Positive results from an international phase 3 clinical study (EMBER-3) evaluating a new hormonal therapy – imlunestrant – were presented for the first time at the San Antonio Breast Cancer Symposium 2024. Conducted in patients with breast cancer metastatic hormone-sensitive, this trial for which the Institut Curie is the first investigative center in the world, shows in particular that the immunoestrant is more effective than the hormone therapies currently used in 2nd line of treatment when combined with an inhibitor of cancer cell proliferation: abemaciclib (an anti-CDK4/6). These results are also the subject of a publication in the New England Journal of Medicine on December 11, 2024.
The vast majority of metastatic breast cancers are hormone dependent. Tumor cells, thanks to the estrogen receptor present on their surface, capture hormones which then stimulate the growth of the cancer. The standard treatment for this type of breast cancer most often consists of hormonal therapy combining an anti-aromatase drug (reducing the production of estrogen) with an inhibitor of cell proliferation (CDK4/6 inhibitor). However, for nearly 40% of patients, mutations occur in the ESR1 gene (coding for the estrogen receptor), leading to resistance to anti-aromatase agents and, ultimately, to a relapse of the cancer.
“The work we are co-publishing today supports a new second-line treatment option in metastatic hormone-sensitive breast cancer. This is based on a new molecule from the SERD family (or selective estrogen receptor inhibitor), oral, more effective and with a profile of moderate and already known side effects.declares Professor François-Clément Bidard, medical oncologist at the Institut Curie, professor at the University of Versailles Saint-Quentin/Paris-Saclay.
Institut Curie and its teams are strongly mobilized and their expertise recognized internationally in targeting ESR1 mutations to improve patient prognosis. And this work is fully in line with the dynamics of the new University Hospital Institute (IHU) Institute of Women’s Cancers co-supported by the Institut Curie, Inserm, PSL University and launched in June 2024: a program of breakthrough in supporting women thanks to its multidisciplinary scientific and medical approach.
Recent progress against resistance to hormone therapy
In the therapeutic arsenal against resistance to hormonal therapy, the only SERD (selective estrogen receptor inhibitor) available until recently was fulvestrant, administered by intramuscular injection and of variable effectiveness. SERDs are hormone therapy molecules that act by destroying the estrogen receptor, regardless of the presence of mutations on the receptor. From this observation, two major clinical trials, reported in 2022, made it possible to clarify how to use these SERDs:
- The international EMERALD trial1 coordinated in France by Professor Francois-Clément Bidard, demonstrated the superiority of a first oral SERD, elacestrant, compared to traditional hormonal therapies (including fulvestrant) in the event of tumor growth linked to a mutation ESR1. This study allowed the approval of elacestrant as monotherapy in cases of ESR1 mutation.
- The PADA-1 French academic test2 driven and coordinated by Professor Francois-Clément Bidard – led by the Unicancer/UCBG and GINECO groups3 showed that a liquid biopsy test developed at the Institut Curie targeting ESR1 mutations once they become detectable and before they have led to cancer progression can significantly delay the recurrence of breast cancer . This pioneering approach of intercepting ESR1 mutations with fulvestrant is now being continued with a new oral SERD in the SERENA-6 trial, with results expected in 2025.
EMBER-3: the breakthrough of the immunoestrant combined with a cell cycle inhibitor
In this context, EMBER-3 is a new randomized phase 3 study to demonstrate the effectiveness of a new new generation oral SERD: imlunestrant, administered as monotherapy or in combination with a CDK4/6 inhibitor ( abemaciclib), compared to traditional hormonal therapies (including fulvestrant), in patients with locally advanced or metastatic HR+ HER2- breast cancer with or without ESR1 mutation, after a first line of hormonal therapy.
The originality of this study is therefore to explore the combination of imlunestrant with a CDK4/6 inhibitor, a class of medication that patients had already been able to receive as first-line treatment. More than 800 women participated in this study. Drawing on its previously acquired clinical experience, Institut Curie was the center that participated the most globally in EMBER-3.
