Targeted Therapy In Tnbcs
Different potential therapeutic options in TNBCs are summarized in Figure 1. Unlike the luminal types and the HER2 overexpressing type of breast carcinomas, TNBC lacks a specific targeted therapy. However, considering TNBCs heterogeneity, it is possible that BRCA1/2 mutations, along with AR may represent potential molecular targets in TNBCs treatment . Also, Pim-2, a serin/threonine kinase strongly involved in breast cancer metastasis, may become a therapeutic target in TNBCs . HJ-PI01, a Pim-2 inhibitor, seems to induce autophagic cell death and apoptosis thus decreasing malignant proliferation in TNBC cell lines . Shindikar et al. highlighted the anticancer properties of curcumin and resveratrol in TNBCs treatment, however, difficulties regarding their in vivo availability, distribution and kinetics along with a poor solubility, limits their routine use in patients . Chemotherapeutic agents such as nab-paclitaxel seems to be beneficial in the treatment of aggressive forms of breast cancer, such as TNBCs and HER2+, as well as in elderly and taxane-pretreated women .
Figure1: Different potential therapeutic options in TNBCs related to the most neglected but important therapeutic targets.
Who Is Most Likely To Have Tnbc
Triple negative breast cancer appears more frequently in women age 40 and younger than in older women. Black and Latina women are more likely to develop TNBC than white women. Women who have the gene change BRCA1 are more likely to develop TNBC than other women. When the BRCA1 gene mutates, it stops preventing cancer and appears to make your bodys cells more vulnerable to cancer.
In Vivo Synthetic Lethality Screen
We utilized a barcoded FDAome shRNA library correspond to targets linked to drugs approved by the Food and Drug Administration to determine potential IACS-10759 synthetic lethal partners. Breast cancer cell line BCX.010-CL was derived from BCX.010 as previously described . BCX.010-CL cells were infected with our FDAome shRNA library, reinjected into mice and treated with either vehicle or IACS-10759. After ten days, xenografts were harvested and DNA was extracted. Deep sequencing was performed to determine shRNA abundance on the basis of shRNA performance supervised analysis. Cumulative Wilcoxon test was done to score statistical gene level significance.
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Pharmacodynamic Markers Of Response To Oxphos Inhibition As Determined By Rna Analysis
We next compared the gene expression profiles of seven PDXs, three less sensitive models and four more sensitive models, treated with IACS-10759 for 12 days by RNASeq. Based on global mRNA expression profiles, sensitive models clustered separately from the less sensitive models . In addition, treated and untreated models clustered as separate groups for each sensitive model. We performed Gene Set Enrichment Analysis with this data using the Reactome and Hallmark databases. We found several profiles downregulated by IACS-10759 treatment, including a lipid metabolism profile and hypoxia profile .
We assessed the role that proliferation plays in response to OXPHOS inhibition by calculating a proliferation index for each model using RNASeq data . We found that the proliferation index was significantly decreased upon IACS-10759 treatment in more sensitive models but not in the resistant models . We next removed the genes comprising the proliferation index and performed cluster analysis. Even without these proliferation specific genes, the more sensitive models and less sensitive models clustered separately .
Triple Negative Breast Cancer Symptoms
Triple negative breast cancer symptoms can vary significantly from patient to patient. As with all types of breast cancer, the most common sign is a lump or thickening in the breast tissue, but sometimes there are no symptoms at all.
While triple negative breast cancer does not look any different from other forms of breast cancer, it has some important distinctions. First, triple negative breast cancer tests negatively for estrogen, progesterone and HER-2/neu hormone receptors. Therefore, hormone therapy, which is often used to treat breast cancer, is rendered ineffective. Second, triple negative breast cancer tumors have cells that tend to resemble the basal, or outer, cells that surround the breast ducts. Finally, triple negative cancers are usually more aggressive than other forms of cancer and have a greater tendency to spread and recur following treatment.
