Annals of Oncology Advance Access originally published online on February 9, 2006
Annals of Oncology 2006 17(4):605-613; doi:10.1093/annonc/mdl006
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© 2006 European Society for Medical Oncology
Biphasic metaplastic sarcomatoid carcinoma of the breast
Departments of 1 Breast Medical Oncology, 2 Biostatistics, 3 Sarcoma, 4 Radiation Oncology and 5 Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, USA
* Correspondence to: Dr B. Hennessy, Department of Medical Oncology, Box 10, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel: +1-713-792-2740; Fax: +1-713-792-3708; E-mail: bhennessy{at}mdanderson.org
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Abstract |
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Background: Breast biphasic metaplastic sarcomatoid carcinoma (MSC) is rare and aggressive. We analyzed 100 patients treated at M. D. Anderson Cancer Center (MDACC) with 213 MSC and 98 carcinosarcoma patients identified through the Surveillance, Epidemiology and End-Results (SEER) database to describe clinical and pathologic characteristics.
Patients and methods: We searched the MDACC (1985–2001) and SEER databases (1988–2001) for breast MSC and carcinosarcoma patients.
Results: We identified 100 MDACC MSC patients: 66% had node-negative disease and 6% distant metastases at presentation. Median recurrence-free survival (RFS) of 94 patients with stages I–III disease was 74 months (range 3–74), with 52% 5-year RFS [95% confidence interval (CI) 0.42–0.63]. Median overall survival in these patients was not reached, with 64% 5-year survival (95% CI 0.54–0.75). The initial stage of the tumor, but not use of adjuvant chemo- or radiotherapy, had a strong association with outcome. The pathologic complete response rate to neoadjuvant chemotherapy was 10%. Median survival from the time of recurrent disease was 14 months (range 1–55). Tumors were usually hormone receptor- and HER2/neu-negative. SEER data were consistent with MDACC findings.
Conclusions: Breast MSC and carcinosarcoma are aggressive, treatment-refractory tumors with shared clinical features and outcome similar to poorly differentiated receptor-negative adenocarcinomas. New therapeutic agents are needed.
Key words: breast, cancer, sarcomatoid, carcinosarcoma
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introduction |
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TopAbstractintroductionpatients and methodsresultsconclusionsReferences |
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Biphasic metaplastic sarcomatoid carcinomas (MSC) of the breast account for <0.1% of all breast malignancies [1
, 2]. They are a form of metaplastic breast cancer with overt carcinomatous and sarcomatous features apparent with both light microscopy and immunohistochemical testing [3–5]. Although the term ‘sarcomatoid carcinoma’ has traditionally been employed if there was obvious microscopic transition between the two components, with the term ‘carcinosarcoma’ reserved for when the demarcation between carcinomatous and sarcomatous components was distinct in all light microscopic fields, increasing evidence suggests these are similar monoclonal tumors developing through a malignant transformation of myoepithelial cells or myofibroblastic metaplasia of malignant epithelial cells [6–12]. Thus, the term ‘biphasic sarcomatoid carcinoma’ may be an appropriate description of all breast carcinomas with overt carcinomatous and sarcomatous features. Where an epithelial component is detected only at electron microscopy or immunohistochemistry, the term ‘monophasic sarcomatoid carcinoma’ is used [12].
Previous reports suggest MSCs behave biologically differently from conventional carcinoma of the breast with sarcomatoid characteristics dominating the clinical course [1, 2]. Generally, these tumors are poorly differentiated and appear to be aggressive. However, there are very few reported series describing the clinical behavior of breast MSCs and even fewer of carcinosarcomas. For the purposes of the current study, we studied the clinical features, management and outcome of MSC of the breast in a series of 100 women treated at The University of Texas M.D. Anderson Cancer Center and in a series of 213 MSC patients identified through the Surveillance, Epidemiology and End-Results (SEER) database to determine if MSC behaves differently from high-grade hormone receptor-negative adenocarcinoma. To determine if the clinical behavior of breast carcinosarcomas is similar to that of MSC, we also analyzed 98 breast carcinosarcoma patients identified from the SEER database.
