Myla Lai-Goldman

Abacavir hypersensitivity: a model system for pharmacogenetic test adoption

A pharmacogenetic marker for abacavir hypersensitivity is rapidly being incorporated into routine medical practice following demonstration of strong clinical utility in pivotal clinical studies. As one of the few pharmacogenetic markers that have crossed from research tools to clinical adoption and utilization, the abacavir hypersensitivity pharmacogenetic marker provides a great model for demonstration of factors that are critical to successful pharmacogenetic test adoption. Several examples of novel diagnostic test implementation are reviewed with focus on factors that are critical to translation into clinical practice. Other pharmacogenetic markers that have not yet been integrated into routine clinical care are discussed and reasons for their lack of acceptance are suggested.

HLA-B*5701 clinical testing : early experience in the United States

HLA-B*5701 testing to provide risk stratification for abacavir hypersensitivity has the potential to reduce incidence of hypersensitivity reactions in susceptible individuals. Early experience with clinical HLA-B*5701 testing of the first 100 specimens, from a large clinical reference laboratory in the United States, is presented. Patient samples were tested using a two-step approach. The first step allowed rapid identification of most HLA-B*5701-negative samples in a high throughput mode. The second step involved resolution of putative positives by DNA sequencing to identify B*5701 specifically as well as other B57 subtypes. Test reporting included a phone call from a genetic counselor to obtain the ethnic background and indication for testing and to provide a patient-specific interpretation. The patients population was comprised of Caucasians, 84%; Hispanics, 13%; and African Americans, 3%. Among the 100 samples tested, 92% were HLA-B*5701-negative and 8% were positive for the HLA-B*5701 allele. All HLA-B*5701 allele positives were identified in Caucasian patients. Where the indication for testing was obtainable (57 patients), pre-abacavir therapy screening was the indication 67% of the time. Clarification of previous suspected history of hypersensitivity was the indication 33% of the time. Among samples tested to help clarify a previous history of hypersensitivity, 16/19 or 84% did not carry the HLA-B*5701 allele whereas 3/19 (16%) were carriers of the HLA-B*5701 allele. Early utilization of HLA-B*5701 testing in community practice was not always consistent with the clinical indications for testing. Post-test communication assisted in providing physician education and interpretation of patient-specific results.

Application of a pharmacogenetic test adoption model to six oncology biomarkers

The ability of genomics to match precise information about the molecular biology of a cancer with the available present and future therapeutics offers tremendous promise for cancer patients. Unfortunately, few genomic-based tests or treatments are available today to benefit these patients. Using a pharmacogenetic test adoption model, previously introduced to model the adoption of HLA-B*5701 testing for abacavir hypersensitivity, six oncology biomarkers, HER2, BCR-ABL quantitation, KRAS mutation, UGT1A1, CYP2D6 for tamoxifen and EGFR expression, test adoption patterns are explored. Developmental milestones and emerging scientific knowledge relating to each of the biomarkers are discussed in the context of their impact on test ordering patterns. Through analysis of the adoption patterns of multiple cancer biomarkers, a pharmacogenetic model emerges which appears to be applicable in five of the six biomarkers. This model may be useful in predicting adoption patterns of new markers and in providing guidance to drug and test developers introducing personalized medicine applications.

Quantitative DNA ploidy analysis of breast carcinoma : A study of the effects of Joint photographer experts Group (JPEG) compression on DNA ploidy images

Telepathology usage in the past has typically been a qualitative procedure rather than a quantitative measurement. DNA ploidy using image analysis has been favorably compared to DNA ploidy analysis by flow cytometry in numerous publications. A step from DNA ploidy analysis using conventional image analysis to DNA ploidy analysis using stored images allows DNA ploidy analysis by image cytometry to become a powerful tool in telepathology. Remote DNA ploidy analysis using stored images has an impact on the field of pathology, as not every hospital or laboratory can afford to perform this type of specialized testing. However, images have large data files and require lengthy transmission times over communication systems to other computers. Joint Photographer Experts Group (JPEG) compression is a computer algorithm that allows the file size of an image to be reduced in order to decrease transmission times to another computer. A study was initiated to investigate the effects of JPEG compression on images of Feulgen stained breast tumor touch preps and the resulting DNA ploidy histograms. Diagn Cytopathol 1996;15:231–236.

Validation of the Lung Subtyping Panel in Multiple Fresh-Frozen and Formalin-Fixed, Paraffin-Embedded Lung Tumor Gene Expression Data Sets.

Context .- A histologic classification of lung cancer subtypes is essential in guiding therapeutic management. Objective .- To complement morphology-based classification of lung tumors, a previously developed lung subtyping panel (LSP) of 57 genes was tested using multiple public fresh-frozen gene-expression data sets and a prospectively collected set of formalin-fixed, paraffin-embedded lung tumor samples. Design .- The LSP gene-expression signature was evaluated in multiple lung cancer gene-expression data sets totaling 2177 patients collected from 4 platforms: Illumina RNAseq (San Diego, California), Agilent (Santa Clara, California) and Affymetrix (Santa Clara) microarrays, and quantitative reverse transcription-polymerase chain reaction. Gene centroids were calculated for each of 3 genomic-defined subtypes: adenocarcinoma, squamous cell carcinoma, and neuroendocrine, the latter of which encompassed both small cell carcinoma and carcinoid. Classification by LSP into 3 subtypes was evaluated in both fresh-frozen and formalin-fixed, paraffin-embedded tumor samples, and agreement with the original morphology-based diagnosis was determined. Results .- The LSP-based classifications demonstrated overall agreement with the original clinical diagnosis ranging from 78% (251 of 322) to 91% (492 of 538 and 869 of 951) in the fresh-frozen public data sets and 84% (65 of 77) in the formalin-fixed, paraffin-embedded data set. The LSP performance was independent of tissue-preservation method and gene-expression platform. Secondary, blinded pathology review of formalin-fixed, paraffin-embedded samples demonstrated concordance of 82% (63 of 77) with the original morphology diagnosis. Conclusions .- The LSP gene-expression signature is a reproducible and objective method for classifying lung tumors and demonstrates good concordance with morphology-based classification across multiple data sets. The LSP panel can supplement morphologic assessment of lung cancers, particularly when classification by standard methods is challenging.

Strategic Issues in the Adoption of Genome-Based Diagnostics

The assimilation of new genomic-based diagnostic capabilities into routine medical practice will undoubtedly have a profound impact on patient management decisions. However, the challenge of translating newly discovered biomarkers into widely utilized medical diagnostic applications remains. This chapter will discuss many of the technical, regulatory, and financial challenges to full adoption of genomic tests in the clinic, and will delineate some of the key drivers of test acceptance along a continuum from early discovery to full utilization.