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Pathological And Molecular Characterization Of Triple Negative Breast Cancer
As a distinct molecular entity, TNBCs appear to be quite heterogeneous at a histopathological level. They frequently show features of ductal invasive carcinomas although metaplastic, medullary and apocrine features are also found . Moreover, TNBCs may present themselves as adenoid cystic lesions, histiocytoid carcinomas and even as invasive lobular carcinomas . A relatively large number of breast cancers that do not exhibit a basal phenotype appeared to have a triple-negative profile . Therefore, from a morphological and molecular point of view, TNBC may somehow be classified into four main categories that include the normal-like and the apocrine subtypes . It appears that some histopathological features of breast cancer such as pleomorphic lobular carcinoma and mixed ductal-lobular carcinoma exhibit a triple-negative molecular profile . Also, most invasive carcinomas that develop from microglandular adenosis areas are in fact triple-negative tumors . Recent studies have shown that metaplastic carcinomas are usually TNBCs . Metaplastic carcinomas are known to be rare, aggressive diseases of the breast that are usually diagnosed at grade 3 and, similar to TNBCs, have no specific therapeutic guidelines .
Patient Cohort For Rnaseq
We performed RNA sequencing on pre-treatment biopsies from 43 patients with operable TNBC who received sequential taxane and anthracycline-based neoadjuvant chemotherapy. All patients gave informed consent for treatment on an open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with TNBC . The study did not show a difference in pCR rate between the arms so pretreatment biopsies from both arms were analyzed together for analysis of transcriptomic features associated with relapse and overall survival.
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How Is Triple Negative Breast Cancer Different From Other Types Of Breast Cancer
Triple negative breast cancer is different from other types of breast cancer because it does not have any of the three receptors commonly found on breast cancer cells:
If you have triple negative breast cancer, you may notice that your treatment is slightly different from that offered to other people with breast cancer.
People with oestrogen and/or progesterone receptor positive breast cancer will usually take tamoxifen or an aromatase inhibitor as part of their treatment. People with HER2 positive breast cancer will usually take a drug called Herceptin. These drugs are not effective against triple negative breast cancer.
Finding The Positive In Triple
volume 2, pages 476478
The treatment of triple-negative breast cancer remains chemotherapy based and lacks targeted drugs. However, immunotherapy combinations have shown promising activity, targeted chemotherapy options via antibodydrug conjugates are in the clinic, and molecular means of identifying targetable subsets are on the horizon. This Clinical Outlook discusses current and future possibilities for treating triple-negative breast cancer.
Triple-negative breast cancer is defined by what it is not. It represents the subset of breast cancers with none of the clinically identified tumor targets: hormone receptors for estrogen and progesterone, or human epidermal growth factor receptor 2 . For this reason, advances in precision oncology have lagged for TNBC, and it remains the subtype of breast cancer with the shortest survival.
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How Is Triple Negative Breast Cancer Treated
- Surgery. You may have part of your breast removed or the whole breast . Your surgeon will probably also remove lymph nodes from your armpit area to see if the cancer has spread there. This is called a sentinel lymph node biopsy. Its usually done at the same time as the surgery to remove the tumour.
- Chemotherapy. You might have chemotherapy before surgery to shrink the cancer and make it easier to remove. Chemotherapy after surgery can reduce the risk of the cancer coming back.
- Radiotherapy. Radiotherapy after surgery can help to reduce the risk of the cancer coming back.
How Do Doctors Diagnose Triple
Breast cancer diagnosis often starts when a person or their doctor notices a lump in the breast, or when a screening test for breast cancer detects unusual breast tissue. After finding a mass, the doctor will perform additional imaging tests, as well as a biopsy.
Several types of imaging tests can capture pictures of the inside of the breast, helping the doctor see whether there are any problems. Imaging tests may include a mammogram, ultrasound, or MRI. An MRI can also help doctors plan for surgery or determine whether cancer cells have spread to other parts of the body.
The only test that can officially diagnose breast cancer is a biopsy. During this test, the doctor uses a needle to remove a small sample of tissue. The tissue is sent to a laboratory, where a pathologist runs tests to determine whether the cells in the sample are cancerous. Laboratory tests can also identify the cancers type, molecular subtype, and grade . Doctors use this information to estimate a persons outlook and know which treatments are likely to work best.
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What Is The Staging Of Triple
Staging is the process of determining the extent of the cancer and its spread in the body. Together with the type of cancer, staging helps determine the appropriate therapy and predict the chances for survival.
To determine if the cancer has spread, medical professionals may use several different imaging techniques, including X-ray, CT scans, bone scans, and PET scans. Staging depends upon the size of a tumor and the extent to which it spread to lymph nodes or distant sites and organs in the body. Examination of lymph nodes removed at surgery and the results of ER, PR, and HER2 tests performed on the tumor tissue also help determine the stage of a tumor. Stage I is the lowest stage, while stage IV is the highest stage and refers to tumors that have metastasized, or spread to areas distant from the breast.
