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Triple Negative Breast Cancer Immunotherapy

What You Need To Know

Immunotherapy for Triple-Negative Breast Cancer
  • Triple-negative breast cancer accounts for about 10% to 20% of all breast cancer cases.
  • Every cancer diagnosis is unique, but in general, triple-negative breast cancer is a more aggressive type of tumor with a faster growth rate, higher risk of metastasis and recurrence risk. Therefore, it often requires chemotherapy as part of the treatment.
  • Surgery is also an important part of treatment, but if a tumor is small and localized, mastectomy may not be necessary. Chemotherapy can shrink triple-negative breast tumors, and patients can become candidates for less-extensive surgery.
  • Triple-negative cancers are more common in patients with hereditary genetic mutations, and genetic counseling and testing should be considered.

Research Agenda For The Next Decade

The introduction of immunotherapy marks a revolution in the treatment of early-stage TNBC. KEYNOTE-522 has shown that, by unleashing anti-cancer immune responses through ICIs, long-term benefits can be obtained for the treatment of this aggressive BC subtype. However, it represents a starting point rather than a finish line, and additional efforts will be required precisely implement immunotherapy for the treatment of TNBC .

Fig. 1: Next decade research agenda for neo immunotherapy in TNBC.

Abbreviations: IO, immunotherapy, TNBC, triple negative breast cancer TMB, tumor mutational burden ADC, antibody-drug conjugate ER, estrogen receptor CD, cluster of differentiation TILs, tumor infiltrating lymphocytes PD-L1, Programmed death-ligand 1 HLA, human leukocyte antigen PD-1, Programmed cell death protein 1 A, adenosine T, thymine C, cytosine G, guanine BRCA, BReast CAncer gene EFS, event-freee survival RD, residual disease me1, mono-methylated form BC, breast cancer. Created with biorender.com.

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.

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Possible Side Effects Of Immune Checkpoint Inhibitors

Side effects of these drugs can include fatigue, cough, nausea, skin rash, poor appetite, constipation, and diarrhea.

Other, more serious side effects occur less often.

Infusion reactions: Some people might have an infusion reaction while getting these drugs. This is like an allergic reaction, and can include fever, chills, flushing of the face, rash, itchy skin, feeling dizzy, wheezing, and trouble breathing. Its important to tell your doctor or nurse right away if you have any of these symptoms while getting these drugs.

Autoimmune reactions: These drugs remove one of the protections on the body’s immune system. Sometimes the immune system starts attacking other parts of the body, which can cause serious or even life-threatening problems in the lungs, intestines, liver, hormone-making glands, kidneys, or other organs.

Its very important to report any new side effects to your health care team quickly. If serious side effects do occur, treatment may need to be stopped and you may get high doses of corticosteroids to suppress your immune system.

Immunotherapy Combined With Antiangiogenic Factor

Immunotherapy for Metastatic Triple Negative Breast Cancer

The impaired function of the tumor blood vessels may contribute to the decreasing levels of cytotoxic T-cells and increasing levels of myeloid-derived suppressor cells and regulatory T-cells . In addition, some research indicates that antiangiogenic therapy leads to the augmentation of PD-L1 expression as well as CD8+ T-cell infiltration in the tumor microenvironment. Thus, a reduction of the immunosuppression, as well as sensitizing the tumor to the immune response could be achieved by restoring proper perfusion .

Consistent with these promising findings, camrelizumab in combination with apatinib ) was was investigated in patients with advanced TNBC. In this two phase clinical trial, this therapy showed a significant ORR of 43.3% and was well-tolerated, irrespective of PD-L1 expression. However, this open-label study had several limitations and large clinical trials with randomization are needed to confirm these results as to compare ICIs in combination with VEGFR2 inhibitors with ICIs plus placebo .

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What Is Triple Negative Breast Cancer

Triple negative breast cancer is:

  • Estrogen receptor-negative
  • Progesterone receptor-negative
  • HER2-negative

Most triple negative tumors are basal-like . Basal-like tumors have cells that look similar to those of the outer cells surrounding the mammary ducts.

Triple negative/basal-like tumors are a molecular subtype of breast cancer.

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.

