The Prognosis and Clinicopathological Characteristics of Metaplastic Breast Cancer: A Meta-Analysis.

doi:10.21203/rs.3.rs-944594/v1

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The Prognosis and Clinicopathological Characteristics of Metaplastic Breast Cancer: A Meta-Analysis.

https://doi.org/10.21203/rs.3.rs-944594/v1

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Background: Due to the rarity of metaplastic breast cancer (MBC), the prognosis and clinicopathologic-

al characteristics of MBC patients are still inconclusive. Large-sample retrospective analysis is still lacking at present.This study aims to conduct a meta-analysis of relevant literature on MBC at home and abroad to obtain the prognostic and clinicopathological characteristics of MBC.

Methods: Cohort studies or case-control studies comparing MBC and triple-negative breast cancer (TNBC) were searched through the internet, and the quality of the included studies was evaluated using the Newcastle-Ottawa scale (NOS). A total of 9 studies with NOS scores of > 6 were included. Meta-analysis was performed using the Review Manager 5.3 provided by the Cochrane Collaboration Network. The hazard ratio (HR) evaluate the disease-free survival (DFS) and overall survival (OS), and the odds ratio (OR) was used to evaluate clinicopathological characteristics, including age, tumor diameter, lymph node metastasis status, distant metastasis status, TNM staging, and histological grade. According to the heterogeneity of the included studies, random effects model or fixed effects model was used.

Results: Compared with TNBC patients, the HR value for 5-year DFS and 5-year OS of MBC patients was 1.64 (95%CI: 1.36-1.98) and 1.52 (95%CI: 1.27-1.81), respectively. The total OR value for age> 50 years old, tumor diameter ≤ 2cm, lymph node positive, distant metastasis, TNM stage III and above, and histological grade 3 was 1.63 (95%CI: 1.45-1.84), 0.29 (95% CI: 0.14-0.58), 0.68 (95%CI: 0.53-0.88), 1.59 (95%CI: 0.89-2.81), 1.49 (95 %CI: 0.80-2.77), and 2.25 (95%CI: 0.85-5.97), respectively.

Conclusion: MBC patients are less likely to have lymph node metastasis and had worse DFS and OS than TNBC patients, which may be related to the pathological characteristics of MBC patients being related to sarcoma. But this also requires verification and further research with large sample sizes. In addition, there were no statistical differences in distant metastasis, TNM staging, and histological grade between MBC and TNBC patients.

Oncology

Surgery

Metaplastic breast cancer

prognosis

clinicopathological characteristics

meta-analysis

Metaplastic breast cancer (MBC) is a clinically rare subtype of breast cancer, accounting for less than 1% of all breast cancers ^[1]. It is a heterogeneous tumor consisting of glandular and non-glandular tissues with a low degree of differentiation. The non-glandular tissues are composed of squamous epithelial cells or mesenchymal components derived from metaplasia of glandular cells in mammary glands, such as spindle cells, squamous cells, cartilage, and bone. From the perspective of receptor expression, many studies have shown that MBC is mostly estrogen receptor (ER) and progesterone receptor (PR) negative and does not overexpress human epidermal growth factor receptor-2 (HER-2) ^[2][-3] and is also in line with the diagnosis of triple-negative breast cancer (TNBC). In 1973, Huvos et al. ^[4] first proposed the concept of MBC. However, it was not until 2000 that MBC was officially recognized as an independent pathological diagnosis.

Based on the different compositions of non-glandular cells derived from glandular cell metaplasia, in 2012, the World Health Organization classified MBC into the following subtypes: squamous cell carcinoma, metaplastic carcinoma with mesenchymal differentiation, low-grade adenosquamous carcinoma, spindle cell carcinoma, fibromatosis-like metaplastic carcinoma, mixed metaplastic carcinoma, and myoepithelial carcinoma [^5]. Because MBC is similar to TNBC in terms of receptor status, many scholars have considered MBC a special type of TNBC. Therefore, when analyzing the prognosis and clinicopathological characteristics of MBC, MBC is often compared with TNBC. However, due to the rarity of MBC, the prognosis and clinicopathological characteristics of MBC patients are still inconclusive. At present, there are only small-sample cohort studies or case-control studies, and large-sample retrospective analysis is still lacking. The prognosis of MBC is still unclear.

