A novel strategy to see and treat breast cancer: translation to intra-operative breast margin assessment

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Abstract With the widespread adoption of mammograms for early cancer detection, modern research has principally pivoted towards a focus on how to reduce over treatment of patients, particularly those with early stage breast cancer. Unfortunately, there remains a distinct lack of tools to reduce overtreatment, while ensuring the best possible outcome for patients. One such example is Breast Conserving Surgery (BCS) followed by radiation therapy. There is a wide-range of re-excision rates reported in the literature, but most groups report that 20-40% of patients undergo at least one re-excision. Taking additional shavings during BCS, new guidelines dictating relationships between margin status after BCS and re-excision, and radiation therapy all strive to maximize removal of residual tumor cells with as few surgeries as possible in patients with a new breast cancer diagnosis. However, secondary cancers from radiation therapy, the potential for cancer dissemination as a result of re-excision surgeries, and the burgeoning costs of repeat visits and interventions to an already depleted health care system necessitate new and innovative solutions to improve health outcomes, patient experience and reduce health expenditures. We propose a new paradigm for the effective visualization and treatment of residual disease at the time of the initial BCS while minimizing risks of re-excision surgeries and radiation and the cost of repeat visits and interventions. In our model, the primary tumor or the tumor cavity will be rapidly assayed for the presence of residual disease. The tumor cells will be selectively visualized using a fluorescently labeled agent that when topically applied targets a ubiquitous signaling node common to the all subtypes of breast cancer, including DCIS. The tumor cells will be localized by easily navigating back and forth between wide-field (to maximize sensitivity) and high-resolution imaging (to maximize specificity). The agent will be designed to have a dual role of selectively targeting tumor cells, at a low dose and demonstrating therapeutic potency at a high dose. This will allow for the same agent to eradicate residual tumor cells when applied topically to the tumor bed for those patients with residual disease. Heat shock protein 90 (Hsp90) stabilizes a number of proteins required for tumor growth. The overexpression of Hsp90 in breast cancer, the presence of ectopic Hsp90 only on breast tumor cells and the therapeutic potency of small molecule Hsp90 inhibitors provides the rationale for pursuing Hsp90 as the agent of choice. The first aim will focus on creating an effective platform for Hsp90 imaging to detect margin positivity and guide local therapy with proof-of-concept demonstration in pre-clinical models. The second aim will specifically focus on translating Hs-27 to the clinic, by first optimizing the protocol for imaging hps90 on pre-clinical issue specimens and then evaluating biopsies from patients undergoing diagnostic biopsy or mammoplasty. Given the overexpression of Hsp90 in breast cancer, the presence of ectopic Hsp90 only on breast cancer and the therapeutic potency of Hsp90 inhibitors, our technology platform will not only benefit margin assessment and treatment, but also diagnostic biopsy, prognostication and patient selection for Hsp90 inhibitor therapy.