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Definition Triple Negative Breast Cancer

Association With Brca1 Mutation Status

How Is Triple-Negative Breast Cancer Treated?

It has been observed that the majority of BRCA1-associated breast cancers are triple-negative and express a high proportion of basal-like cytokeratins , as well as P-cadherin and HER1/EGFR. The BRCA1 tumor-suppressor gene, originally identified in 1994 by positional cloning on chromosome 17q21, is a multifocal protein in many normal cellular functions including DNA repair, transcriptional regulation, cell cycle checkpoint control, and ubiquitination.

Several studies have shown that breast tumors arising in women carrying germline mutations of the BRCA1 tumor-suppressor gene are triple-negative. Gene expression studies support this association among patients with BRCA1 mutations, breast tumors tend to cluster within the basal-like category. As BRCA1 is in part responsible for DNA repair, exploitation of this essential pathway holds therapeutic implications in the context of the triple-negative phenotype and will be discussed further below.

What Questions Should I Ask My Doctor

You will have lots of questions about your cancer, starting with your diagnosis. Here are some basic questions you might ask:

  • What is triple negative breast cancer?
  • How do you know my cancer is triple negative breast cancer?
  • Why did I get this cancer?
  • Do I need genetic testing?
  • Has my breast cancer spread, and if so, how far has it spread?
  • What is the stage of my cancer?
  • What is my prognosis or expected outcome?
  • What treatments do you recommend?
  • Why do you recommend those treatments?
  • What are those treatment side effects?
  • Will I need surgery? If so, what surgery do you recommend and why?
  • Im interested in participating in clinical trials. Are you able to help me find one?
  • Do you know if there are any local support groups?

A note from Cleveland Clinic

Triple negative breast cancer is one of the more challenging breast cancers to treat. You might be discouraged by what you have read about triple negative breast cancer. But there are a number of very effective treatments for triple negative breast cancer, including immunotherapy, chemotherapy, surgery and radiation. And every day researchers learn more about this rare cancer. Their knowledge is your power. If youre concerned you arent getting the straight story about your cancer, ask your healthcare provider to walk you through your diagnosis and treatment options.

What Is The Risk For Triple

The disease can affect anyone, but is more likely to show up in those who are:

  • Younger than age 50 .
  • Black or Latinx.
  • Living with a genetic condition called BRCA mutation that increases the risk for breast cancer and other forms of cancer. Most cancers diagnosed in people with the BRCA1 mutation are triple negative.

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Definitions And Molecular Features

It is important to clarify the relationship between triple-negative breast cancer and the basal-like phenotype. Triple-negative is a term based on clinical assays for ER, PR, and HER2, whereas basal-like is a molecular phenotype initially defined using cDNA microarrays. Although most triple-negative breast tumors do cluster within the basal-like subgroup, these terms are not synonymous there is up to 30% discordance between the two groups. In this review we will use the term basal-like when microarray or more comprehensive immunohistochemical profiling methodology was used, and triple-negative when the salient studies relied on clinical assays for definition.

Tnbc Subtyping And Treatment Regimens

Breast Cancer Definition According To Who

In 2011, Lehmann et al. performed gene expression profiling of tumor samples from 587 TNBC patients and divided TNBC into six subtypes: basal-like 1 , basal-like 2 , mesenchymal , mesenchymal stem-like , immunomodulatory , and luminal androgen receptor . They also performed gene profiling and compared existing TNBC breast cancer cell lines, classifying them into six different subtypes, thus providing an accurate cell model for clinical treatment of TNBC .

Table 1 Genomic TNBC subtypes and assignment of TNBC cell lines to subtypes

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What Is Triple Negative Early Breast Cancer

Triple negative breast cancer is a type of breast cancer that does not have any of the three receptors commonly found on breast cancer cells the oestrogen, progesterone and HER2 receptors. Around 15% of early breast cancers are triple negative.

Triple negative breast cancer generally responds well to chemotherapy. Five years after diagnosis, people with triple negative breast cancer are no more likely to experience a recurrence of their breast cancer than people with other types of breast cancer. In the longer term , a recurrence is less likely with triple negative breast cancer.

