylin-eosin staining by pathologists specializing in breast cancer at Trakya University School of Medicine Department of Pathology. Estrogen receptor (ER) and progesterone receptor (PR) positivity were determined by immunohistochemical staining. Hormone receptor positivity was defined as an ER score greater than or equal to 3 on the Allred Score (17). HER2 positive was defined as a Herceptest score of 3+ or a Herceptest score of 2+ followed by fluorescent in situ hybridization (FISH) positive18. Luminal type was defined as ER positive and HER2 negative. Histological grading was done using the Nottingham histological grading system. Pathological staging for extensive intraductal carcinoma (EIC), lymphovascular invasion (LVI), and perineural invasion (PNI) was done according to the seventh edition of the American Joint Committee on Cancer Staging Manual17. Statistical Analysis Numerical results are expressed as the mean ± standard deviation, and categorical results are shown as n (%). Kaplan-Meier method was used to generate the survival curves. Log-rank test was used to compare the statistical significance of survival among the selected variables. Hazard ratios were estimated using univariate Cox regression analysis. Multivariate Cox regression analysis with backward elimination method was used to estimate hazard ratios and identify independent prognostic factors. All p values are two-sided, and p<0.05 indicates statistical significance. Data analysis was performed using SPSS version 20.0 (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Results Out of 2157 patients, 1814 patients had No-Special Type BC and 342 patients had Special Type BC. No statistically significant difference between DFS and OS was found (Table 1, Figure 1a, 1b). In the second step, we divided our patient series into three groups as No-Special Type BC (n=1814), ILC Special Type BC(n=193), No-Lobular Special Type BC (n=150). The rate of ILC patients in our series was 8.9%. 4.1% (n=8) of ILCs contained pleomorphic components. When all three groups were compared, the differences between the durations of both DFS and OS were statistically significant. The duration of DFS was 226.5 months for the IDC group, 216.7 months for the No-Lobular Special Type group, and 197.2 months for the ILC group, whereas the duration of OS was 233.2 months for the IDC group, 227.9 for the No-Lobular Special Type group, and 209.8 for the ILC group. The duration of both DFS and OS was the lowest in the ILC group (Tables 2, Figure 2a, 2b). The histopathological subgroup distribution, which consisted of ER, PR, Ki67 and CerbB2, was 80.98% Luminal AB, 11.41% Triple Negative, 7.1% HER2 enriched for IDC, while Non-Lobular Special Type was divided as 68.67% Luminal AB, 24.67% Triple negative, 6.67% HER2 enriched, and ILC was divided as 94.30% Luminal AB, 4.66% Triple negative, 1.04% HER2 enriched. The subgroup dominating the histopathological subgroup of ILC was Luminal A-B with a rate of 94.30% (Fig. 3a, 3b, 3c). Patient characteristics of all three groups (IDC, Non-Lobular Special Type, ILC) were analyzed (Table 3). Gender, age, menstruation, family history, histological type, tumor quadrant, T stage, N stage, stage, metastasis site, breast surgery type (modified radical mastectomy/ breast conserving surgery), axillary surgery type (axillary curettage/sentinel lymph node sampling), skin infiltration, surgical margin ( in patients with positive surgical resection margin, re-excision was performed first and the surgical resection margin was positive despite this), tumour grade, mitotic index (MI), ER, PR, Ki67 (<15, ≥15), HER2, EIC, LVI, PNI, subgroup (Luminal A, Luminal B, Triple Negative, HER2 enriched), presence of anti-hormonal therapy, duration of Tamoxifen (TAM) and Aromatase Inhibitor (AI) use, use of Herceptin, and type of chemotherapy (CT) [ No CT, AC+TXT (doxorubicin and cyclophosphamide followed by paclitaxel), FAC (fluorouracil, doxorubicin, cyclophosphamide)-FEC (floro-urasil, epirubisin, cyclophosphamide), -TAC (docetaxel, doxorubicin, cyclophosphamide), FAC-FEC+TXT, Ribociclib + Palbociclib, CMF (Cyclophosphamide Methotrexate Fluorouracil)] were analyzed as numbers and rates. Fisher exact test was used to compare the patient characteristics of the three groups. In the same table was made for the statistically significant patient characteristics of the three groups (Table 3). The distribution of patient characteristics of the 3 histopathological subgroups are shown in Table 3. Of the 193 patients in the Lobular Special Type BC group in our series, 138 were pure ILC, and 55 were IDC+ILC BC patients. All patients in the ILC group were women, mostly over 50 years of age and in the postmenopausal period. There was no significant difference in the presence of family history and bilateral arrangement among the 3 groups. While the rate of MRM in breast surgery was 45.5% (n=982), only 7 of the patients had skin-sparing mastectomy. Periareolar and multifocal localizations were slightly more common in the ILC group. A pairwise comparison of patient characteristics of all three groups were done. ILC/IDC patient characteristics T stage, PNI positivity, ER and PR positivity rates were higher in ILC, while Ki67, CerbB2 positivity, MI (mitotic index) and histological grade rates were higher in IDC. Subgroup, rate of anti-hormonal treatment use, duration of TAM and AI