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Metastatic Triple Negative Breast Cancer Treatment

Treatment Of Early Tnbc

Precision Medicine in Metastatic Triple Negative Breast Cancer

Early TNBC is aggressive, but it can be treated effectively. Its usually treated with some combination of surgery, radiation therapy, chemotherapy and immunotherapy.

TNBC isnt treated with hormone therapy or HER2-targeted therapy because its ER-negative and HER2-negative.

Learn about emerging areas in drug therapies for early breast cancer.

Combination Therapy With Ici And Chemotherapy

Given the low clinical response of ICI monotherapy or combination therapy in most patients with breast cancer, subsequent studies evaluated the combination of ICI with chemotherapy. Preclinical data have demonstrated that chemotherapy can induce tumor antigen release and potentially increase TILs which may stimulate a greater antitumor immune effect,22,23 increasing the enthusiasm for this combination treatment strategy.

Phase I and II studies of ICI and chemotherapy combinations

Phase III studies of ICI and chemotherapy combinations

Atezolizumab

However, another phase III study, IMpassion131 , also assessed the efficacy of atezolizumab in patients with mTNBC, randomizing 651 patients 2:1 to receive atezolizumab or placebo combined with weekly paclitaxel as first-line therapy.32 At the primary PFS analysis, the addition of atezolizumab to paclitaxel did not improve PFS or OS in either the ITT or PD-L1-positive population . Of note, the OS in the PD-L1-positive control population receiving paclitaxel alone was longer than any other first-line study of patients with mTNBC. Given the inability to confirm the OS benefit from atezolizumab demonstrated in IMpassion130, Roche withdrew the indication for atezolizumab with nab-paclitaxel as treatment for patients with mTNBC whose tumors express PD-L1 in consultation with the US FDA in August 2021, although the combination is still approved in many countries.

Pembrolizumab
Checkpoint inhibitors in the early-stage setting

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.

Ici And Targeted Therapy Combinations

Individual xenografts for personalized treatment of women with ...

Given that most patients with mTNBC do not appear to benefit from the addition of ICIs to chemotherapy, there is great interest in improving both PD-L1 expression and TILs with targeted therapy combinations. In the targeted section below, we will discuss combination approaches completed and ongoing studies of targeted therapies and ICI are included in Table 1 and Table 2 respectively.

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Clinical Features Of Metastatic Tnbc

Only 5% of patients with TNBC present with de novo metastatic disease. The majority of patients unfortunately relapse following treatment with curative intent. The biological features of TNBC result in a unique clinical phenotype. It is characterized by a propensity for visceral and brain metastases, absence of bone metastases and typically early relapse .

Data from a Canadian breast cancer cohort with 180 TNBC patients showed that these patients were much more likely to develop distant recurrence or death compared to other breast cancer subtypes. The risk of distant recurrence peaked at three years and declined rapidly thereafter. A large cohort study from MD Anderson Cancer Centre identified similar patterns of distant recurrence and death.

TNBC is most commonly associated with visceral metastases including lung, liver and brain. Jin et al identified 433 women with metastatic TNBC and found that 29% of them had 1 or greater brain metastases. Median survival from time of diagnosis of brain metastases in this study was just 7.3 mo highlighting the significant mortality associated with intracranial disease.

Data Analysis And Meta

Clinical outcomes, including ORR and OS, were qualitatively represented by monotherapy as 1L and 2L+ therapy, as shown in Figs. and . Meta-analyses were performed to synthesize the pooled ORRs for single-agent chemotherapy among studies of 2L+ treatment. Inverse-variance fixed-effects and random-effects meta-analyses were explored. A DerSimonian and Laird random-effects model was used to account for between-trial heterogeneity this model assumes that the true treatment effects of the included studies follow a distribution around an overall mean . The sample size, ORR, 95% confidence interval for each treatment and study, and pooled ORR are presented as forest plots, per PRISMA guidelines . The ORRs were re-estimated using the all-patients-as-treated population to ensure common definition across studies. The ORR proportions were transformed to a logit scale to calculate 95% CIs and then transformed back to proportions.

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Parp Inhibitors For Brca

The DNA damage response process involves sensing and responding to DNA damage, mediating DNA repair, cell cycle regulation, replication stress response, and apoptosis.10 The deficiency of DNA damage response harbors genomic instability in cells, but it also provides therapeutic targets, particularly to DNA-damage agents. Carriers of deleterious heterozygous germline mutations in the BRCA1 and BRCA2 genes demonstrate the deficiency of homologous recombination repair, a conservative process of repairing double strand DNA breaks. PARP inhibitors induce apoptosis in BRCA-deficient tumor cells by mediating stalled replication forks and double-strand DNA breaks.11 For patients with germline BRCA1/2 mutations, PARP inhibitors, including olaparib and talazoparib , are FDA approved as targeted therapies.

