Which People With Breast Cancer Will Be Most Likely To Benefit From Immunotherapy
Researchers are starting to get some clues from clinical trials about who immunotherapy is most likely to help. For example, people with triple-negative breast cancer may get more benefit from immunotherapy than people with other subtypes of breast cancer. Immunotherapy may be more likely to work in people whose breast cancer has more gene mutations or whose tumor cells have higher levels of a protein called PD-L1. In addition, there is some information that suggests immunotherapy may work better if it is given early during treatment.
In late 2018, results from a breast cancer immunotherapy clinical trial were published in the New England Journal of Medicine. The study examined adding atezolizumab to a standard chemotherapy drug called protein-bound paclitaxel in people with metastatic, triple-negative breast cancer who had not previously received treatment for their cancer. Researchers found that adding immunotherapy to the chemotherapy drug may be beneficial for a subset of people, although it increases harmful side effects, also called toxicity. In addition, the findings support the clues found in other clinical trials about who may most benefit from immunotherapy. This treatment combination was approved by the U.S. Food and Drug Administration in March 2019. More research is needed to determine which cancers are most likely to respond to the combination.
Qol And Symptom Monitoring
Currently, the majority of experience with immunotherapy for breast cancer has been in the advanced/metastatic setting. Patients with metastatic breast cancer can experience an accumulation of physical symptoms and psychosocial stressors that adversely affect their QOL throughout their continued treatment. Over time, these effects usually become worse as treatment is ongoing. A robust corpus of literature has described key QOL outcomes for patients receiving chemotherapy, radiotherapy, endocrine therapy, or HER2-directed therapies. In addition, throughout a patientâs journey, multiple intrinsic and extrinsic factors may influence QOL, including AEs associated with therapy as well as other characteristics of the individual being treated . However, data are currently lacking on the QOL implications for the addition of ICIs to chemotherapy or other conventional treatments.
Ongoing trials are also evaluating ICIs in early-stage disease. Patients with early-stage breast cancer also experience both physical symptoms and psychosocial stressors that can adversely affect their QOL. Although survivors of early-stage breast cancer generally report high functioning after the conclusion of treatment, important rehabilitation problems may persist beyond 1 year after primary treatment, including difficulties with physical and recreational activities, body image, sexual interest, sexual function, and dating for those who were single.
Adoptive T Cell Therapy
Adoptive T cell therapy, also referred to as passive immunization, involves the isolation and ex vivo expansion of tumor specific T cells . T cell priming with cancer vaccines prior to isolating the T cells from the patients blood has shown great success in expanding the T cell population . Adoptive T cell therapy using tumor-infiltrating lymphocytes , cytotoxic T lymphocytes , Th cells, Tregs and genetically engineered T cells have shown promising results in melanoma . These studies have now been expanded to other cancer types including breast cancer.
As isolation of tumor specific T cells is difficult, genetically engineered or redirected T cells have been of interest in recent times as a form of adoptive T cell therapy. Genes that encode T cell receptors are used to generate tumor specific T cells. This is done using either the alpha or beta chain of the T cell receptor or using chimeric antigen receptors . CARs are composed of an extracellular domain derived from tumor-specific antibody, linked to an intracellular signaling domain. Plasmid transfection, and mRNA or viral vector transduction are used to introduce these genes into T cells to generate tumor specific T cells. These genetically modified and activated T cells are then reintroduced into the patients blood to target specific tumor proteins.
A list of ongoing CAR T cell clinical trials in breast cancer can be found in Table 2.
Table 2
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What Are The Goals Of Immunotherapy
Typically, immunotherapy is recommended for patients with advanced cancer. While in rare instances, like in President Carter’s case, immunotherapy helps patients move past cancer, the goal of immunotherapy in oncology is to control the disease.
We do, though, find that some patients seem to be able to take a break from treatment, or even discontinue it for a long period of time, without seeing a progression of their cancer. We still dont understand why this sometimes happens, and theres no guarantee itll happen when immunotherapy is used.
