JUNCTION aims to lay the foundations for a completely new paradigm in the field of breast cancer, developing a technique capable of discriminating malignant lesions with high probability to show a pathologic response after neoadjuvant chemotherapy (NAC). This will lead to the future adoption of a novel personalized medicine path before surgery. Breast cancer is still the most diagnosed one and represents the leading cause of cancer death among women, determining an urgent need for new tools demonstrating early diagnostic, prognostic, and monitoring potential. Our goal is to merge the strengths of two orthogonal biophotonic techniques, each one targeting independent risk factor biomarkers, to reinforce the prediction of the NAC outcome. This multimodal investigation will be based on time domain diffuse optics (TD-DO) and surface enhanced Raman scattering (SERS) techniques, respectively sensitive to average tissue composition (e.g., collagen, hemoglobin, water) and to overexpression of peculiar biomolecules (e.g., epidermal growth factor receptor 2, mucin 1, microRNAs). A joint probe tailored for minimally invasive investigations, devised to enable in the future to approach the tumor in vivo, without punching a hole in it, will be designed to allow for combination of TD-DO and SERS techniques into a single examination session. However, this ambitious achievement is subject to preliminary research and developments in both techniques.

TD-DO is traditionally performed using two dedicated optical fibers at a distance of few centimeters in contact with the skin. Building on concrete preliminary results obtained in pioneering works at PoliMi, JUNCTION will develop TD-DO technologies, techniques and data analysis methods allowing broadband interstitial optical biopsies using null/small source-detector separations, paying attention to minimize the probe size by sharing the same optical fibers with the SERS system. SERS instead requires the developments of low-cost materials and process capable of offering stability of the substrates where the Raman signal enhancement takes place and

the design of functionalized biosensors for breast cancer specific bioreceptors. In this field, IFAC-CNR and LINKS have outstanding expertise. After initial efforts towards these goals, the possibility to combine the two analysis techniques will be validated on tissue-mimicking phantoms in laboratory settings, opening the way to future in-vivo studies after JUNCTION. Further, both techniques have already separately demonstrated promising diagnostic potential in the discrimination between malignant and benign lesions and in the capability to early predict the cancer onset. Finally, future adoption of bioresorbable optical fibers could lead to innovative monitoring paradigms, providing real time information during chemotherapy or after surgery, or monitoring of inoperable lesions. JUNCTION can therefore have a vast longer-term impact well beyond the prediction of NAC outcome.