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PGx Abstracts from 2009 American Society of Clinical Oncology's Annual Meeting

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ORLANDO, Fla. — The theme of this year's American Society of Clinical Oncology meeting was personalized medicine, so it's no surprise that various companies and research institutions reported findings on new pharmacogenomics cancer research at the conference. The following is a sampling of some of this work.


Construction of a five-marker protein-based model for stage-independent assessment of prognosis in breast cancer.

Giltnane et al., from Vanderbilt University Medical Center and Yale University School of Medicine, hypothesized that multiplexed quantitative measurement of proteins known to be involved in breast cancer signaling pathways of growth, proliferation, survival, and metastasis can be used to improve clinical methods of predicting prognosis in all patients.

The researchers assessed the expression of twenty-three proteins (ER, PR, EGFR, HER2, HER3, HER4, ERK, PTEN, PI3Kp85α, PI3Kp110α, p27/Kip1,EIF4E, FOXO3,AKT1, AKT2, AKT3, MYC, cyclinD1, FOXO1, mTOR, p70S6Kb, NFkB and BCL2) in four subcellular compartments by automated quantitative analysis of protein expression on tissue microarrays of the archival Yale breast cancer cohort (n=676). They constructed univariate and multivariate logistic regression models using leave-one-out cross-validation and calculated prediction error estimates of each model's value to predict a binary endpoint of 10-year survival. They also constructed univariate and multivariate Cox models of 10-year disease specific survival.

"Our protein-based, multiplexed approach to prognostic classification was superior to traditional methods (TNM or NPI) and single biomarkers in this retrospective cohort," the researchers concluded. Although they acknowledged that these "outcomes are influenced by modern therapies, limiting the direct impact of this analysis," they concluded that "molecular profiling of primary tumor linked to outcome paves the way for the incorporation of new prognostic models into prospective studies."


Combining multigene profiling of molecular subtypes with the 70-gene profile for classification of breast cancer.

Stork-Sloots et al. from Agendia report on a multigene profile for classification of breast cancer into molecular subtypes, which separates tumors into hormone receptor (HR)+/luminal-like, HER2+/ERBB2-like, and triple negative/basal-like subclasses.

The multi-gene profile was developed based on a series of 200 tumor samples of known ER, PR, and HER2 receptor status (concordant IHC and gene expression result) hybridized on 44K microarrays, and was validated using 469 independent samples as well as on two publicly available gene expression datasets.

Researchers reported that the profile classified 66 percent of samples as luminal-like, 18 percent as ERBB2-like, and 16 percent as basal-like. "The ERBB2-like subset of MammaPrint low-risk patients (15 percent) showed an 89 percent survival rate without trastuzumab treatment," the team said in the abstract. "When the luminal-like subtype was separated into 'high-' and 'low-risk' by MammaPrint the survival rate was 56 percent."

As a result, researchers concluded that the multigene profile they developed could classify tumors into luminal-, ERBB2- and basal-like subgroups. "By combining this molecular subtyping with MammaPrint risk-classification specific groups of patients can be recognized that that are at high risk of recurrence," they said. "The low risk patients within the luminal- and ERBB2-like subclasses have a very low risk of recurrence. Implementation of this knowledge can improve the clinical management of breast cancer patients."

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PITX2 methylation and biochemical recurrence in postradical prostatectomy prostate cancer patients.

Heiden et al. from Epigenomics, Duke University Medical Center, University Hospital Erlangen, Erasmus Medical Center, and Baylor College of Medicine validated methylation status of PITX2 — a bicoid-related transcription factor induced by the Wnt pathway and required for effective cell-type-specific proliferation during development — as a predictor of biochemical recurrence following radical prostatectomy.

Although radical prostatectomy may be curative in patients with clinically localized prostate cancer, biochemical recurrence affects between 15 percent and 30 percent of patients undergoing radical prostatectomy. In the study, the researchers assessed PITX2 methylation status in formalin-fixed paraffin-embedded RP tumor tissue samples from 476 patients from multiple institutions in the US and in Europe using customized microarrays.

"PITX2 methylation status identifies prostate cancer patients most likely to experience biochemical recurrence," the researchers report. "This test independently adds to prognostic information provided by standard clinico-pathological analyses improving stratification of RP patients into high- or low-risk for BCR."

According to the research team, their newly developed clinical tool "would be of particular benefit in assessment of intermediate-risk patients or patients with positive surgical margins wherein risk stratification remains a challenge."


Molecular characterization of male breast cancer by standardized quantitative RT-PCR analysis: First large genomic study of 347 male breast cancers compared to 82,434 female breast cancers.

