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Development and External Validation of a Clinical Nomogram for Individually Predicting Survival of Metaplastic Breast Cancer

Open AccessPublished:July 08, 2022DOI:https://doi.org/10.1016/j.clbc.2022.06.006

      Highlights

      • Few studies concerned prognosis of metaplastic breast cancer, a rare subtype with distinct features
      • Nomogram estimating the metaplastic breast cancer survival could guide clinical practice
      • Nomogram based on SEER and validation Asian population have an optimal discrimination

      Abstract

      Background

      Few studies have concerned the prognosis of metaplastic breast cancer (MpBC), a rare and diverse malignancy. A prognostic index estimating the MpBC survival would be attractive in clinical practice.

      Patients and Methods

      We retrospectively analyzed MpBC patients from the Surveillance, Epidemiology, and End Results (SEER) database. Prognostic factors were identified and the final nomogram was developed to predict the 1-, 3-, or 5-year overall survival (OS). Calibration curves were provided to internally validate the performance of the nomogram and discriminative ability was appraised by concordance index (C-index).

      Results

      A total of 1017 MpBC patients diagnosed between 2010 and 2015 were assigned into 3:1 as training set (n = 763) and SEER validation set (n = 254). An external validation was performed by an individual set of 94 MpBC patients from National Cancer Center in China from 2010 to 2018. The nomogram finally consisted of 7 independent prognostic factors and presented a good accuracy for predicting the OS with the C-index of 0.77 (95% CI: 0.751-0.786). Interestingly, the nomogram based on the western (including 92.5% non-Asian) SEER validation population (C-index of nomogram: 0.76, 95% CI: 0.737-0.796) also has an optimal discrimination in Asian population (C-index of nomogram: 0.70). The calibration plots of the nomogram predictions were also accurate and corresponded closely with the actual survival rates.

      Conclusion

      This novel nomogram was accurate enough to predict the OS by using readily available clinicopathologic factors in MpBC general population, which could provide individualized recommendations for patients and clinical decisions for physicians.

      Keywords

      Introduction

      Breast cancer is currently the most common malignancy in women worldwide, accounting for approximately 25% of all the malignancies among female patients.
      • Sung H
      • Ferlay J
      • Siegel RL
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      Metaplastic breast cancer (MpBC) is a rare malignancy, constituting less than 1% of invasive breast carcinoma.
      • Gultekin M.
      • Eren G.
      • Babacan T.
      • et al.
      Metaplastic breast carcinoma: a heterogeneous disease.
      MpBC was officially recognized as a distinct pathologic diagnosis in 2000 by WHO classification, which is characterized by a mixture of adenocarcinoma with “metaplastic” various features, such as histologically of spindle, squamous, osseous, or chondroid differentiation.
      • Lee H.
      • Jung S.Y.
      • Ro J.Y.
      • et al.
      Metaplastic breast cancer: clinicopathological features and its prognosis.
      MpBC differs from breast invasive ductal carcinoma (IDC) in several pathological and clinical characteristics, with few published articles about MpBC patients’ prognosis and treatment strategies are not well studied.
      • Nelson R.A.
      • Guye M.L.
      • Luu T.
      • Lai L.L.
      Survival outcomes of metaplastic breast cancer patients: results from a US population-based analysis.
      ,
      • Li Y.
      • Zhang N.
      • Zhang H.
      • Yang Q
      Comparative prognostic analysis for triple negative breast cancer with metaplastic and invasive ductal carcinoma.
      To date, only seldom case series with small sample size have attempted to evaluate the specific factors that make MpBC different from IDC.
      • Ghosh M.
      • Muneer A.
      • Trivedi V.
      • Mandal K.
      • Shubham S.
      Metaplastic carcinoma breast: a clinical analysis of nine cases.
      It has been reported that MpBC may have poor prognosis compared with typical breast cancer. However, this remains controversial.
      • Aydiner A.
      • Sen F.
      • Tambas M.
      • et al.
      Metaplastic breast carcinoma versus triple-negative breast cancer: survival and response to treatment.
      Since MpBC have distinct clinical characteristics at presentation, this malignancy should be managed differently in clinical practice.
      • Jung S.Y.
      • Kim H.Y.
      • Nam B.H.
      • et al.
      Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer.
      Since few published results were available to guide clinical practice, we hypothesized that MpBC may be managed differently than typical IDC.
      Few studies have concerned the prognosis of this rare and morphologically diverse malignancy.
      • He X.
      • Ji J.
      • Dong R.
      • et al.
      Prognosis in different subtypes of metaplastic breast cancer: a population-based analysis.
      Various clinical experience and limited follow-up duration may result in big bias for clinical guidance. Therefore, the current clinical strategies for MpBC lack high level rigorous guidance and strong evidence.
      • Han Y.
      • Wang J.
      • Xu B.
      Clinicopathological characteristics and prognosis of breast cancer with special histological types: a surveillance, epidemiology, and end results database analysis.
      Nomogram is a reliable and alternative statistical analysis technique to quantify risk by incorporating and specifying key prognostic factors, which could make more precise survival prediction and guide physicians for individual clinical decision. Since there is no available evaluating system for this group of patients to provide prognosis prediction, a prognostic index estimating the clinical treatment outcomes for MpBC would be attractive and promising in current clinical practice. The purpose of this study is to better characterize the clinical management of this disease including the role of chemotherapy, radiotherapy and surgery. In addition, the aim of the present study was to develop and validate an effective nomogram for predicting survival of MpBC.