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patients and methods |
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M. D. Anderson Cancer Center Patients
The M. D. Anderson institutional computerized database was searched to identify patients with a diagnosis of breast MSC evaluated and treated here between 1985 and 2001. One hundred patients were identified. Their medical records were retrospectively reviewed to obtain demographic, clinicopathologic characteristics, treatment and outcome information from an institutional review board-approved protocol.
All patients were initially confirmed to have MSC of the breast after review of the pathologic material at our institution by a breast pathologist. Tumors were classified and staged according to clinical and pathologic information (American Joint Committee on Cancer Staging Manual, 6th edition). For patients who were treated with chemotherapy for metastatic disease, their response status was classified on the basis of standard criteria [13].
SEER patients
We also studied women with MSC and carcinosarcoma of the breast entered in the SEER database program, a population-based tumor registry sponsored by the National Cancer Institute, consisting of tumor registries that collect information on all newly diagnosed cancer cases that occur in persons residing in 11 SEER participating areas. Patients were included in our study if they were women who had stage I–IV breast cancer (American Joint Committee on Cancer Staging Manual, 3rd edition), were diagnosed between 1988 and 2001 and had metaplastic sarcomatoid carcinoma (identified by histologic codes 8030, 8032, 8033, 8572, and 8575) or carcinosarcoma (histologic codes 8980/1).
data analysis
Descriptive statistics were used to characterize the patient population. Recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) curves were calculated using the method of Kaplan and Meier. Overall survival was calculated from the date of surgery to the date of death or at last follow-up. RFS and time to distant recurrence was calculated from the date of surgery to the date of disease recurrence or last follow-up. Patients experiencing disease recurrence locally or in both a distant and a local site were considered censored for distant recurrence at the date of their disease recurrence; patients who died without recurrence were considered censored at their date of death. Time to local recurrence was calculated in the same manner. Survival following disease recurrence was measured among patients who experienced a disease recurrence from the date of recurrence to the date of death or last follow-up. The univariate log-rank test was used to evaluate possible associations between survival and patient covariates. Hazard ratios were estimated with univariate Cox proportional hazards models. All P values presented are two-sided. Statistical analyses were performed with STATA 7.0 software (StataCorp., College Station, TX) in addition to SAS version 8 (Cary, NC) and S-Plus version 6.1 (Seattle, WA). Patients with metastatic disease at diagnosis (M1) were considered separately from patients without metastatic disease (M0) for all analyses. P values are not shown where there are less than 10 patients in a group as statistical inference is limited due to small sample size.
N stage, T stage, overall stage, estrogen receptor (ER) status, grade and type of surgery were identified as being prognostic factors of interest for a multivariable model. Because most patients were ER negative and had grade 3 disease, these variables were excluded from modeling. Cox proportional hazards model were fit for OS, RFS and local recurrence-free survival that included type of surgery, N stage and T stage. The fit of the model and the proportional hazards assumption was assessed visually with residual plots.
For the purposes of comparing the outcomes of the M. D. Anderson MSC patients to those of patients with breast ductal adenocarcinoma, patients with ductal histology were matched 2:1 to the sarcomatoid patients on both ER and PR status. Matching was done using the SAS macro %match [14].
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results |
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Table 1 summarizes the characteristics of the patients and the treatments they received. Their median age was 48 years (range 26–77). Ninety-four patients did not have distant metastatic disease (M0) at diagnosis. Among these patients, the median follow-up was 55 months (range 4–252 months). The majority of tumors were high-grade, lymph node- and hormone receptor-negative and, for those in which HER2/neu status (immunohistochemistry or fluorescent in situ hybridization) was available, HER2/neu-negative.
