Pattern of Recurrence in Radically Treated Triple Negative Breast Cancer Patients ()
1. Introduction
Breast cancer is the most common type of cancer among women in the US with the incidence rate of 12.5%. This disease is the primary cause of mortality among women aged 45 - 55 years and is the second leading cause of cancer-induced death. The incidence of breast cancer is almost 1-in-8 women, requiring complete tissue removal, chemotherapy, radiotherapy, and hormone therapy most of the time [1].
Basal-like tumours in general lack hormone receptors and HER2; thus, the majority of these tumors are also called triple-negative breast cancer (TNBC). Currently there is no molecular-based targeted therapy for TNBC, and unfortunately only approximately 20% of these tumors respond well to standard chemotherapy. Thus, developing improved treatments for TNBC is one of the highest priorities of current breast cancer research. By defining basal-like cancers either in terms of expression of basal immunohistochemical markers or a basal-like RNA expression profile, studies are consistent in their morphological description of this subtype as high grade, largely ductal, but occasionally either metaplastic, atypical or typical medullary, or adenoid cystic cancers [1].
Hormone receptor-negative breast cancers are a heterogeneous group of breast cancers that are generally thought to be aggressive with poor prognosis and with fewer cancer prevention and treatment strategies compared with tumors expressing hormone receptor. In addition, HER2-negative tumors lack the benefit of specific therapy that targets this protein (e.g., trastuzumab-based therapy). Therefore, treatment options for these triple-negative tumors are more limited [2]. The prognostic significance of determining oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 expression (HER2) has been studied by various groups [3].
Triple-negative breast cancers (TNBCs) are characterized by a high proliferation rate and increased aggressiveness compared with other subtypes. Because endocrine and HER2-targeted therapies cannot be offered, conventional cytotoxic chemotherapy followed by adjuvant RT is the standard of care for patients with TNBC [4]. Studies evaluating pathological response of triple negative breast cancer with neoadjuvant chemotherapy are being conducted in several parts of the world [5] [6].
The pattern of spread is distinct from that for hormone receptor-positive tumours: TNBC has a greater propensity for brain and lung metastases, and a lower prevalence of bone metastases. Compared with those having hormone receptor-positive, her2-negative tumours had a worser OS, the difference being most pronounced in the first 2 years [7].
Although triple negative tumors have been reported to be more aggressive, there are limited long-term clinical data evaluating outcome as a function of this classification. Even though clinicians routinely use conventional ER, PR, and HER2/neu status to classify patients as triple negative for clinical decision making, there are no large databases that have evaluated locoregional control in conservatively managed patients. Studies are being conducted to evaluate disease failure patterns and overall survival (OS) of women with TNBC, who undergo breast conservation treatment [8]. The baseline prognosis for patients with basal-like breast cancer is poor in the absence of therapy, so it is critical to identify the best therapeutic targets for these patients. The chemotherapy benefit is high, but there are many promising new targets and approaches for this group, including PARP inhibitors, a potential carboplatin benefit, angiogenesis inhibitors, and HER-1-RAS-mitogen-activated protein kinase/extracellular signal-related kinase pathway inhibitors [9].
The rationale behind conducting this study is to address the pattern of recurrence, i.e., any organ predilection and survival outcomes which will benefit our patients for planning follow up and early detection of metastasis.
2. Methods
This study was conducted in the Department of Radiotherapy and Oncology of Government Medical College, Trivandrum in State of Kerala, India from December 2017 to December 2019. This institution is a tertiary cancer centre of the State. This study was approved by the scientific Institutional Review Board and by the Human ethical committee.
The primary objective is to study the pattern of recurrence in radically treated TNBC patients whether locoregional (breast or nodal pattern) or systemic (organ predilection). The secondary objective is to estimate disease free survival in radically treated triple negative breast cancer patients.
All consecutive patients with biopsy and IHC proven diagnosis of triple negative breast receptor status, who completed the planned radical treatment (chemotherapy, surgery and radiotherapy if indicated) and willing to participate in the study were included.
Female patients in the age group 18 to 75 years, with ECOG performance status of 0 to 2 and stage I - III were included in the study. Metastatic disease at presentation, patients with any other cancers, patients with medical contraindications for chemotherapy and radiotherapy, and poor performance status patients (ECOG 3, 4) were excluded.
After obtaining an informed consent, data was collected using a structured proforma, which detailed patient characteristics, clinical examination findings, histopathology report, and treatment done. Nature of the study was explained to each patient in their respective local language, Malayalam.