Therefore, to clarify the prognosis and clinicopathological characteristics of MBC, this study retrieved the studies comparing the prognosis of MBC and TNBC and performed a meta-analysis.

1.1 Sources of information

“Metaplastic breast carcinoma”, “Metaplastic carcinoma of the breast”, “Squamous cell carcinoma”, “Metaplastic carcinoma with mesenchymal differentiation”, “Spindle cell carcinoma”, “Fibromatosis-like metaplastic carcinoma”, “Mixed metaplastic carcinoma”, and “Myoepithelial carcinoma” were used as keywords to comprehensively search databases such as Pubmed, EMBASE, Ovid, and Cochrane Library. The results are limited by the search formula of the controlled clinical trials designed and provided by the Harvard Library. Figure 1 shows the specific search formula by taking Pubmed database as an example. In addition, Chinese characters identical to “metaplastic breast cancer”, “squamous cell carcinoma”, “metaplastic carcinoma with mesenchymal differentiation”, “low-grade adenosquamous carcinoma”, “spindle cell carcinoma”, “fibromatosis-like metaplastic cancer”, “mixed metaplastic carcinoma”, and “myoepithelial carcinoma” were used as keywords to comprehensively search the Chinese databases such as CNKI, Wanfang Digital Journal Full-text Database, and Weipu Literature Database. The results were limited by the Chinese characters identical to “cohort studies”, “case-control studies”, and “retrospective studies”. The relevant literature data published from the establishment of the database to 2020 on the prognosis and clinicopathological characteristics of MBC were retrieved and selected by referring to the literature inclusion criteria. A comprehensive quantitative meta-analysis was performed on the literature that meets the inclusion criteria.

1.2 Literature inclusion criteria

Publicly published cohort studies and case-control studies were included if they had 1) the pathological diagnosis of the observation group conformed to the definition of MBC, 2) the pathological diagnosis of the control group conformed to the definition of TNBC, and 3) corresponding statistical indicators. Studies were excluded if they 1) were repeated reports, 2) had poor quality, and 3) had less information or incomplete data.

1.3 Literature quality evaluation

Literature quality was evaluated independently by two reviewers based on the Newcastle-Ottawa Scale (NOS), mainly based on eight items and three categories: namely, selection, comparability, and outcome. The inconsistencies between the two reviewers were resolved by discussion and consulting with a third party. Studies with an evaluation score higher than or equal to 6 were included in the study.

1.4 Statistical analyses

The meta-analysis was performed using the Review Manager 5.3 provided by the Cochrane collaboration network. Before the analysis, all studies were examined for heterogeneity. Studies with p values >0.05 were considered not heterogeneous and therefore integrated using the fixed-effect model. Studies with p values ≤ 0.05 were considered heterogeneous and therefore integrated using the random effect model. The degree of heterogeneity was judged by I². The larger the I² value, the higher the heterogeneity. I²=0 indicated no heterogeneity among the studies, I²=25% indicated mild heterogeneity, I²=50% indicated moderate heterogeneity, and I²=75% indicated high heterogeneity. The overall survival (OS) was defined as the time from the diagnosis to the death of any cause. For subjects who were lost to follow-up before death, the last follow-up time was defined as the time of death. Disease-free survival (DFS) was defined as the time from diagnosis to disease recurrence (local recurrence or distant recurrence). For subjects who were lost to follow-up before recurrence, the last follow-up time was defined as the time at which the recurring event occurred. The hazard ratio (HR) value was used to evaluate the survival outcome (OS and DFS), and the odds ratio (OR) was used to evaluate the comparison of clinicopathological characteristics (age, tumor size, lymph node metastasis status, distant metastasis status, TNM stage, histological grade) of MBC patients with TNBC patients. A p<0.05 was regarded as statistically significant.