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Of 94 MDACC patients diagnosed with M0 disease, 62 had modified radical mastectomy (MRM) and 27 segmental mastectomy. The majority of these patients had an axillary node dissection; however, to facilitate analysis, we included two patients in the MRM group who had mastectomy with a sentinel lymph node biopsy and one patient in the segmental mastectomy group who had a sentinel node biopsy, in addition, two patients in each group did not have axillary surgery. The average number of nodes removed was 15 versus 17, respectively. In the 62 MRM and 27 segmental mastectomy patients, no information on margin status was available for 10 and five patients, respectively; two and one patients had an involved margin, while the tumor was within 1–5 mm of the margins in another four and three patients, respectively. Twelve patients in each group had no residual disease at definitive surgery following a prior lumpectomy and one patient in each group had a pathologic complete response to primary chemotherapy. In the remaining patients, there was at least 5–10 mm between the tumor and the margins.
Twenty-six MRM patients had adjuvant radiation therapy, including five of the six patients with positive or close margins. Twenty-three segmental mastectomy patients had adjuvant radiation therapy, including three of the four patients with positive or close margins. This was usually 50 Gy in 25 fractions to the chest wall or breast with or without the nodal basins followed by a 10 Gy boost.
Table 2 shows the results of the univariate analysis of overall survival in those with M0 disease at diagnosis. This analysis includes 89 patients who had survival information available. The other five patients were lost to follow-up. Thirty-five patients died and the proportion of patients who remained alive at 5 years was 0.64 (95% CI 0.54–0.75; Figure 1). Patients with positive lymph nodes had 
2.5 times the risk of death compared with patients with negative lymph nodes [P = 0.01, hazard ratio (HR) 2.51, 95% CI 1.25–5.04]. Patients with T4 tumors had >18 times the risk of death compared with patients with T1 tumors (HR 18.33, 95% CI 4.9–68.51), and patients with stage 3 disease had almost seven times the risk of death compared with patients with stage 1 disease (HR 6.93, 95% CI 1.86–25.85). OS was not statistically different between patients who did and did not receive chemotherapy or radiotherapy. However, these data are not randomized and there were significantly more patients in the chemotherapy-treated group with higher grade (P = 0.005) and higher stage (P = 0.05) tumors.
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Table 3 shows the results of the univariate analysis of RFS in those with M0 disease at diagnosis. This analysis includes 91 patients who had recurrence information available. Forty-four patients have experienced a disease recurrence and the median RFS was 74 months (Figure 2). Patients with T4 tumors had 9.2 times the risk of recurrence compared with patients with T1 tumors (HR 9.2, 95% CI 3.08–27.55), patients with node-positive disease had a HR of recurrence of 1.85 compared with those with node-negative tumors (95% CI 1–3.42), and patients with stage 3 disease had 3.77 times the risk of recurrence compared with patients with stage 1 disease (HR 3.77, 95% CI 1.28–11.1). RFS was not statistically different between patients who did and did not receive chemotherapy or radiotherapy. Again, these data are not randomized. Of 12 patients with T2 node-positive disease treated with adjuvant chemotherapy, eight have relapsed. Of 10 patients with T3/4 node-negative disease treated with adjuvant chemotherapy, seven have relapsed, and of 10 patients with T3/4 node-positive disease treated with adjuvant chemotherapy, six have relapsed.
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RFS and OS tended to be shorter among patients who were ER/PR negative than among patients who were ER/PR positive although this was not statistically significant (P = 0.43 and 0.19, respectively), possibly as a result of limited statistical power.
Of those who recurred, 22 patients experienced a distant recurrence initially, six patients recurred in both local and distant sites and 16 patients initially recurred only locally. The median times to distant and local recurrence have not been attained and the proportions remaining free of distant and local recurrence at 5 years were 0.72 (95% CI 0.63–0.83) and 0.75 (95% CI 0.64–0.87), respectively. The median survival following any disease recurrence was 14 months. Patients who had positive lymph nodes at initial diagnosis tended to have shorter survival following recurrence (P = 0.01). Of six patients diagnosed initially with metastatic disease, all have died and their median survival was 12 months (range 6–55 months).
