|Year : 2019 | Volume
| Issue : 2 | Page : 124-129
Survival and treatment outcomes of metaplastic breast carcinoma: Single tertiary care center experience in Pakistan
Zarka Samoon1, Madiha Beg2, Romana Idress3, Adnan A Jabbar1
1 Department of Oncology, Aga Khan University Hospital, Pakistan
2 Department of Radiology, Aga Khan University Hospital, Pakistan
3 Department of Pathology, Aga Khan University Hospital, Pakistan
|Date of Web Publication||2-May-2019|
Department of Radiology, Aga Khan University Hospital
Department of Oncology, Aga Khan University Hospital
Source of Support: None, Conflict of Interest: None
BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare disease with incidence of less than 1%. MBC present with a larger tumor size, less number of nodes involved, mostly undifferentiated triple negative tumors. We aimed to determine progression-free and overall survival and reported hospital-based incidence of MBC.
MATERIAL AND METHODS: A retrospective closed Cohort study elicited data of 42 patients with MBC from January 2008 to December 2013; followed till August 2016. Kaplan-Meier method was applied to compute overall and progression-free survival analysis. Cox Proportional hazard ratios were computed to assess associations between survival and independent variables.
RESULTS: Hospital-based incidence of MBC was 1.92% (42/2187), 95% CI [1.41-2.56]. The median age at tumor diagnosis was 54 years (range, 25–81 years). Thirty-nine (92.9%) patients had Grade III tumor. The most common histopathology was squamous (69%). The median tumor size was 4.5 cm (range, 0.8–17 cm). Nineteen (45.2%) patients had nodal involvement at diagnosis. Four patients (9.5%) had metastatic disease at presentation. Hormone receptors were positive in 19 (45.2%) patients. Her-2 neu receptor was positive in 9 (19%) patients. Sixteen (38.1%) patients had triple negative disease. Neoadjuvant and adjuvant chemotherapy was received by 10 (31.25%) and 19 (45.2%) patients respectively. Both median progression-free and overall survival was 38 months.
CONCLUSION: Five-year progression-free and overall survival was 79.5% and 76.3%, respectively. We report better survival outcomes when compared to series described earlier despite our patient population presenting mostly with high grade, large tumors, and half of them exhibiting nodal and hormonal involvement.
Keywords: Breast, Kaplan- Meier analysis, metaplasia, neoadjuvant treatments, survival analysis
|How to cite this article:|
Samoon Z, Beg M, Idress R, Jabbar AA. Survival and treatment outcomes of metaplastic breast carcinoma: Single tertiary care center experience in Pakistan. Indian J Cancer 2019;56:124-9
|How to cite this URL:|
Samoon Z, Beg M, Idress R, Jabbar AA. Survival and treatment outcomes of metaplastic breast carcinoma: Single tertiary care center experience in Pakistan. Indian J Cancer [serial online] 2019 [cited 2019 Jul 15];56:124-9. Available from: http://www.indianjcancer.com/text.asp?2019/56/2/124/257565
| » Introduction|| |
Metaplastic breast carcinoma (MBC) is a rare disease. Its incidence is said to be less than 1% amongst all breast cancer sub-types. In a study from India, its incidence was reported as 0.9%. They are a heterogeneous group of diseases having epithelial and mesenchymal components. Two to three different components may occur within the tumor at the same time.,,,,,, According to Wargotz et al. there are five variants of MBC which include matrix producing carcinomas, squamous cell carcinoma, spindle cell carcinoma, carcinosarcoma, and metaplastic carcinoma with osteoclastic giant cells.,,,,, Cumulative five-year survival rates of various subtypes ranges from 49% to 68%.,,,, In comparison to invasive ductal carcinomas (IDC), MBC present with a larger tumor size, less number of nodes involved, mostly undifferentiated tumors, which are usually triple negative.,, When compared with IDC, patients with MBC have a shorter overall survival., In a study by Nelson et al. five-year disease specific survival was 78% in MBC as compared to 93% in those with IDC (p< 0.0001). There is no optimum treatment approach for management of MBC. Its management has been essentially similar to that of IDC.
