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Where Does Triple Negative Breast Cancer Metastasis To

Early Stage Clinical Trials

Stage IV WHAT’S NEXT? TRIPLE NEGATIVE METASTATIC BREAST CANCER

In a proof of concept study published in the Lancet, authors investigated olaparib in patients with advanced metastatic breast cancer with germline BRCA1/BRCA2 mutations. They investigated two doses of olaparib at 400 mg BD and 100 mg BD. Approximately half of patients in this study had TNBC with the remainder having other histological subtypes. Patients were heavily pretreated with a median of 3 prior chemotherapy regimens and platinum sensitivity was not needed for trial enrolment. Overall response rates were impressive in this heavily pre-treated population at 41% in the group receiving the higher dose and 22% in the group receiving the lower dose.

Kaufman et al investigated olaparib further in a large phase 2 basket trial with 298 patients in a single-arm study. Patients with any advanced solid-organ malignancy were included if they harboured a gBRCA mutation. In the breast cohort, patients may have received multiple lines of treatment and there was no requirement for platinum sensitivity. Response rates were modest with only 8 of 62 patients responding in this unselected population.

Breast Cancers Survival Is Influenced By Tumor Grade

Grade identifies the size and shape of the malignant breast cancer cells. At the event the breast cancer cells look very different than normal breast tissue cells, and random in appearance, they can be called, that was badly differentiated and described as âhigh gradeâ. Higher level breast cancer cells tend to really have a poorer prognosis.

Palliative And Supportive Care

Living with advanced TNBC is often difficult, emotionally and physically. Its important to identify and make use of the support that is available, whether it be family, friends, therapists, support groups, financial counselors, social workers or members of the community. Let people know your concerns and what you need from someone, whether it is to watch the kids, provide a ride to your appointment, be another set of ears or a friend who can listen.Its also important to know what services are available to help deal with any physical symptoms that you have. Request a referral to Palliative Care as soon as you get your diagnosis. Palliative Care is there to help with the full range of emotional and physical issues you may encounter throughout the course of your illness.If you are experiencing financial problems, either related to your treatment or to your life, let your health care team know. There are resources that can help with those issues as well.

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A Note About Statistics

Survival rates are statistics, and as such tend to tell us how the “average” person will do with an “average” triple-negative breast cancer; but people and tumors aren’t statistics. Some people will do better and some people will do worse.

Very importantly, statistics are usually several years old. In order to calculate five-year survival rates, a person would have to have been diagnosed at least five years prior. And still there is lag time. The treatment of triple-negative breast cancer is changing, and new drugs have been approved.

Can You Do Anything To Prevent Or Slow The Spread Of Breast Cancer

Frontiers

Like any type of cancer, there are factors that can put you at higher risk. For breast cancer, these include things like smoking, unhealthy diet, lack of exercise and not performing monthly self-breast exams. Its also important to make sure and get your annual mammogram for breast cancer screening.

Other risk factors can include using hormone-based prescriptions, how many children youve had in the past, getting older and at what age you got your period and went through menopause.

In some instances, you cant necessarily prevent breast cancer, but you can sometimes slow it down, stop it from spreading or reduce the size of the tumor, says Dr. Roesch. You can do this by taking your medications as directed, following through with treatments, going to your appointments and being involved in your cancer care.

Youre in control of taking your medication correctly, eating a healthy diet, participating in an exercise program and managing stress. All of these things can contribute to a stronger physical body and better mental attitude both of which can have a positive impact on your breast cancer diagnosis.

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Treating Metastatic Breast Cancer

If you receive a diagnosis of breast cancer thats spread to your colon, your doctor will likely order additional tests to see whether the cancer has spread to other parts of your body.

Once you know exactly whats going on, you and your doctor can discuss the best options for treatment. This may include one or more of the following therapies.

What Is The Prognosis For Triple Negative Breast Cancer

Triple negative breast cancer can be more aggressive and difficult to treat. ;Also, the cancer is more likely to spread and recur. ;The;stage;of breast cancer and the;grade of the tumor;will influence your prognosis. Research is being done currently to create drug therapies that are specific for triple negative breast cancer.

Interested in learning more? i3Health is hosting an upcoming webinar Metastatic Triple-Negative Breast Cancer: Applying Treatment Advances to Personalized Care. Learn more here.

Material on this page courtesy of Johns Hopkins Medicine

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Common Sites Of Metastasis

  • Brain: 7.3%
  • All less common sites: 22.4%

Invasive lobular carcinoma;tends to have a significantly different pattern of metastases than ductal breast cancer. In one 2017 study, almost 70% of people with metastases from lobular carcinoma had peritoneal metastases.

For roughly a third of women ,;cancer spreads to multiple organs at the same time.

Local Or Regional Treatments For Stage Iv Breast Cancer

Case Study: Treating Metastatic Triple-Negative Breast Cancer

Although systemic drugs are the main treatment for stage IV breast cancer, local and regional treatments such as surgery, radiation therapy, or regional chemotherapy are sometimes used as well. These can help treat breast cancer in a specific part of the body, but they are very unlikely to get rid of all of the cancer. These treatments are more likely to be used to help prevent or treat symptoms or complications from the cancer.