Twenty-two patients experienced a local disease recurrence as initial presentation of recurrent disease, in 14 cases following prior adjuvant radiation therapy of whom nine were infield relapses. Only T stage and type of surgery were significantly related to local RFS. Patients with T4 tumors had 11.3 times the risk of local recurrence compared with patients with T1 tumors (95% CI 2.51–50.98). There was no increased risk of local recurrence associated with initial N status. Patients who received radiation had a non-significant increase in the risk of local recurrence compared with patients who did not (HR 1.62, 95% CI 0.65–4.01). Those patients who were treated with adjuvant radiotherapy more often underwent breast-conserving surgery (P = 0.0004), as would be expected, were younger at diagnosis (P = 0.03) and more often had higher stage tumors (P = 0.04). Among the 59 patients with recurrence information who underwent modified radical mastectomy (MRM), 33 did not receive radiotherapy. In the MRM group, OS, RFS and local recurrence-free survival were not statistically different between patients who did and did not receive radiotherapy, nor was there any clear trend in survival between the two groups. Figure 3 shows the Kaplan–Meier curves of local RFS by radiation and surgery treatment groups (P = 0.04). Among patients with MRM and no radiation versus adjuvant radiation, local recurrence-free survival at 5 years was 81% (95% CI 0.66–1) versus 77% (95% CI 0.61–0.97), respectively. Among patients with segmental mastectomy and no radiation versus adjuvant radiotherapy, local recurrence-free survival at 5 years was 50% (95% CI 0.19–1) versus 54% (95% CI 0.35–0.82), respectively.
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Of the patients treated with adjuvant chemotherapy, 21 received primary chemotherapy; this was anthracycline-based in all patients and included a taxane in five patients and ifosfamide in one patient. There were two pathologic complete responses (10%), one complete clinical response (5%) and four clinical partial responses (20%). Of these seven responding patients, all had four or six cycles of conventional 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) chemotherapy prior to surgery.
multivariable model
In the Cox proportional hazards model, only T stage remained statistically significant for OS in those with stages I–III disease at diagnosis. T stage and surgery type were significantly related to both RFS and local recurrence-free survival. Having a segmental mastectomy was associated with 1.47 times the risk of recurrence (P = 0.04) and 2.24 times the risk of local recurrence (P = 0.003) compared with having MRM.
matching to ductal patients
After matching and adjustment for other known prognostic factors including age at diagnosis, grade, N stage, T stage and treatments received in the ductal adenocarcinoma patients, patients with MSC had 0.80 times the risk of death (P = 0.72) and 1.27 times the risk of disease recurrence (P = 0.55) compared with patients with the ductal histology.
SEER database
Between 1988 and 2001, 213 and 98 patients with MSC and carcinosarcoma of the breast who had a median age of 65 and 61 years, respectively, were registered in the SEER database. The younger age of the MDACC patients may reflect referral bias. The total number of breast cancers (all stages) registered in the SEER database during that time was 281 382. As in our series, most MSC and carcinosarcoma patients had tumors that were stage II at diagnosis, poorly differentiated or anaplastic and hormone receptor-negative (Table 1). Fewer patients in the SEER database received adjuvant radiation therapy. Tables 4 and 5 show the 5-year and median OS and DSS rates for MSC and carcinosarcoma patients by stage at diagnosis. For 199 and 81 MSC and carcinosarcoma patients with localized disease (stages I–III) at diagnosis, the 5-year OS rates were 0.63 (95% CI 0.53–0.72; Figure 4A) and 0.60 (95% CI 0.48–0.71), respectively. Their 5-year DSS rates were 0.72 (95% CI 0.62–0.80; Figure 4B) and 0.73 (95% CI 0.60–0.83), respectively.
