Advanced Breast Cancer Translational Laboratory

We aim to reduce the incidence and mortality of Metastatic Breast Cancer (MBC), with the primary goal of increasing early (stage I) diagnosis from 30% to 70% within the next 10 years.

In 2020, in Portugal, almost 7,000 women were diagnosed with and 1,800 died of breast cancer (BC). The BC subtypes differ in key genetic alterations, therapeutic strategies and clinical prognosis, which are largely conditioned by the metastatic behavior of the cancer. In the absence of identified risk factors, a 50-year-old woman is screened by mammogram every two years (until her 70th birthday) through the National Health System. This screening program allows for only about 30% of the women diagnosed to be identified at stage I. Almost 40% of women are diagnosed at stage II, and 20% and 7% are diagnosed at stage III and metastatic IV, respectively. The detection of cancers at later stages has a significant impact on the efficacy of cancer treatments and affects the progression free survival (and evolution towards metastatic stage) and/or the overall survival. The first aim of this mission is to improve the detection of early-stage BC to achieve 70% of women diagnosed within the next 10 years. At the same time, treatment of BC, in particular metastatic disease, raises many challenges, due to resistance to available therapies. Thus, a second goal is to develop and implement custom-made tests that will allow the identification of biomarkers and phenotypic features predisposing to metastatic behavior and therapy resistance. This mission is in complete alignment with Europe’s Beating Cancer Plan (1), with the EU recommending extending breast cancer screening from women aged 50 to 69 to include women between 45 and 74 years of age (2).

To address the two challenges of Mission 2, we propose to design, develop and implement BC comprehensive genomic profiling from blood and fecal samples as a novel, highly sensitive and precise companion test for early detection of BC, for therapy response prediction at the diagnosis stage, and for monitoring therapeutic response throughout the treatment course. To overcome limitations of deep profiling of circulating tumor DNA, due to the difficulty of detection in the early stages of cancer, we propose to take advantage of the emerging relationships between human cancers and the gut microbiome. In fact, growing evidence suggests that circulating microbial DNA (cmDNA) may have predictive value to discriminate between healthy individuals and patients with subtypes of BC. By combining the identification of detailed BC-driving gene copy number and mutations with the detection of specific microbial DNA, our original approach will have increased specificity, innovative character and clinical relevance.

In collaboration with public/private hospitals in the Lisbon area, a prospective breast cancer longitudinal collection of tumor specimens (at diagnosis and post-treatment), adjacent normal tissue, blood and feces, with detailed patient clinical history will be established. We will determine the tumor mutational landscape and local immune response, and the tumor and fecal microbiomes. We will uncover novel associations between selective tumor mutations, specific bacteria species and immune/stromal responses in TME, using dimensionality reduction combined with machine learning methods. This information will be crossed with spatial distribution of tumor cells, phenotype of the TME constituents in situ and the patient clinical data. This will facilitate the revelation of biomarkers predicting treatment response. The therapeutic relevance of these biomarkers will be demonstrated by the detection of circulating tumor DNA and circulating and gut mDNA to create easy- to-use breast cancer comprehensive genomic profiling blood and fecal tests. The most robust biomarkers will be interrogated for their potential role in mechanism(s) of therapy resistance/sensitivity and of cancer progression/ metastasis, allowing identification of novel treatment options preventing the emergence or progression of advanced MBCs.

(1) A cancer plan for Europe

(2) Questions and answers: A new EU approach to cancer screening

Team