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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 150-154

Evaluation of treatment outcomes of triple-negative breast cancer


1 Department of Radiation Oncology, Celal Bayar University Faculty of Medicine, Manisa, Turkey
2 Department of Radiation Oncology, Balikesir Public Hospital, Balikesir, Turkey
3 Department of Radiation Oncology, Yesilyurt Public Hospital, Izmir, Turkey

Date of Web Publication13-Apr-2016

Correspondence Address:
Mustafa Akin
Department of Radiation Oncology, Balikesir Public Hospital, 10010 Balikesir
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.154000

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 > Abstract 


Purpose: Breast cancer is the most common cancer in women. Treatment responses are variable depending on tumor morphological characteristics, clinical characteristics, and hormonal receptor levels. In current medical practice, estrogen receptor (ER), progesterone receptor (PGR), and human epidermal growth factor receptor 2 (HER2) levels have been identified as important prognostic factors; they can change prognosis and treatment modalities. In this study, the prognostic factors of patients with triple-negative breast cancer (TNBC) were examined retrospectively.
Materials and Methods: Some 110 cases with negative prognostic and predictive proteins (ER, PGR, and HER2) were included in this study. Median follow-up was 56 months. Recurrences, overall survival, and prognostic factors were evaluated.
Results: We revealed in our triple-negative series that nodal status, tumor size, whole breast radiation doses, and type of surgery are the most useful prognostic markers.
Conclusion: Triple-negative breast cancers, especially basal-like subtypes, have bad prognoses. They have high histopathological grades and high risk of invasion. This group can make early metastases and expected survival is usually short. We need to focus on new treatment strategy modalities on this group, and pretreatment values of different prognostic markers are well-identified, such as androgen receptors, basal cytokeratin expression, and BRCA gene status.

Keywords: Breast cancer, estrogen receptor, human epidermal growth factor receptor 2, progesterone receptor


How to cite this article:
Cinkaya A, Akin M, Sengul A. Evaluation of treatment outcomes of triple-negative breast cancer. J Can Res Ther 2016;12:150-4

How to cite this URL:
Cinkaya A, Akin M, Sengul A. Evaluation of treatment outcomes of triple-negative breast cancer. J Can Res Ther [serial online] 2016 [cited 2019 Dec 16];12:150-4. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/150/154000




 > Introduction Top


Breast cancer is the most common cancer among women in the United States, the second most common cause of cancer death, and the main cause of death in women aged 45–55 years.[1] Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancers.[2]

Triple-negative breast cancers are a poor prognostic factor for disease-free and overall survival (OS). No effective therapy is available for TNBC. TNBC cases are usually seen in women of African descent, and BRCA1-associated breast cancers with the TNBC phenotype are apparently significant.

Basal-like breast cancer and TNBC are not synonymous. TNBC refers to the immunophenotype of the breast cancer. Basal-like breast cancer refers to the molecular phenotype of the tumor. Basal-like types make up to 75% of TNBC; they are usually high-grade and have a poor prognosis.

Triple-negative breast cancers are biologically aggressive. They respond to chemotherapy better than other types of breast cancer, particularly anthracycline- and taxane-based therapy, but their prognoses are still poor.[3] They continue to show a short disease-free survival (DSF) period.[4]

The principles for the surgical management and radiation therapy options of breast cancer are applied in a similar way across breast cancer subtypes. In addition, the neoadjuvant or adjuvant chemotherapy options for patients with TNBC are similar to the approach used in other breast cancer phenotypes. Neoadjuvant chemotherapy is used particularly in patients with locally advanced breast cancer at diagnosis. Adjuvant chemotherapy is usually recommended for tumor sizes <0.5 cm or with node-positive patients (regardless of tumor size). For the treatment of tumors <0.5 cm, the decision to administer adjuvant chemotherapy must be individualized based on patients. Experimental treatment options are epidermal growth factor receptor (EGFR) inhibitors, angiogenesis inhibitors, poly (adenosine diphosphate ribose polymerase) (PARP) inhibitors of PARP, Src inhibitors, and histone deacetylase (HDAC) inhibitors. There are no specific posttreatment surveillance guidelines for patients with TNBC.


 > Materials and Methods Top


This study includes a retrospective analysis of 110 consecutive TNBC patients treated with radiotherapy and obtained between 2005 and 2013. Median follow-up was 56 months. We reviewed recurrences, prognostic factors, and their correlations with OS.