      Patients and Methods

      Data Resources

      The information of metaplastic breast cancer patients, ranging from January 2010 to December 2015, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, which includes the data on cancer incidence, survival outcome and therapeutic options from 17 population-based cancer registries and represents approximately 28% of the US population.
      The SEER is a publicly accessed database. Data from the SEER database could apply for an exemption of patients’ informed consent, because patients were anonymized and deidentified prior to release.

      Study Population

      The entire group of MpBC patients enrolled in this study was positively confirmed by histopathological examination. The histopathological diagnosis of enrolled MpBC patients categorized into purely epithelial or mixed epithelial and mesenchymal,
      • Aydiner A.
      • Sen F.
      • Tambas M.
      • et al.
      Metaplastic breast carcinoma versus triple-negative breast cancer: survival and response to treatment.
      , including adenosquamous carcinoma (ASC), carcinoma with osseous and chondroid metaplasia (COC), squamous cell carcinoma (SCC), adenocarcinoma with spindle cell differentiation (SPC)and mixed type MpBC, according to the WHO classification.
      • Gultekin M.
      • Eren G.
      • Babacan T.
      • et al.
      Metaplastic breast carcinoma: a heterogeneous disease.
      The overall survival (OS) was regarded as the interval from the initial diagnosis to death due to any cause. Several clinical and disease features were recorded to discuss the prognostic impact on survival, including age, gender, race, laterality, primary tumor size, tumor grade, pathological subtype, molecular subtype, AJCC N stage, surgery, radiotherapy, and chemotherapy in the SEER database.
      The analytical cohort and selection criteria of enrolled participants are shown in Figure 1. Given that HER2 gene and FISH analysis matured after 2010, anti-HER2-targeted therapy has been available after 2010 for HER2 overexpressed patients, including MpBC. Therefore, we selected data after 2010 in the SEER database, patients aged 18 and older who were diagnosed with MpBC in SEER database between January 2010 and December 2015 were included, which is consistent with the enrollment years of the Chinese population data used for our external validation. Patients with unknown tumor characteristics, estrogen receptor (ER), and progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status were excluded. Additional exclusion was missing clinical information regarding therapy or tumor staging in accordance with the American Joint Committee on Cancer (AJCC 7th edition). Patients were assigned into 3:1 as training cohort (n = 763) and SEER validation cohort (n = 254). An external validation was carried out by an individual set of 94 MpBC patients from National Cancer Center in China from 2010 to 2018.
      Figure 1
      Figure 1Analytical cohort and exclusion criteria. Abbreviations: ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor; SEER = surveillance, epidemiology, and end results.