Radiation therapy and/or surgery may also be used in certain situations, such as:

  • When the breast tumor is causing an open wound in the breast
  • To treat a small number of metastases in a certain area, such as the brain
  • To help prevent bone fractures
  • When an area of cancer spread is pressing on the spinal cord
  • To treat a blood vessel blockage in the liver
  • To provide relief of pain or other symptoms

In some cases, regional chemo may be useful as well.

If your doctor recommends such local or regional treatments, it is important that you understand their goalwhether it is to try to cure the cancer or to prevent or treat symptoms.

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Immunogenic Potential Of Tnbc

The tumour microenvironment plays an important role in defining the interaction of our immune system with tumours. In TNBC, the TME is characterized by higher levels of vascular endothelial like growth factor , tumour infiltrating lymphocytes and tumour associated macrophages in contrast to other types of breast cancer. Additionally, there is a high level of expression of TILs in patients with TNBC. These have been shown to be a useful prognostic indicator across malignancies. TNBC has been shown to have consistently elevated TILs in contrast to other subtypes and TILs have been shown to be associated with improved survival. Ibrahim et al found that patients with lymphocyte-predominant breast cancer had a 40% pathological complete response rate compared to 7% of those patients without. High TILS are more frequent in TNBC compared to HER2-positive and luminal tumours and are associated with improved disease free survival and OS in early stage breast cancer. This is consistent with findings in other malignancies demonstrating the important role of the immune system in cancer biology and prognostication. All of these features demonstrate that the TME of TNBC is highly immunogenic.

Stages Of Breast Cancer

The stage of breast cancer is based on the size and location of the tumor, as well as whether the cancer has spread beyond the part of the breast in which it originated. To determine the stage of breast cancer, healthcare professionals use a scale of stage 0 to stage 4.

Stage 0 breast cancers are isolated in one part of the breast, such as a duct or lobule, and show no sign of spreading into other tissue.

Stage 1 is typically localized, although further local growth or spread may cause the cancer to move into stage 2.

In stage 3, the cancer may be larger and has affected the lymph system. Stage 4 cancer has spread beyond the breast and nearby lymph nodes, and into other organs and tissues of the body.

In addition to stages, breast cancers are given grades based on the size, shape, and activity of the cells in the tumor. A higher-grade cancer means a greater percentage of cells look and act abnormal, or they no longer resemble normal, healthy cells.

On a scale of 1 to 3, with 3 being the most serious, TNBC is often labeled grade 3.

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Statistics Don’t Account For Late Recurrences

When comparing triple-negative breast cancer to positive tumors, it’s important to keep in mind late recurrences. Most statistics are presented as five-year survival rate, and in this setting, triple-negative breast cancer can look more ominous. But looking at longer periods of time, say 20 years following diagnosis, this may be different.

Do I Need Genetic Counseling And Testing

Stromal cells affect immune infiltrate in triple

Your doctor may recommend that you see a genetic counselor. Thats someone who talks to you about any history of cancer in your family to find out if you have a higher risk for getting breast cancer. For example, people of Ashkenazi Jewish heritage have a higher risk of inherited genetic changes that may cause breast cancers, including triple-negative breast cancer. The counselor may recommend that you get a genetic test.

If you have a higher risk of getting breast cancer, your doctor may talk about ways to manage your risk. You may also have a higher risk of getting other cancers such as ovarian cancer, and your family may have a higher risk. Thats something you would talk with the genetic counselor about.

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Advanced Cancer That Progresses During Treatment

Treatment for advanced breast cancer can often shrink the cancer or slow its growth , but after a time, it tends to stop working. Further treatment options at this point depend on several factors, including previous treatments, where the cancer is located, and a woman’s age, general health, and desire to continue getting treatment.

Risk Factors And Epidemiologic Features

In addition to a distinct molecular and pathologic profile, the epidemiology and risk factors associated with triple-negative breast cancer are distinct, especially when compared with endocrine-sensitive luminal breast tumors. The Carolina Breast Cancer Study, a population-based, case-control study aimed at determining clinical associations and distributions across distinct breast cancer subtypes, has refined our understanding of the epidemiologic and risk factors associated with triple-negative breast cancer. In the initial study of women diagnosed with invasive breast cancer, the prevalence of breast cancer subtypes within racial and menopausal subsets were determined. Immunohistochemical staining was used to classify specific subtypes in approximately 500 tumors, and basal-like tumors were defined as triple negative and cytokeratin 5/6 positive and/or HER1 positive. Results indicated that those with basal-like tumors were more likely to be African American compared with nonAfrican American and premenopausal compared with postmenopausal . There was a particularly high prevalence of basal-like tumors among premenopausal African American women compared with postmenopausal African American women and nonAfrican American women of any age . The observation that triple-negative breast cancers more commonly arise in younger African American women has been confirmed in several additional studies, although the exact cause for this association is not yet fully understood.,

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The Tumor Microenvironment: Creating A Pre

