|Year : 2015 | Volume
| Issue : 2 | Page : 61-63
What's positive about triple negative breast cancers?
Rajesh Singh Laishram1, Nepram Sanjib Singh2
1 Department of Pathology, Regional Institute of Medical Sciences, Lamphelpat, Imphal, Manipur, India
2 Department of Plastic Surgery, Regional Institute of Medical Sciences, Lamphelpat, Imphal, Manipur, India
|Date of Web Publication||20-Aug-2015|
Nepram Sanjib Singh
Department of Plastic Surgery, Regional Institute of Medical Sciences, Lamphelpat, Imphal - 795 004, Manipur
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Laishram RS, Singh NS. What's positive about triple negative breast cancers?. J Med Soc 2015;29:61-3
Breast cancer is one of the most common cancers in women in the developed countries of the world, and it is the cause of death in approximately 20% of all females.
Breast cancer is considered a complex and heterogeneous disease in terms of histology, cellular origin, mutations, metastatic potential, disease progression, therapeutic response, and clinical outcome. 
Using the combination of molecular biological techniques and histological features, breast tumors occur in at least five clinically important subtypes based on gene expression profiles. These include "luminal A" [estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative], "luminal B" (ER-positive and/or PR-positive, HER2-positive), "HER2 overexpressing" (ER-negative, PR-negative, HER2-positive), "basal-like" [ER-negative, PR-negative, HER2-negative, cytokeratin 5/6-positive and/or epidermal growth factor receptor (EGFR)-positive] and "normal breast-like" tumors.  Besides the gene expression patterns, these subtypes may have separate clinical features and prognoses.  Later, a new subtype classified as "claudin-low" has also been identified. 
Triple-negative breast cancer (TNBC) is defined by the lack of protein expression of ER and PR and the absence of HER2 protein overexpression. TNBC is a subtype of breast cancer that overlaps with the "basal-like" breast cancer and is typically associated with poor prognosis. The reason may be attributable to aggressive tumor phenotype(s), partial response to chemotherapy and lack of clinically established targeted therapies. , Younger women under 40 years of age are more likely to have this type, as are African American women, and the cancers tend to grow and spread aggressively. People carrying an inherited fault in one of their BRCA1 genes are also more likely to develop triple-negative tumors. TNBC constitutes 10-20% of invasive breast carcinomas and has the lowest 5-year survival rate compared with other breast cancer subtypes. 
| Negatives about tnbc|| |
TNBC is less likely to be detected on a mammogram than some other types of breast cancer. It is considered to be an aggressive tumor compared to other types and tends to grow faster. It can be treated, but it may recur early and spread to other parts of the body. Part of the reason is the lack of targeted treatments. There is a lot of "negativity" in these triple-negative breast cancers that causes a problem when it comes to treatment. With no ER, PR, or HER2, neither the hormone-blocking therapies nor Herceptin are likely to work. Thus the available treatment options usually involve a grueling combination of surgery, radiotherapy, and chemotherapy. TNBC has high recurrence and metastatic rates compared to other types. TNBCs are biologically aggressive - Although some reports suggest better response to chemotherapy compared to other types of breast cancer, prognosis remains poor.  This is may be due to two factors: Shortened disease-free interval in the adjuvant and neoadjuvant setting, and a more aggressive clinical course in the metastatic setting.
| Positive about tnbc|| |
As with every bad thing, TNBC, although considered a bad cancer, has positive sides, too. With the advancement in the molecular understanding of TNBC, the negativity about TNBC is turning toward the positive side.
Although there is a higher chance that TNBC will recur within 5 years compared to positive tumors, the survival rates are similar to those of positive tumors if they do not recur.
Recent advances in genomics and gene expression profiling have shed new light on the molecule heterogeneity of TNBC. Several researchers are trying to unfold the mysteries of TNBC. Just as the umbrella term "breast carcinoma" encompasses several different forms, TNBCs can be divided into smaller specific groups based on their genetic and molecular profiles. Broadly, many TNBCs fall into a category of "basal-like." The key to bring about a change in TNBC is to understand the disease better on the genetic level and improve diagnosis and treatment, and to reveal new targets for therapies just as Herceptin targets HER2.
The identification of a TNBC subtype characterized by elevated expression of immune genes suggests that some patients may benefit from immune-based therapies. Among ER negative breast cancers, accumulating evidence suggests that basal TNBC may be the type most regulated by intratumoral T cells, and thus the most responsive to immunotherapies. Liu et al. recently performed a large-scale immunohistochemical (IHC) analysis of cluster of differentiation 8 (CD8) staining on 3400 breast cancer cases representing different subtypes.  Multivariate analysis indicated that among all breast cancer subtypes, only core basal TNBC demonstrated a significant correlation between intratumoral CD8 staining and favorable prognosis. Lactoferrin may thus contribute to a triple-negative phenotype in breast cancer and could represent a novel target to stimulate antitumor immune responses. 
Targeting poly (ADP-ribose) polymerase (PARP) is being investigated. PARPs are a family of enzymes that are involved in many cellular processes guided by an ability to modify various target proteins through the conversion of nicotinamide adenine dinucleotide (NAD+) into long poly (ADP-ribose) (PAR) chains coupled to the proteins. Inhibition of PARP has potential for use in cancer treatment. 
