A Single-Center 18-Year Series of 73 Cases of Metaplastic Carcinoma of the Breast

Aim To examine the clinical management of metaplastic breast cancer (MeBC), particularly the role of chemotherapy. Methods This retrospective study included patients with MeBC (n = 73) from a tertiary breast cancer center: the “Centre des Maladies du Sein of the CHU de Québec–Université Laval.” The specimens were reviewed by two pathologists. Patient and tumor characteristics, systemic therapy (neoadjuvant and adjuvant), disease-free survival (DFS), and overall survival (OS) were recorded. Results The median follow-up was 57.2 months. The mean tumor size was 39.5 ± 32.1 (range, 1–200) mm. Most were in grade 3 (75.3%), without evidence of clinical nodal involvement (75.3%), and triple-negative (79.5%). Chemotherapy was given to 49 (67.1%) patients. Thirty-seven patients (50.7%) underwent a mastectomy, and 22/37 (59.5%) received radiotherapy. Adjuvant chemotherapy was given to 36 patients (49.3%), and nine (12.3%) patients were treated with neoadjuvant chemotherapy. The 5-year OS and DFS rates were 60.2% and 66.8%. Among the nine patients who received neoadjuvant chemotherapy, three (33.3%) achieved a partial response, three (33.3%) had stable disease, and three (33.3%) had disease progression. The use of chemotherapy, especially in the adjuvant setting, had a significant positive effect on 5-year OS (P=0.003) and 5-year DFS (P=0.004). Nodal involvement was associated with worse OS (P=0.049) but similar DFS (P=0.157). Lumpectomy was associated with better 5-year OS (P < 0.0001) and DFS (P=0.0002) compared with mastectomy. Conclusion MeBC represents a rare heterogeneous group of malignancies with poor prognosis. Adjuvant chemotherapy was associated with improved OS and DFS. Patients should be carefully selected for neoadjuvant chemotherapy.


Introduction
Breast cancer is responsible for 11.6% of the new cases of cancer each year and 6.6% of cancer-related mortality worldwide [1].Metaplastic breast cancer (MeBC) represents a rare heterogeneous group of malignancies comprising 0.2%-5% of all invasive breast cancers [2].
Te current World Health Organization classifcation of MeBC includes low-grade adenosquamous carcinoma, fbromatosis-like metaplastic carcinoma, squamous cell carcinoma, spindle cell carcinoma, carcinoma with mesenchymal diferentiation, and mixed MeBC [3,4].Except for low-grade adenosquamous carcinoma and fbromatosis-like variants, MeBCs are typically aggressive, resistant to chemotherapy, and have a greater propensity for metastases than nonmetaplastic breast tumors [5][6][7][8].Tey often present with a triple-negative phenotype, a high tumor stage, and a high tumor grade.Tese tumors arbor unique pathological features and, currently, the molecular drivers for these tumors are not entirely understood.Previous studies showed that MeBCs are more aggressive than triple-negative breast cancers in terms of disease-free survival (DFS) and overall survival (OS) [5][6][7][8].
Te standard treatment for most MeBCs includes surgery ± radiation therapy, but the use of chemotherapy is based on clinical trials involving typical triple-negative invasive breast cancers.Patients with MeBCs often receive chemotherapy, reaching 73% in retrospective cohorts, but it is known that MeBCs are relatively chemoresistant [9][10][11].In addition, they tend to have a low rate of pathological complete response (pCR) to neoadjuvant chemotherapy [11].
Despite the recognition of the MeBC entity in the early 2000s, there is a lack of evidence on managing patients with MeBC because they are treated as conventional invasive ductal carcinoma (IDC).Terefore, this study aimed to examine the clinical management of MeBC, particularly the role of chemotherapy.Te results could help improve the management of patients with MeBC.

Study Design and Patients. At the Center des Maladies du
Sein of the CHU de Québec-Université Laval, all breast cancer patients are prospectively compiled in a cancer registry by oncology registrars or nurses trained in oncology.Tis retrospective study included patients diagnosed with MeBC from January 2004 to November 2020.Patients were included if they were diagnosed and treated at our center.All specimens and slides of the identifed patients were reviewed by two breast pathologists.Each tumor was reclassifed according to the recent World Health Organization classifcation WHO [3,4].Tumors were considered pure if the morphology was found in more than 90% of the tumor.If more than one histologic subtype was found or an invasive carcinoma NOS was admixed, the tumor was classifed as mixed metaplastic carcinoma.Tree patients were excluded because of the absence of histological slides or diagnostic changes after review.Tis study was approved by the ethics committee of the CHU de Québec-Université Laval (#2021-5649).Te requirement for individual informed consent was waived by the committee because of the retrospective nature of the study.