      Statistical Analysis

      Prognostic factors were identified based on Cox regression analyses. The OS was analyzed using Kaplan-Meier methods, with the usage of log-rank tests to compare subgroup significance. Prognostic factors with P < .10 in Kaplan-Meier analyses were following conjugated within multivariate analysis. We choose the identified prognostic factors (P < .05) from the final (after forward selection) Cox model to develop the nomogram and predict the OS of MpBC patients. The performance of the nomogram was internally validated by providing calibration curves, and its discriminability was assessed by the concordance index (C-index).
      Final clinical nomogram was developed to predict the 1-, 3-, or 5-year predicted OS. To evaluate the calibrating power, we randomly stratified patients into 3:1 as training set and SEER validation set. Bootstrap-corrected OS rates were calculated by averaging the Kaplan-Meier estimates based on 1000 bootstrap samples. The model was validated using bootstrap resampling of SEER validation set and a Chinese cohort for external validation.
      All statistical analyses were conducted using SPSS version 25.0 and R Version 3.6.0, and P < .05 was considered with statistical significance.

      Results

      Patient and Treatment Characteristics

      After excluding 477 cases from SEER database who were not eligible with unknown basic clinical and treatment information, finally a total of 1017 MpBC patients were conducted for our analysis. Almost all of the patients were female (99.7%).Patients with age ≥60 (51.4%), white race (70.7%), high tumor grade (85.3%), tumor size ≥5 cm (21.1%), metaplastic carcinoma (90.9%), TNBC subtype (69.4%), and lymph node metastasis positive (25.6%) were enrolled. Most MpBCs, ie, 94.9% of cases were treated with surgery. 485 (47.7%) cases received chest wall or breast radiotherapy while 731 (71.9%) cases received chemotherapy in all patients. Clinical characteristics of MpBC cohorts from SEER database and external Chinese population were shown in Table 1. In addition, there was no statistically significant difference between training and validation SEER sets.
      Table 1Characteristic of MpBC Cohorts From SEER Database and External Population
      CharacteristicTraining Sets[n (%)] (N = 763)Validation Sets[n (%)] (N = 254)P*External Validation Sets From China[n (%)] (N = 94)P*Univariable Analysis P
      Age, years59.7 ± 13.260.4 ± 13.20.60052.8 ± 12.20.000.001
      <60367 (48.1)127 (50.0)66 (70.2)
      ≥60396 (51.9)127 (50.0)28 (29.8)
      Gender0.7380.234.455
      Female761 (99.7)253 (99.6)93 (98.9)
      Male2 (0.3)1 (0.4)1 (1.1)
      Race0.678-.331
      White539 (70.6)180 (70.9)-
      Black165 (21.6)55 (21.7)-
      Others59(7.8)19 (7.4)-
      Laterality0.6250.981.374
      Left392 (51.4)126 (49.6)48 (51.1)
      Right371 (48.6)128 (50.4)46 (48.9)
      Tumor grade0.7650.000.001
      Grade I, II114 (14.9)36 (14.2)68 (72.3)
      Grade III, IV649 (85.1)218 (85.8)26 (27.7)
      Tumor size0.6830.015.001
      <5 cm604 (79.2)198 (78.0)84 (89.4)
      ≥5 cm159 (20.8)56 (22.0)10 (10.6)
      Pathological type0.3480.123.753
      Metaplastic carcinoma680 (89.1)235 (92.5)65 (69.3)
      Squamous cell carcinoma38 (5.0)10 (3.9)2 (2.1)
      Spindle cell carcinoma19 (2.5)6 (2.4)7 (7.4)
      Malignant myoepithelioma7 (0.9)0 (0.0)2 (2.1)
      Adenocarcinoma mixed19 (2.4)3 (1.2)18 (19.1)
      Molecular subtype0.2280.957.696
      Non-TNBC241 (31.6)70 (27.6)29 (30.9)
      TNBC522 (68.4)184 (72.4)65 (69.1)
      AJCC N stage0.8460.159.001
      N0567 (74.3)190 (74.8)78 (83.0)
      N1133 (17.4)41 (16.1)12 (12.8)
      N2,N363 (8.3)23 (9.1)4 (4.3)
      Surgery0.7390.931.001
      No38 (5.0)14 (5.5)5 (5.3)
      Yes725 (95.0)240 (94.5)89 (94.7)
      Radiotherapy0.3190.449.001
      No406 (53.2)126 (49.6)53 (56.4)
      Yes357 (46.8)128 (50.4)41 (43.6)
      Chemotherapy0.6790.224.003
      No212 (27.8)74 (29.1)32 (34.0)
      Yes551 (72.2)180 (70.9)62 (66.0)
      Abbreviations: AJCC N stage = American Joint Committee on Cancer Node stage; HER2 = human epithelial growth factor receptor 2; MpBC = metaplastic breast carcinoma; TNBC = triple-negative breast cancer.
      P*: X2 test, chi-squared test.