Intratumoral Agents And Other Emerging Immunotherapy Strategies

Case Study: Treating Metastatic Triple-Negative Breast Cancer

There is also interest in studying the safety and efficacy of intratumoral therapies, which can increase local drug concentration, directly cause malignant cell apoptosis, and also have an immunotherapy effect through activation of local and systemic immune responses.54 For example, talimogene laherparepvec is a modified herpes simplex virus that has been studied in the treatment of cancer.5557 In early-stage breast cancer, there are data that the combination of T-VEC and neoadjuvant chemotherapy is safe and feasible.58 There are ongoing studies evaluating the combination of T-VEC and chemotherapy or endocrine therapy for patients with unresectable, recurrent, or metastatic HER2-negative disease . Besides oncolytic viruses, there has also been interest in directly injecting immune modulating agents into the TME either alone or in combination with systemic immunotherapy. For example, tavokinogene telseplasmid is a plasmid encoding interleukin -12, which is a pivotal regulator of innate and adaptive immunity.59 There is currently a phase II trial evaluating the safety and efficacy of intratumoral tavo in combination with systemic pembrolizumab in patients with inoperable locally advanced or mTNBC . Preliminary results from 11 of the planned 25 patients were presented at the San Antonio Breast Cancer Symposium in 2018 and 3 of the 11 patients had a partial response .60

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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.

Are We Close To A Cure

Every cancer is different, so finding a one-size-fits-all cure is unlikely anytime soon.

Research is targeting various methods, including gene editing, that have potential benefit for future treatments. Research is ongoing and new therapies are continually tested.

While living with metastatic breast cancer, there are ways to help improve your physical, emotional, and financial well-being.

In 2018, the released guidelines for improving the quality of life for people undergoing treatment.

The guidelines suggest the following steps:

  • Talk with your healthcare professional about managing pain and side effects from your treatment, such as nausea or fatigue, as well as other potential issues, like sexual health and fertility.
  • If youre experiencing depression or anxiety, check to see if a therapist or counselor is available at your cancer center, or join a breast cancer support group. Your healthcare team may have recommendations.
  • For help covering the cost of your treatment, talk with a financial counselor about assistance programs.

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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.

Systemic Treatments For Stage Iv Breast Cancer

#VisualAbstract: Sacituzumab govitecan increased survival in metastatic ...

Treatment often continues until the cancer starts growing again or until side effects become unacceptable. If this happens, other drugs might be tried. The types of drugs used for stage IV breast cancer depend on the hormone receptor status, the HER2 status of the cancer, and sometimes gene mutations that might be found.

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Genomic Features Of Tnbc

Triple negative breast cancer is characterised by the absence of expression of ER/PR/HER2. Almost 20 years ago breast cancer was classified using gene expression profiling into four main subtypes Luminal A , Luminal B , HER2-overexpressing and basal-like. Although basal-like broadly corresponds to TNBC, the terms are not synomonous. In one study, 70% of TNBC belonged to the basal subtype and 76% of basal-type tumours would be classified as TNBC. A small proportion of basal-like tumours express ER or express HER2.

Importantly, basal-like tumours express cytokeratins such as CK5/6, cadherin as well as epidermal like growth factor . Contrary to previous doctrine, it appears that basal-like tumours do not arise from normal breast tissue but instead arise from luminal progenitor cells.

Phase Iii Impassion 131

The IMpassion-131 study investigated if nab-paclitaxel could be replaced with paclitaxel in combination with atezolizumab in the first-line setting of advanced TNBC. Inclusion criteria were identical to the IMpassion130 trial, but the primary endpoint pertained to investigator-assessed PFS/OS tested first in the PD-L1 positive population. Patients were randomised in a 2:1 ratio to atezolizumab/paclitaxel vs placebo/paclitaxel . In the PD-L1 positive population, there was no significant improvement in the atezolizumab arm with a PFS of 6 mo compared to 5.7 in the placebo arm . There were also no significant differences in PFS in the overall population . In an interim OS analysis, there was no significant differences in OS in the PD-L1 population or the ITT population . The trend towards an improvement in OS was somewhat of a concern for investigators and the medical oncology community. Further analysis demonstrated that patients in both arm had an equivalent exposure to paclitaxel. The reasons for this trend however remain unclear. Speculation includes the potential immune mitigating effects of dexamethasone usage for paclitaxel treatment. This trial resulted in an FDA alert warning against the use of paclitaxel in combination with atezolizumab in TNBC. No new safety signals emerged.