Most doctors specifically adjust breast cancer treatments to the type of cancer and the staging group.
Many women with breast cancer will require surgery. Broadly, the surgical therapies for breast cancer consist of breast-conserving surgery and mastectomy .
Types of chemotherapy include the following:
Other therapies for triple-negative breast cancer
Causes Of Triple Negative Breast Cancer
The risk factors for triple negative breast cancer are not clear. Some breast cancers depend on hormones to grow. These can be linked with risk factors to do with hormones and having children. But triple negative breast cancer does not seem to share these risk factors.
Most women with triple negative breast cancer have no strong history of breast cancer in their family . But some women with triple negative breast cancer have an altered BRCA1 gene. This will have been inherited from a parent.
An altered BRCA 1 gene can cause breast cancer to run in families. Most breast cancers caused by BRCA1 are triple negative.
If you have triple negative breast cancer, you may be offered genetic testing. This is even if you do not have a family history of breast cancer. Your cancer doctor or breast care nurse can explain more about this to you.
The tests are the same as for any type of breast cancer. You usually have a:
A mammogram is an x-ray of the breast.
- Ultrasound scan
An ultrasound scan uses sound waves to produce a picture of the breast tissue and the lymph nodes in the armpit.
- Breast biopsy
When you have a breast biopsy, your cancer doctor or breast care nurse takes small samples of cells or tissue from your breast. The samples are looked at under a microscope to check for cancer cells. They also do other tests to find out if the cells have receptors for hormones, or for HER2.
The staging and grading is the same as for other types of breast cancer.
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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.
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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What Causes Triple Negative Breast Cancer
While we know many of the factors that affect your chance of developing breast cancer overall, we still dont fully understand why some women develop triple negative rather than other types of breast cancer.
We do know that if you develop breast cancer at a young age, its more likely to be triple negative. Black women are also more likely to develop it.
If you carry a fault in the BRCA1 gene, youre also more likely to develop triple negative breast cancer in fact, most breast cancers caused by BRCA1 faults are triple negative. Because of this, if you dont have a known history of breast cancer in your family but youre diagnosed with triple negative breast cancer under the age of 50, youll be eligible for specialist genetic services to look for BRCA faults. You can read more about BRCA faults in our family history guide.
Identifying Rational Combinations With Iacs
Building on the finding that AXL is highly expressed in PDXs that are less reliant on OXPHOS, we hypothesized that targeting AXL may enhance sensitivity to IACS-10759. We thus tested IACS-10759 in combination with cabozantinib, a multi-kinase inhibitor that targets AXL and is approved by the FDA for the treatment of renal cell carcinoma, medullary thyroid cancer and hepatocellular carcinoma. We tested the combination in two less sensitive models with high expression of AXL and one more sensitive model . In both less OXPHOS dependent PDXs, we found that the combination of cabozantinib and IACS-10759 significantly prolonged tumor inhibition compared to either single agent .4B). We also observed tumor regression in the more OXPHOS sensitive model compared to stable disease with single agent treatment . We assessed signaling in the BCX.010 treated samples by RPPA and found that S6 phosphorylation was inhibited significantly more in the combination group .
Targeting AXL1 expressing TNBC with combination of cabozantinib and IACS-10759.
We also tested IACS-10759 plus an AXL specific inhibitor in AXL high BCX.010. BGB-324 added no benefit over IACS-10759 alone . We also assessed effect of AXL knocked down by shRNA. AXL played an important growth regulatory role, as demonstrated by the significant growth inhibition seen by AXL shRNA in BCX.010 . However, IACS-10759 did not further enhance growth inhibitory effect.
Where Do These Numbers Come From
The American Cancer Society relies on information from the SEER* database, maintained by the National Cancer Institute , to provide survival statistics for different types of cancer.
The SEER database tracks 5-year relative survival rates for breast cancer in the United States, based on how far the cancer has spread. The SEER database, however, does not group cancers by AJCC TNM stages . Instead, it groups cancers into localized, regional, and distant stages:
- Localized: There is no sign that the cancer has spread outside of the breast.
- Regional: The cancer has spread outside the breast to nearby structures or lymph nodes.
- Distant: The cancer has spread to distant parts of the body such as the lungs, liver or bones.
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.
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