The goals of immunotherapy may expand in the future as researchers continue to make advances in the field. Some clinical trials are now using immunotherapy to treat nonmetastatic, early-stage cancers. Being able to achieve the same long-term outcome without the long-term side effects associated with chemotherapy would be a win for patients and oncologists alike.
What Are The Types Of Immunotherapy
Several types of immunotherapy are used to treat cancer. These include:
- Immune checkpoint inhibitors, which are drugs that block immune checkpoints. These checkpoints are a normal part of the immune system and keep immune responses from being too strong. By blocking them, these drugs allow immune cells to respond more strongly to cancer.
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Learn more about immune system modulators.
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How Does Immunotherapy Work Against Cancer
As part of its normal function, the immune system detects and destroys abnormal cells and most likely prevents or curbs the growth of many cancers. For instance, immune cells are sometimes found in and around tumors. These cells, called tumor-infiltrating lymphocytes or TILs, are a sign that the immune system is responding to the tumor. People whose tumors contain TILs often do better than people whose tumors dont contain them.
Even though the immune system can prevent or slow cancer growth, cancer cells have ways to avoid destruction by the immune system. For example, cancer cells may:
- Have genetic changes that make them less visible to the immune system.
- Have proteins on their surface that turn off immune cells.
- Change the normal cells around the tumor so they interfere with how the immune system responds to the cancer cells.
Immunotherapy helps the immune system to better act against cancer.
Treatment Led To Complete Regression
The novelty of this new, experimental form of immunotherapy consists of using cells called tumor-infiltrating lymphocytes to target the tumor mutations.
In this individual case, the breast cancer patient joined the trial after chemotherapy and hormonal treatment had failed her.
Dr. Rosenberg and team analyzed the DNA and RNA of the patients tumor and compared them with those of normal tissue in order to find out which genetic mutations were specific to this particular cancer.
The researchers revealed 62 different mutations and tested which TILS had the ability to recognize these mutations. They found some TILS that could recognize four mutations.
While these TILS were collected and grown in the laboratory, the patient also took pembrolizumab, which is a so-called checkpoint inhibitor that helps the immune system to react more strongly to cancer.
After the treatment, the breast cancer disappeared completely it has been 22 months since the cancers complete regression, and the tumors have not returned since.
The senior investigator is hopeful that the findings are generalizable and will soon be applicable to a wide range of patients.
Weve developed a high-throughput method, says Dr. Rosenberg, to identify mutations present in a cancer that are recognized by the immune system.
The director of CCR, Tom Misteli, Ph.D., echoes the same sentiment. He says, This is an illustrative case report that highlights, once again, the power of immunotherapy.
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Treatment Of Stage Iv Breast Cancer
Stage IV cancers have spread beyond the breast and nearby lymph nodes to other parts of the body. When breast cancer spreads, it most commonly goes to the bones, liver, and lungs. It may also spread to the brain or other organs.
For women with stage IV breast cancer, systemic drug therapies are the main treatments. These may include:
- Some combination of these
Surgery and/or radiation therapy may be useful in certain situations .
Treatment can often shrink tumors , improve symptoms, and help some women live longer. These cancers are considered incurable.
Immunotherapy For The Treatment Of Breast Cancer: Emerging New Data
Abstract: Breast cancer is the most common type of cancer affecting women in the United States. Triple-negative breast cancer remains the most aggressive molecular subtype secondary to a lack of therapeutic targets. The search for a target has led us to investigate immunotherapeutic agents. Immunotherapy has recently demonstrated significant breakthroughs in various types of cancers that are refractory to traditional therapies including melanoma and Non-Small Cell Lung Cancer . Breast cancer however remains one of the tumors that was initially least investigated because of being considered to have a low immunogenic potential and a low mutational load. Over the past few years, antiPD1/PDL1 drugs have started to make progress in the triple-negative subtype with more promising outcomes. In this report, we review the treatment of triple-negative breast cancer and specifically shed light on advances in immunotherapy and newly approved drugs in this challenging disease.