Data Collection.
Te following clinicopathologic data were recorded: age at diagnosis, TNM, biomarkers (estrogen receptors (ER), progesterone receptor (PR), and HER2), locoregional treatment (surgery and radiation therapy), systemic therapy (neoadjuvant and adjuvant), and survival data, including disease-free survival (DFS) and OS.DFS was defned as the time from diagnosis to developing any recurrence (distant or locoregional) or death.OS was defned as the time from diagnosis to death from any cause.In the absence of a DFS or OS event, survival was censored at the last follow-up.

Neoadjuvant Chemotherapy Subgroup.
While most patients were treated with adjuvant chemotherapy and radiation therapy, nine with a locoregional disease received neoadjuvant chemotherapy (Table 2).Six patients had a cT3 tumor, and two had a cT4 tumor.After preoperative chemotherapy, three patients (33.3%) achieved a clinical partial response, three patients (33.3%) had stable disease, and three patients (33.3%) had disease progression.Despite neoadjuvant chemotherapy, most patients underwent a total mastectomy (77.8%).One (11.1%) patient had a pCR.

Discussion
Because of the rarity of MeBCs, the knowledge about the treatment patterns and outcomes of these tumors is limited, and data are missing on the optimal management of this historically known aggressive type of breast cancer.Tis single-center retrospective study of 73 patients with MeBC evaluated the correlation between clinicopathological features and the choice of therapy on survival outcomes.MeBCs appear to have multiple clinicopathologic parameters that diferentiate them from other types of breast cancer.Compared with IDC, they tend to occur in older women and present with larger tumor sizes, refecting a more rapid growth rate [7,9,[12][13][14].In the present study, patients with a locoregional disease (n � 68) had a 5-year DFS and OS of 60.2% and 66.8%, respectively.Tese results were consistent with previous retrospective studies that showed worse OS for MeBCs than other breast cancer subtypes [7,8,14,15].
Data are conficting about the efectiveness of chemotherapy for MeBC [7,14,16].A review from Tzanninis et al. [17] comprising 12 studies did not demonstrate an OS beneft with neoadjuvant or adjuvant chemotherapy.On the other side, a contemporary large retrospective study using the National Cancer Database (NCDB) compared 5142 MeBC with 50,705 TNBC cases and found that the omission of chemotherapy led to worse OS (HR � 1.527; P � 0.007) [8].Accordingly, our results showed that omission of chemotherapy was associated with worse 5-year DFS (P � 0.004) and OS (P � 0.003).Terefore, controversy remains about the real efectiveness of chemotherapy in patients with MeBC, although often it is still administered given the triple-negative and aggressive nature of this cancer.
We reported nine (11.5%) patients who underwent neoadjuvant chemotherapy.Tree patients had stable disease (33.3%), three had a partial clinical response (33.3%), and three (33.3%)had progressive disease while on neoadjuvant chemotherapy.Despite receiving neoadjuvant therapy, most patients underwent a total mastectomy (77.8%), refecting a low conversion rate to partial mastectomy.Tese results confrm those of the literature.A recent report from the Mayo Clinic Rochester, including 18 patients with MeBC receiving neoadjuvant chemotherapy, showed that fve (27.8%) patients progressed on treatment, including two who became metastatic [18].Wong et al. [19] identifed 44 patients with MeBC treated with neoadjuvant Based on these results and previous studies, we might hypothesize that upfront surgery is safer for patients with an initially operable tumor, followed by systemic therapy.Multicenter studies are necessary to examine that hypothesis.Some metaplastic carcinoma subtypes have better survival than others and possibly diferent susceptibilities to chemotherapy [11].Previous studies showed that low-grade adenosquamous carcinoma and fbromatosis-like metaplastic carcinoma histologic subtypes have a relatively good prognosis [3].Although the present study included a few patients, a 100% 5-year OS was also observed among these two subtypes, and the association between the histological subtypes and OS was statistically nonsignifcant (P � 0.423).On the other hand, some subtypes, such as high-grade  Te Breast Journal spindle cell carcinoma, carcinoma with pleomorphic components, and squamous cell carcinoma, show a higher propensity for metastases [20].Consistent with previous reports, the results reported here showed that a higher clinical T stage (cT3-T4 vs. cT1-T2) signifcantly predicted poorer DFS and OS [14].It could explain the worse survival observed among patients who underwent a total mastectomy, with a 5-year OS of 43.5%, compared with 90.3% among patients who underwent breast-conserving surgery (P < 0.0001) in the present study.
As with stage T, lymph node status is also an important prognostic factor.Although metaplastic carcinoma gives rise to lymph node metastases less often than intraductal invasive cancers [8,9,13], lymph node involvement is an independent prognostic factor [12,13,15,21], as supported by the present study.Most of our patients (n � 60, 76.1%) had no lymph node involvement, and 53.4% underwent sentinel lymph node biopsy, but the prognosis of those with lymph node involvement remained poor, showing a 5-year OS of 42.9% vs. 73.5% (P � 0.036) among patients without node metastases.
Te available therapies seem to improve the poor prognostic of MeBCs, but still, novel treatments are needed.MeBCs are characteristically triple-negative, eliminating the

