Genetic And Molecular Features
Triple-negative breast tumors are characterized by low expression or absence of expression of progesterone and estrogen receptors and by the lack of overexpression or amplification of human epidermal growth factor receptor-2 .
The advance in transcriptomic technologies has allowed a deeper characterization of the genetic and molecular features of triple-negative tumors, with implications for diagnosis and the search for new therapies. Gene expression profiling showed that 1520% of women with TNBC carry BRCA1 or BRCA2 gene mutations or deficiencies, which impair DNA stability and repair, promoting carcinogenesis . Microarray assays demonstrated that 20% of TNBCs are claudin-low, characterized by genomic instability and a propensity for epithelial-to-mesenchymal transition and thus more prone to metastization. In triple-negative tumors, 80% are basal-like , featuring the expression of proliferation-related genes , the presence of a high number of mutations of tumor suppressor genes and of the PIK3CA oncogene , along with the expression of proliferation and EMT-related molecules, such as cytokeratines , epidermal growth factor receptor , and vimentin . These properties corroborate TNBCs aggressiveness and poor clinical prognosis .
Hrqol Analysis Of Keynote
Patients with triple-negative breast cancer who received pembrolizumab in the neoadjuvant and adjuvant settings demonstrated similar health-related quality-of-life scores compared with patients who received placebo.
Patients who received pembrolizumab to treat early-stage, triple-negative breast cancer reported similar scores across global health score , function, and breast symptom domains, compared with patients who received placebo, according to a patient-reported outcomes analysis of the KEYNOTE-522 trial presented during the 2022 European Society of Medical Oncology Congress.
Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in statistically significant and clinically meaningful improvement in pathological complete response and event-free survival vs neoadjuvant chemotherapy alone in patients with early-stage TNBC, Rebecca Dent, MD, MSc, senior consultant at the National Cancer Center in Singapore, said in a presentation of the findings. Together with the efficacy and safety findings of KEYNOTE-522, these PRO results support neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as an effective standard-of-care treatment regimen in this setting, without meaningful impact on health-related quality of life , she added.
For many of us, these was very reassuring, she added.
Reference
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Early Stage Chemotherapy Combination Regimens
Due to the promising results in the metastatic setting of combination chemotherapy and ICIs, studies have now been conducted in early stages of TNBC. They have demonstrated preliminary success thus far. In the I-SPY 2 trial, patients with stage II/III disease treated with combination chemotherapy and pembrolizumab had estimated the pCR rate to be nearly three times that of those individuals with chemotherapy alone . The KEYNOTE-522 trial also demonstrated improved pCR rates and 18-month event-free survival when pembrolizumab was delivered in combination with chemotherapy in both the neoadjuvant and adjuvant settings . In contrast to the aforementioned findings, the NeoTRIPaPDl1 study demonstrated that standard chemotherapy in combination with atezolizumab did not significantly impact pCR rates in patients with early stage high-risk or locally advanced TNBC . High-risk disease was defined as disease with high proliferation or grade. The contrasting results of these two studies may be explained by chemotherapy backbones or due to differences in the ICI activity, given that PD-1 inhibitors but not PD-LA inhibitors block PD-L2 inhibitory signaling .
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Immunotherapy Agents Approved In Tnbc
The high mutational burden of the TNBC was determined to lead to the synthesis of abnormal proteins, acting as “neoantigens” which will be recognized by the antigen presenting cells and would initiate an antitumor immune response.
Early-stage TNBC has a high TIL infiltrate but breast cancer has not traditionally been considered immunogenic. Recent trials demonstrate TIL infiltrate has a high expression of PD-1 . TNBC has potential therapeutic targets such as immune checkpoint inhibitors in metastatic and the early-stage scenario .
Chemotherapeutic Agents Used In Combination With Immunotherapy
It is generally accepted that most TNBC is chemotherapy-sensitive, but the optimal treatment regimen continues to be investigated. Most chemotherapy regimens include anthracyclines, taxanes, and/or platinum compounds, dose-dense AC , or TC . The addition of platinum to standard chemotherapy has shown to increase the pathologic complete response rate . Multiple guidelines support the use of chemotherapy in the neoadjuvant setting for early stage TNBC . Often a surrogate endpoint for clinical trials, pathological complete response after neoadjuvant chemotherapy is predictive of long-term survival outcomes . Administration of anthracycline and taxane-based chemotherapy sequentially is the most common neoadjuvant approach, with the consideration of adding carboplatin, as it has been demonstrated to improve the pathologic complete response rate .