EGFR is a membrane receptor and has been shown to play an important role in the growth and survival of many solid tumors. Among breast carcinomas, EGFR is more commonly expressed in TNBC.  EGFR has been explored as a potential target for therapy based on its expression in some variants of TNBC. TBCR 001, a randomized phase 2 trial, evaluated the role of EGFR inhibition in metastatic TNBC.  Eligible women in this study received the anti-EGFR monoclonal antibody cetuximab with carboplatin or received cetuximab alone with a planned crossover to carboplatin at disease progression. Although cetuximab alone was basically ineffective and this treatment arm was closed early, response to cetuximab combined with carboplatin was 17%, with clinical benefit evident in 29% of pretreated patients.  Two classes of EGFR inhibitors are currently in clinical use: The monoclonal antibodies and the small-molecule tyrosine kinase inhibitors. 
Angiogenesis is the production by a tumor of a new blood vessel system for the purpose of providing nutrients to the tumor. Therapies for inhibiting angiogenesis are being investigated. Also under investigation for efficacy in patients with TNBC is the angiogenesis inhibitor bevacizumab, which targets vascular endothelial growth factor. In one of the trials patients with operable TNBC are randomized to receive standard chemotherapy with or without 1 year of adjuvant bevacizumab.  Angiogenesis inhibitors are not particularly specific for TNBC, however, and may be associated with variable response with a variety of other carcinomas as well.
Targeted endocrine therapy is an important treatment strategy for ER-positive and/or PR-positive breast cancer, but it rarely affects TNBC. Androgen receptor (AR) has recently received attention in breast cancer treatment; the data reviewed suggest that it has relevance to breast cancer biology and may be an important therapeutic target in AR-positive TNBC, especially TNBC that exhibits less AR/ER interaction. It is believed that the development of AR-targeted therapy may improve the outcome in patients with TNBC. In one recent phase 2 study of 424 metastatic breast carcinomas exploring the benefits of bicalutamide (an androgen inhibitor) in AR + , ER− , and PR− tumors, AR was expressed in 12% of the ER/PR-negative breast cancers.  This study showed minimal toxicity and efficacy for androgen blockade in a select group of patients.  AR is the most commonly expressed hormone receptor among all breast carcinomas, with a prevalence of 25-75% among TNBCs. Therefore, we strongly support the routine assessment of AR in TNBC, and preferably in all breast carcinomas. 
Many solid tumor types, including breast cancer, exhibit a functional hierarchy of cancer cells, of which only a small subpopulation of replenishing stem-like cells can give rise to the differentiated cells that comprise the bulk tumor. Cancer stem cell (CSC)-specific pharmaceutical interventions are being developed that may eliminate both primary and acquired CSC chemoresistance. This may dramatically improve the treatment of cancer by abrogating the potential for CSC-induced tumor regrowth and systemic disease spread after initial treatment. 
TNBC remains a challenge in medical practice. Among the new therapeutic options for TNBC, cellular or molecular immunotherapies appear to be very promising approaches. In conclusion, TNBC itself is a heterogeneous disease and with a better molecular understanding, many positive avenues regarding management has begun to erupt.
| References|| |
Ossovskaya V, Wang Y, Budoff A, Xu Q, Lituev A, Potapova O, et al
. Exploring molecular pathways of triple-negative breast cancer. Genes Cancer 2011;2:870-9.
Choi J, Jung WH, Koo JS. Clinicopathologic features of molecular subtypes of triple negative breast cancer based on immunohistochemical markers. Histol Histopathol 2012;27: 1481-93.
Boyle P. Triple-negative breast cancer: Epidemiological considerations and recommendations. Ann Oncol 2012;23(Suppl 6):vi7-12.
Malhotra GK, Zhao X, Band H, Band V, et al
. Histological, molecular and functional subtypes of breast cancers. Cancer Biol Ther 2010;10:955-60.
Podo F, Buydens LM, Degani H, Hilhorst R, Klipp E, Gribbestad IS, et al
. Triple-negative breast cancer: Present challenges and new perspectives. Mol Oncol 2010;4:209-29.
Brady-West DC, McGrowder DA. Triple negative breast cancer: Therapeutic and prognostic implications. Asian Pac J Cancer Prev 2011;12:2129-43.
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.
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.
Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res 2012;14:R48.
Stagg J, Allard B. Immunotherapeutic approaches in triple-negative breast cancer: Latest research and clinical prospects. Ther Adv Med Oncol 2013;5:169-81.
Zhang YW, Regairaz M, Seiler JA, Agama KK, Doroshow JH, Pommier Y. Poly (ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. Nucleic Acids Res 2011;39:3607-20.
Viale G, Rotmensz N, Maisonneuve P, Bottiglieri L, Montagna E, Luini A, et al
. Invasive ductal carcinoma of the breast with the "triple-negative" phenotype: Prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat 2009;116:317-28.
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.
Burness ML, Grushko TA, Olopade OI. Epidermal growth factor receptor in triple-negative and basal-like breast cancer: Promising clinical target or only a marker? Cancer J 2010;16:23-32.
Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, et al
.; Translational Breast Cancer Research Consortium (TBCRC 011). Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 2013;19:5505-12.
Safarpour D, Tavassoli FA. A targetable androgen receptor-positive breast cancer subtype hidden among the triple-negative cancers. Arch Pathol Lab Med 2015;139:612-7.
Hu Y, Fu L. Targeting cancer stem cells: A new therapy to cure cancer patients. Am J Cancer Res 2012;2:340-56.