ABSTRACT
BACKGROUND: Although genetic profiling of tumors is a potentially powerful tool to predict drug sensitivity and resistance, its routine use has been limited because clinicians are often unfamiliar with interpretation and incorporation of the information into practice. We established a Molecular Tumor Board (MTB) to interpret individual patients' tumor genetic profiles and provide treatment recommendations. PATIENTS AND METHODS: DNA from tumor specimens was sequenced in a Clinical Laboratory Improvement Amendments-certified laboratory to identify coding mutations in a 50-gene panel (n = 34) or a 255-gene panel (n = 1). Cases were evaluated by a multidisciplinary MTB that included pathologists, oncologists, hematologists, basic scientists, and genetic counselors. RESULTS: During the first year, 35 cases were evaluated by the MTB, with 32 presented for recommendations on targeted therapies, and 3 referred for potential germline mutations. In 56.3% of cases, MTB recommended treatment with a targeted agent based on evaluation of tumor genetic profile and treatment history. Four patients (12.5%) were subsequently treated with a MTB-recommended targeted therapy; 3 of the 4 patients remain on therapy, 2 of whom experienced clinical benefit lasting >10 months. CONCLUSION: For the majority of cases evaluated, the MTB was able to provide treatment recommendations based on targetable genetic alterations. The most common reasons that MTB-recommended therapy was not administered stemmed from patient preferences and genetic profiling at either very early or very late stages of disease; lack of drug access was rarely encountered. Increasing awareness of molecular profiling and targeted therapies by both clinicians and patients will improve acceptance and adherence to treatments that could significantly improve outcomes. IMPLICATIONS FOR PRACTICE: Case evaluation by a multidisciplinary Molecular Tumor Board (MTB) is critical to benefit from individualized genetic data and maximize clinical impact. MTB recommendations shaped treatment options for the majority of cases evaluated. In the few patients treated with MTB-recommended therapy, disease outcomes were positive and support genetically informed treatment.
Subject(s)
Decision Support Techniques , Neoplasms/drug therapy , Neoplasms/genetics , Precision Medicine/methods , DNA, Neoplasm/analysis , DNA, Neoplasm/genetics , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/pathology , Pathology, Molecular/methodsABSTRACT
This study examined overexpression of the opioid growth factor receptor (OGFr) in squamous cell carcinoma of the head and neck and phenotypic repercussions on tumorigenicity. Tumors from 3 SCC-1 cell lines (OGFr-9, OGFr-18, OGFr-22) stably transfected with OGFr cDNA (OGFr-1) had 2.5- to 3.7-fold more OGFr than empty vector (EV) or wild-type (WT) neoplasias. No differences in OGFr number were detected between tumors of EV and WT animals. Only 16 and 28% of the mice in the OGFr-18 and OGFr-22 groups, respectively, receiving 2 million tumor cells had a measurable tumor on day 12 compared to 70% of the EV group; 25% of the OGFr-22 animals given 5 million cells expressed a tumor relative to the EV group (100%). Latencies for tumor appearance were extended by 25 and 80% for animals in the OGFr-18 and OGFr-22 groups, respectively, compared to EV animals given 2 million cells, and were lengthened by 2-fold in OGFr-22 animals injected with 5 million cells. Tumor weight of all animals overexpressing OGFr were 48-67% of EV mice, and the number of cells undergoing DNA synthesis in these tumors with amplified OGFr was reduced 46-65% of the EV group. Tumor volumes of OGFr-9 animals inoculated with 2 million cells and followed for over 7 weeks were reduced 36-70% from the WT group on days 31-54. Tumor weights on day 54 for the OGFr-9 group were 2.6-fold less than those for the WT animals. These data support OGFr gene function as a regulator of cell proliferation that impacts on tumorigenic expression of SCCHN, and suggests that molecular and pharmacological manipulation of OGFr may prevent or delay human head and neck squamous cell cancers.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/prevention & control , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/prevention & control , Receptors, Opioid/biosynthesis , Animals , Body Weight , Cell Line, Tumor , Disease Progression , Humans , Kinetics , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Time FactorsABSTRACT
This study examined overexpression of the opioid growth factor receptor (OGFr) in pancreatic cancer cells and phenotypic changes in tumorigenicity. Tumors of MIA PaCa-2 cells transfected with OGFr cDNA (OGFr-1) had 3.3 times more OGFr than empty vector (EV) neoplasias, and 4.3 times more OGFr than tumors from wild-type (WT) mice. No differences in OGFr binding were detected between tumors of EV and WT animals. Tumor incidence in OGFr-1 animals was reduced by up to 50% from EV mice. Latency times for OGFr-1 tumor expression were increased 30%, tumor volume was decreased 70%, and DNA synthesis was reduced 24% relative to EV mice. Exogenous OGF reduced OGFr-1 tumor volume up to 55% compared to OGFr-1 mice given vehicle. These data support OGFr gene function as a regulator of cell proliferation that impacts on tumorigenic expression, and suggest that molecular and pharmacological manipulation of OGFr may prevent or delay human pancreatic cancer.