2.1 Literature searching results

A total of 715 studies were retrieved. After removing duplicate studies, 640 studies remained. After reading the abstracts, 23 reviews, 40 case reports, and 542 irrelevant studies were excluded. Among the remaining 35 studies, 16 studies that did not meet the inclusion criteria were excluded after reading the full texts. After quality evaluation ^[⁻^] of the remaining 19 studies, a total of 9 high-quality studies were included. Figure 2 summarizes the literature screening process.

2.2 Quality evaluation of the included studies

According to the NOS scale, the quality evaluation of the 9 included studies is shown in Table 1.

Table 1

Literature included in the study
Author	Publication	Observation indicators	Study quality
Aydiner, et al [6]	2015	Age, lymph node status, tumor size, staging	8
Bae, et al [7]	2011	lymph node status, tumor size, histological grade, staging	6
Eizein, et al [8]	2017	Overall survival, disease-free survival	7
Evan, et al [9]	2020	Overall survival, disease-free survival	8
He. Et al [10]	2018	Age, lymph node status, distal metastasis	7
June, et al [11]	2020	Overall survival, disease-free survival, lymph node status, distal metastasis, tumor size, histological grade, staging	6
Lee. H, et al [12]	2012	Overall survival, disease-free survival, age, lymph node status, distal metastasis, tumor size, histological grade, staging	6
Li, Et al [13]	2019	Overall survival, disease-free survival, age, lymph node status, distal metastasis, tumor size, histological grade, staging	8
Song, et al [14]	2013	lymph node status, tumor size, histological grade, staging	8

2.3 Meta-analysis results

2.3.1 HR value of the 5-year DFS

A total of 5 studies provided the HR value and 95% CI of patients’ 5-year DFS. Figure 3 shows the integrated data. The heterogeneity test showed P=0.06 and I²=25%, indicating that these studies were slightly heterogeneous. Thus, the fixed-effects model was adopted for data integration. The total HR value of MBC patients compared with TNBC patients was 1.64 (95%CI: 1.36−1.98), and the intergroup difference in 5-year DFS was statistically significant (Z=5.15, P<0.05), indicating that the 5-year DFS was shorter for MBC patients than for TNBC patients.

2.3.2 HR value of the 5-year OS

A total of 5 studies provided the HR value and 95% CI of patients’ 5-year OS. Figure 4 shows the integrated data. The heterogeneity test showed P=0.36 and I²=9%, indicating that these studies were slightly heterogeneous. Thus, the fixed-effects model was adopted for data integration. The total HRvalue of MBC patients compared with TNBC patients was 1.52 (95%CI: 1.27−1.81), and the intergroup difference in the 5-year OS was statistically significant (Z=4.64, P<0.05), indicating that the 5-year OS was shorter for MBC patients than for TNBC patients.

2.3.3 Age over 50 years

A total of 3 studies provided patients’ age information. In these studies, the observation group included 1752 MBC patients with 1369 patients at the age of >50 years, and the control group included 40169 TNBC patients with 28126 patients at the age of >50 years. Figure 5 shows the total OR value and 95% CI of each study. The heterogeneity test showed P=0.40 and I²=0%, indicating these studies were homogeneous. Thus, the fixed-effect model was adopted for data integration. The total OR value was 1.63 (95%CI: 1.45−1.84), and the intergroup difference in age >50 years was statistically significant (Z=8.14, P<0.05), indicating that compared with TNBC patients, MBC patients are more likely to be at the age of >50 years.