The patient files were searched retrospectively for age, comorbidities, the presence of family history of cancer, breast cancer detection methods, pregnancy/number of children, height, weight, body surface area, Eastern Cooperative Oncology Group, biopsy date, type of surgery, tumor size/tumor, node, metastasis stage and localization, axillary nodal status, the presence of the tumor in the border of surgery, and pathologic evaluation, and the chemotherapy options (i.e. chemotherapy regimen series, number of cycles, the start/end dates) and data were recorded. Surveillance after treatment for early-stage breast cancer was performed every 3 months for the first 2 years, every 6 months for the next 3 years, and then every year after 5 years. Patients with metastatic disease were followed with a surveillance routine after receiving three and six cycles of chemotherapy. DSF was defined as the time from diagnosis to the date of breast cancer-derived relapse/metastasis, and OS was defined as the time from diagnosis to the date of death.

Statistical analysis

Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) 16.0 statistical software. We examined prognostic markers and survival in the triple-negative phenotype tumors. The association with survival was analyzed using Kaplan–Meier plotting and log-rank testing, and also with cox regression analysis to adjust for other prognostic indicators. P < 0.05 was considered as significant.


 > Results Top


A total of 52 (47.3%) of patients were younger than 50. Most of the cases were invasive ductal carcinoma (85.5%). The second most common was invasive lobulary carcinoma. Twenty-one percent of tumors were grade II, and 76% were grade III. Vascular invasion (32.7%) and lymphatic invasion (54.5%) were determined. Of the tumors, 27.3% were T1 (0–2 cm), 56.4% were T2 (2–5 cm), 8.2% were T3 (> cm), and 8.2% were T4. There was no lymph node metastasis in 49.9% of the patients; 25.5% were N1 (1–3), 15.5% were N2 (4–9), and 9.1% were N3. Modified radical mastectomy was performed in 48.2% of patients while 51.8% underwent breast conserving surgery. Nearly all (96.4%) had undergone chemotherapy and radiotherapy. All of the patients had undergone conformal radiotherapy. Whole-breast radiation doses were 50–54 Gy, and primary tumor bad doses were 6–18 Gy. [Table 1] shows the main characteristics of patients and tumors. During the 56 months follow-up, local recurrence occurred in 8 (7.3%) cases; four of these patients had distant metastases determined at the same time. Although there were no local recurrences in 17 (15%) patients, distant metastases did occur. Metastases locations were in the brain (36.4%), bones (27.3%), lungs (18.2%), and liver (13.6%) [Figure 1]. Two years survival was 89% and 5 years survival was 77% [Figure 2]. We determined in our triple-negative series that nodal status, tumor size, whole-breast radiation doses, and type of surgery are the most useful prognostic markers [Figure 3],[Figure 4],[Figure 5],[Figure 6].
Table 1: Main characteristics of patients tumor and treatment

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Figure 1: Sites of distant metastases in the triple negative tumors

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Figure 2: Survival curve with dependent time

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Figure 3: Correlation between tumor size and survival in the triple negative tumors

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Figure 4: Correlation between nodal status and survival in the triple negative tumors

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Figure 5: Correlation between whole breast radiation doses and survival in the triple negative tumor

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Figure 6: Correlation between type of surgery and survival in the triple negative tumor

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 > Discussion Top


Hormone receptor-negative breast cancers are a heterogeneous group of breast cancers that are generally thought to be aggressive with poor prognosis, and treatment options are more limited. They have worse breast cancer-specific survival, worse OS and increased death rates within 2 years of diagnosis.[5]

Currently, routine prognostic factors of breast cancers include nodal status, tumor histological grade, and primary tumor size.[6],[7] In our study, nodal status, tumor size, whole-breast radiation doses, and type of surgery were the most useful prognostic markers. However, we found no significant relationship between histopathological grade and survival.

Triple-negative breast cancer is more commonly diagnosed in premenopausal women.[8] Contrary to the literature, 47.3% of patients were younger than 50 in our study. Some studies suggest that TNBCs are diagnosed clinically rather than mammographically.[9]

Triple-negative breast cancer is usually high-grade, and the most common histology is infiltrating ductal carcinoma.[10] This feature was found in our study to be similar to that in the literature; most of the patients' histology was invasive ductal carcinoma (85.5%) and was high-grade (79%).

The triple-negative clinical phenotype is mostly comprised of the basal-like molecular subtype. It has a worse prognosis than the other subgroups of TNBC. It is characterized by a genomic expression that includes the EGFR, basal cytokeratins 5/6, and c-Kit; the proliferation cluster; and low expression of the hormone-receptor and human epidermal growth factor receptor 2-related genes.[10],[11],[12],[13] Gene expression analysis has also revealed that the tumor suppressor gene p53 and several DNA repair genes, particularly the BRCA genes, are either mutated or aberrantly expressed in TNBC, especially in basal-like molecular subtypes.

Women diagnosed at 60 years or younger with a TNBC undergo BRCA mutation testing regardless of family history. All patients with TNBC (at any age) should be offered a referral to a genetic counselor to discuss genetic testing.