use, CT type, and metastasis location were the features that showed significant difference between ILC and IDC. Breast and axillary surgery type and surgical margin positivity were not different between the two histopathological groups (Table 3). Although not statistically significant, MRM was detected in 47.9% of the IDC and 51.6% of the ILC. While 83.2% of breast cancer patients with IDC histopathology received chemotherapy, this rate was 78.2% in the ILC histopathological subgroup, and this difference was calculated differently at the level of statistical significance. ILC/No-Lobular Special Type patient characteristics N stage, stage, surgery type (breast and axillary surgery type), PNI, LVI, subgroup, ER and PR positivity, HG, duration of anti-hormonal therapy, duration of TAM and AI use, RT type, CT type, recurrence/metastasis rates and mortality rate were significantly higher in the ILC group (Table 3). While the MRM rate was 51.6% more preferred in ILC in surgical treatment, BCS was preferred with 66.2% in No-Lobular Special Type BC, and this difference was statistically significant. In No-Lobular Special Type BC, the rate of administration of chemotherapy was 71.3%, the histopathological subgroup in which the least chemotherapy was preferred. IDC/ No-Lobular Special Type patient characteristics The quadrant where the tumor is located, T stage, N stage, stage, surgical type (breast and axillar surgery), PNI, LVI, EIC, subgroup, ER and PR positivity, Ki67 rate, CerbB2 positivity, HG, presence of anti-hormonal therapy, RT type, CT type, metastasis location, recurrence/metastasis rate and death rate were found to be significantly higher in the IDC group. While MRM was preferred 47.9% in IDC histopathology, 33.8% preferred in No-Lobular Special Type BC histopathology. In the axillary surgery option, 25% in SLND, IDC, 30.4% in No-Lobular Special Type BC, and 75% and 69.6% in AK, respectively (Table 3). Cox regression test was used to examine the histopathological subgroups and patient characteristics with these three different clinical and pathological features. Multivariate factors that were significant risk factors for DFS in our study were age, being in the postmenopausal period, multicentric location, T stage, stage, HER2 positivity and MI, while duration of TAM and AI use, and use of Herceptin were the significant protective factors for DFS (Tables 4, 5). Multivariate factors that were significant risk factors for OS were ILC histopathology (p=.045), T stage, N stage, stage, skin infiltration, positive surgical margins, high histological grade and mitotic index. Modified radical mastectomy (MRM), chemotherapy (CT), radiotherapy (RT) and use of TAM and AI for more than 5 years were significant protective factors for OS (Tables 6, 7) Discussion The classification of special types of breast cancer recommended by the World Health Organization is beginning to take a wider place in literature because of their distinct biological behavior and clinical characteristics compared to no-special types of breast cancer15. Additionally, subtypes in the special breast cancer group may behave very differently from each other. ILC is considered notable for its distinctive biological behavior and unusual organ metastases and is included in Special Type BC because of studies showing it has a better prognosis than IDC6, 20-24. However, studies with longer periods of follow-up show that ILC has worse prognosis than IDC6, 14, 25. Survival data, which differ from each other and change over the years, call into question the status of ILC in the Special Type BC group. A separate classification may be necessary for subtypes in this group. When the patients in our study were divided into two subgroups (No-Special Type BC, Special Type BC), no significant difference was observed regarding DFS and OS. When the data was later reanalyzed by removing ILC from the Special Type BC and treating it as a third, distinct subgroup, ILC was found to have the lowest duration of DFS and OS. There was a significant difference between the duration of DFS and OS of IDC and No-Lobular Special Type BC. The duration of DFS and OS showed significant difference in ILC and No-Lobular Special Type BC as well. Although IDC and ILC did not have a statistically significant difference regarding DFS and OS, the difference was still remarkable. ILC and IDC have similar durations of DFS in the first 6 years. After 6 years however, the survival curve for ILC was lower than of IDC, and the difference becomes more pronounced after the 17th year. OS for ILC showed a lower course than IDC after 14 years. Although the difference between the duration of OS in ILC and IDC were not statistically significant, ILC significantly increased the risk of death by 1.457(1.009-2.104) times, (p=.045) in the Cox regression risk analysis. Special Type-BC has a lower incidence, which may have resulted in limited knowledge of the clinical and biological features of the histopathological subtypes within the group. However, recent studies with longer follow-up periods have reported a lower survival rate, especially for ILC, contrary to current information14, 26. The increase of incidence and low survival rates may force the clinicians to reconsider treatment options and the frequency of follow-ups. A study by Toikkanen et al7 showed ILC had better prognosis than IDC despite 30 