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Principal Investigator: James Peter Basilion
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $409,926
Funding agency: National Cancer Institute
Project Summary/Abstract: Breast cancer is the most common cancer in women, with an estimated 246,660
cases (and 40,450 deaths) in the US during 2015. Due to better screening techniques cancers are caught earlier
and 75% of patients are candidates for breast conserving surgery (BCS) to remove the cancer. BCS is
cosmetically preferable to the alternative (mastectomy) and long-term survival rates are equivalent [1]. The
success of BCS is assessed post-operatively by pathology. The status of the microscopic margins of excision of
the lumpectomy specimen is still the most important prognostic and risk factor for local recurrence [2,3]. A
positive margin indicates that invasive carcinoma or ductal carcinoma in situ is touching a tissue edge of a
lumpectomy specimen. Among patients treated by BCS and radiation therapy, positive margins are associated
with a 2-fold increase in the risk of local recurrence when compared with negative margins [4]. A finding of
positive margins is estimated to occur between 8% to 86% of the time, requiring patients to return for further
treatment often associated with poorer cosmetic results and increases in local and distant recurrence of the
disease. Current pathology methods only assess about 1/10 of 1% of the entire volume of the removed specimen.
A consequence of margin undersampling is that local recurrence occurs in 5-16% of patients with pathologically
clean margins, suggesting that one or more regions of tumor had not been sampled during pathological analysis
resulting in tumor remaining in the patient. In addition, there is still no universal agreement among breast
surgeons on what constitutes an adequate negative margin for patients undergoing BCS [5]. Together these
data demonstrate the unmet clinical need for technologies that rapidly and globally identify cancerous tissues in
the surgical cavity and can be used to guide their surgical resections during the procedure. Molecular imaging
guided resections of tumors during surgeries are now being developed. However, most approaches employ IV
administration of optical imaging agents, which require hours or days to highlight tumor tissues. Moreover,
infiltrating cancer cells in tissues surrounding the main mass may not have developed a vasculature and likely
would not be identified using injected agents. Finally, illuminating the entire cancer mass may create a high
background signal from tumor that is not “at the margin” of the lumpectomy. Exploiting increased protease
expression at the edge of breast cancers we introduce the novel concept of in vivo topical administration of
quenched fluorescent molecular imaging probes to identify cancer that may remain in the surgical cavity after
standard-of-care resection. This builds on years of preclinical studies and seeks to characterize, perform
toxicology, and finally a Phase 1A & B clinical trial to demonstrate the utility of this novel approach. It has the
potential to reduce re-excisions as well as the false negative rate from pathology undersampling, with a
consequent savings in healthcare costs and, enhancement in patient life quality.
Terms: <Abscission><Academic Medical Centers><Agreement><Animals><Body Tissues><Breast><Breast Cancer><Breast Conservation Treatment><Breast Neoplasms><Breast Reconstruction><Breast Tumors><Breast-Conserving Surgery><Cancerous><Cancers><Carcinoma><Cell Communication and Signaling><Cell Signaling><Cessation of life><Clinical><Clinical Trials><Cosmetics><Cyclic GMP><Cytology><DCIS><Data><Death><Detection><Development><Diffusion><Distant><Dose><Drug Kinetics><Ductal Breast Carcinoma In Situ><Ductal Carcinoma In Situ><Epithelial cancer><Esteroproteases><European><Evaluation><Excision><Extirpation><FDA approved><Fixation><Fluorescence><Fluorescent Probes><Formalin><Freeze Sectioning><Frozen Sections><General Prognostic Factor><Goals><Guanosine Cyclic Monophosphate><Health Care Costs><Health Costs><Healthcare Costs><Home><Hour><Human><Image><Imaging Device><Imaging Instrument><Imaging Tool><Infiltration><Intracellular Communication and Signaling><Intraductal Carcinoma><Intraductal Carcinoma of the Breast><Limited Resection Mastectomy><Local Excision Mastectomy><Lumpectomy><Malignant Breast Neoplasm><Malignant Cell><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasms><Malignant Tumor><Mammaplasty><Mammary Cancer><Mammary Neoplasms><Mammectomy><Mammoplasty><Mastectomy><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Methods><Microscopic><Modern Man><Molecular Probes><Morbidity><Morbidity - disease rate><Non-Infiltrating Ductal Breast Adenocarcinoma><Non-Infiltrating Ductal Carcinoma of the Breast><Non-Infiltrating Intraductal Adenocarcinoma><Non-Infiltrating Intraductal Breast Adenocarcinoma><Non-Invasive Ductal Breast Adenocarcinoma><Non-Invasive Ductal Carcinoma of the Breast><Non-Invasive Intraductal Breast Adenocarcinoma><Noninfiltrating Intraductal Carcinoma><Operative Procedures><Operative Surgical Procedures><PK/PD><Paraffin Embedding><Pathologic><Pathology><Patients><Peptidases><Peptide Hydrolases><Performance><Pharmacokinetics><Phase><Post-Operative><Postoperative><Postoperative Period><Procedures><Process><Prognostic Factor><Prognostic/Survival Factor><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><QOL><Quality of life><Radiation therapy><Radiotherapeutics><Radiotherapy><Recurrence><Recurrent><Recurrent disease><Relapsed Disease><Removal><Reoperation><Repeat Surgery><Research Specimen><Residual Cancers><Risk><Risk Factors><Safety><Sampling><Savings><Signal Transduction><Signal Transduction Systems><Signaling><Specimen><Surface><Surgeon><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Survival Rate><Techniques><Technology><Testing><Time><Tissue Sample><Tissues><Topical Drug Administration><Topical application><Touch><Touch sensation><Toxicology><Translating><Translational Research><Translational Science><Translations><Tumor Tissue><University Medical Centers><Vascularization><Woman><acute toxicity><administer topically><apply topically><biological signal transduction><breast conservation surgery><breast conserving treatment><breast lumpectomy><cGMP><cancer cell><clinical applicability><clinical application><clinical imaging><clinical translation><clinically translatable><cosmetic product><death risk><deliver topically><developmental><diffused><diffuses><diffusing><diffusions><epithelial carcinoma><experience><first in man><first-in-human><healthy volunteer><homes><image guidance><image guided><imager><imaging><imaging agent><imaging probe><imaging study><in vivo><industrial partnership><industry partner><industry partnership><malignancy><malignant breast tumor><mammary tumor><manufacturing capabilities><manufacturing capacity><manufacturing facility><manufacturing plants><molecular imaging><molecule imaging><mortality risk><neoplasm/cancer><new approaches><next generation><novel><novel approaches><novel strategies><novel strategy><optic imaging><optical imaging><pharmacokinetics and pharmacodynamics><photonics><pre-clinical imaging><pre-clinical study><preclinical imaging><preclinical study><prevent><preventing><production plants><radiation treatment><resection><sample fixation><screening><screenings><standard of care><success><surgery><tactile sensation><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><translation><translation research><translational investigation><treat topically><treatment with radiation><tumor>