The results of the EMBER-3 study show that imlunestrant is more effective as monotherapy in cases of ESR1 mutation, with a reduction in the risk of progression of 38%. More interestingly, the combination of imlunestrant combined with a CDK4/6 inhibitor led to an additional 43% reduction in the risk of progression compared to imlunestrant alone in all patients, regardless of ESR1 status. Furthermore, the data on tolerance and safety from the study are very reassuring.
« The international recognition and expertise of the Institut Curie allows us to offer women who are being treated for their breast cancer numerous trials with innovative molecules, offering a glimpse of new therapeutic hopes, for today and for the future. future generations. Thanks to these results published in the New England Journal of Medicinethe EMBER-3 study establishes a new standard of treatment in second-line treatment of hormone-sensitive breast cancers, paving the way towards the use of oral SERDs in combination » specifies Professor François-Clément Bidard. “ This research should be compared with other work carried out at the Institut Curie which explores the mutational status of the ESR1 gene as a therapeutic decision-making tool, in particular to intercept and anticipate the progression of the disease via tests to detect circulating biomarkers. ».
French Breast Cancer Intergroup Unicancer (UCBG), Group of National Investigators for the Study of Ovarian and Breast Cancers (GINECO)
Many doctors from the Institut Curie are participating in the San Antonio Breast Cancer Symposium (SABCS) which takes place from December 10 to 13, 2024 in Texas (United States).
Awards and spotlight on infiltrative lobular breast cancers
On the occasion of SABCS 2024, Dr Lounes Djerroudi, physician researcher and pathologist at the Institut Curie, receives a prize from the Lobular Breast Cancer Alliance for his science thesis work carried out on infiltrating lobular carcinomas. In particular, two posters are presented during the congress. Infiltrating lobular carcinomas – overwhelmingly hormone-dependent – constitute the second most common type of breast cancer (10 to 15% of breast cancers) for which much research is underway to better understand the histological, biological, molecular, etc. specificities of these cancers.
Dr. Lounes Djerrudi will present a poster discussion on the study of the tumor microenvironment of these infiltrative lobular cancers. Driven by Professor Anne-Vincent Salomon, director of the IHU Women’s Cancer Institute and Dr Fatima Mechta Grigoriou, deputy director of the Cancer, heterogeneity, instability and plasticity unit (Inserm, Institut Curie), this work highlights highlights the role of an adhesion protein: E-cadherin on cells in the tumor microenvironment. The results demonstrate how inactivation of this protein – in lobular tumor cells – prevents the differentiation of fibroblastic cells and prevents the action of certain cells of the immune system. Other work, also carried out in the team of Professor Anne Vincent-Salomon on hereditary lobular cancers. These studies are carried out in collaboration with Dr Emmanuelle Fourme-Mouret, Dr Chrystelle Colas, Victoire Montecalvo, Rigleta Brahimaj and aim to understand the specificities of these hereditary forms of lobular cancers.
- E-cadherin inactivation shapes tumor microenvironment specificities in invasive lobular carcinoma (poster-discussion le 12 décembre) Clinico-pathological Characteristics of Breast Invasive Lobular Carcinoma in non-CDH1 genetic predisposition. Experience from the Institut Curie.
- Professor Anne Vincent-Salomon participates on December 11 in a session of clinical case discussions with congress participants (Clinical Case discussions)
To be continued
Dr Emanuela Romano, medical oncologist, medical director of the Cancer Immunotherapy Center at the Institut Curie spoke at the “Translational Workshop: Cancer Immunology Discovery Approaches into Clinical Trials” on December 10.
In this session, Dr. Emanuela Romano presented data revealing how single-cell sequencing of tumor-infiltrating T cell RNA can be used to determine factors associated with treatment response in triple-negative breast cancers. Thanks to collaboration with colleagues from the Immunity and Cancer Unit (U932, Institut Curie / Inserm), very positive results were obtained. They show how a specific subtype of CD8 T cells (late effector, dysfunctional CD8 T cells) and TCR (T cell receptor) dynamics – in particular clonal expansion – are important not only for a protective immune response against tumor but also for the response to treatment by chemo-immunotherapy in advanced triple negative breast cancers. Dr. Romano plans to validate these results in prospective cohorts of patients with triple negative breast cancer.
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