years of follow-up, which precludes interpretation by the length of follow-up alone. As a result, when ILC is analyzed yearly, an increase in its incidence is seen. Earlier studies1, 2, 4, 7 show ILC to have lower grade, mitotic activity, T stage, N stage, stage, and ER positivity with a higher rate of bilateral arrangement, while more recent studies14, 26 report higher histologic grade and mitotic activity, and diagnosis at more advanced stages. Our study shows that ILC is associated with larger tumor size, older age, more advanced T and N stage, lower grade, higher ER and PR positivity, and lower HER2 expression, while the rate of bilateral arrangement was not higher. This may suggest that the biological behavior of ILC has become more aggressive over the years. It should be noted that the lack of difference between IDC and ILC in terms of surgical margin positivity, breast surgery and axillary surgery type in our series is evidence that it does not show a worse prognosis due to residual disease or incomplete treatment. In the multivariate analysis for DFS, neither breast nor axillary surgery type increased the risk of events. In OS, the risk increased 1.5 times at the statistical significance level (p=0.008) in patients who underwent MRM. In the axillary surgery type, the risk increased by 1.4 in patients who underwent AC which was close to statistical significance (p=0.099). In this case, it is proof that more radical surgical interventions are preferred in patients with high risk. This proves that incomplete surgery or less aggressive surgical methods are not preferred when interpreting the results in our series with peace of mind. Recent studies suggest whether IDC is the most common histopathological subgroup with the worst prognosis should be re-evaluated. Having the lowest course on the survival curve, patients with ILC may require a more careful approach. Our study suggests that reviewing the current treatment guidelines may be required. Increased incidence of ILC may be linked to improved diagnostic approach. Whether ILC has a better or similar prognosis and higher rates of bilateral arrangement in comparison to IDC deserves restatement. In fact, when studies are handled individually and carefully, we can see clues that may belong to a poor prognosis. For example, studies in which pathological complete response to neoadjuvant chemotherapy is rare and positive surgical margin rate is higher in ILC.13, 22,26 This uncertainty has even made mastectomy a more common treatment option for ILC than IDC6,7,14. Again in a retrospective series, with only larger tumor size as a poor prognostic factor, ILC had lower survival compared to IDC6. Pestalozzi et al., on the other hand, associated the difference in survival with stage and reported that the early-stage prognosis of ILC is better than IDC, but the late-stage prognosis of ILC is worse14,25. Since ILC presents itself with diffuse or spreading lesions rather than a mass, it has been stated that breast MRI is more helpful than mammography in the diagnosis of such lesions being satisfied with mammography alone may cause delays in the diagnosis of ILC.26,27. Failure to encode the E-Cadherin protein encoded by the CHD1 gene due to somatic mutation is a pathognomonic condition for ILC compared to IDC. The E-Cadherin protein not only plays a role in the adhesion of cells to each other to form tissues and in the transmission of chemical signals within the cell, cell maturation and controlling cell movement, it also functions as a tumor suppressor protein28-30. Deletion of E-Cadherin and PI3K pathways may be the cause of infiltrative growth pattern and frequent surgical margin positivity31,32. Precisely for this reason, the results of the ROSALINE (NCT04551495) phase II study with entrectinib, a tyrosine kinase inhibitor targeting TRK, ROS1 and ALK tyrosine kinases, with promising in vivo results are eagerly awaited. It is aimed to measure the antitumor efficacy of entrectinib and endocrine therapy as neoadjuvant in ER-positive, HER2-negative ILC BC patients33. Metastatik ILC'si olan hastalar için, CDH1, NF1, PIK3CA ve TBX3'teki mutasyonlar, tümör mutasyon yükü (TMB) olarak ölçülür ve metastatik IDC'si olan hastalara göre daha yüksektir. The effect of atezolizumab, a carboplatin and immune checkpoint inhibitors (ICIs), will be measured in the GELATO study, which is planned for metastatic lobular breast cancer assessing efficacy with mutationa burden (TMB)34. The limitation of our study is that, apart from a retrospective series and comparison of clinical features and treatment outcomes for ILC, no additional molecular comparison could be made. However, pre-clinical and clinical molecular studies have been and continue to be conducted in order to explain the clinical process difference in ILC. The fact that the reason for the different clinical course and biology of the ILC subtype of breast cancer has begun to be revealed raises our hopes that the treatment options will also differ in the coming years and that the risk of developing late recurrence and metastasis will be reduced or eliminated with more effective treatments. Conclusion The increase in the incidence of the ILC histopathological subgroup of breast cancer in recent years has not only made it possible to understand that it has a different course compared to IDC, but also has led to the fact that systemic