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ASCO 2010 PGx Abstract Highlights


This year's annual meeting of the American Society of Clinical Oncology, held June 4-8 in Chicago, featured a number of pharmacogenomically guided studies. The following is a roundup of some of the meeting's PGx highlights.

A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR mutations (LUX-Lung 2).

Researchers from National Taiwan University Hospital, Boehringer Ingelheim, Memorial Sloan-Kettering Cancer Center, and elsewhere conducted a Phase II study of Boehringer Ingelheim's BIBW 2992, an irreversible inhibitor of EGFR and HER2 in non-small cell lung cancer. In the study, researchers enrolled 444 patients with stage IIIB/IV lung adenocarcinoma who had EGFR mutations in exons 18-21, identified by direct sequencing. Of these patients, who had either received no prior chemotherapy or had disease progression after first-line treatment with a cytotoxic chemotherapy, 129 were given BIBW 2992 until their disease progressed. Patients were assessed at four, eight, and 12 weeks, at eight weekly intervals. The primary endpoint was objective response rate and the secondary endpoint was progression-free survival.

In the study, the researchers noted tumor size reduction in 90 percent of patients. The objective response rate and the disease control rate were 62 percent and 94 percent, respectively, for del19; 52 percent and 85 percent for L858R; and 43 percent and 78 percent for other mutations based on investigator assessment.

Median PFS for the overall groups was estimated to be one year. Specifically, PFS was 12 months in del19; 16.3 months in L858R; and 15.6 months when combined. Drug-related adverse events seen in 95 percent of patients were diarrhea and rash/acne.

"Administration of BIBW 2992 resulted in a high ORR, DCR and PFS in NSCLC patients with EGFR mutations," the researchers concluded. "Gastrointestinal and skin disorders were the most frequently observed AEs and were manageable with adequate supportive care and dose reduction."

The researchers plan to report updated response and PFS data based on independent imaging review.

Pharmacogenetics of tamoxifen in relation to disease-free survival in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

Researchers from Leiden University Medical Center and Erasmus Medical Center conducted a study that enrolled 747 Dutch cancer patients who were randomized to receive tamoxifen followed by exemestane two-and-a-half to three years after the TEAM trial, who were genotyped for 29 germline genetic variants in 12 candidate genes encoding enzymes that are involved in the metabolic and pharmacodynamic pathway of tamoxifen. According to the researchers, these variants were related to disease-free survival during the period when patients were treated with tamoxifen.

"The clinical characteristics of the genotyped patients were similar to the entire Dutch TEAM cohort randomized to tamoxifen (n = 1,379)," the researchers reported. "DFS was associated with UGT2B15*2 and the estrogen receptor-1 polymorphism ESR1 PvuII," Additionally, univariable analysis revealed an association between DFS and CYP2C19*2, but this association "lost significance when adjusted for the ESR1 PvuII polymorphism." Furthermore, researchers identified no association between the CYP2D6 genotypes and DFS.

"This translational study suggests that common and therefore relevant polymorphisms in UGT2B15 and the estrogen receptor-1 impact DFS in breast cancer patients treated with adjuvant tamoxifen," researchers concluded. "The previously reported association between CYP2D6 genotype and tamoxifen efficacy was not confirmed in our study."

No industry disclosures were made related to this abstract.

Relationship of HLA-DQA1*0201 and lapatinib-induced hepatotoxicity in women with advanced breast cancer.

Spraggs et al. from GlaxoSmithKline conducted a pharmacogenetic investigation of lapatinib-induced alanine aminotransferease (ALT) elevations in the treatment of advanced or metastatic breast cancer patients, when they received lapatinib (GSK's Tykerb) as monotherapy or in combination with letrozole. The research was undertaken after prior studies showed that a "small proportion" of patients in clinical trails have had serious hepatobiliary adverse events after being treated with lapatinib.

In the study, researchers analyzed gene marker associations from approximately 300 candidate genes and conducted genome-wide screening of one million SNPs in an exploratory dataset of up to 37 ALT cases and 285 controls, derived from 12 trials involving advanced/metastatic breast cancer patients treated with lapatinib. Markers that achieved pre-specified clinical significance were advanced to an independent confirmation dataset of 24 ALT cases and 154 controls from a single lapatinib plus letrozole trial involving advance/metastatic breast cancer patients

"Four out of 61 significant variants from the exploratory dataset maintained associations in the confirmation dataset," the researchers noted. "These variants resided in the same MHC genomic locus and included HLA-DQA1*0201."

In confirmatory analysis, DQA1*0201 allele carriage was present in 71 percent of ALT cases compared to 21 percent of controls, with an odds ratio for ALT cases of 9.3 and negative and positive predictive values of 0.97 (0.95-0.99) and 0.18, respectively. "The class II MHC HLA-DQA1*0201 allele is associated with lapatinib-induced ALT elevation," the researchers concluded. "The study suggests that a test based on HLA-DQA1*0201 allele carriage may have clinical utility to support patient management of liver safety risk during lapatinib treatment."

