Project Summary Despite dramatic progresses, many challenges still exist and significant efforts are needed in breast cancer researches, such as: (1) distinguish active (or aggressive) from inactive (or less aggressive) breast cancers and (2) conquer the problems of overdiagnosis and overtreatment. Very small tumors in breasts (VST, <10 mm, stage T1a, T1b) are detected more and more due to increasing sensitivity of screening technologies. Compared with relatively large lesions (>10 mm), VSTs are much more difficult to be radiographically diagnosed because tumor’s diagnostic features have not been well developed. Evaluation of VST’s activeness via imaging is even more challenging. Thus, the diagnosis and prognosis of VSTs have to rely on pathological and genetic assessments, which generates a large amount of unnecessary biopsies and patient’s anxiety, and significantly increases medical cost. In fact, biopsy results show about 80% VSTs are benign. About 15% are inactive or low grade cancers (less aggressive or indolent) and only about 5% are aggressive cancers. If missing the aggressive VSTs or leaving them untreated, it can increase breast cancer mortality. However, if conducting biopsy for each VST, it can lead to a large amount of unnecessary biopsies, and over-diagnosis and over-treatment are significant. If VST’s activeness can be evaluated via an imaging technology, patients can be appropriately stratified into different groups based on the acquired activeness/aggressiveness before biopsies. For inactive or benign VSTs, biopsies may be avoided and these VSTs can be monitored in a relatively long period of time (such as in a year). For less active tumors, biopsies can be an option depending other indications. Closely monitoring can be followed up (such as in 6 months). For obvious active VSTs, pathological and genetic assessments can be suggested. If these assessments show highly active/aggressive but metastases have not occurred, lumpectomy can be suggested. If metastases are also found, mastectomy may be an option. For those patients whose VSTs are evaluated as active and surgically removed, systemic adjuvant treatments (such as chemotherapies) can be suggested to reduce the recurrence and metastasis rates. While those patients whose VSTs are evaluated as less inactive or low grade but are surgically removed, local radiation adjuvant therapy (not systemic therapies) can be suggested to avoid side-effects or over- treatment. We propose to develop a new imaging technology to quantify tumor’s activeness or aggressiveness by mapping tissue’s local temperature and metabolic rate. The logic is that active or aggressive cancer cells have high metabolic rate and lead to high local tumor temperature. This goal can be achieved using our recently discovered temperature super-sensitive probes and a high-resolution imaging technology in centimeter-deep tissues, ultrasound-switchable fluorescence. The specific aims of this proposal include: (1) further develop the proposed imaging method; (2) validate and characterize the proposed method in ex vivo tissue samples; (3) validate and characterize the proposed method in live animals with breast tumors.

Project Narrative The proposed technology can quantify breast tumor’s activeness or aggressiveness by mapping tissue’s local temperature and metabolic rate. Thus, active, less active and inactive breast lesions can be distinguished before biopsies based on the acquired activeness. Therefore, patients can be appropriately stratified into different groups and suggested with different diagnostic and treatment plans for avoiding overdiagnosis and overtreatment.