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What This Means For You

While the results of the KEYNOTE-522 study seem promising and the results of the NeoTRIPaPDL1 study seem disappointing, its important to know that the follow-up time for these studies so far is very short only about a year. Longer follow-up time will offer more information on how long cancers respond to Keytruda, as well as event-free survival rates in the Tecentriq study. It also will be important to know if either medicine improves overall survival, which is how long a person lives whether or not the cancer comes back.

If you’ve been diagnosed with early-stage triple-negative breast cancer and are deciding on treatments, you may want to talk to your doctor about these studies. You also may want to ask if its possible to do PD-L1 testing on the cancer to see if you might benefit the most from a medicine like Keytruda or Tecentriq. You also may want to ask about other trials looking at these medicines and whether any of them might be a good fit for your unique situation.

For more information on immunotherapy medicines, how they work, and their possible side effects, visit the Breastcancer.org Immunotherapy pages.

To talk with others about these studies and immunotherapy, join the Breastcancer.org Discussion Board forum Immunotherapy – Before, During, and After.

Integrating Immunotherapy Into An Expanding Arsenal Of Treatment Options

First immunotherapy success for triple-negative breast cancer

Important new data has also recently emerged on neoadjuvant chemotherapy for TNBC. The BrighTNess trial, assessing the addition of veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy for high-risk stage IIIII TNBC, has previously shown that the addition of carboplatin to anthracyclines and taxanes significantly improve pCR rates. Survival results from this trial were recently presented at ESMO Congress 2021: the addition of carboplatin significantly improved 4-year EFS , whereas no benefit was observed with the addition of veliparib. These results appear to confirm a long-term benefit of adding carboplatin, although its still unclear whether the same benefit is retained when adding ICIs: indeed, a survival benefit was also observed in the GeparNuevo trial, which did not include carboplatin in the neoadjuvant regimen. In this setting, the inclusion of carboplatin appears reasonable in fit, high-risk, stage IIIII TNBC patients, but new research efforts to clarify the need for platinum in the presence of pembrolizumab are urgently required, to understand if more flexibility is acceptable regarding the backbone chemotherapy regimen. Similarly, efforts will be needed to clarify if there is any role for associating dose-dense chemotherapy regimens to immunotherapy, based on the benefits observed with this strategy in prior trials.

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Immune Checkpoint Inhibitors For Breast Cancer

An important part of the immune system is its ability to keep itself from attacking normal cells in the body. To do this, it uses proteins on immune cells that need to be turned on to start an immune response. Breast cancer cells sometimes use these checkpoints to avoid being attacked by the immune system. Drugs that target these checkpoint proteins, help restore the immune response against breast cancer cells.

Durvalumab With Neoadjuvant Therapy

As previously mentioned, ICIs showed promising therapeutic benefits, especially in combination with chemotherapy. In the GeparNuevo phase two clinical trial, the combination of durvalumab with standard neoadjuvant chemotherapy was evaluated in early TNBC. In this study, the patients were randomized in terms of stromal tumor-infiltrating lymphocytes. Two weeks before starting treatment with chemotherapy, the patients received durvalumab or a placebo in monotherapy. Subsequently, the patients were treated with durvalumab or placebo and nab-paclitaxel for 12 weeks, followed by durvalumab or placebo and epirubicin/cyclo- phosphamide . The use of durvalumab in combined therapy with nab-paclitaxel and EC demonstrated a higher pCR rate than the placebo group , however without statistical significance . Nevertheless, the patients who had received durvalumab as a monotherapy two weeks before the main treatment showed a higher pCR rate than the placebo group . Thus, these findings suggest the potential benefits derived from using durvalumab with anthracycline/taxane-based therapy, particularly in patients pretreated with durvalumab as a single agent before the main therapy .

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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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European Commission Approves Keytruda Plus Chemotherapy As Neoadjuvant Treatment Then Continued As Adjuvant Monotherapy After Surgery For Locally Advanced Or Early

Advances in Triple

May 24, 2022 6:45 am ET

Approval based on event-free survival benefit demonstrated in Phase 3 KEYNOTE-522 trial

This KEYTRUDA combination is the first immunotherapy option approved in the EU for high-risk early-stage TNBC

RAHWAY, N.J.—-Merck , known as MSD outside the United States and Canada, today announced that the European Commission has approved KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery for adults with locally advanced or early-stage triple-negative breast cancer at high risk of recurrence.