Shak et al., from Genomic Health and Indiana University School of Medicine, reported on a study of quantitative gene expression by gender status in tumor specimens submitted for recurrence score testing.

Researchers examined estrogen receptor-positive tumor specimens in the Genomic Health laboratory from June 2004 through December 2008, and measured quantitative expression for each gene by the 21-gene panel Oncotype DX assay on a scale from 0 to 15. A one-unit increment was associated with a 2-fold change in expression.

In the study, samples from 347 male breast cancer patients, with a mean age of 64 years, and 82,434 female breast cancer patients, with a mean age of 57 years, were compared. Both male and female breast cancer samples displayed a wide variation in gene expression and the distribution of the recurrence score was also similar between genders.

However, one notable difference between male and female breast cancer samples was that mean expression of ER, PR, and SCUBE2 was 0.5 units higher in males. Mean expression of the proliferation genes, Ki-67, MYBL2, Survivin, Cyclin B1, and STK15, was also 0.5 units higher in males. Mean expression of STMY3 was 0.9 units higher in males.

In addition, unlike in female breast cancer, where the level of quantitative ER increases with age, there was little increase in ER in males in the study.

"This large genomic study of male BC reveals a heterogeneous biology as measured by the standardized quantitative oncotype DX breast cancer assay, similar to that observed in female BC," researchers reported. "Some differences, which may reflect the differences in hormone biology between males and females, were noted and deserve further study."

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A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study

Kerr et al., from Genomic Health, University of Oxford, University of Birmingham Clinical Trials, Leeds Institute of Molecular Medicine, NSABP, and the Cleveland Clinic Foundation, performed four development studies to select the genes for prediction of recurrence and 5FU/LV benefit in stage II colon cancer patients. Then, to determine clinical utility of the prespecified assay, researchers performed a large, independent, prospectively designed, clinical validation study in stage II colon cancer patients from the QUASAR trial.

In the trial, gene expression was quantitated by RT-PCR from 30 µm manually microdissected fixed paraffin-embedded primary colon cancer tissue. Recurrence-free interval (RFI), disease-free survival (DFS), and overall survival (OS) were analyzed using Cox regression.

Researchers identified 48 genes significantly associated with recurrences risk and 66 predictive of 5FU/LV benefit, following combined analysis of the four development studies. Multivariate analysis revealed 18 genes — 7 prognostic genes, 6 predictive genes, and 5 reference genes — as well as separate prognostic recurrence score and predictive treatment score algorithms.

In the primary analysis of RFI in patients following surgery, the RS predicted recurrence risk, as well as DFS. The data show that recurrence risk increased along with the recurrence score. However, predictive treatment score was not validated as a predictor of 5FU/LV benefit.

"The colon cancer recurrence score is a validated, independent predictor of individualized recurrence risk for stage II colon cancer patients following surgery," the research team concluded.


Genotypic characterization of phenotypically defined triple-negative breast cancer

Sparano et al., from Sanofi-Aventis, Genomic Health, the North American Breast Cancer Intergroup, Albert Einstein Cancer Center, Fox Chase Cancer Center, Indiana University School of Medicine, University of Pittsburgh Cancer Institute, and the Eastern Cooperative Oncology Group, evaluated the genotypic features of triple-negative breast cancer compared with hormone receptor-positive disease. Researchers also looked at the genotypic features associated with disease recurrence.

Researchers extracted RNA from tumor samples obtained from 764 patients with stage I-III breast cancer and then analyzed these samples by RT-PCR for 371 genes. All patients received adjuvant chemotherapy (plus hormonal therapy in HR-positive disease) in trial E2197. HR and HER2 expression were evaluated by immunohistochemistry in a central lab.

According to the data, "the top 10 percent of genes exhibiting higher expression the triple-negative group included genes associated with nucleosome assembly (CENPA), kinase activity (TTK), cell division (KIFC2), proliferation (BUB1), intracellular signaling (DEPDC1), DNA repair (CHK1), anti-apoptosis (GSTP1), and transcriptional regulation (MYBL2)," the research team reported.

Particularly, they noted increased expression of genes for which inhibitors are currently being evaluated, including AURKB and CHK1 in TNBC, and IGF1R and RhoC in HR-positive disease.

"Although GRB7 expression was significantly lower in the TN group, increased expression of GRB7 was the only gene in the triple-negative breast cancer group (but not the HR-positive group) associated with increased recurrence, and did not correlate with nodal status, tumor size, or grade," they said.

As a result, the team concluded that there were "significant differences in gene expression between the TN and HR-positive groups, including genes for which targeted agents are currently being evaluated in the clinic."

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