Treatment For Triple Negative Breast Cancer

The main treatments for triple negative breast cancer are surgery, chemotherapy and radiotherapy. The treatment you need depends on:

  • where the cancer is
  • the size of the cancer and whether it has spread
  • how abnormal the cells look under the microscope
  • your general health

You might have surgery to remove:

  • an area of the breast
  • the whole breast

When you have your surgery, the surgeon usually takes out some of the lymph nodes under your arm. They test these nodes to see if they contain cancer cells. The surgeon might check the lymph nodes closest to the breast using a procedure called sentinel lymph node biopsy. Testing the lymph nodes helps to find the stage of the cancer and decide on further treatment.

After breast conserving surgery you usually have radiotherapy to the rest of the breast tissue.

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Survival Rates For Triple

Triple-negative breast cancer is considered an aggressive cancer because it grows quickly, is more likely to have spread at the time its found, and is more likely to come back after treatment than other types of breast cancer. The outlook is generally not as good as it is for other types of breast cancer.

Survival rates can give you an idea of what percentage of people with the same type and stage of cancer are still alive a certain amount of time after they were diagnosed. They cant tell you how long you will live, but they may help give you a better understanding of how likely it is that your treatment will be successful.

Keep in mind that survival rates are estimates and are often based on previous outcomes of large numbers of people who had a specific cancer, but they cant predict what will happen in any particular persons case. These statistics can be confusing and may lead you to have more questions. Talk with your doctor about how these numbers may apply to you, as they are familiar with your situation.

Clinical Characteristic And Outcomes Of Basal

Your Healthy Family: What is triple negative breast cancer?

There are several consistent clinical characteristics of this subtype. The basal-like group accounts for â¼15% of all invasive breast cancers. Pathologically, most basal-like breast cancers possess high histologic and nuclear grade, poor tubule formation, high mitotic and proliferative indices, and can have a pushing border. Most are infiltrating ductal, although some unusual histologies such as metaplastic breast cancer share features of basal-like breast cancer . Despite the relatively poor prognosis noted in historical data sets, this subtype presents at generally similar stage to other subtypes , but the highly proliferative nature of this tumor may explain the association with interval cancer .

Multiple data sets have consistently identified a poorer clinical outcome for women with basal-like breast cancer , although modern chemotherapy may alter this history. Among triple-negative tumors, the risk of recurrence is higher in the first 3 to 5 years after diagnosis than in women with estrogen receptorâpositive tumors, with relatively few systemic recurrences after the first 5 years, suggesting that a substantial number of women are cured if they remain recurrence-free for the first several years after a diagnosis .

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The Immune Milieu As A Prognostic And Predictive Factor For Tnbc

Gene expression profiling has allowed significant progress in our ability to assess prognosis and predict response to therapy in breast cancer. First-generation prognostic signatures, which rely markedly on proliferation-related genes, allow reliable stratification of ER-positive breast cancer, however these have a limited utility in TNBC, mainly due to the high proliferative nature of most ER-negative cancers, and, therefore, the lack of discriminatory power of first-generation prognostic signatures in triple-negative disease. Activation of immune response genes was shown, however, to be a good prognostic factor in ER-negative cancers., Second-generation signatures based on immune response-related genes have been developed , although these signatures allow for the stratification of TNBC patients according to overall and relapse-free survival, their clinical utility remains negligible owing to the high number of events in this population, even in patients with favorable signatures.

Symptoms Of Triple Negative Breast Cancer

The symptoms of triple negative breast cancer are similar to other breast cancer types.

Symptoms can include:

  • a new lump or thickening in your breast or armpit
  • a change in size, shape or feel of your breast
  • skin changes in the breast such as puckering, dimpling, a rash or redness of the skin
  • fluid leaking from the nipple in a woman who isnt pregnant or breast feeding
  • changes in the position of nipple

Make an appointment to see your GP if you notice anything different or unusual about the look and feel of your breasts.