2.3.4 Tumor diameter ≤ 2 cm

A total of 6 studies provided patients’ tumor sizes. In these studies, the observation group included 831 MBC patients with 631 patients with tumor size ≤ 2 cm, and the control group included 20175 TNBC patients with 17490 patients with tumor size ≤ 2 cm. Figure 6 shows the total OR value and 95% CI of each study. The heterogeneity test showed P<0.0001 and I²=84%, indicating these studies were highly heterogeneous. Thus, the random effect model was adopted for data integration. The total OR value was 0.29 (95%CI: 0.14−0.58), and the intergroup difference in patients with tumor size ≤ 2 cm was statistically significant (Z=3.46, P<0.05). Therefore, sensitivity analysis was performed, and the fixed-effect model was also used for data integration. The total OR value was 0.46 (95%CI: 0.39−0.54), and the overall effect test showed Z=8.92 and P<0.05, which were similar to those of the random effect model, indicating that the results obtained using the random effect model were robust. Overall, the results showed that compared with TNBC patients, MBC patients often had a larger tumor diameter, more likely to be > 2 cm, at the diagnosis.

2.3.5 Positive lymph nodes

A total of 7 studies provided patients’ lymph node metastasis status. In these studies, the observation group included 1935 MBC patients, including 514 patients with positive lymph nodes, and the control group included 41366 TNBC patients, including 14778 patients with positive lymph nodes. Figure 7 shows the total OR value and 95% CI of each study. The heterogeneity test showed P=0.008 and I²=66%, indicating these studies were moderately heterogeneous. Thus, the random effect model was adopted for data integration. The total OR value was 0.68 (95%CI: 0.53−0.88), and the intergroup difference in positive lymph nodes was statistically significant (Z=2.93, P<0.05), indicating that compared with TNBC patients, MBC patients are less likely to develop lymph node metastasis.

2.3.6 Distant metastasis

A total of 4 studies provided patients’ distant metastasis status. In these studies, the observation group included 1800 MBC patients, including 108 patients with distant metastasis, and the control group included 41111TNBC patients, including 2436 patients with distant metastasis. Figure 8 shows the total OR value and 95% CI of each study. The heterogeneity test showed P=0.002 and I²=79%, indicating these studies were highly heterogeneous. Thus, the random effect model was adopted for data integration. The total OR value was 1.59 (95%CI: 0.89−2.81), and the intergroup difference in distant metastasis was not statistically significant (Z=1.58, P=0.11).

2.3.7 TNM stage III and above

A total of 6 studies provided patients’ TNM staging status. In these studies, the observation group included 834 MBC patients, with 184 being with TNM stage III and above, and the control group included 20,170 TNBC patients, with 4141 patients being TNM stage III and above. Figure 9 shows the total OR value and 95% CI of each study. The heterogeneity test showed P<0.0001 and I²=81%, indicating these studies were highly heterogeneous. Thus, the random effect model was adopted for data integration. The total OR value was 1.49 (95%CI: 0.80−2.77), and the intergroup difference in TNM staging was not statistically significant (Z=1.25, P=0.21).

2.3.8 Histological grade 3

A total of 5 studies provided patients’ histological classification. In these studies, the observation group contained 722 MBC patients, with 576 patients being histological grade 3, and the control group had 19,916 TNBC patients, with 15981 being histological grade 3. Figure 10 shows the total OR value and 95% CI of each study. The heterogeneity test showed P<0.0001 and I²=89%, indicating that these studies are highly heterogeneous. Thus, the random effect model was adopted for integration. The total OR value was 2.25 (95%CI: 0.85−5.97), and the intergroup difference in histological grade 3 was not statistically significant (Z=1.63, P=0.10).