In this study, we reviewed a single center attempt to report outcome in terms of overall and progression-free survival of MBC patients. We analyzed several parameters such as menopausal status, tumor grade, stage, hormonal receptor, and Her 2 Neu status. This study reports the hospital-based incidence rate/proportion of MBC among all breast cancer subtypes. There was a lack of scientific literature from the developing countries regarding treatment options of MBC. Therefore, the study results may help in meeting the void.
| » Material and Methods|| |
Overview of study
A retrospective close cohort study was designed to collect data. Data in this study were mainly collected from the Aga Khan University Hospital cancer registry and Health Information and Management System (HIMS) from January 2008 till December 2013. This system established in 2009, is managed by the HIMS to identify all new cases. According to the Cancer Registry Regulations, this system identifies cancer in patients who report to our hospital for medical advice from all over Pakistan. The Aga Khan University Hospital (AKUH) is one of the main private cancer hospitals in the region. The follow up of patients with MBC was prospectively done until August 2016 regarding disease progression and survival.
All cases in the AKUH cancer registry and management system were identified by the coding system of the International Classification of Diseases for Oncology, 3rd Revision (ICD-03), from the World Health Organization. In order to confirm the diagnosis of MBC and examine the changes on coding, we retrospectively collected and checked records of diagnosis and pathological reports of these cases. A review of the biopsy specimen was done by an experienced pathologist in order to confirm the diagnosis of MBC. A total of 42 patients who were diagnosed from August 2008 to December 2013 were recruited to calculate the progression-free survival and overall survival in this study. Non-probability purposive sampling methodology was employed to enroll patients for the study from the Health Information and Management System (HIMS). Patients aged 16 and above diagnosed with MBC and treated at the hospital were recruited. Patients were excluded if they were treated at another center, did not have a histologically confirmed diagnosis or sufficient staging information. Patients with bilateral disease were also excluded.
Exposure variables under study
The following variables were recorded at baseline for each patient including age, menopausal status, tumor grade, histological subtype, tumor size, nodal status, and metastatic involvement at presentation. Hormone receptor status including estrogen receptor (ER), progesterone receptor (PR) and Her-2 positivity were also documented. Type of surgery, chemotherapy received, be it neo-adjuvant, adjuvant or palliative, types of radiation received were also recorded. Development of locally recurrent disease and sites of distant metastasis were documented.
Estrogen receptor (ER), and progesterone receptor (PR) was defined according to Allred scoring as positive when the sum of proportion and intensity was two and above. Her-2 positivity was defined as more than 10% strong complete membrane staining or positive with fluorescent in situ hybridization technique (FISH).
We examined two outcomes in terms of progression-free survival and overall survival. Progression-free survival (PFS) was calculated from the date of diagnosis until disease progression, death for any reason or the date of last contact. Overall survival (OS) was calculated from the date of diagnosis until death for any reason or the date of last contact. The follow up was prospectively done; PFS and OS were recorded by reviewing the charts and documenting last clinic visit. Hospital-based incidence rate/proportion of MBC was also computed. This was calculated by taking into account the number of newly diagnosed MBC patients and dividing them with all breast cancer subtypes that reported to the hospital from 2008 till 2013.
The study protocol was initially accepted from the Ethical Review Committee of Aga Khan University Hospital, Karachi, Pakistan, with ERC #3026-Med-ERC-14.
Data were entered into IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY: IBM Corp. software and were transported and analyzed on STATA. Hospital-based incidence rate/proportion of MBC was computed. Mean and standard deviation was computed for continuous variables and proportions were reported for categorical variables. The purpose of the analysis was to report progression-free survival and overall survival. Survival analysis was applied in order to determine progression-free survival rate and overall survival rate of patients with MBC. A P value of less than 0.05 was considered as statistically significant. Log rank test and Breslow test were assessed to check Proportional Hazard assumptions, P value 0.049 and 0.061, respectively. Therefore, the assumptions of survival analysis were met. Cox Proportional hazard ratios were computed to assess associations between survival and independent variables. The independent variables were menopausal status, tumor size, tumor grade, ER, PR, and Her 2 neu status, nodal involvement and disease stage. By applying non-parametric Kaplan-Meier survival curve technique, we estimated the PFS and OS rate.
| » Results|| |
A total of 42 women were included from January 2008 until December 2013 in the study. They were followed up till August 2016. Their mean ± SD age at diagnosis was 55.52 ± 12.473 years. The median age at tumor diagnosis was 54 years (range, 25–81 years). The mean ± SD follow up period was 39.77 ± 24.19 months. Their median follow-up period was 34 months (range, 0–94 months). There were 3 censored cases and 9 deaths. The data were censored under circumstances of being diagnosed at AKUH, but not seeking treatment from our center. One patient died because of myocardial infarction while on surveillance; seven died due to disease progression and one due to unknown cause. At data cut off, thirty patients were alive, three with disease and twenty-seven without disease.
Hospital-based incidence rate of MBC was 1.92% (42/2187), 95% CI [1.41-2.56].