      OS Analysis

      There were a total of 244 (24.0%) patients died due to progressive OS at the time of analysis. At a median follow-up time of 84.2 months, the median OS in MpBC patients was 33 months, and the 1-, 3- and 5-year OS of patients were 90.5%, 79.4%, and 76.3%. All clinical stages at 5 years’ OS rate (stage I-II, 21.0% vs. III-IV, 7.9%; P < .001) and at 3 years’ OS rate (Stage I-II, 49.9%, vs. III-IV 26.6%; P < .001) were demonstrated in this study. Each survival curve of potential prognostic variable in univariate Kaplan-Meier analyses were represented in Figure 2. These factors included age (P = .001; median OS = 36.0 and 30 months for age <60 and ≥60, Figure 2A), primary tumor size (P < .0001; median OS = 35.0 and 23.0 months for tumor size <5 cm and ≥5 cm, Figure 2B), tumor grade (P = .009; median OS = 37.0 and 32.0 months for grade I, II and grade III, IV, Figure 2C), AJCC N stage (P < .0001; median OS = 35.0, 28.0, and 21.0 months for N0, N1, and N2&N3, Figure 2D), molecular subtype (P = .695; median OS = 46.0 and 32.0 months for non-TNBC and TNBC, Figure 2E), primary tumor resection (P < .0001; median OS = 34.0 and 12.0 months for with and without surgery, Figure 2F) and radiotherapy (P < .0001; median OS = 37.0 and 29.0 months for with and without radiotherapy, Figure 2G). Especially, OS was remarkable longer for patients who received chemotherapy compared to those who did not (P = .003; median OS = 33.0 and 31.0 months, Figure 2H). The 1-, 3- and 5-year OS of patients treated with chemotherapy were 92.2%, 81.4%, and 78.7%, comparing to 86.0%, 74.1%, and 70.3% of 1-, 3- and 5-year OS without chemotherapy, which have striking differences in survival.
      Figure 2
      Figure 2Kaplan-Meier overall survival curves according to different potential variables with P < .10. (A) Kaplan-Meier overall survival curve according to age. (B) Kaplan-Meier overall survival curve according to tumor size (C) Kaplan-Meier overall survival curve according to tumor grade. (D) Kaplan-Meier overall survival curve according to AJCC N stage. (E) Kaplan-Meier overall survival curve according to molecular subtype. (F) Kaplan-Meier overall survival curve according to primary tumor resection. (G) Kaplan-Meier overall survival curve according to radiotherapy. (H) Kaplan-Meier overall survival curve according to chemotherapy.

      Selected Prognostic Factors for OS

      After univariable analysis, the variables of gender, race, laterality, pathological type, and molecular subtype were not related to survival, and were excluded from further analysis (Table 1). The multivariable analysis finally demonstrated 7 independent prognostic factors including age, tumor grade, tumor size, AJCC Node stage, surgery, chemotherapy, and radiotherapy for OS (Table 2).
      Table 2Multivariable Cox Model of MBC After Forward Selection of Variables With P < .10 in Univariate Kaplan-Meier Analyses.
      CharacteristicsHRCIPValue
      Age, years
      ≥60 vs. <601.7211.256-2.356.001
      Tumor grade
      Grade III, IV vs. Grade I, II2.0891.255-3.477.005
      Primary tumor size
      ≥5 cm vs. <5 cm2.7041.957-3.735.000
      AJCC N stage
      N2,3 vs. N1 vs. N02.1121.746-2.554.000
      Radiotherapy
      Yes vs. No0.6010.435-0.829.002
      Surgery
      Yes vs. No0.2690.165-0.436.000
      Chemotherapy
      Yes vs. No0.6020.432-0.840.003
      Abbreviations: CI = confidence interval; HR = hazard rate.

