From left to right: Diana Saraiva, Rute Salvador, Bruna Correia, Guadalupe Cabral and António Jacinto
Did you know that chemotherapy is not always an appropriate treatment for breast cancer? That's the premise of the study recently published in Cancers journal, led by researcher Guadalupe Gabral from António Jacinto's Tissue Repair and Inflammation lab at CEDOC
They suggest a new biomarker to predict the successful treatment of breast cancer with chemotherapy and could also potentiate the beneficial effects of chemotherapy in patients that are not responsive to this treament. Read what Guadalupe had to say about this study, a collaboration between CEDOC, NOVA Medical School, Faculty of Medicine from Universidade de Lisboa, Hospital CUF and Hospital de Vila Franca de Xira.
What discoveries led you to the research described in your publication?
Neoadjuvant chemotherapy (NACT), applied before surgery, is the standard treatment for locally advanced or inflammatory breast cancer. However, less than 50% of patients respond to this treatment and the implementation of reliable biomarkers of response are needed.
We now understand the role of immune infiltration in tumors progression and in the likelihood of patients to respond effectively to a treatment. Namely, tumor infiltrating lymphocytes (TILs) have been associated with improved outcome of patients submitted to NACT. However, it is also well known that the suppression mechanisms may impair the lymphocyte antitumor responses, contributing to therapeutic failure. So, the usefulness of evaluating global TILs is still being debated.
We have previously reported that a specific subset of cytotoxic T lymphocytes expressing high levels of HLA-DR can assess patients that will respond to NACT, more accurately than TILs, and we proposed it as a potential predictive biomarker of NACT response. However, validation of this marker is still necessary, as well as alternative therapeutic options for breast cancer patients with a modest response to the conventional treatment.
What were you trying to understand and what is the main discovery of this work?
In this paper we wanted to contribute to the urgent need of implementing in the clinic, biomarkers of response to NACT treatment. Therefore, we validated in a second and independent cohort of breast cancer patients that HLA-DR level in cytotoxic T lymphocytes is a simple and robust predictive factor of these patients response to NACT, independently of several factors, such as patients age or breast cancer subtype. We also developed a predictive probability model, which we believe is a valuable tool to help clinicians to select in advance NACT-responders. Moreover, we found that this biomarker could also have a general prognostic value, which might be relevant for long-term breast cancer management.
Considering the importance of developing new alternative therapies for NACT non-responders, this study additionally suggests that increasing the expression of HLA-DR in cytotoxic T lymphocytes of NACT non-responders, consequently improving the ability of these cells to kill tumour cells, could be a promising therapeutic approach to improve advanced breast cancer treatment and the survival rates of this disease.
Why is this important?
Breast cancer (BC) is the most frequent type of cancer in women worldwide, accounting for up to 2 million new cases per year and remains the main cause of cancer-related death in women despite the advances in early diagnosis and treatment.
NACT is a widely accepted treatment for inoperable BC tumors or to downstage large tumors, improving surgical options. Besides, a complete tumor remission following NACT is strongly associated with BC patients good prognosis. Less than 50% of the patients achieve this goal, meaning that numerous BC patients are submitted to a 6 month-regime of aggressive, potentially toxic chemotherapy, without any benefit, probably delaying a more effective treatment and even with the chance of developing more severe forms of the disease. It is also well documented that chemotherapy in certain conditions, might support cancer progression and resistance to treatment. So, biomarkers that can effectively determine which patients would not benefit from this treatment and should promptly be directed to more targeted approaches are urgently necessary.
Nevertheless, the discovery of new predictive biomarkers should go hand-in-hand with the development of new treatments, to generate more options to patients that will not respond to conventional therapies.
Can you use an analogy to help us understand your work?
Although antibiotics are employed to treat infections in general, it is now well accepted that these medicines shouldn´t be used to treat, for instance, a cold or a flu, because these infections are caused by virus and antibiotics only work against bacteria. Even considering only bacterial infections, common antibiotics do not work equally for all of them. Sometimes is necessary to perform antibiograms to test which antibiotic is suitable to combat a specific infection. Indeed, lately, the world has been changing the way antibiotics are used as their misuse led to an increased generalized antibiotic resistance.
Similarly, although standard cancer treatments are effective in some cases, tumors and the overall tumor microenvironment that influences tumors’ development, are very heterogeneous, hence the type of response to the employed therapy, could be very diverse. Therefore, it is also crucial to change the paradigm of cancer treatments and walk more each day towards a scenario where patients are treated with a custom therapeutic approach.
Our study aimed to contribute to this issue, by developing a tool that could help to reduce the number of breast cancer patients that perform NACT without a clear advantage and additionally by providing advances in the development of novel immunotherapies for breast cancer patients.
What questions remain to be asked?
This study opened many other questions, that hopefully we will continue investigating. For instance, we still want to find answers to following:
- It is possible to use this biomarker also for other types of cancers?
- How exactly does this marker contribute to help the chemotherapeutic agents used in NACT treatment to eliminate the tumor?
- What strategies could be employed to increase this marker in the tumor microenvironment in order to improve BC treatments?
This article, titled "Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer" can be found at Cancers (here) and was also featured in Sábado magazine with an interview with Guadalupe (here).