Thirteen patients (31%) were premenopausal, the remaining postmenopausal. Nineteen patients (45.2%) were reported as hormone receptor positive and nine patients (19%) as Her 2-neu positive disease. Sixteen (38.1%) patients presented with triple negative disease. Squamous cell was the most common histology found in twenty-nine patients (69%). The mean tumor size was 4.7 cm ± 3.210 SD, (range, 0.8–17 cm); 90% of patients presented with tumor size > 2 cm. In this study, 19 (45.2%) patients presented with nodal involvement at diagnosis. Even though majority (57.1%) of the patients were diagnosed with stage two diseases, most (92.9%) of them existed as Grade III tumor patients. Four patients (9.5%) presented with metastatic disease at presentation, lung being the most common site involved, followed by bone and liver. All four of them had squamous histology. The baseline characteristics are given in [Table 1].
|Table 1: Baseline characteristics of patients with Metaplastic breast cancer patients|
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Neoadjuvant chemotherapy was received by 10 patients (31.25%). Among these 8 (80%) were of squamous histology. Anthracycline- and taxane-based chemotherapy was the most common (70%) regimen used in this setting. Among these five (50%) had a complete response.
Twenty-seven (64.3%) patients underwent modified radical mastectomy, which was the most common surgery. Four (9.5%) patients underwent simple mastectomy and sentinel lymph node biopsy (+/- axillary lymph node dissection) and 8 (19%) underwent lumpectomy and sentinel lymph node biopsy (+/- axillary lymph node dissection).
Nineteen patients (45.2%) received adjuvant chemotherapy among which 16 (84.2%) were of squamous histology. Anthracycline- and taxane-based chemotherapy was again the most common (57.9%) regimen used.
Twenty-eight (66.6%) patients received adjuvant radiation out of which 16 (38.1%) received radiation to the chest wall and axilla.
Fourteen (33.33%) patients received adjuvant hormonal therapy among whom 9 (64.29%) received anastrozole and 5 (35.71%) received tamoxifen.
The details of treatment in the curative setting are given in [Table 2].
At a median follow-up of 34 months (range, 0–94 months), metastatic disease was seen in 4 (9.52%) [4/42] patients with lung being the most common site followed by bone and liver. Out of them, 1 died due to disease and 3 were lost to follow up. Progressive disease was observed in 9 (24.32%) [9/37] patients. Out of them, 6 died due to disease, 2 were lost to follow up, and 1 was alive at data cutoff. Among the patients with progressive disease, lung was the most common site followed by bone. Palliative treatment modalities and survival outcomes are given in [Table 3].
Most of the patients with progressive disease had hormone receptor negative disease (77.7%). Three patients received hormonal treatment in the palliative setting.
By applying non-parametric Kaplan-Meier survival curve technique, we estimated the five-year PFS rate as 79.5% and five year OS rate as 76.3% [Figure 1]a and [Figure 1]b. The median progression-free survival (PFS) and overall survival (OS) was 38 months (range, 2–94 months) and 38 months (range, 4–94 months), respectively. The censored patients were excluded from the survival analysis. The overall survival based on independent variables is given in [Table 4].
|Figure 1: (a) Overall survival of Metaplastic breast cancer patients. (b) Progression-Free Survival of Metaplastic breast cancer patients|
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The two primary endpoints were PFS and OS among patients diagnosed as MBC. Factors associated with better progression-free and overall survival were tumor grade and menopausal status. When stratified based on Her-2 neu status, tumor size, nodal size, tumor stage, or progesterone receptor status, neither of these factors were associated with any improvement in progression-free or overall survival. Adjusted analysis of MBC patient's survival is given in [Table 5].
|Table 5: Adjusted analysis of Metaplastic breast cancer patient's survival|
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| » Discussion|| |
MBC is a rare and heterogeneous group of diseases.,, In our study it accounted for 1.92% (42/2187) of all invasive breast cancers. The median age at presentation varies between 45 to 61 years.,,,, Our study reports a median age of 55.5 years, which is in concordance with published literature. There is a variability among the median tumor size ranging from 3.4-5.7 cm.,, The median tumor size in our study was 4.5 cm supporting international data of these tumors presenting with a large tumor size. It is usually associated with negative nodal involvement with studies reporting between 4.4 to 35% lymph node metastasis.,, This is in contrast to our series in which 53.1% patients had lymph nodes involved. However, in a similar Turkish study, 63.4% patients had axillary lymph nodes involved suggesting that the Asian population had a propensity to involvement of lymph nodes. Leyrer et al. reported 35% rate of distant metastasis; our study reported 24.32%.