      Prognostic Nomogram for OS

      The positive variables in multivariable analysis were integrated into the nomogram scoring system (Figure 3). The nomogram finally consisted of 7 independent prognostic factors including age, tumor grade, tumor size, AJCC Node stage, surgery, chemotherapy, and radiotherapy. The value of each variable was given a score on the scale axis. Estimated probabilities of 1-year, 3-year, and 5-year OS were calculated by scoring and locating on the total score scale. The nomogram presented a good accuracy for predicting the OS with the C-index of 0.77 (95% CI: 0.751-0.786) for the training set (Figure 4A) and 0.76 (95% CI: 0.737e0.796) for the internal validation sets (Figure 4B), respectively. Interestingly, the nomogram based on the western (including 92.5% non-Asian) SEER validation population(C-index of nomogram: 0.76) also has an optimal discrimination in Asian population (C-index of nomogram: 0.70) as external validations (Figure 4C). The calibration plots of the nomogram predictions were also accurate and corresponded closely with the actual survival rates.
      Figure 3
      Figure 3Nomogram for predicting 1-, 3- and 5-year overall survival. Sum the points of each variable (age, tumor grade, primary tumor size, AJCC N stage, radiotherapy, surgery, chemotherapy) and locate this sum on the total point's axis. Then respectively draw the “1-year survival”, “3-year survival” and “5-year survival” axis to find the predicted overall survival time.
      Figure 4
      Figure 4. Nomogram model calibration curves of actual cancer specific survival with 95% confidence interval by decile (y-axis), over predicted cancer specific survival (x-axis) by nomogram: (A) 1-year nomogram calibration curve. (B) 3-year nomogram calibration curve. (C) 5-year nomogram calibration curve.

