MyPROBE

MyProbe: predicting the risk of breast cancer relapse

The MyProbe project aims to develop effective tools to identify patients with a high risk of breast cancer recurrence, and thus reduce the use of additional costly and burdensome treatments for patients with a low risk. This project is coordinated by Prof. Fabrice André, oncologist at Gustave Roussy, Villefuif.

Breast cancer is the most common cancer in women. It is estimated that approximately 1.7 million women worldwide develop breast cancer each year. In Western countries, breast cancer is diagnosed at an early stage in the vast majority of cases (> 95%). For about 15% of patients, the cancer will progress to the metastatic stage. This situation results in two challenges:

• Developing new drugs to reduce the risk of relapse,
• Predicting the risk of relapse in order to avoid administering heavy treatment to patients who do not need it.

This work is supported by the French National Research Agency (ANR-17-RHUS-008), as part of the future investment programme.

This project is made possible by the collections of biological samples constituted within the framework of the various clinical trials promoted by Unicancer Research. All information on the use of the personal data collected can be consulted on the dedicated website.

Context

The last few decades have seen many advances in the treatment of breast cancer. In particular, the improvement of hormonal therapies as well as the development of chemotherapies have reduced the risk of relapse to about 15%. As a result, a new need has emerged to identify in advance those patients who are at high risk of relapse, or on the contrary those whose cancer has a good prognosis.

This should make it possible to

• Reduce the cost of cancer management by avoiding the prescription of unnecessary and costly treatments to women who do not need them.
• Avoid the toxicities associated with over-treatment of patients with good prognosis cancer.
• Accelerate the development of new, more targeted drugs to reduce the need for chemotherapy, through the identification of biomarkers predictive of relapse

A first generation of tests called “genomic signatures” has been developed in the last decade. These signatures have made great strides in understanding the risk factors for cancer relapse, but have a number of limitations for their use in cancer management. The first is that these tests are only able to conclude a low risk of relapse for a small proportion of patients. Thus, only 15% of patients can actually benefit from them to avoid unnecessary treatment.

The second limitation is that the contribution of these tests compared to the diagnosis made by specialised anatomical-cyto-pathologists is low. Finally, these tests are not effective in assessing the risk of relapse in patients who have previously received chemotherapy. Thus, although these tests have allowed an indisputable advance in the field of precision medicine, they are not optimal for the management of patients and there is a need to identify new, more precise signatures.

Objectives

The objective of MyProbe is to develop and validate three new molecular tests to better characterize the prognosis of early breast cancer:

1. To develop a predictive signature of relapse for luminal cancers with a high risk of relapse.

This objective is a continuation of the first generation genomic signatures and should improve the assessment of the risk of relapse. This project consists of identifying new predictive biomarkers using tumour exome sequencing approaches as well as comparative genomic hybridisation (CGH) techniques. Two main approaches are envisaged to identify biomarkers of interest:

– To search for biomarkers associated with poor prognosis by identifying those that are most frequently altered in metastatic cancers.

– Assessing tumour heterogeneity to identify treatment-resistant tumour subclones.

2. Develop a test based on circulating tumour DNA.

In recent years, techniques for detecting circulating DNA have evolved considerably. They can now detect very small amounts of DNA released into the bloodstream by tumour cells. These techniques have the advantage of being minimally invasive compared to a biopsy and of allowing regular biological monitoring. MyProbe’s goal is to develop a test based on these techniques to identify relapse early, before the relapse is visible.

3. Development of an immune response signature for triple negative breast cancer.

Triple negative cancers are a subtype of breast cancer with the highest risk of recurrence. However, it appears that mobilising the patient’s immune system is associated with a better prognosis. Thus, MyProbe aims to develop a relapse predictive signature specific to these cancers based on a measure of the immune response.

Expected benefits

1. Public health

The potential savings for the health care system are potentially in excess of €500M per year in France. This will be possible thanks to a reduction in the use of unnecessary treatments for patients with a low risk of relapse.

• Chemotherapy-related toxicities avoided for more than 10,000 women per year in France.
• Acceleration of the development of new treatments through the identification of new therapeutic targets.

2. Industrial development

Commercialisation of diagnostic tests that can be used in clinical diagnosis for a potential turnover estimated at between €15 and 36 million per year.

Partner teams

Project organisation

Objective 1: Predictive signature of relapse in luminal cancers

WP1: Gene copy number alterations; teams involved: Institut Curie, Gustave Roussy, Unicancer.

WP2: Evaluation of intratumoral heterogeneity and identification of tumour subclones; teams involved: Institut Curie, Gustave Roussy, Unicancer.

WP3: Characterisation of genetic polymorphisms; teams involved: Centre Léon Bérard, Unicancer.

WP4: Integration of the results of WP1 to 3, development and validation of a unique signature; teams involved: Gustave Roussy.

Objective 2: early detection of relapse based on circulating tumour DNA

WP5: detection of residual disease on circulating tumour DNA; teams involved: Institut de Recherche en Cancérologie de Montpellier

Objective 3: Immune signatures of triple negative breast cancer

WP6: identification and validation of molecular markers; teams involved: Centre Léon Bérard, Veracyte, Unicancer.  

Objective 4: Project coordination, valorisation

WP7 : teams involved: Gustave Roussy, Unicancer.

Composition of the Scientific Committee

Judith Bliss – ICR – The Institute of Cancer Research – London

Carlos Caldas – CRUK – Cambridge institute – Cambridge

Nancy Lin – Dana-Farber Cancer Institute – Boston

Ann Partridge – Dana-Farber Cancer Institute – Boston

Lajos Pusztai – Yale Cancer Center – New Haven

Mark Robson – MSKCC – New York

Marjanka Schmidt – Netherdlands Cancer Institute – Amsterdam

Eric Winer – Dana-Farber Cancer Institute – Boston

Tony Ng – King’s College – London

Sibylle Loibl – German Breast group – Francfort

Giuseppe Curigliano – ESMO – Milan

Publications

• Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early Stage Triple Negative Breast Cancers.
  S Loi , D Drubay , S Adams, G Pruneri , P.A Francis, M Lacroix Triki, H Joensuu, M.V Dieci , S Badve , S Demaria , R Gray, E Munzone , J Lemonnier, C Sotiriou , MJ Piccart , P L Liisa Kellokumpu Lehtinen , A Vingiani , K Gray, F André, C Denkert , R Salgado, S Michiels.
  Journal of Clinical Oncology, 2019.
  DOI: 10.1200/JCO.18.01010

• Association between FGFR1 copy numbers, MAP3K1 mutations, and survival in axillary node positive, hormone receptor positive, and HER2 negative early breast cancer in the PACS04 and METABRIC studies.
  D Carene , A Tran Dien , J Lemonnier, F Dalenc, C LevyJ Y Pierga, W Jacot, J L Canon, C Richon , L Lacroix, C Caux, F André, S Michiels.
  Breast Cancer Research and Treatment, 2019.
  DOI: 10.1007/s10549 019 05462 y

• Prognostic value of tumour infiltrating lymphocytes in patients with early stage triple negative breast cancers (TNBC) who did not receive adjuvant chemotherapy.
  J. H Park, S.F Jonas, G Bataillon, C Criscitiello , R Salgado, S Loi , G Viale , H. J Lee, M. V Dieci , S B Kim, A Vincent Salomon, G Curigliano , F Andre, S Michiels.
  Annals of Oncology, 30: 1941 1949, 2019.
  DOI: 10.1093/ annonc /mdz395