and local treatment decisions are different over time. In our study and other studies with long follow-up, we show that ILC has the lowest DFS and OS among all histological subgroups. Therefore, the classification of ILC into Special Type BC should be reassessed and current treatment guidelines may need to be revised, particularly as ILC-specific study results begin to emerge. Acknowledgments Disclosure The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. The authors declare that this study has received no financial support. Informed consent form was obtained from the patients, their legal guardians or relatives of the deceased patients to use relevant information. Any data was used after informed consent forms were signed by the patients, their legal guardians or relatives of the deceased patients. References 1. Li CI, Anderson BO, Porter P, Holt SK, Daling JR, Moe RE. Changing incidence rate of invasive lobular breast carcinoma among older women. Cancer 2000;88: 2561–2569. 2. Arpino G, Bardou VJ, Clark GM, Elledge RM. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res. 2004 6(3):149-56. 3. Christgen M, Cserni G, Floris G, Marchio C, Djerroudi L, Kreipe H, et al. 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DFS and OS times, comparative Log-rank test, p-value values of Non-Special Type BC and Special Type BC subgroups obtained using Kaplan-Meier method Non-Special Type BC Special Type BC P value (Long-rank test) DFS Mean± SD 226,5 ± 3,4 208,2 ± 6,6 .234 95% CI 219,8-233,1 195,2- 221,2 OS Mean± SD 233,2 ± 3,5 221,8 ± 6,4 .379 95% CI 226,3 – 240,1 209,2 – 234,4 Table 2. DFS and OS times, comparative Log-rank test, p-value values of Non-Special Type BC and Non-Lobular Special Type BC, ILC subgroups obtained using Kaplan-Meier method DFS No-Special Type BC (IDC) No-Lobular Special Type BC Lobular Special Type BC (ILC) P value Mean±SD 226,5 ± 3,4 216,7±8,7 197,2 ± 8,9 (Long-rank test) 95% CI 219,8-233,1 199,6-233,7 179,6 – 214,7 No-Special Type BC (IDC) Lobular Special Type BC (ILC) .020 .717 .029 OS Mean±SD 233,2 ± 3,5 227,9 ± 7,9 209,8±8,7 95% CI 226,3 – 240,1 212,3 – 243,5 192,6-227,0 Non-Special Type BC (IDC) .024 .504 Lobular Special Type BC (ILC) .018 DFS: Disease free survival, OS: Overall survival, SD: Standard deviation, CI: Confidence Interval Table 3. Distribution of patient characteristics Non-Special Type BC (IDC) Invasive Lobular Special Type BC (ILC) Non-lobular Special Type BC N % n % n % Gender Female 1800 99.2 193 100 150 99.33 Male 15 0.8 0 0 0 0.7 Age 92 5.10% 11 5.7 9 6 <35 35-50 696 38.4 85 44 58 38.7 >50 1026 56.6 97 50.3 83 55.3 Menstruation State Premenopausal 701 38.9 81 42 54 36.2 Postmenopausal 1099 61.1 112 58 95 63.8 Presence of Family History 536 29.5 54 28 37 24.7 Histological Type IDC 1761 97.1 ILC 138 71.5 IDC+ILC 55 28.5 Mucinous 44 29.3 Medullary 34 22.7 Papillary 25 16.7 Tubular 12 8 Adenoid Cystic 4 2.7 Secretory 2 1.3 Apocrine 15 10 Metaplastic 11 7.3 Epidermoid 3 2 Breast Right 869 47.9 103 53.4 69 46 Left 885 48.8 82 42.5 75 50 Bilateral 60 3.3 8 4.1 6 4 Tumor Quadrant*** Inner 351 19.3 44 22.8 40 26.7 Outer 1085 59.8 104 53.9 89 59.3 Periareolar 239 13.2 29 15 11 7.3 Multifocal 139 7.7 16 8.3 10 6.7 Tm Size* T1 609 33.6 54 28 51 34 T2 948 52.3 98 50.8 80 53.3 T3 135 7.4 26 13.5 15 10 T4 122 6.7 15 7.8 4 2.7 Number of Infiltrated Axillary Nodes**, *** 0 736 40.6 74 38.3 90 60 1-3 476 26.2 59 30.6 29 19.3 4-9 394 21.7 32 16.6 21 14 ≥10 208 11.5 28 14.5 10 6.7 Stage*, *** I 366 20.2 38 19.7 41 27.3 II 778 42.9 78 40.4 75 50 III 538 29.7 66 34.2 29 19.3 IV 132 7.3 11 5.7 5 3.3 Site of Metastasis None 1460 80.5 152 78.8 134 89.3 Bone 123 6.8 18 9.3 5 3.3 Lung 16 0.9 3 1.6 4 2.7 Liver 13 0.7 1 0.5 0 0 Brain 21 1.2 2 1 1 0.7 Multiple 181 10 16 8.3 6 4 Breast Surgery Type **, *** MRM 834 47.9 98 51.6 50 33.8 BCS 907 52.1 92 48.4 98 66.2 AxillarySurgery Type SLND 435 25 48 25.3 45 30.4 AC 1306 75 142 74.7 103 69.6 Skin Infiltration 147 8.1 14 7.3 7 4.7 Positive Surgical Margin 337 18.6 41 21.2 27 18 Histological Grade*, **, *** 1 219 12.1 25 13 45 30 2 859 47.4 111 57.5 55 36.7 3 736 40.6 57 29.5 50 33.3 Mitotic index *, *** 1 285 15.7 41 21.2 37 24.7 2 895 49.3 99 51.3 79 52.7 3 634 35 53 27.5 34 22.7 ER Positive *, **, *** 1434 79.1 177 91.7 101 67.3 PR Positive *, **, *** 1175 64.8 165 85.5 81 54 Ki67 *, *** <15 603 33.3 86 44.6 65 43.3 ≥15 1209 66.7 107 55.4 85 56.7 HER2 Positive 459 25.3 24 12.4 25 16.7 EIC Positive *** 309 17 33 17.1 16 10.7 LVI Positive **, *** 881 48.6 99 51.3 45 30 PNI Positive *, **, *** 342 18.9 47 24.4 11 7.3 Subgroup *, **, *** HER2 enriched 138 7.6 2 1 10 6.7 Triple Negative 207 11.4 9 4.7 37 24.7 Luminal A 483 26.6 79 40.9 50 33.3 Luminal B 986 54.4 103 53.4 53 35.3 Anti-Hormonal Treatment Received *, **, *** 1467 80.9 181 93.8 103 68.7 Duration of TAM Use N/A*, **, *** 1051 57.9 97 50.3 101 67.3 ≤ 5 years 679 37.4 82 42.5 43 28.7 >5 years 84 4.6 14 7.3 6 4 Duration of AI Use N/A*, ** 734 40.5 59 30.6 72 48 ≤ 5 years 850 46.9 113 58.5 62 41.3 >5 years 230 12.7 21 10.9 16 10.7 Herceptin *Eligibility 380 20.9 20 10.4 23 15.3 RT Received 1589 87.6 167 86.5 129 86 RT Type N/A**, *** 215 11.9 26 13.5 20 13.3 Breast Only 515 28.4 43 22.3 69 46 Locoregional 1084 59.8 124 64.2 61 40.7 CT Received N/A**, *** 303 16.7 42 21.8 43 28.7 Neoadjuvant 236 13 20 10.4 10 6.7 Adjuvant 1275 70,3 131 67.8 97 64.7 CT Type *, **, *** N/A 303 16.7 