      Discussion

      MpBC represents a rare aggressive histologic subtype of breast tumors, with different clinical features, behavior and response to treatments compared with invasive ductal or lobular carcinoma.
      • Zhang Y.
      • Lv F.
      • Yang Y.
      • et al.
      Clinicopathological features and prognosis of metaplastic breast carcinoma: experience of a major Chinese cancer center.
      Prospective data are limited for treatment strategy of MpBC given the rarity of the diagnosis and evidence from single-institution with small sample series or case reports. Since most of its molecular subtyping phenotypes are triple-negative receptor status for ER, PR, and HER2 amplification,
      • El Zein D.
      • Hughes M.
      • Kumar S.
      • et al.
      Metaplastic carcinoma of the breast is more aggressive than triple-negative breast cancer: a study from a single institution and review of literature.
      clinical diagnosis and treatment are mostly conducted according to the basal-like triple negative breast cancer. Generally, there is no high-level evidence of adjuvant hormonal therapy in the treatment of MpBC patients.
      • Ghosh M.
      • Muneer A.
      • Trivedi V.
      • Mandal K.
      • Shubham S.
      Metaplastic carcinoma breast: a clinical analysis of nine cases.
      ,
      • Takala S.
      • Heikkila P.
      • Nevanlinna H.
      • Blomqvist C.
      • Mattson J.
      Metaplastic carcinoma of the breast: prognosis and response to systemic treatment in metastatic disease.
      Patients over the age of 60 may have poorer overall survival outcomes than younger patients. Patients with low tumor grade had longer OS than those with high tumor grade. Lymphatic metastases of MpBC are rare and vary widely.
      • Corso G.
      • Frassoni S.
      • Girardi A.
      • et al.
      Metaplastic Breast cancer: prognostic and therapeutic considerations.
      The incidence of lymph node diffusion has been reported to be between 0% and 63%.
      • Moreno A.C.
      • Lin Y.H.
      • Bedrosian I.
      • et al.
      Outcomes after treatment of metaplastic versus other breast cancer subtypes.
      In this study, we analyzed SEER database and reported the frequency of lymph node metastasis was 25.6%. Here we can make a comment on the possible effect of lymph node metastasis as a prognostic factor on survival. The survival outcomes in our study are comparably favorable with previously reported series; with 3-year OS of 79.4% and 5-year of 76.3%, respectively, which is consistent with previous reports.
      • Han Y.
      • Wang J.
      • Xu B.
      Clinicopathological characteristics and prognosis of breast cancer with special histological types: a surveillance, epidemiology, and end results database analysis.
      It has been confirmed in this study that there is no clear correlation between pathological subtype of MpBC and prognosis of these patients. In addition, the role of chemotherapy and radiation therapy in MpBC has been confirmed in this study. Previous studies demonstrated that the effectiveness of standard radiation and chemotherapy regimens for MpBC is controversial,
      • Tseng W.H.
      • Martinez S.R.
      Metaplastic breast cancer: to radiate or not to radiate?.
      since MpBCs considered to be chemo-resistant.
      • Tseng W.H.
      • Martinez S.R.
      Metaplastic breast cancer: to radiate or not to radiate?.
      It has also been suggested in our study that chemotherapy and radiation therapy should be included as the multi-disciplinary treatment for MpBC patients with high risk features undergoing mastectomy, in contrary to the literature.
      Effective prognostic assessment is crucial for MpBC patients. However, at present, there is no complete evaluating system to accurately assess the prognosis of these patients.
      • Takala S.
      • Heikkila P.
      • Nevanlinna H.
      • Blomqvist C.
      • Mattson J.
      Metaplastic carcinoma of the breast: prognosis and response to systemic treatment in metastatic disease.
      ,
      • Yu K.D.
      • Zhu R.
      • Zhan M.
      • et al.
      Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer.
      The nomogram, a simple statistical predictive tool, can more accurately predict survival and prognosis and visualize results, further improving patient compliance and treatment outcomes. The SEER database provides strong data support for developing nomograms. Previous retrospective study with a small sample in a single center suggested that the prognosis of MpBC was significantly worse than that of basal-like TNBC patients.
      • Jung S.Y.
      • Kim H.Y.
      • Nam B.H.
      • et al.
      Worse prognosis of metaplastic breast cancer patients than other patients with triple-negative breast cancer.
      ,
      • El Zein D.
      • Hughes M.
      • Kumar S.
      • et al.
      Metaplastic carcinoma of the breast is more aggressive than triple-negative breast cancer: a study from a single institution and review of literature.
      Some scholars also analyzed the survival of MpBC patients with a poor prognosis by using SEER data alone.
      • Han Y.
      • Wang J.
      • Xu B.
      Clinicopathological characteristics and prognosis of breast cancer with special histological types: a surveillance, epidemiology, and end results database analysis.
      However, widespread use of SEER database is limited by the fact that it represents only the U.S. population and lacks data on Asian populations or other racial population. How to make survival prediction and treatment decision more accurately is an urgent problem to be solved.
      In this study, we utilize the existing clinical pathologic factors in SEER database, found that age, tumor stage, tumor size, AJCC N staging, surgery, chemotherapy and radiotherapy as the main prognostic factors affecting patients' overall survival. Our study entirely demonstrated the characteristics and survival outcomes of this special breast cancer malignancy. To our knowledge, this novel prognostic index systematically discusses the specific clinical features and estimates the clinical outcomes for this group of MpBC patients, which would be attractive in current clinical practice. Here we also performed by an individual set of 94 MpBC patients from National Cancer Center in China from 2010 to 2018 for external validation, which also has an optimal discrimination. Since the disease characteristics of Chinese patients with breast cancer vary from those in the United States. Chinese women have a higher proportion of early-onset breast cancer (EBC) and the majority of EBC are in early rather than advanced stage, as experienced from our Chinese external validation cohort. This nomogram could accurately predict the survival of patients and guide effective treatment. In addition, the C index and internal validation also indicated that this nomogram survival chart is a reliable OS assessment tool for MpBC patients. We believe that these prediction tools should be accurate and feasible enough at different levels of breast cancer in different population subgroup.
      Our study has some inevitable limitations. First, some prognostic indicators, such as Ki67 index or intravascular invasion, are not recorded in this open database and therefore cannot be used for analysis, which may create discrepancies in the routinary classifications of molecular subtypes and also weaken the persuasive power of this study. In addition, the confirmation of chemotherapy regimens, duration and response is unavailable in the SEER database, which could latently add bias to our research.
      This study overcomes the drawback that it is difficult to obtain data for prognostic analysis through large sample study for low-incidence tumors and provides basis for clinical decision making. Due to the rarity and heterogeneity of MpBC tumors, there is no standard treatment for these patients. Optimizing systemic therapy options, which have been confirmed as significant prognostic factors of overall survival, should be a priority for managing MpBC in clinical practice. Current standard of alternative therapy with PI3K pathway aberration has been recommended for this unique MpBC population,
      • Basho R.K.
      • Gilcrease M.
      • Murthy R.K.
      • et al.
      Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer: evidence from a phase 1 trial of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab.
      including recent clinical trials of liposomal doxorubicin, bevacizumab (VEGF-antibody), and everolimus (mTOR inhibitor).
      • Moroney J.
      • Fu S.
      • Moulder S.
      • et al.
      Phase I study of the antiangiogenic antibody bevacizumab and the mTOR/hypoxia-inducible factor inhibitor temsirolimus combined with liposomal doxorubicin: tolerance and biological activity.
      Prospective and multi-center studies randomized trials are necessary and promising to demonstrate the best treatment strategies for these MpBC patients. Potential specific MpBC biomarkers and therapeutic targeted points should also be identified through translational research in the future.
      • Djomehri S.I.
      • Gonzalez M.E.
      • da Veiga Leprevost F.
      • et al.
      Quantitative proteomic landscape of metaplastic breast carcinoma pathological subtypes and their relationship to triple-negative tumors.