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Genetic Heterogeneity Of Tnbc

Given that the unifying feature of TNBCs is the lack of three biomarkers, the genomic heterogeneity of these tumors should not come as a surprise. As a group, TNBCs have been shown to be characterized by high levels of genetic instability, with a median of 1.7 mutations/Mb,, and complex patterns of copy number alterations and structural rearrangements. Unlike other forms of breast cancer, where several genes have been found to be mutated in > 10% of cases, the only known cancer genes targeted by somatic mutations in 10% or more of TNBCs are TP53 and PIK3CA . Importantly, however, TNBCs display a great variation in mutational content. Although some TNBCs harbor a limited number of somatic mutations, others display a high mutational burden affecting genes pertaining to numerous signaling pathways. In a way akin to ER-positive breast cancers, the most frequently mutated genes in TNBCs are TP53 and PIK3CA, which are mutated in 82 and 10% of consecutive TNBCs, respectively. In contrast to ER-positive carcinomas, however, TP53 somatic mutations in TNBCs are enriched for nonsense single-nucleotide variants and indels., Importantly, however, somatic mutations affecting other known cancer driver genes, including PTEN, RB1, NF1, BRCA1, BRCA2, ERBB3, ERBB4, ALK, are found in small subsets of TNBCs .

Figure 2

When Should I Go To The Emergency Room

Dr arun Triple Negative Breast cancer Presentation

You might also have unusually strong side effects from your cancer treatment. While your healthcare provider likely gave you medication to help control your side effects, you should go to the emergency room if your side effects continue despite medication.

Many cancer treatments affect your immune system, increasing the chance you will develop infections. Symptoms that might require an emergency room visit during treatment are:

  • Fever of 100.5 and above.
  • Persistent nausea and vomiting.

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What Does Triple Negative Mean In Terms Of Breast Cancer

Normal breast cells have receptors that respond to hormones such as estrogen and progesterone, which allows them to grow and regress in response to the hormone level. Hormone receptors may or may not be present in breast cancer. About two-thirds of breast cancers are positive and contain these receptors like normal breast cells do. These are less aggressive cancers that are less likely to need chemo and are often treated with hormone therapy and surgery. Radiation may or may not be needed.

HER2/neu , is a protein molecule that has a role in cell proliferation in normal cells. In some breast cancers, this protein is overly produced or positive. For HER2-positive tumors, there a specific medication that targets this protein.

Triple-negative breast cancers are not positive for estrogen receptors, progesterone receptors or HER2 protein. Since these targets are absent in triple-negative breast cancer, chemotherapy is needed, Sun says. Triple-negative breast cancer is often very sensitive to chemotherapy, which, despite the side effects, is an effective treatment that can save lives. Because this is an aggressive cancer, treatment is aggressive also. But there are several ways we can address it.

Detection Of Minimal Residual Disease In Triple

Research by Shane R. Stecklein, M.D., Ph.D., Junior Faculty, Kansas Institute for Precision Medicine COBRE.

Triple-negative breast cancer accounts for 15% of breast cancers and is defined by its lack of expression of estrogen receptor , progesterone receptor , and the human epidermal growth factor receptor 2 . As a disease defined by what it lacks, TNBC is a collection of biologically heterogeneous tumors. Because there is no unifying biology in TNBC, responses to standard-of-care chemoimmunotherapy are highly variable and compared to other subtypes of breast cancer, TNBC has the worst prognosis.

We are using a variety of in vitro, in vivo, human tissue-based, and computational approaches to understand the biological heterogeneity of TNBC, how this heterogeneity shapes the tumor-immune microenvironment, and how we can use biology and molecular biomarkers to personalize treatment for individual TNBC patients.

Extracellular vesicles and circulating tumor cells are two additional biomarkers that have been shown to have prognostic value in TNBC. In this work, we hypothesize that integrated analysis of ctDNA, CTCs, and EVs will improve our ability to detect MRD and allow us to define MRD categories that better correlate with recurrence risk. This will in turn enable better identification of patients who benefit from standard adjuvant therapy or are candidates for adjuvant intensification strategies.

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Research Into Triple Negative Early Breast Cancer

Research has identified a number of different sub-types of triple negative breast cancer, providing opportunities for new treatments that target these sub-types to be developed.

Targeted treatments are currently being investigated using PARP inhibitors for BRCA related cancers, and PI3K/AKT inhibitors and immunotherapy drugs for other sub-types.