Patients were observed prospectively, and no alteration is done in the standard ongoing treatment for the purpose of study. Surgery followed by adjuvant chemotherapy and radiation as per standard current guidelines were administered. Patients received four 3-week cycles of epirubicin 90 mg/m2 or doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 followed by the combination of four 3-week cycles of docetaxel 75 mg/m2 or other standard chemotherapy schedules according to performance status and body mass index. Patients received local radiation treatment either as 50 Gy/25fr or 40 Gy/15fr. Clinical examination after each cycle and after completion of treatment was done for clinical response and toxicity manifestations.
Suspected cases of Loco regional relapses were confirmed with FNAC/biopsy. Investigations were done according to patient symptoms and systemic recurrences confirmed by radiological investigations as per standard guidelines.
Data analysis was done with the help of Excel 2010 and SSPS 18 statistical software. Site of recurrence, organ involved, date of treatment completion and disease-free survival rates has been entered in Excel 2010 work sheet for each variable. Pattern of failure was noted and organ with higher predilection for systemic metastasis was identified. 1 year disease free survival rates and 6-month disease free survival rates were estimated.
3. Results
A total of 171 patients satisfying the selection criteria were included in this study (Tables 1-5, Figure 1).
Median age of the population under study was found to be 53 years. Majority of patients (>90%) presented with a lump in the breast. Only less than 10% patients presented with symptoms such as nipple retraction, nipple discharge and pain in breast. More than 60% patients included in the study had a performance status of 1 and hence were able to complete the planned radical treatment. Patients with poor performance status were excluded from the study. Most of the patients included in the study were married and had children. Only 9 out 141 patients (6%) who did not have a recurrence were nulliparous. In this study majority of the women were of the post-menopausal group (>70%).
In this study 107 patients (61%) belonged to the early T stage (T1 and T2) and 64 patients (38%) belonged to the advanced T stage (T3 and T4).
Out of 171 patients included in the study 75 patients (44%) were node negative. 52 patients (30%) had N1 disease, 28 patients (16%) had N2 disease, and 16 patients (9%) had N3 disease.
In this study 11 patients (6%) presented in Stage I, 88 patients (51%) presented in Stage II, and 72 patients (42%) presented in Stage III. More than 95% of patients had the histological subtype infiltrating ductal carcinoma and the rest
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Table 1. Base line characteristics of the patients.
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Table 3. Treatment characteristics.
of the patients had metaplastic carcinoma and other histological variants. Majority of the tumour were of grade 3 (50%) among those 30 patients who had recurrence. 24 patients (14%) showed lympho-vascular space invasion in the histology.
163 patients underwent modified radical mastectomy, and 7 patients underwent breast conservation surgery, and 1 patient underwent toilet mastectomy. 32 patients (19%) took neoadjuvant chemotherapy, and 139 patients (81%) took adjuvant chemotherapy.
The most used chemotherapy regimen among our study population was 4 cycles of Adriamycin and cyclophosphamide followed by 4 cycles of taxane which is the standard treatment regimen for triple negative breast cancer according to literature. 133 patients (77%) received adjuvant radiation treatment. 30 patients (17%) out of 171 patients with triple negative breast cancer had recurrence of disease.
Among 30 patients who recurred 14 patients (47%) had locoregional recurrence and 16 patients had systemic recurrence with the most common organ with metastatic deposits being lung (6 patients) followed by brain (4 patients), liver and bone (2 patients each)/of the locoregional relapses, it was found that ipsilateral chest wall had a higher propensity to failure following MRM and that in those patients who underwent BCS the failure was in ipsilateral breast itself. 6 months disease free survival of the study population was found to be 91.8% and 1 year DFS was found to be 70.2%.
4. Discussion
Triple negative subtype lacks any specific target and currently is subject to vigorous investigations to improve its outcome. TNBC also is a biologically extremely heterogeneous group of breast cancer, with a high likelihood of recurrence during the first 2 - 3 years after diagnosis.
The incidence of recurrence in this study which is 17.5% is more than that seen in the study conducted by Abdulkarim et al. [4] which is 10%. The incidence of systemic metastasis (53%) is more than the incidence of locoregional recurrence (47%). This observation is similar to the study conducted by Prasad et al. [10]. Like other studies, lung metastasis is the most common site for systemic metastases and ipsilateral chest wall the site for loco-regional recurrence. The 6 months disease free survival of 91.8% and 1 year disease free survival of 70.2% is almost like the results obtained in various other studies conducted among Western and Asian population [5] [10]. Our study has its own limitations. There is lack of long term follow up and the sample size is small in our study.
5. Conclusion
Triple negative breast cancer constitutes a heterogeneous group of breast cancer patients who have an aggressive behaviour, the incidence of recurrence in radically treated triple negative breast cancer patients included in this study was found to be 17.5% of which local recurrence is the major share.
Ethical Approval
The study was approved by the Institutional Human Ethics Committee of Government Medical College, Thiruvananthapuram, Kerala, India.