      Conclusions

      Although the MpBC patients only occupy a small proportion in breast cancer malignancy, the incidence has increased in recent years with more concern. In conclusion, this novel nomogram was accurate and promising to predict the OS by using readily available clinicopathologic factors in MpBC general population. This prognostic index proposed here could provide individualized recommendations for MpBC patients of prognosis and survival at the diagnosis and further provide better clinical decisions for both physicians and patients.

      Clinical Practice Points

      A prognostic index estimating the clinical outcomes for metaplastic breast cancer (MpBC), a rare and diverse malignancy, would be attractive in current clinical practice.
      This nomogram provides a reasonable and effective method to predict the prognosis of MpBC and to further guide better clinical decisions for both physicians and patients.

      Ethics Approval and Consent to Participate

      This study was approved by the Independent Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College institutional review board (Approval No.21/042-2713). All procedures were carried out in accordance with the Declaration of Helsinki.

      Consent for Publication

      Not applicable.

      Availability of Data and Materials

      The data used to support the findings of this study are available from the corresponding author on reasonable request.

      Authors' Contributions

      Conception and design: J. Wang, Q. Li, Y. Luo and B. Xu. Development of methodology: J.Wang, Q. Li and B. Xu. Acquisition of data (acquired and managed patients and database, etc.): J. Wang, Q. Li, Y. Luo, Y. Han, F. Ma, R. Cai, Q. Li, Y. Fan, J. Wang, P. Zhang and B. Xu. Analysis and interpretation of data (eg, statistical analysis, computational analysis): Y. Han, J. Wang .Writing, review, and/or revision of the manuscript: J. Wang, Q. Li and B. Xu. Administrative, technical, or material support (ie, reporting or organizing data, constructing databases): J. Wang, Q. Li and Y. Han. Study supervision: B. Xu

      Disclosure

      The authors have stated that they have no conflicts of interest.

      Acknowledgments

      We thank the participants in this study and gratefully acknowledge the collaboration of all investigators for their contributions. We thank Chenxi Ma and Xu Guan from National Cancer Center for assisting us with data analysis. We thank Editage language for editorial assistance.
      Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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