42 21.8 43 28.7 AC+TXT 875 48.2 74 38.3 67 44.7 FAC-FEC-TAC 358 19.7 57 29.5 28 18 FAC,FEC+TXT 209 11.5 16 8.3 8 5.3 Ribociclib+Palbociclib 6 0.3 0 0 0 0 Pertuzumab 22 1.2 0 0 0 0 CMF 41 2.3 4 2.1 5 3.3 Recurrence **, *** 372 20.5 45 23.3 19 12.7 Death **, *** 328 18.1 43 22.3 16 10.7 ER: Estrogen Receptor, PR: Progesterone Receptor, HER2: Human Epidermal Growth Factor Receptor 2, EIC: Extensive Intraductal Carcinoma, LVI: Lymphovascular Invasion, PNI: Perineural Invasion, TMX: Tamoxifen, AI: Aromatase Inhibitor, RT: Radiotherapy, CT: Chemotherapy, AC: Axillary Curettage SLND: Sentinel Lymph Node Dissection, AC: Adriamycin, Cyclophosphamide, TXT: Taxotere, FAC: Cyclophosphamid, Adriamycin, 5-Fulourouracil, FEC: 5-Fulouracil, Epirubicine, Cyclophosphamide, TAC: Taxotere, Adriamycin, Cyclophosphamid, RIBO+PABLO: Ribociclib+ Palbociclib, CMF: Cyclophosphamide, Methotrexate, Fluorouracil. * Pairwise comparison of all three groups with Fisher's exact test (p<.0.5) in terms of patient characteristics (IDC/ILC). ** Pairwise comparison of all three groups with Fisher's exact test (p<.0.5) in terms of patient characteristics (ILC/No-Lobular Special Type). *** Pairwise comparison of all three groups with Fisher's exact test (p<.0.5) in terms of patient characteristics (IDC/No-Lobular Special Type). Table 4. Univariate analysis results affecting DFS Recurrence Univariate Cox Regression N/A Present p HR (95% CI) Age <35 83 (4.8) 29(6.7) 1 (Reference) 36-50 691 (40.2) 148 (33.9) .035 .652(.438-.970) >50 947 (55) 259 (59.4) .557 .891(.607-1.308) Gender Female 1714 (99.6) 428 (98.2) .001 3.265(1.622-6.574) Male 7 (0.4) 8 (1.8) Menstruation Status Premenopausal 688 (40.1) 148 (34.6) .006 1.320(1.081-1.611) Postmenopausal 1026 (59.9) 280 (65.4) Family History Present 513 (29.8) 114 (26.1) .117 1.187(.958-1.469) N/A 1208 (70.2) 322 (73.9) Histological Subtype Group – 1 No-Special Type BC 1442 (83.8) 372 (85.3) .237 .852(.653-1.1111) Special Type B 279 (16.2) 64 (14.7) Histological Subtype Group – 2 Non-Special Type BC 1442 (83.8) 372 (20.5) 1 (Reference) Invasive Lobular Special Type BC 148 (8.6) 45 (10.3) .724 1.057(.776-1.441) Non-lobular Special Type BC 131 (7.6) 19 (4.4) .022 .584(.368-.925) Arrangement Unilateral 1674 (97.3) 409 (93.8) .003 1.808(1.225-2.670) Bilateral 47 (2.7) 27 (6.2) Breast Left 841 (48.9) 201 (46.1) 1 (Reference) Right 833 (48.4) 208 (47.7) .833 1.021(.841-1.240) Bilateral 47 (2.7) 27 (6.2) .003 1.828(1.223-2.732) Inner 351 (20.4) 84 (19.3) 1 (Reference) Outer 1034 (60.1) 244 (56) .954 1.007(.786-1.291) Tumor Quadrant Periareolar 222 (12.9) 57 (13.1) .597 1.095(.782-1.533) Multicentric 114 (6.6) 51 (11.7) <.001 1.876(1.324-2.657) T Stage T1 648 (37.7) 66 (15.1) 1 (Reference) T2 889 (51.7) 237 (54.4) <.001 2.401(1.827-3.154) T3 131 (7.6) 45 (10.3) <.001 2.803(1.919-4.095) T4 53 (3.1) 88 (20.2) <.001 12.650(9.156-17.479) N Stage N0 818 (47.5) 82 (18.8) 1 (Reference) N1 478 (27.8) 86 (19.7) .001 1.658(1.225-2.244) N2 293 (17) 154 (35.3) .000 4.808(3.676-6.289) N3 132 (7.7) 114 (26.1) .000 6.817(5.130-9.060) Stage I 422 (24.5) 23 (5.3) 1 (Reference) II 825 (47.9) 106 (24.3) .001 2.181(1.390-3.424) III 469 (27.3) 164 (37.6) <.001 5.605(3.622-8.672) IV 5 (0.3) 143 (32.8) <.001 104.241(66.093-164.408) Site of Metastasis N/A 1719 (99.9) 27 (6.2) 1 (Reference) Bone 1 (0.1) 145 (33.3) <.001 167.63(110.55-254.18) Lung 0 (0) 23 (5.3) <.001 159.811(90.86-281.08) Liver 0 (0) 14 (3.2) <.001 174.24(90.66-334.87) Brain 0 (0) 24 (5.5) <.001 179.70(102.60-314.73) Multiple 1 (0.1) 203 (46.5) <.001 171.71(113.89-258.88) ER Positive 1393 (80.9) 319 (73.2) <.001 1.476(1.194-1.824) Negative 328 (19.1) 117 (26.8) PR Positive 1167 (67.8) 254 (58.3) <.001 1.499(1.239-1.814) Negative 554 (32.2) 182 (41.7) HER2 Positive 383 (22.3) 125 (28.7) <.001 .668(.542-.823) EIC N/A Present 1459 (84.8) 262 (15.2) 340 (78) 96 (22) <.001 1.536(1.224-1.927) LVI Present 809 (47) 216 (49.5) .312 .908(.752-1.095) N/A 912 (53) 220 (50.5) PNI Present 311 (18.1) 89 (20.4) .580 .936(.742-1.182) N/A 1410 (81.9) 347 (79.6) Ki67 <15 670 (39) 84 (19.3) <.001 2.481(1.955-3.148) ≥15 1049 (61) 352 (80.7) Mitotic Index 1 342 (19.9) 21 (4.8) 1 (Reference) 2 913 (53.1) 160 (36.7) <.001 2.739(1.738-4.318) 3 466 (27.1) 255 (58.5) <.001 8.114(5.197-12.669) Histologic Grade Grade I 261 (15.2) 28 (6.4) 1 (Reference) Grade II 845 (49.1) 180 (41.3) .002 1.877(1.261-2.795) Grade III 615 (35.7) 228 (52.3) <.001 3.223(2.176-4.774) Skin Infiltration Present 82 (4.8) 86 (19.7) <.001 .214(.168-.272) N/A 1639 (95.2) 350 (80.3) Surgical Margin Negative 1387 (80.6) 365 (83.7) .664 .945(.732-1.219) Positive 334 (19.4) 71 (16.3) Subgroup (Luminal) Luminal A-B 1422 (82.6) 332 (76.1) 1 (Reference) Triple Negative 199 (11.6) 54 (12.4) .406 1.130(.847-1.506) HER2 Enriched 100 (5.8) 50 (11.5) <.001 2.139(1.588-2.881) Subgroup HER2 Enriched 100 (5.8) 50 (11.5) 1 (Reference) Triple Negative 199 (11.6) 54 (12.4) .001 .527(.359-.775) Luminal A 547 (31.8) 65 (14.9) <.001 .246(.170-.356) Luminal B 875 (50.8) 267 (61.2) .001 .597(.441-.808) Surgery N/A 8 (0.5) 70 (16.1) <.001 .054(.041-.071) Present 1713 (99.5) 366 (83.9) Breast Surgery Type BCS 970 (56.6) 127 (34.7) <.001 2.049(1.652-2.542) MRM 743 (43.4) 239 (65.3) Axillary Surgery N/A 8 (0.5) 70 (16.1) <.001 .054(.041-.071) Present 1713 (99.5) 366 (83.9) Axillary Surgery Type SLND 481 (28.1) 47 (12.8) <.001 1.966(1.445-2.674) AK 1232 (71.9) 319 (87.2) Anti-Hormonal Treatment Present 1419 (82.5) 332 (76.1) .001 1.454(1.167-1.813) N/A 302 (17.5) 104 (23.9) Duration of TAM Use N/A 1059 (61.5) 190 (43.6) 1 (Reference) ≤ 5 years 570 (33.1) 234 (53.7) .000 1.885(1.555-2.284) >5 years 92 (5.3) 12 (2.8) .071 .584(.326-1.047) Duration of AI Use N/A 669 (38.9) 196 (45) 1 (Reference) ≤ 5 years 819 (47.6) 206 (47.2) .075 .837(.688-1.018) >5 years 233 (13.5) 34 (7.8) <.001 .429(.298-.619) RT Present 1579 (91.7) 306 (70.2) <.001 3.580(2.914-4.398) N/A 142 (8.3) 130 (29.8) RT Type N/A 134 (7.8) 127 (29.1) 1 (Reference) Breast Only 580 (33.7) 47 (10.8) <.001 .124(.089-.174) Locoregional 1007 (58.5) 262 (60.1) <.001 .350 (.283-.433) Herceptin Eligibility Eligible 331 (19.2) 92 (21.1) .023 .765(.607-.965) Ineligible 1390 (80.8) 344 (78.9) CT N/A 318 (18.5) 46 (10.6) 1 (Reference) Neoadjuvant 184 (10.7) 82 (18.8) <.001 2.812(1.959-4.035) Adjuvant 1219 (70.8) 308 (70.6) .025 1.424(1.044-1.943) CT Type N/A 328 (19.1) 60 (13.8) 1 (Reference) AC+TXT 863 (50.1) 153 (35.1) .986 .997(.740-1.344) FAC-FEC-TAC 310 (18) 132 (30.3) .015 1.465(1.077-1.994) FAC-FEC+TXT 189 (11) 44 (10.1) .932 .983(.666-1.452) RIBO+PABLO 0 (0) 6 (1.4) <.001 20.437(8.755-47.704) PERJETA 2 (0.1) 20 (4.6) <.001 16.309(9.751-27.276) CMF 29 (1.7) 21 (4.8) <.001 2.663(1.619-4.379) ER: Estrogen Receptor, PR: Progesterone Receptor, HER2: Human Epidermal Growth Factor Receptor 2, EIC: Extensive Intraductal Carcinoma, LVI: Lymphovascular Invasion, PNI: Perineural Invasion, TMX: Tamoxifen, AI: Aromatase Inhibitor, RT: Radiotherapy, CT: Chemotherapy, AC: Axillary Curettage, SLND: Sentinel Lymph Node Dissection, AC: Adriamycin, Cyclophosphamide, TXT: Taxotere, FAC: Cyclophosphamid, Adriamycin, 5-Fulourouracil, FEC: 5-Fulouracil, Epirubicine, Cyclophosphamide, TAC: Taxotere, Adriamycin, Cyclophosphamid, RIBO+PABLO: Ribociclib+ Palbociclib, CMF: Cyclophosphamide, Methotrexate, Fluorouracil Table 5. Multivariate analysis results affecting DFS Recurrence Multivariate Cox Regression N/A Present p HR (95% CI) Age <35 83 (4.8) 29 (6.7) 1 (Reference) 36-50 691 (40.2) 148 (33.9) .05 .629(.395-1.000) >50 947 (55) 259 (59.4) .175 .671(.377-1.194) Menstruation Status Premenopausal 688 (40.1) 148 (34.6) .025 1.524(1.054-2.205) Postmenopausal 1026 (59.9) 280 (65.4) Histological Subtype Group- 2 Non-Special Type BC 1442 (83.8) 372 (85.3) 1 (Reference) Invasive Lobular Special Type BC 148 (8.6) 45 (10.3) .766 1.053(.748-1.483) Non-Lobular Special Type BC 131 (7.6) 19 (4.4) .589 .871(.529-1.436) Arrangement Unilateral 1674 (97.3) 409 (93.8) .004 2.265(1.306-3.927) Bilateral 47 (2.7) 27 (6.2) Location of BC Left 841 (48.9) 201 (46.1) 1 (Reference) Bilateral 47 (2.7) 27 (6.2) .004 2.265(1.306-3.927) Multicentric 114 (6.6) 51 (11.7) .053 .874(762-1.001) T Stage T1 648 (37.7) 66 (15.1) 1 (Reference) T2 889 (51.7) 237 (54.4) .003 1.737(1.214-2.486) T3 131 (7.6) 45 (10.3) .156 1.417(.875-2.295) T4 53 (3.1) 88 (20.2) .015 2.059(1.154-3.675) N Stage N0 818 (47.5) 82 (18.8) 1 (Reference) N1 478 (27.8) 86 (19.7) .226 1.304(.849-2.002) N2 293 (17) 154 (35.3) .269 1.349(.793-2.296) N3 132 (7.7) 114 (26.1) .232 1.396(.808-2.413) Stage I 422 (24.5) 23 (5.3) 1 (Reference) II 825 (47.9) 106 (24.3) .433 1.265(.703-2.279) III 469 (27.3) 164 (37.6) .021 2.275(1.129-4.583) IV 5 (0.3) 143 (32.8) <.001 32.105(15.256-67.563) ER Positive 1393 (80.9) 319 (73.2) .086 1.688(.928-3.071) Negative 328 (19.1) 117 (26.8) PR Positive 1167 (67.8) 254 (58.3) .651 1.071(.796-1.442) Negative 554 (32.2) 182 (41.7) HER2 Positive 383 (22.3) 125 (28.7) .536(.358-.802) .002 Ki67 <15 670 (39) 84 (19.3) .622 1.076(.804-1.440) ≥15 1049 (61) 352 (80.7) Mitotic Index 1 342 (19.9) 21 (4.8) 1 (Reference) 2 913 (53.1) 160 (36.7) .009 1.951(1.180-3.224) 3 466 (27.1) 255 (58.5) <.001 2.753(1.607-4.715) Tm Grade Grade I 261 (15.2) 28 (6.4) 1 (Reference) Grade II 845 (49.1) 180 (41.3) .154 1.416(.878-2.283) Grade III 615 (35.7) 228 (52.3) .384 1.257(.751-2.102) Skin Infiltration Present 82 (4.8) 86 (19.7) .237 .753(.470-1.205) N/A 1639 (95.2) 350 (80.3) EIC N/A 1459 (84.8) 340 (78) .112 1.243(.950-1.627) Present 262 (15.2) 96 (22) Subgroup HER2 Enriched 100 (5.8) 50 (11.5) Triple Negative 199 (11.6) 54 (12.4) Luminal A 547 (31.8) 65 (14.9) Luminal B 875 (50.8) 267 (61.2) Breast Surgery Type BCS 970 (56.6) 127 (34.7) .356 1.131(.871-1.468) MRM 743 (43.4) 239 (65.3) Axillary Surgery Type SLND 481 (28.1) 47 (12.8) .267 .813(.563-1.172) AK 1232 (71.9) 319 (87.2) Anti-Hormonal Treatment Present 1419 (82.5) 332 (76.1) .437 .737(.342-1.590) N/A 302 (17.5) 104 (23.9) Duration of TAM Use N/A 1059 (61.5) 190 (43.6) 1 (Reference) 570 (33.1) 234 (53.7) .021 1.499(1.062-2.117) ≤ 5 years >5 years 92 (5.3) 12 (2.8) .642 .847(.421-1.704) Duration of AI Use N/A 669 (38.9) 196 (45) 1 (Reference) ≤ 5 years 819 (47.6) 206 (47.2) .249 .824(.593-1.145) >5 years 233 (13.5) 34 (7.8) .047 .607(.371-.993) RT Present 1579 (91.7) 306 (70.2) .524 .631(.153-2.607) N/A 142 (8.3) 130 (29.8) RT Type N/A 134 (7.8) 127 (29.1) 1 (Reference) Breast Only 580 (33.7) 47 (10.8) .222 .397(.090-1.747) Locoregional 1007 (58.5) 262 (60.1) .174 .367(.086-1.558) Herceptin Eligibility Eligible 331 (19.2) 92 (21.1) .032 1.638(1.043-2.572) Ineligible 1390 (80.8) 344 (78.9) CT Received N/A 318 (18.5) 46 (10.6) 1 (Reference) Neadjuvant 184 (10.7) 82 (18.8) .586 1.151(.694-1.911) Adjuvant 1219 (70.8) 308 (70.6) .119 .708(.459-1.093) ER: Estrogen Receptor, PR: Progesterone Receptor, HER2: Human Epidermal Growth Factor Receptor 2, EIC: Extensive TMX: Tamoxifen, AI: Aromatase Inhibitor, RT: Radiotherapy, CT: Chemotherapy, AC: Axillary Curettage SLND: Sentinel Lymph Node Dissection Table 6. Univariate analysis results affecting OS Survival Status [n (%)] Univariate Cox Regression Alive Deceased p HR (95% CI) Age <35 87 (4.9) 25 (6.5) 1 (Reference) 36-50 722 (40.8) 117 (30.2) .013 .577(.375-.889) >50 961 (54.3) 245 (63.3) .894 1.028(.681-1.552) Gender Female 1761 (99.5) 381 (98.4) .014 2.753(1.228-6.168) Male 9 (0.5) 6 (1.6) Menstruation State Premenopausal 718 (40.8) 118 (31) <.001 1.664(1.338-2.068) Postmenopausal 1043 (59.2) 263 (69) Family History Present 536 (30.3) 91 (23.5) .005 1.402(1.108-1.773) N/A 1234 (69.7) 296 (76.5) Histological Subtype Group- 1 No-Special Type 1486 328 .379 .883(.669-1.165) Special Type 284 59 Histological Subtype Group- 2 No-Special Type 1486 328 (84.7) 1 (Reference) Invasive Lobular BC 150 43 (11.1) .502 1.115(.811-1.532) Non-lobular Special Type BC 134 (7.6) 16 (4.1) .026 .566(.343-.935) Arrangement Unilateral 1713 (96.8) 370 (95.6) .690 1.104(.679-1.795) Bilateral 57 (3.2) 17 (4.4) Breast Left 855 (48.3) 187 (48.3) 1 (Reference) Right 858 (48.5) 183 (47.3) .695 .960(.783-1.177) Bilateral 57 (3.2) 17 (4.4) .757 1.082(.658-1.777) Tumor Quadrant Inner 356 (20.1) 79 (20.4) 1 (Reference) Outer 1052 (59.4) 226 (58.4) .962 .994(.769-1.284) Areola 234 (13.2) 45 (11.6) .667 .923(.640-1.331) Multicentric 128 (7.2) 37 (9.6) .074 1.428(.966-2.110) T Stage T1 654 (36.9) 60 (15.5) 1 (Reference) T2 920 (52) 206 (53.2) <.001 2.212(1.659-2.949) T3 134 (7.6) 42 (10.9) <.001 2.636(1.777-3.912) T4 62 (3.5) 79 (20.4) <.001 13.115(9.330-18.436) N Stage N0 804 (45.4) 96 (24.8) 1 (Reference) N1 490 (27.7) 74 (19.1) .338 1.160(.856-1.571) N2 319 (18) 128 (33.1) <.001 3.398(2.607-4.429) N3 157 (8.9) 89 (23) <.001 4..318(3.234-5.764) Stage I 420 (23.7) 25 (6.5) 1 (Reference) II 812 (45.9) 119 (30.7) <.001 2.113(1.373-3.252) III 470 (26.6) 163 (42.1) <.001 4.783(3.139-7.286) IV 68 (3.8) 80 (20.7) <.001 21.748(13.828-34.204) Metastatic Site N/A 1621 (91.6) 125 (32.3) 1 (Reference) Bone 69 (3.9) 77 (19.9) <.001 9.199(6.922-12.226) Lung 9 (0.5) 14 (3.6) <.001 10.972(6.311-19.075) Liver 4 (0.2) 10 (2.6) <.001 17.278(9.058-32.959) Brain 2 (0.1) 22 (5.7) <.001 26.432(16.733-41.753) Multiple 65 (3.7) 139 (35.9) <.001 15.046(11.794-19.193) Surgery N/A 30 (1.7) 48 (12.4) <.001 .091(.067-.125) Present 1740 (98.3) 339 (87.6) Breast Surgery Type BCS 998 (57.4) 99 (29.2) <.001 2.385(1.887-3.016) MRM 742 (42.6) 240 (70.8) Axillary Surgery N/A 30 (1.7) 48 (12.4) <.001 .091(.067-.125) Present 1740 (98.3) 339 (87.6) Axillary Surgery Type SLND 497 (28.6) 31 (9.1) <.001 2.298(1.586MNNMZ3.331) AC 1243 (71.4) 308 (90.9) Skin Infiltration Present 86 (4.9) 82 (21.2) <.001 .170(.132-.218) N/A 1684 (95.1) 305 (78.8) Surgical Margin Negative 1441 (81.4) 311 (80.4) .023 1.340(1.042-1.723) Positive 329 (18.6) 76 (19.6) Tm Grade Grade I 286 (16.2) 3 (0.8) 1 (Reference) Grade II 866 (48.9) 159 (41.1) <.001 15.313(4.886-47.986) Grade III 618 (34.9) 225 (58.1) <.001 30.243(9.680-94.487) Mitotic Index 1 360 (20.3) 3 (0.8) 1 (Reference) 2 918 (51.9) 155 (40.1) <.001 18.444(5.884-57.817) 3 492 (27.8) 229 (59.2) <.001 51.199(16.389-159.950) ER Positive 1438 (81.2) 274 (70.8) <.001 1.675(1.345-2.085) Negative 332 (18.8) 113 (29.2) PR Positive 1194 (67.5) 227 (58.7) <.001 1.537(1.255-1.881) Negative 576 (32.5) 160 (41.3) HER2 Positive 406 (22.9) 102 (26.4) .002 .697(.555-.876) Negative 1364 (77.1) 285 (73.6) Ki67 <15 681 (38.5) 73 (18.9) <.001 2.493(1.932-3.217) ≥15 1087 (61.5) 314 (81.1) EIC N/A 1502 (84.9) 297 (76.7) <.001 1.678(1.325-2.125) Present 268 (15.1) 90 (23.3) LVI Present 827 (46.7) 198 (51.2) .078 .836(.685-1.020) N/A 943 (53.3) 189 (48.8) PNI Present 314 (17.7) 86 (22.2) .313 .884(.695-1.123) N/A 1456 (82.3) 301 (77.8) Subgroup Luminal Luminal A-B 1468 (82.9) 286 (73.9) 1 (Reference) Triple negative 198 (11.2) 55 (14.2) .034 1.366(1.023-1.823) HER2 enriched 104 (5.9) 46 (11.9) <.001 2.415(1.767-3.301) Subgroup HER2 enriched 104 (5.9) 46 (11.9) 1 (Reference) Triple negative 198 (11.2) 55 (14.2) .004 .565(.381-.836) Luminal A 559 (31.6) 53 (13.7) <.001 .209(.141-.310) Luminal B 909 (51.4) 233 (60.2) <.001 .532(.387-.731) Anti-Hormonal Treatment Present 1466 (82.8) 285 (73.6) <.001 1.723(1.374-2.160) N/A 304 (17.2) 102 (26.4) Duration of TAM Use N/A 1034 (58.4) 215 (55.6) 1 (Reference) ≤ 5 years 640 (36.2) 164 (42.4) .938 1.008(.822-1.237) >5 years 96 (5.4) 8 (2.1) .001 .294(.145-.595) Duration of AI Use N/A 691 (39) 174 (45) 1 (Reference) ≤ 5 years 832 (47) 193 (49.9) .116 .848(.691-1.041) >5 years 247 (14) 20 (5.2) <.001 .237(.149-.377) Herceptin Eligibility Eligible 361 (20.4) 62 (16) .665 .941(.715-1.239) Ineligible 1409 (79.6) 325 (84) RT Present 1591 (89.9) 294 (76) <.001 2.380(1.884-3.006) N/A 179 (10.1) 93 (24) RT Type N/A 171 (9.7) 90 (23.3) 1 (Reference) Breast Only 574 (32.4) 53 (13.7) <.001 .236(.168-.331) Locoregional 1025 (57.9) 244 (63) <.001 .506(.397-.645) CT N/A 316 (17.9) 48 (12.4) 1 (Reference) Neadjuvant 206 (11.6) 60 (15.5) .002 1.839(1.258-2.689) Adjuvant 1248 (70.5) 279 (72.1) .864 1.027(.756-1.396) CT Type N/A 333 (18.8) 55 (14.2) 1 (Reference) AC+TXT 888 (50.2) 128 (33.1) .503 .898(.654-1.232) FAC-FEC-TAC 312 (17.6) 