by Vera Martinella
Italian-British research helps understand which patients with a particularly aggressive type of cancer could benefit from new immunotherapy drugs
An important step forward for the treatment of a type of cancer, the so-called “triple negative” breast cancer, which is particularly aggressive and is more frequently diagnosed in young women, before the age of 40. A discovery that comes after research lasting five years and with results that are so relevant as to be published in the scientific journal Nature: thanks to the collaboration between the Michelangelo Foundation, the Cancer Research UK Institute and the San Raffaele Hospital, tumor characteristics have been identified that predict response to immunotherapy. «About 8 thousand women in our country fall ill with triple negative breast cancer every year – explains Giampaolo Bianchini, head of breast oncology at the IRCCS San Raffaele Hospital in Milan -. It is still among the most difficult to treat today, but fortunately scientific research is making important progress and new therapeutic combinations are able to prolong the survival of patients, with a good quality of life. However, further, more effective strategies are needed and with this study we have made significant progress: we have understood that the type and spatial localization of some cells in these tumors could be used to predict whether patients with triple-negative breast cancer are able to to respond to immunotherapy.”
More often in young women
With 55 thousand new cases diagnosed in 2020 and 37 thousand Italians living with a metastatic neoplasm, breast cancer is the most widespread not only among females, but in the entire population. Despite the many progress made (fortunately 87% of patients are alive 5 years after diagnosis) it remains the leading cause of death from cancer among Italians. Triple-negative carcinoma, which represents 15% of breast cancers and is most frequently diagnosed in young women (before the age of 40), is among the most difficult forms to fight because it is biologically more aggressive than other tumor subtypes. In fact, the term triple-negative indicates the absence of all three markers that in some way “guide” the treatment in other forms of cancer which instead have well-defined receptors. In this case, however, the neoplastic cells do not have either the estrogen or progesterone receptor, i.e. those receptors that lead to defining the hormone-dependent tumor and make it possible to focus on anti-hormonal therapy.
The therapies
Until recently, only classic chemotherapy was available for triple negatives. For a couple of years, however, new drugs have arrived for advanced metastatic forms and it is now clear that the biopsy is a necessary step to understand which specific breast cancer is present in the individual patient, before starting any therapy, even before surgery. Why? «We understood that the triple negative is a very heterogeneous subtype, on average biologically aggressive, but not necessarily: there are some that are very aggressive and others that are more “good” – replies Bianchini, who is also scientific coordinator of Translational Research at the Michelangelo Foundation and co-senior author of the study just published in Nature -. Immunotherapy exploits the body’s natural defenses to fight cancer and the results of this new research indicate that for it to be effective, not only specific types of immune cells are needed, but also in the right spatial context. We found that it was possible to identify unique characteristics that differed between a patient who was able to respond to immunotherapy and one who was not. In particular, the presence in the tumor, before starting therapy, of both tumor cells and the immune system with specific functional state characteristics, was able to identify patients with greater benefit from immunotherapy. Furthermore, the presence of close interactions between B lymphocytes and cytotoxic T cells and tumor cells was also indicative of a likelihood of benefit.”
I study
In their analysis, the San Raffaele researchers used 660 biopsy samples of triple-negative tumors collected from patients enrolled in the NeoTRIP clinical study, designed and conducted by the Michelangelo Foundation. This study compared in the neoadjuvant phase (before surgery) the use of chemotherapy alone with chemotherapy associated with atezolizumab, an immune checkpoint inhibitor that has the PD-L1 protein as its molecular target. The samples were then searched for the presence of 43 key proteins, indicative of the characteristics and behavior of the different cells. Using an extremely sophisticated and innovative technique called mass cytometry imaging (of which Raza Ali of the Cancer Research Institute in Cambridge, co-senior author of the study, is one of the world‘s leading experts), detailed images were produced, which revealed exactly how each of the 43 proteins was distributed on each single cell, therefore giving extremely precise spatial information.
Towards precision immuno-oncology
«The study of biopsies collected after the first cycle of therapy showed that the increase in cytotoxic T cells was associated with benefit and conversely the increase in a protein called CD15 on tumor cells was associated with resistance, representing a new potential target therapeutic – concludes Raza Ali -. It is a significant contribution towards precision immuno-oncology. We are now taking this research forward by investigating whether a simple test could be used to identify which tumors are likely to respond to immunotherapy, so that it can be used in a routine clinical setting.” Understanding the mechanisms of resistance to immunotherapy in triple-negative tumors may therefore allow us to identify new therapeutic strategies to extend its benefit to an ever-increasing number of patients with this aggressive form of breast cancer. The research was supported by Cancer Research UK, the AIRC Foundation for Cancer Research and the Breast Cancer Research Foundation.
October 10, 2023 (modified October 10, 2023 | 08:56)
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