Hopes for a new therapeutic strategy in triple negative breast cancer

Claudia Legris
02/20/2020
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A collaboration between Institut Curie and the US National Cancer Institute paves the way for new treatments.
Elisabetta Marangoni

Triple negative breast cancer cases - highly aggressive - represent 15 to 20% of breast cancers. They are specific in that they have no hormone receptors and therefore cannot be treated via hormone therapy. In addition to surgery and radiotherapy, chemotherapy is the main treatment option for this type of breast cancer.

New treatment options could soon be available according to research produced by a collaboration between several Institut Curie research teams and its hospital, and a team from the National Cancer Institute (NCI-NIH, based in the USA). Elisabetta Marangoni initiated and coordinated this multi-discipline project, published in the journal Science Translational Medicine.

The focal point of the research is Irinotecan, a chemotherapy treatment that targets the enzyme Topoisomerase 1, whose effectiveness is closely linked to the inability of tumors to repair DNA damage. Irinotecan is used to treat patients suffering from lung or colorectal cancers, but not for patients with breast cancer. "Our hypothesis was that triple negative breast cancer could respond favorably to this chemotherapy due to a major and frequent repair failure in this category of breast cancers."

Elisabetta Marangoni's team in Institut Curie's translational research department tested Irinotecan on 40 xenografts taken from patient tumors, known as PDX (patient-derived xenograft). A pre-clinical model developed at Institut Curie and close to the clinical setting.

The new results show that of the 40 tumors tested, one third responded with disappearance or significant regression of the tumor, and one third with stabilization of the cancerous mass.

In the next phase, the team searched for predictive response biomarkers in order to test patients likely to respond to this treatment in a clinical setting. Marc-Henri Stern's team developed a molecular signature to detect BRCAness, which causes the DNA repair failures. "We found that the tumors with BRCAness have a better chance of responding to Irinotecan."

When analyzing gene expression in sensitive tumors, two other biomarkers were also identified, the Schlafen 11 gene (SLFN11), more strongly expressed in sensitive tumors, and the RB1 gene (retinoblastoma), less strongly expressed.

The teams then combined the three markers and discovered that their association helps identify the tumors that respond best. "These three biomarkers are easy to test in clinical practice," explains Elisabetta Marangoni. 

Lastly, the team tested a new class of chemotherapy with the same action mechanism as Irinotecan, but with fewer side effects. These new chemotherapies - known as Indotecan and Indimitecan - were developed by Yves Pommier at the National Cancer Institute. The tests carried out with these new anti-cancer medications proved very positive. They pave the way for clinical trials in patients with triple negative breast cancer.