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Autophagy And Breast Cancer
Autophagy is a word derived from the Greek language meaning âself-eatingâ, first named by Christian de Duve, more than 50 years ago. This highly regulated catabolic intracellular process plays an essential housekeeping role in removing toxic byproducts of metabolism, and eliminating misfolded or degraded protein aggregates, non-functional or aged organelles, and microbial components . In times of stress, such as nutrient or oxygen deprivation, infection, or exposure to non-physiological conditions, the level of autophagy increases to enhance cell survival . Autophagic dysregulation that results in an impairment of intracellular homeostasis and metabolism has been associated with the pathogenesis of different diseases, including cancer . Interestingly, autophagy has a dual role in malignancies, acting both in an inhibitory manner by preventing the aberrant accumulation of dysfunctional cytosolic proteins and organelles in healthy cells, and, conversely, by promoting continued cell survival in malignantly transformed cells .
Monotherapy Vs Combined Regimens
The first study to evaluate the efficacy of checkpoint inhibition in TNBC was the KEYNOTE-012 trial , which assessed the clinical activity of single-agent pembrolizumab in heavily pretreated patients with PD-L1-positive metastatic TNBC. An acceptable ORR of 18.5% was demonstrated, later confirmed in the cohort b KEYNOTE-086 trial, with an ORR of 21.4% and a median duration of response of 18 months . Atezolizumab monotherapy showed similar results in the PCD4989g trial, with an ORR of 24% and a median OS of 17.6 months as first-line therapy . Single-agent durvalumab had a modest ORR of 5.2% in advanced or metastatic TNBC .
As for anti-PD-1 antibody pembrolizumab, its simultaneous combination with the chemotherapeutic regimen resulted in increased benefit , with pCR rates up to 38% higher than chemotherapy alone . In fact, it has been approved by the FDA since November 2020 for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 . and as neoadjuvant treatment, in addition to, since July 2021, use as a single agent in an adjuvant setting after surgery, in patients with early-stage high-risk TNBC . As for anti-PD-1 antibody pembrolizumab, its simultaneous combination with chemotherapeutic regimens resulted in increased benefit , with pCR rates up to 38% higher than for chemotherapy alone .
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Immunotherapy For Breast Cancer
Immunotherapy is the use of medicines to boost a persons own immune system to recognize and destroy cancer cells more effectively. Immunotherapy typically works on specific proteins involved in the immune system to enhance the immune response. These drugs have side effects different from those of chemotherapy.
Some immunotherapy drugs, for example, monoclonal antibodies, work in more than one way to control cancer cells and may also be considered targeted therapy because they block a specific protein on the cancer cell to keep it from growing.
Immunotherapy is used to treat some types of breast cancer.
Radiation: A Potential Complement To Checkpoint Inhibition
Radiation is also part of the arsenal available for TNBC management, especially after surgery, as adjuvant therapy addressing the minimal residual disease. Radiation has an immunosuppressive impact on cancer patients immune systems . Lymphopenia and decreased immune cell activity are possible consequences of radio-sensitivity of hematopoietic cells and lack of precision of traditional techniques. However, it may also stimulate immunity in the tumor microenvironment, which is now considered a stage in radiobiology principles. This effect depends on the radiation technique employed and dose, and the pre-existing composition of the tumor microenvironment . It is hypothesized that radiation increases tumors mutational load, prompting antigen presentation and T-cell activation, proliferation, and migration into the tumor microenvironment, and maybe even leading to a decrease in immune suppressors. Therefore, radiotherapy can function as an inductor of tumor immunity, complementing immunotherapy . Several clinical trials have been ongoing for a variety of cancers, with a number of phase I , phase II , and phase III studies testing for its combination with anti-PD-1 therapies against TNBC. These studies may be particularly important for patients with a higher risk of recurrence and lower sensitivity to chemotherapy.
