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04Sep 2019

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'Breast cancer is coming within reach of immunotherapy’

Marleen Kok

Breast cancer has not hitherto been at the forefront of immunotherapy treatment. At the 17th Bossche Mamma Congress, Dr. Marleen Kok (of The Netherlands Cancer Institute) explains why, and how immunotherapy is gradually gaining traction in the treatment of breast cancer.

In contrast to the treatment of melanoma or lung cancer, for instance, immunotherapy in the form of checkpoint inhibitors does not yet form part of the standard toolkit in the treatment of breast cancer. This has a number of causes, explains Marleen Kok. "To start with, breast cancer is a disease with a relatively favourable prognosis for which many effective forms of treatment already exist. This makes the need for research into new treatments, including immunotherapy, less urgent than it originally was for metastatic melanoma or lung cancer. But at least as significant is the fact that breast tumours form a less straightforward target for checkpoint inhibitors than do melanomas and lung tumours. After all, these inhibitors work by strengthening the body's existing immune response against the tumour, and this is exactly what may be absent in many breast tumour cases. In the absence of a strong endogenous immune response to the tumour, there isn't much for checkpoint inhibitors to do. What isn't there, can't be strengthened."

This does not, however, imply that the use of checkpoint inhibitors could never be successful in the treatment of breast cancer. "In the studies that have been carried out into the use of checkpoint inhibitors for breast cancer, a small percentage of the patients did, in fact, show a long-term response," Kok notes. "For triple negative breast tumours in particular, clinically relevant results were obtained in the first-line use of checkpoint inhibitors." It is not so strange that it was the triple negative breast tumours that responded comparatively well to checkpoint inhibitors: "Triple negative breast tumours generally contain relatively large numbers of tumour-specific cytotoxic lymphocytes, so-called TILs," Professor Christine Desmedt (KU Leuven, Belgium) explained in an earlier lecture at the 17th Bossche Mamma Congress. "And the presence of TILs in the tumour is a good indicator of success in treatment using checkpoint inhibitors."

For instance, in the KEYNOTE-173 study, in which women with triple negative breast cancer were given neoadjuvant treatment with the checkpoint inhibitor pembrolizumab (plus chemotherapy or placebo), the degree of pathologically complete response (pCR) to the neoadjuvant treatment was correlated with the number of TILs in the tumour. "The tumours of patients showing a pCR contained a relatively large number of TILs, both at the start of neoadjuvant treatment, but particularly during this treatment." Desmedt showed that in the metastatic setting, too, a clear correlation existed between the number of TILs and survival rates during/after treatment with a checkpoint inhibitor.

Warming up 'cold' tumours

The insight that treatment with checkpoint inhibitors can only be successful if an immune response is already taking place in the tumour has opened the way for a new treatment strategy. Kok: "When a tumour does not excite an endogenous immune response we call it a 'cold' tumour. What we are now trying to do in a number of studies is to elicit an immune response to the tumour before starting immunotherapy. We want to 'warm up' cold tumours, so to speak, using chemotherapy and/or radiotherapy."

The Dutch phase 2 TONIC study of 66 women with metastatic, triple negative breast cancer examined the effects of five different two-week treatments preceding immunotherapy with nivolumab. "Inductive therapy for two weeks using a low dose of cisplatin or doxorubicin was linked to relatively high response percentages, namely 23% and 35% respectively. The preliminary results of this study were recently published in Nature Medicine. We are now completing the second part of the TONIC study, in which we further examine the effects of pre-treatment with doxorubicin in a larger group of patients." A similar approach was adopted in the Dutch phase 2 GELATO study, in which women with metastatic lobular carcinoma of the breast - also a 'cold' tumour - were given a low weekly dose of carboplatin which was combined with atezolizumab from the third week onwards. The idea is that carboplatin-induceed DNA damage brings about a stress reaction in the cancer cell which triggers an endogenous immune response. The atezolizumab can then strengthen this response. Another Dutch study is the national triple B study being carried out by the Breast Cancer Research Group (BOrstkanker OnderzoeksGroep, BOOG) on immunotherapy, a four-pronged study examining the use of atezolizumab immunotherapy as a first-line treatment for patients having metastatic triple negative breast cancer in combination with paclitaxel or carboplatin/cyclophosphamid chemotherapy.

Neoadjuvant immunotherapy

Finally, the Dutch phase 2 BELLINI study, which is about to begin, will compare the effect of adding low-dose chemotherapy or new forms of checkpoint inhibition to neoadjuvant treatment with nivolumab. Other studies of neoadjuvant immunotherapy for triple negative and high-risk, oestrogen receptor positive breast cancer are in preparation in the Netherlands. Kok: "All in all, immunotherapy has also become an important research theme in breast cancer treatment."

Source: Oncologie Up-to-date 2019 vol 10 number 4

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