Keywords: breast cancer, immunotherapy, PD1, PDL1, atezolizumab
Background
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How Often Do You Receive Immunotherapy
How often and how long you receive immunotherapy depends on:
- your type of cancer and how advanced it is
- the type of immunotherapy you get
- how your body reacts to treatment
You may have treatment every day, week, or month. Some types of immunotherapy given in cycles. A cycle is a period of treatment followed by a period of rest. The rest period gives your body a chance to recover, respond to immunotherapy, and build new healthy cells.
An Exception: Autoimmune Disorders
If you have an autoimmune disorder, you may be unable to tolerate immunotherapy even if you would otherwise qualify for treatment. With an autoimmune disease, such as lupus, rheumatoid arthritis, Crohns disease or ulcerative colitis, your immune system mistakenly attacks healthy cells. Autoimmune diseases are treated with drugs that suppress the immune system. Immunotherapy, on the other hand, revs up the immune system and stimulates T-cells. So, immunotherapy may cause your autoimmune disease to flare up, or it may produce other toxic side effects. A potent immune response may even cause your T-cells to start attacking your organs.
Symptoms of an autoimmune response to immunotherapy may include diarrhea, inflammation of the liver, a skin rash or inflammation of the lung. Sometimes, we may be able to successfully treat the flare-up and continue immunotherapy. For example, if you develop symptoms of hypothyroidism, but you respond to treatment for the condition, we may be able to continue immunotherapy.
A new clinical trial, sponsored by the National Cancer Institute , is testing the use of an immunotherapy drug on cancer patients who have a preexisting autoimmune disease when the risks of cancer outweigh the potential harms of an autoimmune response. So, while having a known autoimmune disease may disqualify you from receiving immunotherapy, advances in treatment research may eventually change that.
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Local Or Regional Treatments For Stage Iv 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 or painful wound in the breast
- To treat a small number of metastases in a certain area, such as the brain
- To help prevent or treat bone fractures
- When a cancer is pressing on the spinal cord
- To treat a blood vessel blockage in the liver
- To provide relief of pain or other symptoms anywhere in the body
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 the goalwhether it is to try to cure the cancer or to prevent or treat symptoms.
The Role Of The Lymphocytic Infiltrate In Breast Cancer
The presence of tumor-infiltrating lymphocytes is observed in some breast tumors and has been reported to be a good prognostic feature for certain types of BCs, particularly for ER-negative tumors and HER2-positive subtypes. Furthermore, TILs have been negatively correlated with the patient’s age at diagnosis. More recently, the nature of TILs has been better characterized. Ruffell et al. have reported that TILs are composed mainly of CD3+/CD56 T cells but that a minority consisted of NK cells or CD20+ cells. The majority of CD3+ cells were either CD4+ or CD8+ T cells. Interestingly, CD8+ cells did not express granzyme B at baseline, which means that they did present inactivation status, but they did express granzyme B after neoadjuvant chemotherapy in one-third of the patients. Finally, a minority of TILs presented T and NK-cell features. The genomic characteristics of TIL+ tumors are important to understand which molecular mechanisms lead to lymphocyte infiltration. Genomic instability may promote anti-tumor immune response through tumor-associated antigens . Some mechanisms of chemokine release by the tumor have been described and correlated with lymphocyte attraction. TILs have been associated with CXCL9 and CXCL13 expression by the tumor. TIL + tumors present a specific methylation pattern on immune-related genes, including CCL5, and a cluster of chemokines is lost in a subset of BC.
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Personal Genetic Testing For Inherited Gene Mutations
The National Comprehensive Cancer Network recommends everyone diagnosed with metastatic breast cancer get genetic testing for BRCA1 and BRCA2 inherited gene mutations . If you have a mutation in one of these genes, a PARP inhibitor may be included in your treatment plan.
Learn more about genetic testing.