This study showed that in terms of the clinicopathological characteristics, compared with TNBC, MBC patients were often characterized by age> 50 years, tumor diameter> 2 cm, and negative lymph nodes at the time of diagnosis. However, there was no statistical difference in the occurrence of distant metastasis, TNM staging, and histological grade. In terms of prognosis, compared with TNBC, the HR for the 5-year DFS and 5-year OS of MBC patients was 1.64 (95%CI: 1.36−1.98) and 1.52 (95%CI: 1.27−1.81), respectively. The prognosis of MBC patients in terms of DFS and OS was worse than that of TNBC patients. It is generally believed that the initial metastasis of invasive breast cancer is through lymph node metastasis to the ipsilateral axilla. Thus, the status of lymph node metastasis is also considered a traditional prognostic factor for breast cancer. However, MBC patients often have negative lymph nodes and poor prognosis, suggesting that the pathological manifestations of MBC may be more biased towards sarcoma. Because primary breast sarcoma is a highly aggressive tumor that seldom involves axillary lymph nodes and more often spreads through blood, it often has a higher lung and brain metastasis rate and high mortality ^[^]. Although this study did not reach a statistical difference between MBC and TNBC in the distant metastasis status, many other related studies have shown that MBC tends to spread through hematological pathways and has a high systemic metastasis rate. On the contrary, its axillary lymph node metastasis is very rare ^[^]. These characteristics are more consistent with the pathological characteristics of sarcoma.

As mentioned at the beginning, MBC is composed of glandular tissues and non-glandular tissues. Of them, non-glandular tissues are the mesenchymal components derived from the metaplasia of breast glandular cells. Therefore, the tumor tissues of MBC patients contain both deteriorating epithelial cancer cells and sarcoma with deteriorating mesenchymal components and are special manifestations between cancer and sarcoma, which also explains why the pathological manifestations of MBC are more biased towards sarcoma.

From the perspective of receptor status, MBC also has the characteristics of triple-negative cancer. This study showed that its prognosis is far worse than that of non-special triple-negative cancer, which might be related to the fact that MBC patients are often older and have tumors with larger diameters at the diagnosis. In addition, it may also relate to that MBC patients are often treated by referring to invasive ductal carcinoma treatment in clinics. For cancer and sarcoma, the indications of radiotherapy and chemotherapy and specific chemotherapy regimens are different. However, clinically, the treatment of MBC often refers to the treatment regimen of invasive ductal carcinoma, which is obviously inappropriate. Therefore, when treating MBC patients, clinicians need to make more informed decisions, such as adopting more treatment methods that favor soft tissue sarcoma. But this also requires verification and further research with large sample sizes.

MBC：Metaplastic breast cancer,ER:estrogen receptor,PR:progesterone receptor, HER-2:human epidermal growth factor receptor-2,TNBC:triple-negative breast cancer,HR:hazard ratio,OS:overall survival,DFS:disease-free survival,OR:odds ratio, NOS:Newcastle-Ottawa Scale

Ethics approval and consent to participate: This study is a retrospective study. All the data we collected are from published literature from different datebases. And all the cohort studies or case-control studies we included had been approved by the Ethics.

Consent for publication:Not applicable

Availability of data and materials:Allthe data we collected are from 9 sthdies we included which is shown in Table 1 . Anyone who wants to get the exact data can contact email [email protected].

Competing interests：Not applicable

Funding:Not applicable

Authors' contributions: TZ conceived and designed the experiment and contributed analysis tools. XY performed the experiments and anaylzed the data and was the major contributor in writing the manuscript. All authors read and approved the final manuscript.

Acknowledgements:Not applicable

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The Prognosis and Clinicopathological Characteristics of Metaplastic Breast Cancer: A Meta-Analysis.

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Abstract

Figures

Introduction

1 Materials And Methods

1.1 Sources of information

1.4 Statistical analyses

2 Results

2.2 Quality evaluation of the included studies

2.3 Meta-analysis results

2.3.1 HR value of the 5-year DFS

2.3.2 HR value of the 5-year OS

2.3.3 Age over 50 years

2.3.4 Tumor diameter ≤ 2 cm

2.3.5 Positive lymph nodes

2.3.6 Distant metastasis

2.3.7 TNM stage III and above

2.3.8 Histological grade 3

3 Discussion

Abbreviations

Declarations

References

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