The surgical approach has been comparative to patients with IDC, with breast conserving therapy showing similar overall survival to mastectomy in the appropriate patients. About 64.3% of our patients underwent modified radical mastectomy bearing in mind that 90% patients had a tumor size of more than 2 cm.
Standard chemotherapy regimens used for patients with IDC have little effect in women with MBC. In a study by Rayson et al. 9 patients received adjuvant chemotherapy, among which 7 developed disease recurrence (77.7%). In our series 19 patients received adjuvant chemotherapy and one developed disease recurrence (5.2%). We report 70% (50% PCR, 20% PR) response to neoadjuvant chemotherapy which is way higher than data reported in the past. In a study from Cleveland, 39% patients had a pCR. In a Turkish study, none of the patients had a pCR, and 6.2% partial response. Outcomes are better in patients who achieve pCR. In our study none of the patients with pCR developed metastatic disease versus 60% (3/5) in those without pCR. The percentage of metastatic disease was 11% vs. 50% in those with and without pCR in a similar study.
Historically majority (71%) of MBC cases are triple negative., Hence, hormonal therapy largely has no role in these patients. In our series a total of 38.1% patients were found to have triple negative disease. In a study by Gultekin et al. none of the patients were her 2-neu receptor positive; however, 9.4% of our patients were Her-2 neu receptor positive. Estrogen and progesterone receptor positivity has been reported up to11.3% and 10.4% respectively by Pezzi et al. In our patients 45.2% were ER and PR receptor positive. Bae et al. report giving hormonal treatment to three patients, with no recurrence in the follow up period. Rayson et al. gave palliative tamoxifen to 4 patients, but none of them reported any response. Thirteen patients received adjuvant hormonal treatment among which one patient developed progressive disease. Only one patient in this study received palliative hormonal treatment and did not have progression till 18 months of follow up. She however was lost to follow up later.
The five-year PFS from International data is reported between 30% and 69%.,, We report a five-year PFS of 79.5%. Similarly, various studies report five-year OS between 65% and 69%.,,, In our study the five-year OS was 76.3%. Both the PFS and OS of our patient population are higher than survivals reported from the West. However, the higher survival is similar to that reported from three Asian countries, namely of patients reported from Turkey by Gultekin et al. (76% and 80% five-year PFS and OS, respectively), from China by Zhang et al. (67.9% and 78.7% five-year PFS and OS, respectively) and from Korea by Bae et al. (78.1% three-year PFS).,, Comparison of previous literature in terms of PFS and OS of MBC patients with our study is given in [Table 6].
|Table 6: Comparison of previous literature in terms of five -year progression-free and overall survival of MBC patients|
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MBC is associated with high potential of metastatic disease with lungs being the most common site involved., In our study nine (9/42; 21.42%) patients developed metastatic disease, out of which six had lung involved. The median overall survival after disease progression was 21 months which is higher in comparison to previous study.
In a study by Rayson et al. women younger than 60 years and with prior history of estrogen use were associated with decreased disease-free survival. In contrast, women younger than 50 had better survival in our series. Negative nodal involvement was associated with better outcomes in a study reported by Dave et al.. No such association was found in our study. In a study by Leyrer et al., there was no difference in outcomes based on histologic subtype. Squamous cell histology was the most common subtype in our series. However, outcome analysis could not be performed comparing various subtypes as the proportion of these was very small.
Unanswered questions and future directions for research
Multiple studies prove that MBC is said to have the worst prognosis among all cancer subtypes. There have been case reports of use of doxorubicin, ifosfamide, and etoposide in sarcomatoid and carcinosarcoma variant of MBC., However, clinical trials are required to explore these potential new therapies.
Strengths of study
To the best of our knowledge, this is the first single center study reported at a tertiary care hospital from our region. We report 70% (50% PCR, 20% PR) response to neoadjuvant chemotherapy, which is way higher than the data reported in the past.
Limitations of study
There were several limitations of the study. This was a retrospective study with a small sample. Some patients were lost to follow up and data regarding their treatment was not available.
| » Conclusion|| |
In conclusion, MBC is a rare and aggressive variant of breast cancer. Five-year progression-free and overall survival was 79.5% and 76.3%, respectively. We report better survival outcomes when compared to series described earlier despite our patient population presenting mostly with high grade, large tumors, and half of them exhibiting nodal and hormonal involvement. Literature exploring molecular targets and clinical trial exploring tumor-specific therapies is required to improve disease prognosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]