The approval is based on results from the pivotal Phase 3 KEYNOTE-522 trial, in which KEYTRUDA in combination with chemotherapy before surgery and continued as a single agent after surgery prolonged event-free survival , reducing the risk of EFS events or death by 37% compared to neoadjuvant chemotherapy alone in this patient population. Median follow-up time for all patients was 37.8 months .

KEYNOTE-522 was the first large, randomized Phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and III TNBC. With this decision, this KEYTRUDA combination becomes the first immunotherapy option approved for patients in the European Union in this setting.

About KEYNOTE-522

About triple-negative breast cancer

About Mercks early-stage cancer clinical program

About KEYTRUDA® injection, 100 mg

Melanoma

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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.

Immunotherapy For Breast Cancer

Immunotherapy is sometimes used to treat locally advanced or metastatic triple-negative breast cancer. Immunotherapy helps to strengthen or restore the immune systems ability to fight cancer. Immunotherapy is sometimes called biological therapy.

You may have immunotherapy to:

  • kill breast cancer cells
  • stop breast cancer tumours from growing and spreading
  • control symptoms of metastatic breast cancer

Your healthcare team will consider your personal needs to plan the drugs, doses and schedules of immunotherapy. You may also receive other treatments.

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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.

Identifying Responders To Immunotherapy: Current Status And Future Perspectives

2020 PEA Program Metastatic Triple-Negative Breast Cancer Immunotherapy Options & Side Effects

KEYNOTE-522 results prompted a rapid change in clinical practice, leading to the FDA approval of the first immunotherapy agent for early-stage TNBC. This landmark achievement, however, has raised a multitude of scientific questions, requiring a new set of prospective clinical trials.

Besides baseline biomarkers, one established dynamic biomarker, namely the achievement of pCR after neoadjuvant treatment, showed a critical value in KEYNOTE-522. Indeed, a major absolute benefit in terms of EFS was observed among patients not achieving pCR, with a 10% improvement in 3-year EFS for patients receiving pembrolizumab, whereas only a 2% difference was observed in those patients achieving pCR. This finding – together with the results of GeparNuevo showing survival outcomes similar to KEYNOTE-522 with immunotherapy administered only before surgerysupport the experimental testing of strategies to de-escalate adjuvant immunotherapy in patients achieving pCR with chemo-immunotherapy. Nonetheless, until prospective evidence is available, current standards of care should include the adjuvant administration of pembrolizumab to all patients receiving it in the neoadjuvant setting without experiencing concerning irAEs. Moreover, when comparing EFS curves from patients achieving pCR in the two arms, it is important to stress the fact that the addition of pembrolizumab led to more patients achieving pCR, ultimately enriching the population of patients achieving a favorable EFS.

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Immunotherapy As Adjuvant Or Neoadjuvant Therapy

While immunotherapy has been looked at most often as a treatment for metastatic breast cancer, researchers believe it may have a role in the earlier stages of breast cancer as well.

Studies are in place looking at the use of immunotherapy before breast cancer surgery for people with triple negative breast cancer or HER2 positive breast cancer. There are also studies examining immunotherapy after surgery using the checkpoint inhibitors duralumab and tremelimumab for people with estrogen receptor positive stage 2 or stage 3 breast cancer.

What Is The Treatment For Triple

Chemotherapy.Chemotherapy is almost always called for, Sun says. Chemo can downstage tumors . While Sun says the chemotherapy for triple-negative breast cancer can be intense, she adds that regimen can be tailored to the individual and adjusted for older or frailer patients.

In those cases where we get complete response, we know we gave you the right medicine and your prognosis is good, Sun says.

Surgery can remove more of the tumor. Surgery for triple-negative breast cancer does not always have to be a mastectomy, Sun says. Effective chemotherapy done first opens up the possibility of less-invasive surgical options that are less of an ordeal for the patient. If the tumor is small enough after chemo, outpatient procedures or a lumpectomy may be possible.

Surgical samples of the cancerous tissues taken from surgery can provide more information on the cancer and how it is behaving so chemotherapy can be tailored accordingly.

Radiation therapy involves the use beams of radiation to destroy cancer cells, using various techniques to prevent damage to healthy surrounding tissue.

Medical treatments are being tested on triple-negative breast tumors in clinical trials.

Immunotherapy and PARP inhibitors are very exciting and theres lots of research going on, including here at Johns Hopkins, Sun says.

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