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Monoclonal Antibodies Targeting Immune Checkpoints In Metastatic Setting
Immune checkpoints are molecules that protect against normal tissue damage caused by over-activity of T-cells . PD-1 and its ligand PD-L1, the most widely studied immune checkpoint receptors in the treatment of breast cancer, are expressed on activated T-cells, B-lymphocytes, and natural killer cells and are associated with tumor immune resistance . An abundancy of genes involved in immune cell processes and high levels of tumor-infiltrating lymphocytes implying high immunogenicity for the IM subtype of TNBC . These characteristics suggest that immune checkpoint inhibitors are feasible therapeutic agents for TNBC. ICIs were first investigated amongst metastatic TNBC patients as a monotherapy. Subsequently, there have been trials to investigate ICIs in combination with chemotherapy agents to enhance response rates, as well as using ICIs in the neoadjuvant setting.
Research Progress And Future Questions
After the 2020 approval of the combination of pembrolizumab and chemotherapy for advanced triple-negative breast cancer, FDA approved the combination therapy for people with early-stage disease in 2021.
That approval was based on results from a different trial, KEYNOTE-522. In that study, patients with high-risk, early-stage triple-negative breast cancer benefited from pembrolizumab given with chemotherapy before surgery, and then continued as a single agent as an additional, or adjuvant, treatment after surgery.
This is an exciting time for research on triple-negative breast cancer, said Dr. Lee. We have now seen a benefit from an immune checkpoint inhibitor and chemotherapy in a subgroup of patients in both the advanced and early stages of the disease.
Dr. Lee cautioned, however, that more than half of all patients with triple-negative breast cancer have PD-L1 combined positive scores of less than 10, so more work is needed to find effective treatments for these patients.
In his editorial, Dr. Pivot noted that people diagnosed with triple-negative breast cancer are not a homogeneous group. Future studies, he added, will try to identify which individuals are more or less likely to benefit from pembrolizumab.
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How Does Your Immune System Work
Your immune system produces special proteins called antibodies that find and destroy anything foreign including germs, viruses or cancer cells. An antibody works by sticking to another protein called an antigen. Your antibodies circulate throughout your body until they find and attach to any foreign antigen. Then they tell all the other parts of your immune system to destroy the cells containing that specific antigen. Because cancer begins in healthy, normal cells, antibodies in your immune system have a difficult time identifying the antigens in cancer cells as foreign.
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Demystifying Immunotherapy For Early
Hope S. Rugo, MD, FASCO
Immunotherapy has become a potential strategy in treating triple-negative breast cancer, though many questions remain to be answered before long-term survival is achieved by all patients. This exciting field of breast cancer research was explored at the 2022 Miami Breast Cancer Conference by Giants of Cancer Care® honoree Hope S. Rugo, MD, FASCO, Professor of Medicine and Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.1 The Giants of Cancer Care recognition program celebrates the achievements of experts whose discoveries have propelled the field of oncology forward and established the building blocks for future advances.
Starting Point
Although this subtype is heterogeneous, triple-negative breast cancer generally carries a high risk of recurrence within 2 to 3 years. Its particularly important to optimize our therapy while still trying to individualize it, Dr. Rugo said.
I think the direction of neoadjuvant therapy now is to replace our adjuvant trials with neoadjuvant trials and power them to look at both pathologic complete response and event-free survival, she added.
Pivotal Trials
Both trials demonstrated a marked improvement in pathologic complete response at the time of surgery. Although adverse events were increased with the checkpoint inhibitor, many patients completed treatment with pembrolizumab and atezolizumab.
REFERENCES
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Study Supports Immunotherapy For Treating Triple
A study by an international group of researchers has found for the first time that a combination of immunotherapy and chemotherapy can extend lives of women with triple-negative breast cancer. A new treatment option would be significant because triple-negative breast cancers dont respond to hormone therapy or targeted therapy. In addition, they tend to grow and spread faster than most other types of breast cancer. The study was published October 20, 2018 in New England Journal of Medicine and presented at the European Society for Medical Oncology 2018 Congress in Munich.
“While chemotherapy is the current standard of treatment for triple-negative breast cancer, there is an urgent need for newer, more effective therapies,” said Leisha Emens, MD, PhD, co-author of the study, in a statement. “The results of this trial showed that adding the immunotherapy drug atezolizumab to chemotherapy was well-tolerated and resulted in a clear increase in clinical benefit for some patients with triple-negative breast cancer.”
The study included 902 women in 41 different countries with advanced triple-negative breast cancer that could not be removed through surgery. They all received the chemotherapy drug Abraxane and were randomly assigned to also receive either the immunotherapy drug Tecentriq or a placebo. Tecentriq has been previously approved by the US Food and Drug Administration to treat people with bladder cancer and non-small cell lung cancer.