Epidermal growth factor receptor-1 expression is seen in 50–70% of TNBC cases.[14] The detection of EGFR-1 positivity shows that this receptor may be the target of treatment. Cetuximab is used in combination with chemotherapy. Its efficiency was shown in a phase II clinical trial. With respect to angiogenesis inhibitors, there are no prospective data about impact on survival. Bevacizumab can improve progression-free survival. Olaparib, veliparib, and iniparib are well-known PARP inhibitors. With respect to Src inhibitors, dasatinib is being studied in the setting of advanced TNBC. With respect to HDAC inhibitors, vorinostat is used in the setting of endocrine-resistant disease; it appears to restore sensitivity in select patients. We performed well-designed prospective clinical trials of these experimental treatments.

In terms of prognostic factors used, our results are similar to those of previous studies that have shown prognostic factors to include nodal status [15],[16] and tumor size.[17],[18] The results of this study presented additional factors in that we found that whole-breast radiation dose and type of surgery are also significant prognostic factors for OS. There are some limitations of the study as being a multicentric study, many of which have few patients; therefore, the outcomes may not be applicable to other centers in other countries. As a consequence, we could not address the potential importance of the new treatment strategies; future prospective studies should, therefore, be focused on this subject.


 > Conclusion Top


Triple-negative breast cancers, especially basal-like subtypes have poor prognoses. They have high histopathological grades and high risk of invasion. This group can cause early metastasis, and expected survival is usually short. We need to focus on new treatment strategy modalities for this group. Pretreatment values of different prognostic markers are well-identified, such as androgen receptors, basal cytokeratin expression, and BRCA gene status.

 
 > References Top

1.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225-49.  Back to cited text no. 1
    
2.
Kaplan HG, Malmgren JA, Atwood MK. Impact of Triple Negative Phenotype on Breast Cancer Prognosis. Poster Presented at: 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX; 2006.  Back to cited text no. 2
    
3.
De Giorgi U, Rosti G, Frassineti L, Kopf B, Giovannini N, Zumaglini F, et al. High-dose chemotherapy for triple negative breast cancer. Ann Oncol 2007;18:202-3.  Back to cited text no. 3
    
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Kaplan HG, Malmgren JA, Atwood MK. T1N0 Triple Negative Breast Cancer: Adjuvant Chemotherapy Treatment and Risk of Recurrence. Presented at the 30th Annual San Antonio Breast Cancer Symposium, San Antonio, TX; 2007.  Back to cited text no. 4
    
5.
Lin NU, Vanderplas A, Hughes ME, Theriault RL, Edge SB, Wong YN, et al. Clinicopathologic features, patterns of recurrence, and survival among women with triple-negative breast cancer in the National Comprehensive Cancer Network. Cancer 2012;118:5463-72.  Back to cited text no. 5
    
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Mori I, Yang Q, Kakudo K. Predictive and prognostic markers for invasive breast cancer. Pathol Int 2002;52:186-94.  Back to cited text no. 6
    
7.
Hayes DF, Isaacs C, Stearns V. Prognostic factors in breast cancer: Current and new predictors of metastasis. J Mammary Gland Biol Neoplasia 2001;6:375-92.  Back to cited text no. 7
    
8.
Trivers KF, Lund MJ, Porter PL, Liff JM, Flagg EW, Coates RJ, et al. The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control 2009;20:1071-82.  Back to cited text no. 8
    
9.
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res 2007;13:4429-34.  Back to cited text no. 9
    
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Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006;19:264-71.  Back to cited text no. 10
    
11.
Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, et al. TBCRC 001: Randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 2012;30:2615-23.  Back to cited text no. 11
    
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Korsching E, Packeisen J, Agelopoulos K, Eisenacher M, Voss R, Isola J, et al. Cytogenetic alterations and cytokeratin expression patterns in breast cancer: Integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Invest 2002;82:1525-33.  Back to cited text no. 12
    
13.
Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004;10:5367-74.  Back to cited text no. 13
    
14.
Dairkee SH, Ljung BM, Smith H, Hackett A. Immunolocalization of a human basal epithelium specific keratin in benign and malignant breast disease. Breast Cancer Res Treat 1987;10:11-20.  Back to cited text no. 14
    
15.
Galea MH, Blamey RW, Elston CE, Ellis IO. The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 1992;22:207-19.  Back to cited text no. 15
    
16.
Ikeda T. Recent prognostic factors for breast cancer. Gan To Kagaku Ryoho 1997;24:635-43.  Back to cited text no. 16
    
17.
Reed W, Hannisdal E, Boehler PJ, Gundersen S, Host H, Marthin J. The prognostic value of p53 and c-erb B-2 immunostaining is overrated for patients with lymph node negative breast carcinoma: A multivariate analysis of prognostic factors in 613 patients with a follow-up of 14-30 years. Cancer 2000;88:804-13.  Back to cited text no. 17
    
18.
Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 1989;63:181-7.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
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