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Identification of candidate genetic markers predicting sensitivity to sorafenib and sunitinib.

Researchers from the Karmanos Cancer Institute at Wayne State University employed a genome-wide approach to identify genetic markers associated with in vitro sensitivity to sorafenib (Bayer's Nexavar) and sunitinib (Pfizer's Sutent) in a panel of 60 cancer cell lines (NCI-60).

Researchers analyzed the antiproliferative activities of both drugs in the NCI-60 cell lines with an MTS proliferation assay. Using the publicly available data on the NCI-60 cell lines generated by the Affymetrix 100K SNP and HG-U133A arrays, the researchers analyzed the associations between genotype and IC50, gene expression and IC50, and genotype and gene expression.

"The expressions of 173 gene probe sets were identified to be significantly associated with sorafenib IC50; while only 16 gene probe sets were associated with sunitinib IC50; and only one overlap between two list," the researchers reported. "Similarly, 434 SNPs and 187 SNPs were associated with the IC50 of sorafenib and sunitinib, respectively; and only 5 overlaps." The researchers enriched the significant genes associated with sorafenib sensitivity in cell cycle and immune cell trafficking.

Based on their findings, researchers concluded that "sorafenib and sunitinib exhibited distinct genomic signatures that were associated with their in vitro sensitivity." Li et al. are working on validating these signatures predicting response to sorafenib and sunitinib in independent cell lines and patient tumor samples.

No industry disclosures were made in association with this abstract.

Single nucleotide polymorphisms in FAS and FASL and sensitivity to gefitinib in patients with advanced non-small cell lung cancer.

Ma et al. from the Chinese Academy of Medical Sciences assessed the possibility that SNPs in FAS and FASL could predict patient response to gefitinib (AstraZeneca's Iressa) with advanced NSCLC.

Researchers applied a candidate polymorphic loci approach to determine the functional polymorphisms, and assessed SNPs in the promoter region of the FAS (-1377G/A and -670A/G) and FASL (-844T/C) in 88 advanced NSCLC gefitinib-treated patients. They then determined the genotypes by PCR-restriction fragment length polymorphism. The association between genotypes and sensitivity to gefitinib was validated by statistical tests.

"For FAS -1377G/A, the clinical benefit rates (CBR) of gefitinib in advanced NSCLC patients were 31.3 percent, 61.1 percent, or 74.3 percent in AA, GA, or GG genotypes, respectively," the researchers reported. "For FAS -670A/G, the CBR were 32.0 percent, 78.0 percent, or 57.9 percent in GG, AG or AA genotypes."

For FASL - 844T/C, researchers reported CBR of 65.2 percent , 57.1 percent, or 50 percent in CC, CT or TT genotypes. Additionally, researchers noted that patients who carried FAS -670 GG genotypes had "a significantly shorter survival time" following gefitinib treatment than variation allele carriers (AG or AA genotypes). The overall survival times were 26 and 47 months in patients with GG genotypes versus variation allele carriers, respectively.

Based on these findings, "FAS -1377G/A and -670A/G polymorphisms may be predictive for sensitivity to gefitinib in patients with advanced NSCLC," the researchers concluded.

No industry disclosures were made in association with this abstract.

Personalized dosing of tamoxifen (Tam) based on polymorphisms of CYP2D6 (2D6) and/or low serum endoxifen levels.

Researchers from Mount Sinai School of Medicine and the Queens Cancer Center analyzed serum tamoxifen, tamoxifen metabolites, and 19 CYP2D6 alleles in breast cancer patients taking tamoxifen 20 mg/day for 90 days. Researchers conducted CYP2D6 genotyping by PCR and assessed metabolites by liquid chromatography or tandem mass spectrometry.

At the time the abstract was presented at ASCO, 110 patients had enrolled in the trial. Researchers recorded age, ethnicity, BMI, concomitant medications, and adherence. At that point, 17 percent of patients who had low serum endoxifen and 2 percent of those without 2D6 allele function increased their tamoxifen doses to 30 mg/day. All patients' serum endoxifen increased to greater than 40 nMol by day 14.

"Subtherapeutic serum endoxifen can be found in any 2D6 phenotype, although it is more common in patients with decreased or no 2D6 allele function," the researchers stated in the abstract. "Subsequently, it is likely that other gene variants are involved in tamoxifen metabolism." Furthermore, the researchers acknowledged that it may be "possible to achieve therapeutic serum endoxifen/tamoxifen metabolite levels by optimizing the dose of tamoxifen," and that "tamoxifen dosages can be individualized."