130 (33.6) .378 1.154(.839-1.587) FAC-FEC+TXT 185 (10.5) 48 (12.4) .815 .955(.647- 1.408) RIBO+PABLO 5 (0.3) 1 (0.3) .268 3.061(.423-22.183) PERJETA 20 (1.1) 2 (0.5) .905 1.090(.265-4.476) CMF 27 (1.5) 23 (5.9) <.001 2.627(1.613-4.279) ER: Estrogen Receptor, PR: Progesterone Receptor, HER2: Human Epidermal Growth Factor Receptor 2, EIC: Extensive Intraductal Carcinoma, LVI: Lymphovascular Invasion, PNI: Perineural Invasion, TMX: Tamoxifen, AI: Aromatase Inhibitor, RT: Radiotherapy, CT: Chemotherapy, AC: Axillary Curettage, SLND: Sentinel Lymph Node Dissection, AC: Adriamycin, Cyclophosphamide, TXT: Taxotere, FAC: Cyclophosphamid, Adriamycin, 5-Fulourouracil, FEC: 5-Fulouracil, Epirubicine, Cyclophosphamide, TAC: Taxotere, Adriamycin, Cyclophosphamid, RIBO+PABLO:Ribociclib+Palbociclib, CMF: Cyclophosphamide, Methotrexate, Fluorouracil Table 7. Multivariate analysis results affecting OS Survival Status Multivariate Cox Regression Alive Deceased p HR (95% CI) Age <35 87 (4.9) 25 (6.5) 1 (Reference) 36-50 722 (40.8) 117 (30.2) .555 1.185(.675-2.079) >50 961 (54.3) 245 (63.3) .168 1.578(.825-3.019) Menstruation Status Premenopausal 718 (40.8) 118 (31) .981 1.005(.675-1.495) Postmenopausal 1043 (59.2) 263 (69) Family History Present 536 (30.3) 91 (23.5) .191 1.205(.911-1.593) N/A 1234 (69.7) 296 (76.5) HistologicalSubtype Group - 2 No-Special Type 1486 328 (84.7) 1 (Reference) Invasive Lobular BC 150 43 (11.2) .045 1.457(1.009-2.104) Non-Lobular Special Type BC 134 (7.6) 16 (4.1) .579 .861(.507-1.462) T Stage T1 654 (36.9) 60 (15.5) 1 (Reference) T2 920 (52) 206 (53.2) .191 1.301(.877-1.929) T3 134 (7.6) 42 (10.9) .021 1.791(1.094-2.932) T4 62 (3.5) 79 (20.4) .005 2.486(1.315-4.700) N Stage N0 804 (45.4) 96 (24.8) 1 (Reference) N1 490 (27.7) 74 (19.1) .790 1.056(.707-1.578) N2 319 (18) 128 (33.1) .002 2.358(1.384-4.018) N3 157 (8.9) 89 (23) .007 2.184(1.243-3.836) Stage I 420 (23.7) 25 (6.5) 1 (Reference) II 812 (45.9) 119 (30.7) .058 1.802(.980-3.314) III 470 (26.6) 163 (42.1) .825 1.090(.507-2.343) IV 68 (3.8) 80 (20.7) .112 1.987(.853-4.631) Skin Infiltration Present 86 (4.9) 82 (21.2) .034 .598(.372-.961) N/A 1684 (95.1) 305 (78.8) Surgical Margin Negative 1441 (81.4) 311 (80.4) <.001 1.666(1.275-2.176) Positive 329 (18.6) 76 (19.6) Duration of TAM Use N/A 1034 (58.4) 215 (55.6) 1 (Reference) ≤ 5 years 640 (36.2) 164 (42.4) <.001 .430(.295-.625) >5 years 96 (5.4) 8 (2.1) <.001 .177(.074-.423) Duration of AI Use N/A 691 (39) 174 (45) 1 (Reference) ≤ 5 years 832 (47) 193 (49.9) .015 .609(.407-.909) >5 years 247 (14) 20 (5.2) <.001 .143(.077-.266) ER Positive 1438 (81.2) 274 (70.8) .395 1.307(.706-2.419) Negative 332 (18.8) 113 (29.2) PR Positive 1194 (67.5) 227 (58.7) .584 .910(.650-1.275) Negative 576 (32.5) 160 (41.3) HER2 Positive 406 (22.9) 102 (26.4) .197 .790(.552-1.130) Negative 1364 (77.1) 285 (73.6) Ki67 <15 681 (38.5) 73 (18.9) .502 .836(.496-1.410) ≥15 1087 (61.5) 314 (81.1) Mitotic Index 1 360 (20.3) 3 (0.8) 1 (Reference) 2 918 (51.9) 155 (40.1) .025 2.616(1.131-6.053) 3 492 (27.8) 229 (59.2) .005 3.530(1.475-8.449) Tm Grade Grade I 286 (16.2) 3 (0.8) 1 (Reference) Grade II 866 (48.9) 159 (41.1) .091 2.080(.889-4.868) Grade III 618 (34.9) 225 (58.1) .025 2.748(1.139-6.631) Chemotherapy N/A 316 (17.9) 48 (12.4) 1 (Reference) Neoadjuvant 206 (11.6) 60 (15.5) <.001 .141(.053-.373) Adjuvant 1248 (70.5) 279 (72.1) <.001 .161(.066-.392) EIC N/A 1502 (84.9) 297 (76.7) .281 1.180(.873-1.595) Present 268 (15.1) 90 (23.3) Breast Surgery Type BCS 998 (57.4) 99 (29.2) .008 1.546(1.122-2.130) MRM 742 (42.6) 240 (70.8) Axillary Surgery SLND 497 (28.6) 31 (9.1) .099 1.443(.933-2.234) Type AK 1243 (71.4) 308 (90.9) RT Present 1591 (89.9) 294 (76) .122 2.447(.788-7.600) N/A 179 (10.1) 93 (24) RT Type N/A 171 (9.7) 90 (23.3) 1 (Reference) Breast Only 574 (32.4) 53 (13.7) .026 3.729(1.167-11.913) Locoregional 1025 (57.9) 244 (63) .431 1.609(.492-5.262) Site of Metastasis N/A 1621 (91.6) 125 (32.3) 1 (Reference) Bone 69 (3.9) 77 (19.9) <.001 9.010(6.481-12.524) Lung 9 (0.5) 14 (3.6) <.001 10.887(6.034-19.644) Liver 4 (0.2) 10 (2.6) <.001 14.829(6.774-32.464) Brain 2 (0.1) 22 (5.7) <.001 26.076(15.484-43.914) Multiple 65 (3.7) 139 (35.9) <.001 11.479(5.457-17.249) ER: Estrogen Receptor, PR: Progesterone Receptor, HER2: Human Epidermal Growth Factor Receptor 2, EIC: Extensive Intraductal Carcinoma, LVI: Lymphovascular Invasion, PNI: Perineural Invasion, TMX: Tamoxifen, AI: Aromatase Inhibitor, RT: Radiotherapy, CT: Chemotherapy, AC: Axillary Curettage, SLND: Sentinel Lymph Node Dissection Figure Legends Figure 1a. Survival curve DFS of Non-Special Type BC and Special Type BC subgroups using Kaplan-Meier method Figure 1b. Survival curve of OS times of Non-Special Type BC and Special Type BC subgroups using Kaplan-Meier method Figure 2a. Survival curve of DFS times of Non-Special Type BC and Non-Lobular Special Type BC and ILC subgroups using Kaplan-Meier method. There are 2066 patients at the beginning of the DFS curve, as 91 of a total of 2157 breast cancer patients had metastatic presentation at baseline. Figure 2b. Survival curve of OS times of Non-Special Type BC and Non-Lobular Special Type BC and ILC subgroups using Kaplan-Meier method Figure 3. Subgroup distribution according to histopathological subgroup differentiation, 3a. Non-Special Type BC, 3b. Invasive Lobular Special Type BC, 3c. Non-Lobular Special Type BC