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Will Ever Be A Cure For Triple

Triple-negative breast cancer is curable when a doctor diagnoses it during the first three stages , said Dr. Jacoub. He treats stages 13 with everything he can in order to remove and destroy the cancer.

However, the ability to cure triple-negative breast cancer is hindered by recurrence or metastasis past the lymph nodes. Triple-negative breast cancer is the most likely form of breast cancer to return.

The outlook for people with localized triple-negative breast cancer over a 5-year period is good. Around 91% of people will survive to the 5-year mark.

If the cancer spreads to local tissue or lymph nodes, however, the 5-year survival rate drops to 65%. If it spreads to other organs or tissue, the rate falls to 12%.

These figures are based on data for people who received treatment in the past. Newer methods have changed the outlook, which will continue to shift as different treatments become available.

Anecdotally, Dr. Nan has a segment of patients who have responded to immunotherapy treatment for longer than 5 years.

Maybe if follows these long enough, some may still be alive after more than 10 or 15 years, then we can say cured, he said. With developed or newer types of immunotherapy, may be able to cure stage 4 cancer in the future.

Dr. Jacoub agreed that the outlook is changing with newer treatments. He also noted that although some people have a reduced quality of life while undergoing treatment, others can maintain a good quality of life.

Other Adcs Under Investigation

Treatment Options in Metastatic TNBC

There are also other ADCs that are under evaluation in early phase clinical trials that have exciting potential. For example, SAR566658 is a humanized DS6 antibody that is directed against the tumor-associated protein sailoglycotope CA6 and linked to DM4 . A phase 1 study enrolled 114 patients, including patients with breast cancer with CA6 expression, and demonstrated a reasonable toxicity profile.105 A subsequent study evaluated the safety and efficacy of SAR566658 in patients with CA6-positive mTNBC , but results have not yet been reported. Other promising ADCs under investigation include patritumab deruxtecan , AVID100 , and CAB-ROR2 . Future studies are needed to determine the safety and efficacy of these agents in patients with breast cancer.

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Targeting Homologous Recombination Deficiency In Tnbc

PARPi offer a biologically appealing treatment for patients with intrinsic HRD. HRD renders cells vulnerable to neoplastic transformation. However, this vulnerability to neoplastic changes also renders tumour cells vulnerable to genotoxic cell death via PARP inhibition as cells are reliant on base excision repair by PARP so it represents an Achilles Heel. By inhibiting two pathways of DNA repair, the tumour cells have impaired DNA replication. The combination of PARP inhibition and BRCA1/BRCA2 mutations is termed synthetic lethality.

Current Treatment Landscape And Emerging Therapies For Metastatic Triple

Supplements and Featured Publications

Abstract

Am J Manag Care. 2021 27:S87-S96.

Introduction

Worldwide, breast cancer is the most frequently diagnosed cancer in women. In the United States, it accounts for 30% of all cancers in women and is the second leading cause of cancer-related mortality, surpassed only by lung cancer. In 2021, an estimated 284,200 new cases of breast cancer and 44,130 deaths related to breast cancer will have occurred, representing 15% of all new cancer cases and 7.3% of all cancer deaths.1,2

TNBC

Epidemiology and Prevalence

TNBCs account for approximately 15% to 20% of all newly diagnosed breast cancers. Incidence rates in non-Hispanic Black women are almost double the rates compared with other racial/ethnic groups, which may account for the fact that they experience 40% higher breast cancer-associated death rates.6,7

Prognosis and Pathogenesis

Metastatic TNBC

Current Standard of Care

Second Line and Beyond

The Evolving Immunotherapy Landscape

Immunotherapy in Combination With Chemotherapy

A New Standard of Care: Atezolizumab plus nab-Paclitaxel

The combination of atezolizumab and nab-paclitaxel is included in the NCCN guidelines as a category 1 preferred treatment option for the initial treatment of mTNBC in patients with PD-L1positive disease, as determined by an FDA-approved companion diagnostic.25

Atezolizumab plus Paclitaxel

Pembrolizumab plus Chemotherapy

Nivolumab plus Chemotherapy

PD-L1 Expression

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