TNBC exhibits numerous CSC-like traits and is more likely to lead to BM. The short time to BM occurrence in TNBC and the short survival time after BM diagnosis may be indicative of an innate ability of TNBC cells to adapt to the brain microenvironment.67 The vascular basement membrane presents the soil in BM. Although more than 95% of early brain micrometastases were shown to coexist with blood vessels, there is little evidence for isolated neurogenic growth.68 When TNBC cells invade the brain parenchyma, an adequate blood supply is needed to provide the nutrients necessary for tumor growth and proliferation. Tumor angiogenesis depends on the balance between pro- and anti-angiogenic factors at the local tissue level and is regulated by the local microenvironment.69

Phase Iii Keynote 355 Trial

Metastatic Triple-Negative Breast Cancer

The much anticipated KEYNOTE-355 trial was presented at the inaugural virtual ASCO annual meeting in June 2020. This trial investigated pembrolizumab/chemo vs chemo in patients with treatment-naïve, metastatic TNBC. Patients were excluded if they had active brain metastases or recurrence of disease < 6 mo prior to primary treatment. PD-L1 was assessed with the IHC 22C3 pharmDx CPS assay in a central laboratory. The primary outcome measure was pre-defined as OS and PFS in the PD-L1 positive population and the ITT population. In this trial, a hierarchial statistical testing method involved statistical testing of OS and PFS in the CPS > 10 group initially, followed by CPS > 1 and then the ITT population. The trial included 566 patients in the chemotherapy/IO arm vs 281 in the chemotherapy arm. In patients with a CPS score of 10 or greater, the median PFS favoured pembrolizumab with a PFS of 9.6 mo vs 5.6 mo . In patients with a CPS score of 1 or greater, the median PFS favoured the pembrolizumab arm with a PFS of 7.6 mo vs 5.6 mo . This was not statistically significant. This was similar to the ITT population where the PFS was 7.5 mo in the pembrolizumab arm and 5.6 mo in the placebo arm . OS data is awaited. This progression free survival improvement led to accelerated FDA approval for pembrolizumab in combination with chemotherapy in the first-line setting in November of 2020.

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Nitrofen Reduces In Vitro Invasive Activity Of Breast Cancer Cells

Using an in vitro Matrigel invasion assay, we observed that TNBC cell lines showed higher invasive potential than non-TNBC cell lines . Further, nitrofen treatment reduced invasive potential of TNBC lines to a greater extent than non-TNBC lines . We further determined the effect of nitrofen on the invasive potential of the luciferase expressing MDA-MB-231 cell line . Accordingly, we used MDA-MB-231-luc-D3H2LN cells to carry out in vitro cell invasion assays in the presence and absence of 1 and 10;M nitrofen. We observed significant reduction in invasive potential of MDA-MB-231-Luc cells in the presence of 1 and 10;M nitrofen relative to untreated control . AlamarBlue assay done under the same conditions shows that there is no change in relative viability of cells upon any treatments .

Figure 1

Quantification of Matrigel invasion assay demonstrating that nitrofen significantly reduces the invasive potential of MDA-MB-231-Luc cells. Invasion assay was carried out using 40,000 cells/well, incubated for 24;h. Nitrofen was dissolved in Ethanol to prepare the stock concentration of 100;mM and diluted in DMSO to a final concentration of 1 uM and 10 uM. AlamarBlue cell viability assay done under the same conditions shows that there is no change in relative viability of cells upon treatments. Data representative of 6 separate experiments each done in triplicate. **significantly altered from untreated control p<0.01.

Risk Factors For Triple

Doctors aren’t sure what makes you more likely to get triple-negative breast cancer. Not many women do — it only affects up to 20% of those who have breast cancer. You’re most at risk for triple-negative breast cancer if you:

  • Are African-American or Latina
  • Are under 40
  • Have what your doctor will call a BRCA mutation , especially the gene BRCA1

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Questionable Issues In Tnbcs

TNBCs are known to metastasize via hematogenous routes and this may be in contradiction with the study of Liu previously mentioned, a study which clearly stated that TNBCs have an active lymphangiogenic process which, normally may favour lymphovascular but not hematogenous dissemination. Currently, the molecular features that differentiate or are able to differentiate lymph node positive TNBCs from lymph node negative TNBCs still remain at a hypothetical level and none of them proved to be useful in the clinical and therapeutic approach of TNBCs patients. But most of the TNBCs cancers have preferentially hematogenous metastases. Besides the high mitotic rate and increased nuclear grade, TNBCs also include pushing border of invasion, frequent tumor necrosis and a large central acellular zone . TNBCs usually exhibit a solid/sheet-like growth pattern and may be associated with an increased lymphocytes infiltrate . Despite the fact that these tumors do not usually metastasize through the lymphatic pathways, TNBCs may be characterized by lymphatic invasion and by an increased LVD . However, not all TNBCs are associated with a poor long term survival, although in a low percentage . EGFR, Src kinase pathway and Cdc42-interacting protein 4 are known to promote TNBCs metastasis . CIP4 inhibition seems to decrease the rate of lung metastasis .

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