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12/08/2021 - Press release

Way to avoid treatment resistance for one of the most aggressive breast cancers identified

Researachers have validated the relationship between the levels of a protein, neuregulin, and the generation of resistance to one of the main treatments for HER2-positive breast cancer

A study led by doctors and researchers from Hospital del Mar, the Hospital del Mar Medical Research Institute (IMIM), and CIBER Oncology (CIBERONC) has demonstrated the role a protein, neuregulin, plays in generating resistance to the most common treatment for HER2-positive breast cancer, one of the most aggressive types. The study, published in the journal Clinical Cancer Research, and in which leading Italian researchers Luca Gianni from the Fondazione Gianni Bonnadonna and Giampaolo Bianchini from the IRCCS Ospedale San Raffaele have collaborated, has identified that in patients with high levels of this protein, the success rate with the monoclonal antibody trastuzumab, the first-line drug, drops. Conversely, when combined with another monoclonal antibody, pertuzumab, the situation is reversed and full pathological response levels are restored.

The study involved an analysis of in vitro data and the results were confirmed using tumour samples from patients participating in a previous study, NeoSphera. The results show that in cases with high levels of neuregulins, the trastuzumab-only approach does not achieve complete remission of tumour cells, as treatment resistance develops. But if a second drug, pertuzumab, is added, the results change. "When the tumours from the NeoSphera study with the highest expression of neuregulins were treated with trastuzumab and chemotherapy, pathological complete response was not achieved, but when they were treated with pertuzumab, trastuzumab and chemotherapy, a positive response was observed. Given that this study is a prospective randomised study, the value of this confirmatory finding is very high, and it validates the results obtained in the laboratory", explains Dr Joan Albanell, lead author of the study, head of the Medical Oncology Service at Hospital del Mar and director of the Cancer Research Programme at IMIM-Hospital del Mar.

Dr. Joan Albanell.

A little-studied protein

Neuregulin is a protein that binds to one of the receptors present on tumour cells, HER3. This bond combines with another receptor, HER2, forming a pair that has the greatest capacity for proliferation and tumoral invasion among the possible activation pathways in HER2-positive breast cancer. This type of tumour accounts for 15-20% of breast cancers and, in almost half of the cases, a complete pathological response is not achieved.

Now, for the first time, it has been possible to establish a correlation between the levels of this protein, present in 13.2% of the tumours analysed, and the decreased treatment success seen with trastuzumab, as well as the role of pertuzumab in reversing this situation. The study will serve to "optimise which patients can benefit from pertuzumab, better classify those who need a double block with both trastuzumab and pertuzumab, and maximise the benefit", as well as enabling "continued research into neuregulins in other clinical scenarios, where the benefit of pertuzumab is limited. We need to see which populations benefit most and also validate its role for selecting those patients who can benefit most from pertuzumab in the postoperative setting, as a neoadjuvant treatment in cases of metastasis", continued Dr Albanell.

In addition, the study has identified fibroblasts, connective tissue cells present in tissues, as originating neuregulins, confirming the importance of the tumour microenvironment, its surroundings, in the proliferation of cancer cells. The IMIM-Hospital del Mar has already participated in several clinical studies in this field, involving the study of therapies directed against these cells.

"Identifying neuregulins as a biomarker that determines the most appropriate treatment for a particular type of breast cancer will enable more personalised and effective treatment. This kind of finding is the perfect example of the type of research that we want to develop at the Hospital del Mar-IMIM", says Dr Joaquín Arribas, author of the study and Director of the IMIM.

Personalised care and cutting-edge cancer research at Hospital del Mar

Personalised care for cancer patients at Hospital del Mar is provided through pioneering and cutting-edge work in multidisciplinary functional units specific to each type of tumour. The units, comprising professionals specialising in each cancer type, offer the best therapeutic options in a model of shared decision-making with the patient. Nurse managers guide patients through the diagnostic and therapeutic process. This quality care is combined with groundbreaking cancer research at the Hospital del Mar Medical Research Institute (IMIM) and an extensive programme of clinical trials. The research areas focus on furthering immunotherapy and liquid biopsy, searching for biomarkers and new therapeutic targets, and developing new surgery and radiotherapy strategies to improve efficacy and the quality of life of patients. This research generates almost 200 articles in scientific publications each year, two out of three of which are in high-impact journals. This state-of-the-art care and research are the basis for teaching excellence at the Hospital del Mar Campus.

Reference article

Cristina Guardia, Giampaolo Bianchini, Oriol Arpí-LLucià, Silvia Menendez, David Casadevall, Barbara Galbardi, Matteo Dugo, Sonia Servitja, Juan Carlos Montero, Luis Soria-Jiménez, MohammadA Sabbaghi, Raul Peña, Juan Madoz-Gúrpide, Belen Lloveras, Ana Lluch, Pilar Eroles, Joaquin Arribas, Atanasio Pandiella, Luca Gianni, Federico Rojo, Ana Rovira, and Joan Albanell. Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer. Clin Cancer Res. Published online August 12, 2021. doi: 10.1158/1078-0432.CCR-20-2915

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