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Te Breast Journal options of hormone and anti-HER2 therapies.Additional analyses of these tumors have pointed out molecular and genomic alterations that could be potential therapeutic targets.In this way, MeBCs are frequently associated with mutations in TP53 (26%-75%) and PIK3CA (23%-70%) [22].Other mutations identifed include PTEN, NF1, HRAS, and PIK3R1.Tese mutations could lead to future studies evaluating the efectiveness of targeted treatments.Pivotal trials demonstrated the oncological equivalence of lumpectomy with radiation therapy compared with mastectomy [23,24], but a recent study of 48,986 Swedish women showed that lumpectomy with radiation therapy achieved better survival than mastectomy, irrespective of radiation therapy [25].Population-based studies also showed better OS after lumpectomy with radiation therapy compared with mastectomy [26][27][28][29].Te change in paradigm between the original pivotal trials [23,24] and the recent ones [25][26][27][28][29] could be due to several factors, including improvements in systemic therapies and radiation therapy.Furthermore, studies also showed that mastectomy has no survival beneft over lumpectomy with radiation therapy in younger patients and in those with triplenegative breast cancer [30][31][32].A study in MeBC also reported a higher (but not statistically signifcant) 5-year PFS for lumpectomy compared with mastectomy (69% vs. 61%, P � 0.22) [33], supporting the present study.Still, the diferences between lumpectomy and mastectomy were important in the present study (OS: 90.3% vs. 43.5%;DFS: 81.4% vs. 38.1%).Te reasons for the diferences could not be determined based on the present study.
Tis study has several limitations.It is a retrospective single-center cohort study, and the sample size is small.As a retrospective study, treatment characteristics were missing, the patients were treated in diferent manners, some patients received older systemic regimens, and some data were missing for some patients.Although all patients were discussed in tumor boards, the discussions and rationale for the fnal treatment decision were not indicated in the charts.In addition, as a result of the small cohort, it was impossible to perform multivariable analyses because of the few events (recurrence and death) in specifc subgroups.Te population was predominantly white and non-Hispanic and the results might not refect other populations.Data about follow-up were only available for the consultations at the CHU de Québec-Université Laval, and patients who received treatment outside our institution may not have been documented.
In conclusion, MeBCs represent a rare, heterogeneous group of malignancies with poor outcomes, even worse than TNBC.Te literature about MeBCs suggests benefts for chemotherapy for a disease that we thought was relatively chemoresistant.Still, previous studies and the present one revealed a signifcant rate of progression on neoadjuvant chemotherapy, suggesting that upfront surgery followed by systemic therapy might be safer for patients with an initially operable tumor, but that point must be confrmed in largescale multicenter studies.

Figure 1 :
Figure 1: Kaplan-Meier curves of overall survival according to (a) T stage, (b) chemotherapy, (c) type of chemotherapy, and (d) pathological subtype.
Patients.Seventy-six cases were reported as MeBC in the cancer registry, but the pathological slide review confrmed 73 cases.Te patient and tumor characteristics are detailed in Table 1.Te study included 29

Table 2 :
Characteristics of the patients treated with neoadjuvant chemotherapy (n � 9).