Metastatic Chemotherapy Combination Regimens
Combination regimens of PD-1/L1 inhibitors plus chemotherapy have demonstrated more success in mTNBC than single-agent ICIs . Among early trials including both PD-L1positive and PD-L1negative tumors, pembrolizumab with eribulin, a microtubule inhibitor that suppresses transforming growth factor ,24 which has been associated with intratumoral CD8-positive T-cell exclusion,25 yielded an ORR of 26.4% in 106 patients treated with 0 to 2 prior lines of therapy for metastatic disease in the ENHANCE-1 trial .26 Similarly, the smaller phase Ib trial of atezolizumab and nab-paclitaxel showed a promising ORR of 39.4% in 33 patients, also treated with 0 to 2 prior lines,27 perhaps related to the ability of taxanes to promote toll-like receptor activity and dendritic cell activation.28 The subsequent randomized IMpassion130 phase III trial in treatment-naïve mTNBC showed that atezolizumab added to nab-paclitaxel resulted in a clinically meaningful OS improvement of 7 months in the PD-L1positive subgroup but not in the entire cohort,29 which is notable because the trials hierarchical statistical design required overall benefit to formally test the subgroup effect.28 These results led the FDA and the European Commission to approve atezolizumab and nab-paclitaxel in PD-L1positive mTNBC, establishing the first immunotherapy approval in breast cancer.
Ongoing AntiPD-1/L1 Combination and Novel Immunotherapy Trials in TNBC
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Tnbc And Immune Viral Therapy
Recent trends in viral genetic engineering have allowed the development of oncolytic viruses with enhanced recognition capability to receptors overexpressed in tumor tissues, and viruses encoding or packaging suicide or pro-apoptotic genes or agents for delivery to cancer cells . Viruses can be manipulated to upregulate antigen presentation and T cell anti-tumor response. Talimogene laherparepvec , an attenuated and genetically engineered herpes simplex virus that overexpresses granulocyte-macrophage colony-stimulating factor , is the only oncolytic virus approved for clinical use in the United States and Europe . Some studies have shown that cell vaccines primarily based on oncolytic vesicular stomatitis virus can improve the prognosis of TNBC by enhancing the functions of natural killer cells and CD8+ T cells . An oncolytic herpes simplex virus, which encodes the fundamental anti-tumor cytokine, interleukin 12 , , can selectively kill cancer cells while inducing anti-tumor immunity , which is mainly manifested by the upregulation of CD8+ T cells activation markers in tumor microenvironment and the inhibition of tumor angiogenesis . Immunovirotherapy may be a promising method to treat TNBC patients.
Triple Negative Breast Cancer
Autophagy was shown to be necessary for survival in nutrient-rich environments for some TNBC subtypes. In these cancer cell lines, autophagy led to paracrine secretion of IL-6, a pro-inflammatory cytokine, leading to increased signal transducer and activator of transcription phosphorylation and breast cancer stem-cell proliferation . This was further supported by evidence that, even when autophagy was inhibited, IL-6 administration led to cancer stem-cell maintenance. Paradoxically, IL-6 had the opposite role in nutrient-poor environments: autophagy resulted in decreased IL-6 secretion, which led to increased breast cancer stem-cell maintenance.
The restriction of tumor aerobic glycolysis in two TNBC mouse models was found to inhibit the expression of tumor granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor through a complex molecular network involving the autophagy pathway. This led to augmentation of T cell immunity, immune-mediated tumor reduction, reduced metastasis, and prolonged survival . These results highlight the need to specify the context of autophagy and immunoregulatory mechanisms for prognostic and therapeutic purposes.
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Immune Checkpoint Inhibition In Tnbc
Of the three different subtypes of breast cancer , triple negative is considered more immunogenic given the increased presence of tumor infiltrating lymphocytes found in the microenvironment and the higher levels of expression of PD-L1. Triple-negative breast cancer is also associated with increased tumor mutational burden.
As Dr. Tolaney explained, however, response rates to checkpoint inhibitor monotherapy have been very low, especially among patients who have received prior therapies. Thus, the field is moving towards more novel combinations, she said, not just for triple-negative disease but also for other subtypes of breast cancer.