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14May 2019

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New study on immunotherapy in triple negative breast cancer

Pretreatment with chemo can improve the effect of immunotherapy on aggressive breast cancer

It sounds complicated: giving cancer patients chemotherapy or radiotherapy, not with the aim of killing cancer cells, but to put the immune system to work so that it will respond better to immunotherapy. Nonetheless, preclinical studies have shown that this is a promising new way to increase the chance of success of immunotherapy. It can strengthen the good immune cells and weaken immune cells that aid cancer. 

Researchers at the Netherlands Cancer Institute investigated whether this is indeed the case in patients with metastasized triple negative breast cancer, an aggressive form of breast cancer that does not respond to a number of standard treatments. 

The results of part 1 of the Netherlands Cancer Institute's TONIC study, a phase 2 study with 67 patients with metastatic triple-negative breast cancer, are promising. In particular, pretreatment with cisplatin and doxorubicin appears to increase the effect of immunotherapy.  

The researchers, led by medical oncologist and researcher Marleen Kok, published their results on Monday, May 13, 2019, in the leading journal Nature Medicine. 

Triple-negative breast cancer

Triple-negative breast cancer is an aggressive form of breast cancer that often affects young people. This form of breast cancer is not hormone sensitive - not to estrogen or progesterone - and therefore does not respond to hormone therapy. It is also insensitive to treatment with Herceptin. If the tumor spreads to other organs, the cancer cells quickly become resistant to chemotherapy and patients die from this condition.


However, a small number of recent studies (the TONIC study is the fifth worldwide, but the first by a scientific institution instead of a pharmaceutical company) have shown that immunotherapy for triple negative breast cancer does have a chance of success. Immunotherapy does not fight cancer itself but helps the immune system to do so. It focuses primarily on T cells, white blood cells that cancer cells can recognize and kill.  

With most forms of breast cancer, the chance of success of immunotherapy is limited because there are few T cells in and around the tumor. But with triple negative breast cancer, the amount of T cells around the tumor cells is relatively high.

In March 2019, the American Food and Drug Administration (FDA)  approvedimmunotherapy for a subgroup of patients with metastatic triple-negative breast cancer. This made  CNN newsbecause it was the first time this has happened for breast cancer. The treatment has not yet been approved in Europe.  

Can we improve immunotherapy?

However, immunotherapy only works on a minority (on average 5% and at most 23% in a specified subgroup) of patients with metastatic triple-negative breast cancer. "Our question was: can we improve that?" says internist-oncologist Marleen Kok, who is leading the TONIC study.

Low dose chemotherapy or radiotherapy

The researchers have now been the first to investigate whether they can increase the chances of success of immunotherapy by giving patients a low dose of chemotherapy or radiotherapy for two weeks prior to immunotherapy. 

Research in the lab and in mouse models, including at the Netherlands Cancer Institute, has shown that this can have a stimulating effect on the immune system. "But then, the question is whether it will also work like that for breast cancer patients," says researcher Maarten Slagter. "We have now investigated this in patients with metastases from triple-negative breast cancer." 

Five 'baskets'

Patients were divided into five cohorts, or 'baskets' as they are called in this type of clinical study.  Cohort one only received immunotherapy (drug nivolumab), cohort two was pre-treated for two weeks with radiotherapy, and the remaining three cohorts were pre-treated for two weeks with three different forms of low-dose chemotherapy. 

Positive effect with cisplatin and doxorubicin

Clinician-researcher Leonie Voorwerk, who conducted the research together with Maarten Slagter: "We actually expected that all of these pre-treatments would have a positive effect on the immune system based on preclinical results, but to our surprise, we saw this mainly with cisplatin and doxorubicin and less with the other two pre-treatments: cyclophosphamide and radiation."

At the Netherlands Cancer Institute's immunology lab, the tumor biopsies were thoroughly examined to see what happened at a molecular-biological level. The researchers did indeed see T cells entering the tumor after pre-treatment with chemotherapy (cisplatin and doxorubicin) and subsequent immunotherapy. These T cells also appear to do their cancer-killing work better in these patients during immunotherapy.   

Part two: continuing with doxorubicin

Pre-treatment with doxorubicin appears to be the most successful in the first small group of patients: after pretreatment with this medicine, 35% of patients responded well to immunotherapy. In the second part of the TONIC study, which is currently ongoing, the researchers are, therefore, continuing with doxorubicin. The patients are now divided into two groups. One group is pre-treated with doxorubicin and then receives immunotherapy. The other group immediately starts immunotherapy. 

"We hope to validate the findings of the first part of the study in more patients in the second part," says Leonie Voorwerk. "We also already have a reasonable impression of which patients have a chance of being helped by the immunotherapy and for which patients the immunotherapy does not work as well. The next step is to realize an actual test for selecting the right patients for immunotherapy, with or without pre-treatment." 

Study: TONIC
Type of study: phase 2
Open or closed: open
If you think you are eligible for this study, please discuss it with your oncologist.

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