Work Package 1 Context

Objectives:

WP1 will identify the risk factors for breast cancer-related secondary lymphedema. As women developed lymphedema months, sometimes years after surgery, we postulate that secondary lymphedema is not only a side effect of the surgery and our goal is to identify which factor can induce the lymphatic dysfunction.  Women who develop lymphedema exhibit a normal lymphatic vasculature before the cancer treatment, then, they develop lymphedema after up to 5 years of treatment. Therefore, we postulate that treatments, radio- and chemotherapy, can induce a lymphatic vascular dysfunction. Partner 7 (CNRS) is a specialist of the effect of radiotherapy on tumor angiogenesis. Importantly, they try to decipher the detrimental effect of proton vs photon therapy on the lymphatic endothelium.

Photons deposit their radiation doses close to their entrance into the body, whereas protons deposit most of their energy at the end of their paths. Thus proton therapy delivers localized radiation, decreasing integral radiation dose to normal tissues and avoiding surrounding tissue damage. Despite these potential advantages, a fundamental issue with protons is the ability to stop the proton at the targeted site, as proton beam is less sharp due to considerable scattering. Therefore, it is not clear whether photon vs proton therapy must be use in breast cancer and they both need to be investigated in our study.

Also, the effect of first line chemotherapy on the lymphatic endothelium has been poorly investigated. Partner 7 is collaborating with partner 1 to investigate the role of paclitaxel, a conventional treatment for breast cancer, on the lymphatic endothelium function. They expect to cover a large spectrum of cytotoxic agents to determine their role on promoting a lymphatic dysfunction.

The major lymphangiogenic growth factor identified for lymphatic repair is VEGFC. In theralymph project, we expect to combine VEGFC with another molecule to perform multiple gene therapy for secondary lymphedema. In this WP, we propose to investigate the effect of radio- and chemotherapy on VEGFC synthesis as partner 7 previously shown regulations in tumor models.

The second objective of the effects of radiotherapy and chemotherapy on the lymphatic collector architectures will be to compare the data to those obtained in WP2 by partner 4 – Uppsala Universitet (lymphatic signature in lymphedema).