Drug Resistance And Response To Therapy As A Pharmacodynamic Biomarker

Risk factors for developing triple-negative breast cancer

Tumor heterogeneity is the major factor that contributes to both intrinsic and acquired resistance, and is a major barrier to curative therapy. Although sensitive populations of tumor cells may be eradicated, there is undoubtedly selective enrichment of residual tumor cells that are often genetically and histologically distinct from sensitive cells . There is also evidence that some cytotoxic agents may promote epithelial-to-mesenchymal transition and/or enrich for tumor, initiating cells that can promote metastasis , although it is likely that these cells existed in the initial population prior to therapy. Other agents are purported to reverse EMT, thereby suppressing metastasis , albeit in cell and mouse tumor model-based contexts.

Resistance to kinase inhibitors is often mediated by feedback loops that are hard-wired to adapt to changes in activity within a signaling network , and such observations have been used to rationalize combinatorial strategies to circumvent these adaptations.

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Risk Factors For Triple Negative Early Breast Cancer

Anyone can get triple negative breast cancer, however there are some things that increase a persons risk.

Having an inherited BRCA mutation

Everyone has BRCA1 and BRCA2 genes. These genes normally prevent cancers from developing. However if there is a fault, called a mutation, in one of these genes, it can increase a persons risk of developing breast cancer and other cancers including ovarian cancer and prostate cancer in men. These gene mutations can be passed down through families.

About 5-10% of all people diagnosed with breast cancer have an inherited BRCA1 or BRCA2 gene mutation.

A BRCA1 mutation is associated with a higher risk for triple negative breast cancer. Not all breast cancers caused by BRCA mutations are triple negative, however, and not all triple negative breast cancers are caused by inherited BRCA mutations.

BRCA2 mutations are more likely to be present in oestrogen receptor positive breast cancer.

If you have a strong family history of breast and/or ovarian cancer , it is possible that you and your relatives could carry a BRCA mutation. For more information on breast cancer and family history, visit thebreast cancer in the family section of this website.

Being premenopausal

Premenopausal women have a higher rate of triple negative breast cancer than postmenopausal women. Scientists do not yet understand why this is the case, however research is currently underway in this area.

Special Histologic Subtypes Of Tnbc

Metaplastic breast carcinoma is a rare entity, comprising less than 1% of all breast carcinomas. It is most often triple negative on immunophenotyping, and genomic profiling places them with the basal-like breast carcinomas. This type of tumor is histologically heterogeneous and can be entirely epithelial in nature or mixed epithelial and mesenchymal. These tumors can be purely metaplastic in composition or can be admixed with other types of invasive carcinoma. Components seen in these tumors that are not typically seen in other breast carcinomas include squamous differentiation, a spindle cell component, and chondroid , osseous, and rhabdomyoid elements. These carcinomas often express EGFR and have a poor prognosis. In patients with lymph node metastasis who underwent adjuvant chemotherapy, the 3-year disease-free survival rate was 44.4% in metaplastic breast carcinomas and 72.5% in triple-negative invasive ductal carcinomas.

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Taking Care Of Yourself

After your treatment is over, your doctor will want to see you often to make sure the cancer doesn’t return. For the first 3 years, you’ll likely see them every 3 to 6 months. For 2 years after that, you’ll probably visit every 6 to 12 months. Once you’ve been cancer-free for 6 years, you’ll probably go back only once a year. Tell the doctor right away if you get any new symptoms or if you have pain or other problems that relate to your breasts.

Tnbcs: The Importance Of Histologic Subtyping

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The large majority of TNBCs are high-grade invasive carcinomas of no special type displaying pushing invasive borders, central necrosis, brisk lymphocytic infiltrates, marked nuclear pleomorphism, and numerous mitoses., Nevertheless, there is a multitude of rare histologic special types of breast cancer that are consistently of TN phenotype .

Some high-grade special histologic types of breast cancer, including carcinomas with apocrine features, carcinomas with medullary features, and metaplastic breast carcinomas almost invariably display a TN phenotype. Notably, among TNBCs, carcinomas with apocrine features are the ones most likely to express androgen receptor and display a molecular apocrine or LAR gene expression profile. Thus, their identification may suggest potential sensitivity to anti-androgen receptor agents and may trigger androgen receptor testing, but does not carry definite prognostic information as their outcome is uncertain and has been reported to be comparable to that of conventional invasive carcinomas of no special type. Likewise, contradictory data have been published regarding the prognostic impact of androgen receptor expression in TNBCs.,

Figure 4

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