Need For More Predictive Biomarkers
Clinical biomarkers may have diagnostic, predictive, prognostic, or pharmacogenomic value. Predictive biomarkers are the most useful in daily practice because they enable selection of patients who will obtain the greatest benefits from a treatment, as well as exclusion of patients who are unlikely to respond. Prognostic biomarkers are predictive of patient outcomes irrespective of treatment, and they are therefore used less frequently for treatment decisions. The successful development of clinically significant biomarkers depends upon three features: their biological role with respect to malignant transformation and tumor progression the ability to detect them with robust, reliable, and clinically applicable analytical genomic tests and their prognostic or predictive value, as validated in clinical trials.
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Tucatinib Neratinib And Lapatinib
The tyrosine-kinase inhibitors FDA-approved for metastatic breast cancer treatment are:
- Tucatinib
- Neratinib
- Lapatinib
Tyrosine-kinase inhibitors are a class of drugs that target enzymes important for cell functions . These drugs can block tyrosine-kinase enzymes at many points along the cancer growth pathway.
A tyrosine-kinase inhibitor in combination with trastuzumab and chemotherapy can be used to treat HER2-positive metastatic breast cancer. This combination may give women with HER2-positive metastatic breast cancer more time before the cancer spreads compared to treatment with trastuzumab and chemotherapy alone .
Adding the tyrosine-kinase inhibitor tucatinib to treatment with trastuzumab and chemotherapy may also increase overall survival in women with HER2-positive metastatic breast cancer who were treated with trastuzumab in the past .
Neratinib is also used to treat HER2-positive early breast cancer.
Tucatinib, neratinib and lapatinib are pills.
Learn about neratinib and treatment of early breast cancer.
Tucatinib, neratinib and lapatinib and brain metastases
Many drug therapies cannot pass through the blood to the brain . So, they cant treat breast cancer that has spread to the brain.
However, tucatinib, neratinib and lapatinib can pass through the blood-brain barrier and may be used to treat some metastatic breast cancers that have spread to the brain.
Advanced Er+ Breast Cancer
KEYNOTE-028 was a phase Ib, open-label, multicohort study that investigated the safety and antitumor activity of pembrolizumab in patients with PD-L1+ advanced solid tumors, including 25 patients with estrogen receptor positive /HER2-negative advanced breast cancer, among whom three experienced partial response , leading to an ORR of 12% . The clinical benefit rate +PR+SD ) was 20% and the median duration of response was 12 months . In the phase Ib JAVELIN study, which evaluated the anti-PD-L1 avelumab in 72 women with HR+/HER2â disease , an ORR of 2.8% was observed.
Pembrolizumab has been evaluated in combination with eribulin mesylate for ER+ metastatic breast cancer in a randomized phase II trial that enrolled 88 patients. At a median follow-up of 10.5 months, no significant difference in median PFS and ORR was observed with the addition of pembrolizumab to eribulin mesylate compared with eribulin mesylate alone . PD-L1 testing by the 22C3 assay was performed for 65 patients, and 24 were found to have PD-L1+ tumors . PD-L1 status was not associated with PFS, although the group of patients with PD-L1+ tumors was small and thus had limited power to assess benefit.
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Baseline Factors For Consideration
The decision to proceed with immunotherapy depends on the likelihood that the tumor will respond to treatment and the patientâs projected ability to tolerate therapy. For patients with early-stage disease, the potential for benefit with immunotherapy must also be weighed against the risk of irAEs. Patients with autoimmune disorders, chronic viral infections, AIDS, ongoing clinically significant immunosuppressant use, organ dysfunction, pregnancy, older age, and impaired functional status are generally considered to be challenging populations to treat with checkpoint inhibitors. As more patients receive checkpoint inhibitors in real-world settings, however, emerging data are painting a clearer picture of the risk/benefit tradeoffs in some groups of patients, and it is becoming clear that some of these âchallenging populationsâ may safely receive treatment.
Analyses of outcomes among older patients receiving checkpoint inhibitors in clinical trials and real-world settings suggest that the toxicity profiles and response rates for immunotherapy in the elderly do not differ markedly from those in the general population. Those results must be interpreted with a note of caution, however, as the older patients that were included were all relatively fit . Geriatric assessments for elderly individuals may be useful to evaluate the potential safety of more intense therapeutic regimens including immunotherapy.