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conclusions |
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TopAbstractintroductionpatients and methodsresultsconclusionsReferences |
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Biphasic metaplastic sarcomatoid carcinomas (MSC) of the breast account for
0.08% of all breast malignancies. They are usually poorly differentiated and negative for hormone receptors and HER2/neu. We have confirmed previous smaller reports suggesting that MSCs are aggressive. Table 6 compares the outcomes of breast MSC and carcinosarcoma patients in the MDACC and SEER series' with the outcomes of all breast cancer patients registered in the SEER database between 1988 and 2001. For the most common stage (II) at diagnosis, outcomes are indeed worse for metaplastic cancer patients, although we did not find a statistically significant difference between the outcomes of MSC patients and those of a matched group of M. D. Anderson high-grade receptor-negative ductal adenocarcinoma patients, consistent with previous reports. Notably, there were few, if any, failures after the median follow-up of the MSC patients, reminiscent of inflammatory and other high-grade high-risk tumors. However, as previously reported, there also seem to be some differences between MSC and conventional breast adenocarcinomas [1, 2]. For example, the axillary lymph nodes are less frequently involved by MSC of the breast and are not as strong a predictor of prognosis as T stage.
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Although data interpretation is restricted by the retrospective and uncontrolled nature of the results and by wide CIs, it seems the administration of conventional radiotherapy may not adequately reduce the incidence of local recurrences for those with this rare cancer who undergo breast-conserving surgery. Margin information was not included in univariate analysis of local recurrence because of sparse data. Our data suggest that MRM should be considered for patients with breast MSC, particularly for patients with T2 and higher stage disease. Certainly, the optimization of locoregional control is critical in these patients. New radiation approaches and possibly concomitant radiosensitizing agents are needed.
The RFS rate of patients with an average age of 48 years who have high-grade hormone receptor-negative breast cancer given no adjuvant systemic treatment is 36.7% at 10 years for T2N1 tumors, 47.3% for T3N0 tumors and 25.1% for T3/4 node-positive disease [15]. Although our patient numbers are small and interpretation is limited by cross-trial comparisons, the outcomes of similar patients with breast MSC in our series treated with adjuvant chemotherapy (described in the Results section) are similar to these untreated rates. In addition, the activity of primary chemotherapy is certainly less than that reported in conventional adenocarcinoma of the breast, especially when one considers that high-grade hormone receptor-negative adenocarcinomas are particularly sensitive to primary anthracycline/taxane-based chemotherapy [16]. Interestingly, although patient numbers are very small, all three patients treated with adjuvant sarcoma-type chemotherapy are relapse-free (Table 1), although one of these patients treated in the neoadjuvant setting had only stable disease as best response. Although limited numbers preclude definitive statistical assessment, the outcome of cyclophosphamide, methotrexate and 5-fluorouracil-treated breast MSC patients was very poor, while those patients treated with adjuvant anthracyclines did seem to do better, suggesting that CMF chemotherapy is less effective than anthracycline-based therapy in breast MSC (Tables 2 and 3).
In summary, although aggressive, breast MSCs are clinically similar to carcinosarcomas and probably no more aggressive than high-grade receptor-negative breast adenocarcinomas. However, the responsiveness of breast MSCs to neoadjuvant chemotherapy suggests that these patients may derive less benefit from conventional breast cancer chemotherapy. Recently, the use of gene profiling has identified most receptor-negative breast cancers as a unique ‘basal’ form of breast cancer thought to arise from progenitor cells in the ductal epithelium [17–20]. Since breast MSCs have many similarities with this breast cancer subtype but also some ‘sarcoma-like’ features (node negativity and the predominant importance of T size to outcome), it is possible that breast MSCs are breast adenocarcinomas originating from a basal progenitor cell in the breast with a degree of maturational plasticity leading to the acquisition of both morphologic and clinical sarcomatoid characteristics. The application of gene profiling to MSCs of the breast will help us to clarify this. The high risk of local recurrence with breast MSC should make oncologists consider whether breast-conserving surgery is the right option for patients with this disease, particularly with T2 and higher T stages. Novel agents are required to improve prognosis and biological studies are urgently required to identify potential molecular targets. A sarcoma-like chemotherapy regimen may be useful as a potential starting place.
Received for publication November 18, 2005. Accepted for publication December 22, 2005.
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