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Molecular classification of metastatic breast cancer enables the prediction of the disease prognosis and the benefit of a cell cycle inhibitor

From left to right, Nuria Chic, Laia Paré, Olga Martínez-Sáez, Fara Brasó and Aleix Prat. Photo: Francisco Avia - Hospital Clínic

From left to right, Nuria Chic, Laia Paré, Olga Martínez-Sáez, Fara Brasó and Aleix Prat. Photo: Francisco Avia - Hospital Clínic

29/03/2021

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A research team from Hospital Clínic-IDIBAPS, the University of Barcelona and the academic research group on oncology SOLTI has shown that the molecular classification of breast cancer, which divides it into four sub-types (Luminal A, Luminal B, HER2-enriched and Basal-like) is useful in patients with advanced hormone-sensitive breast cancer. This is the largest study so far to show the value of the biomarker and the first to do so in the context of the CDK4/6 inhibitors such as ribociclib.

The study, published in the American Society of Clinical Oncology’s Journal of Clinical Oncology, has been coordinated by Aleix Prat, lecturer at the Department of Medicine of the UB, head of the Department of Medical Oncology in Hospital Clínic and head of the group Translational Genomics and Targeted Therapies in Solid Tumours at IDIBAPS, and president of SOLTI.

Breast cancer affects 2.3 million people and causes the death of 571,000 every year. Among the different breast cancers, the hormone-sensitive one accounts for the 70% of all cases. When the disease is at an early phase, the local treatment, chemotherapy and hormonal treatment for five or ten years prove to have benefits on the long run regarding survival. However, about 20-30% of the patients show metastasis during the follow-up period. In this context, survival is comprised and biomarkers and specific treatments are required.

Over the last years, new therapies have been introduced for the advanced-state hormone-sensitive disease, such as the introduction of CDK4/6 inhibitors, a key protein in the cell cycle. “The recent introduction of CDK4/6 inhibitors like ribociclib has improved the survival of patients with advanced hormone-sensitive breast cancer. However, this disease is clinically and biologically heterogeneous and there can be, at least, four molecular sub-types. To date, we did not know about the real value of this molecular classification in the advanced hormone-sensitive disease”, notes Aleix Prat.

Over the last five years, the research line of the laboratory led by Aleix Prat enabled the description of the biological heterogeneity of the hormone-sensitive disease and the identification of four molecular groups: Luminal A, Luminal B, HER2-enriched and Basal-like, with different prognosis and sensitivities to treatments. “We asked ourselves how this biological classification behaved in the advanced hormone-sensitive breast cancer”, notes Aleix Prat. “Two previous studies, led by our group, on patients with advanced hormone-sensitive breast cancer that were treated with hormonal therapy showed that the Luminal A subtype has a better prognosis, while the HER2-enriched and Basal-like subtypes have the worst prognosis. However, Luminal B has a fair prognosis. In this context, we had to confirm the findings and see the impact of the CDK4/6 inhibitors, since these are the current standard treatment”, he adds.

In the article published in Journal of Clinical Oncology, the researchers analysed the expression of 152 genes in 1,160 patients with advanced hormone-sensitive breast cancer treated in three III phase clinical trials in the MONALEESA program, which led to the health authorities’ approval of the ribociclib. A total of 448 patients received the hormone therapy alone, and 672 patients received hormonal therapy combined with ribociclib. The molecular subtype Luminal A was the most common (47%), followed by Luminal B (24%), HER2-enriched (13%) and basal-like (3%). Compared to Luminal A, the risk of the disease progressing was higher in the other molecular subtypes. For instance, the risk of progression in subtypes HER2-enriched and Basal-like was 2 and 4 times higher compared to Luminal A.

Researchers saw that all molecular subtypes benefited from ribociclib, except for Basal-like. “On the one hand, our study validates previous observation on the prognostic value of the molecular classification. On the other, we show for the first time the high clinical value of ribociclib in the HER2-enriched subtype, an aggressive tumour group when it comes to hormonal therapy alone. Last, our study states that we should know the molecular subtype will become more important every time”, concludes Aleix Prat. Future studies will establish the predictive value of the molecular classification of the hormone-sensitive breast cancer in other contexts. Specific examples would be the search for new targeted therapies for the aggressive Her2-enriched and Basal-like subtypes. In this line, SOLTI cooperative group, led by Alexi Prat, is carrying out multi-center clinical trials for each of these groups, which assess innovative therapies such as immunotherapy.

This study was funded by Novartis, the Carlos III Health Institute, the Breast Cancer Research Foundation, the Breast Cancer Now Foundation, the Catalan Government within the Peris Program, La Marató TV3 Foundation, the European funds Horizon 2020 (RESCUER project), the Scientific Foundation of the Spanish Association against Cancer (AECC), and the associations Save the Mama, Pas a Pas and Metastatic Breast Cancer.

 

Study reference:

A. Prat, A. Chaudhury, N. Solovieff, L. Paré, D. Martínez, N. Chic, O. Martínez, F. Brasó-Maristany, A. Lteif, T. Taran, N. Babbar i F. Su. "Correlative biomarker analysis of intrinsic subtypes and efficacy across the MONALEESA Phase III studies". Journal of Clinical Oncology, February, 2021. DOI: 10.1158/1538-7445.SABCS20-GS1-04

 

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