In the view of the researchers, further investigation into personalizing doses of tamoxifen could significantly improve patient outcomes. No industry disclosures were made in association with this abstract.

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The contribution of UGT1A and ABCB1 to irinotecan-induced toxicity: A prospective pharmacogenetic study of patients with metastatic colorectal cancer

Researchers from the Centre Hospitalier Universitaire de Québec Research Center, Laval University, and the Ottawa Hospital Cancer Centre investigated candidate pharmacogenetic markers of chemotherapy toxicity in a prospective study of metastatic colorectal cancer. Researchers recruited 115 metastatic colorectal cancer patients treated with irinotecan-based chemotherapy, looking specifically at 20 polymorphisms in the UGT1A metabolic gene and 19 in the ABC/OATP transporter genes. The primary aim of the study was to analyze the relationship between gene variations and toxicity. The secondary aim was to gauge the link between gene markers and tumor response.

In univariate analyses, researchers found several functional UGT1A variants, including UGT1A1*28, ABCC1, and ABCB1 variants, to significantly influence severe hematological toxicity. Multivariate analyses showed that UGT1A6 c.184 and UGT1A7 c.208 were linked to severe neutropenia.

Meanwhile, a newly defined UGT1A haplotype (H1a), "corresponding to the reference sequence but varying in the 3'-UTR," was "highly predictive" of the absence of severe neutropenia. Additionally, ABCB1 c.1236 was a predictor of severe delayed diarrhea and better response, while UGT1A7 c.208 was associated gastrointestinal protection.

"This study suggests that specific polymorphisms in the major detoxifying systems involving UGT1A and ABC transporters influence irinotecan-associated toxicity and drug response, and these polymorphisms should be considered to refine pharmacogenetics testing," the researcher concluded.

This research was supported by the Canadian Institutes of Health Research. Roche and Sanofi Aventis provided honoria for this research.

Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score

Researchers from the National Surgical Adjuvant Breast and Bowel Project, the Cleveland Clinic Foundation, the University of Birmingham, and elsewhere compared pathological markers and gene expression by stage in four colon cancer studies conducted to develop the 12-gene recurrence score for Genomic Health's colon cancer recurrence test. Gene expression was gauged by RT-PCR from 30 µm manually microdissected FPE colon cancer tissue, and pathologic markers and expression of 375 genes were compared between 634 stage II and 844 stage III patients.

According to the abstract, nodal status was "a strong predictor of recurrence," and researchers found stage II patients to be more "likely to be mismatch repair deficient and have mucinous histology." Researchers reported small absolute differences between stage II and III in mean expression of 375 genes. Five genes showed significant differences in expression by stage in all four studies; 45 genes showed evidence of expression by stage interaction, but researchers expect 37 of these genes to be false discoveries.

Furthermore, the recurrence score showed no interaction with stage and unsupervised cluster analysis suggested similar patterns of gene expression by stage. "Quantitative analysis by RT-PCR identified very similar expression in stage II and III disease for the vast majority of genes tested," the researchers concluded. "Future studies should examine the clinical significance of differences identified between stage II and III, including mismatch repair, grade, and a small number of individual genes."

Research funding was provided by Genomic Health.

Comparative analysis of the chromosomal origins of circulating nucleic acids in breast and prostate cancer.

Researchers from Chronix Biomedical and Vanderbilt University analyzed the potential of circulating nucleic acid sequences to assess breast or prostate cancer in patients compared to healthy controls.

In this study, researchers extracted DNA from serum samples of 178 breast cancer and 197 prostrate cancer versus 200 gender- and age-matched healthy controls. These samples were amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on a 454 Titanium system, and aligned to the human genome.

Researchers generated 1.7 million breast cancer, 1.9 million prostate cancer, and 1.9 million healthy control sequences, representing 0.91 billion nucleotides in total. "Analysis revealed a number of small areas (2 kbp to 50 kbp in length) where hits from cancer samples uniquely clustered," the abstract notes. "Utilizing these 'hot spots,' 92 percent of breast cancer and prostate cancer patients and 100 percent of healthy controls could be classified correctly." Additionally, researchers noted that there was no overlap between the prostate cancer and breast cancer "hot spots".

Based on these results, researchers concluded that "comparative massive parallel sequencing of serum DNA from cancer patients versus controls identified unique chromosomal hotspots for prostate and breast cancer of high sensitivity and specificity amenable to translation to a clinical diagnostic platform."

Furthermore, "the identified genomic areas in these two distinct carcinomas derived from hormonally regulated epithelium are apparently prone to distinct neoplasm specific genomic anomalies, which can be detected in the blood and may provide not only diagnostic improvements to existing screening methods but also potential targets for therapeutic intervention."

Research funding was provided by Chronix Biomedical.