Showing papers by "Myriad Genetics published in 2013"

Validation of a Cell-Cycle Progression Gene Panel to Improve Risk Stratification in a Contemporary Prostatectomy Cohort

Abstract: Purpose We aimed to validate a previously described genetic risk score, denoted the cell-cycle progression (CCP) score, in predicting contemporary radical prostatectomy (RP) outcomes. Methods RNA was quantified from paraffin-embedded RP specimens. The CCP score was calculated as average expression of 31 CCP genes, normalized to 15 housekeeper genes. Recurrence was defined as two prostate-specific antigen levels ≥ 0.2 ng/mL or any salvage treatment. Associations between CCP score and recurrence were examined, with adjustment for clinical and pathologic variables using Cox proportional hazards regression and partial likelihood ratio tests. The CCP score was assessed for independent prognostic utility beyond a standard postoperative risk assessment (Cancer of the Prostate Risk Assessment post-Surgical [CAPRA-S] score), and a score combining CAPRA-S and CCP was validated. Results Eighty-two (19.9%) of 413 men experienced recurrence. The hazard ratio (HR) for each unit increase in CCP score (range, −1.62 to 2....

Prognostic Utility of Cell Cycle Progression Score in Men With Prostate Cancer After Primary External Beam Radiation Therapy

Abstract: Purpose To evaluate the prognostic utility of the cell cycle progression (CCP) score, a RNA signature based on the average expression level of 31 CCP genes, for predicting biochemical recurrence (BCR) in men with prostate cancer treated with external beam radiation therapy (EBRT) as their primary curative therapy. Methods and Materials The CCP score was derived retrospectively from diagnostic biopsy specimens of men diagnosed with prostate cancer from 1991 to 2006 (n=141). All patients were treated with definitive EBRT; approximately half of the cohort was African American. Outcome was time from EBRT to BCR using the Phoenix definition. Median follow-up for patients without BCR was 4.8 years. Association with outcome was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. Results Of 141 patients, 19 (13%) had BCR. The median CCP score for patient samples was 0.12. In univariable analysis, CCP score significantly predicted BCR ( P =.0017). The hazard ratio for BCR was 2.55 for 1-unit increase in CCP score (equivalent to a doubling of gene expression). In a multivariable analysis that included Gleason score, prostate-specific antigen, percent positive cores, and androgen deprivation therapy, the hazard ratio for CCP changed only marginally and remained significant ( P =.034), indicating that CCP provides prognostic information that is not provided by standard clinical parameters. With 10-year censoring, the CCP score was associated with prostate cancer-specific mortality ( P =.013). There was no evidence for interaction between CCP and any clinical variable, including ethnicity. Conclusions Among men treated with EBRT, the CCP score significantly predicted outcome and provided greater prognostic information than was available with clinical parameters. If validated in a larger cohort, CCP score could identify high-risk men undergoing EBRT who may need more aggressive therapy.

Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer

Abstract: The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate. The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer. The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60–4.73; P=3.1 × 10−14). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2–24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses. In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.

Validation of a Proliferation-Based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma

Abstract: Purpose: New prognostic markers to guide treatment decisions in early stage non–small cell lung cancer are necessary to improve patient outcomes. In this report, we assess the utility of a predefined mRNA expression signature of cell-cycle progression genes (CCP score) to define 5-year risk of lung cancer–related death in patients with early stage lung adenocarcinoma. Experimental Design: A CCP score was calculated from the mRNA expression levels of 31 proliferation genes in stage I and stage II tumor samples from two public microarray datasets [Director9s Consortium (DC) and GSE31210]. The same gene set was tested by quantitative PCR in 381 formalin-fixed paraffin-embedded (FFPE) primary tumors. Association of the CCP score with outcome was assessed by Cox proportional hazards analysis. Results: In univariate analysis, the CCP score was a strong predictor of cancer-specific survival in both the Director9s Consortium cohort ( P = 0.00014; HR = 2.08; 95% CI, 1.43–3.02) and GSE31210 ( P = 0.0010; HR = 2.25; 95% CI, 1.42–3.56). In multivariate analysis, the CCP score remained the dominant prognostic marker in the presence of clinical variables ( P = 0.0022; HR = 2.02; 95% CI, 1.29–3.17 in Director9s Consortium, P = 0.0026; HR = 2.16; 95% CI, 1.32–3.53 in GSE31210). On a quantitative PCR platform, the CCP score maintained highly significant prognostic value in FFPE-derived mRNA from clinical samples in both univariate ( P = 0.00033; HR = 2.10; 95% CI, 1.39–3.17) and multivariate analyses ( P = 0.0071; HR = 1.92; 95% CI, 1.18–3.10). Conclusions: The CCP score is a significant predictor of lung cancer death in early stage lung adenocarcinoma treated with surgery and may be a valuable tool in selecting patients for adjuvant treatment. Clin Cancer Res; 19(22); 6261–71. ©2013 AACR .

PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival

Abstract: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates the phosphoinositide-3-kinase (PI3K) signaling pathway. In colorectal cancer (CRC), observed frequencies of loss of PTEN expression, concordant expression in primary tumors and metastases, and the association of PTEN status with outcome vary markedly by detection method. We determined the degree to which PTEN expression is consistent in 70 matched human CRC primaries and liver metastases using a validated immunohistochemistry assay. We found loss of PTEN expression in 12.3% of assessable CRC primaries and 10.3% of assessable liver metastases. PTEN expression (positive or negative) was concordant in 98% of matched colorectal primaries and liver metastases. Next we related PTEN status to mutations in RAS and PI3K pathway genes (KRAS, NRAS, BRAF, and PIK3CA) and to overall survival (OS). PTEN expression was not significantly associated with the presence or absence of mutations in RAS or PI3K pathway genes. The median OS of patients whose tumors did not express PTEN was 9 months, compared to 49 months for patients whose tumors did express PTEN (HR = 6.25, 95% confidence intervals (CI) (1.98, 15.42), P = 0.0017). The association of absent PTEN expression with increased risk of death remained significant in multivariate analysis (HR = 6.31, 95% CI (2.03, 17.93), P = 0.0023). In summary, PTEN expression was consistent in matched CRC primaries and in liver metastases. Therefore, future investigations of PTEN in metastatic CRC can use primary tumor tissue. In patients with liver-only metastases, loss of PTEN expression predicted poor OS. We observed concordant PTEN expression in 98% of colorectal cancer (CRC) primary and liver metastasis pairs using a validated immunohistochemistry assay. Consistent PTEN expression at both disease sites is significant because tumor tissue is usually available from CRC primaries but not metastases. Loss of PTEN expression associated with poor survival of CRC patients with liver-only metastases.

An End to the Myth: There Is No Drug Development Pipeline

Abstract: A new map is presented for creating an open, collaborative, and coordinated system for drug development.

Prolaris: A novel genetic test for prostate cancer prognosis.

Abstract: 5005 Background: The natural history of prostate cancer is highly variable and difficult to predict. Improved tools are needed to match treatment more appropriately to a patient’s risk of progressi...

Abstract P6-05-10: Association between BRCA1/2 status and DNA-based assays for homologous recombination deficiency in breast cancer

Abstract: Homologous recombination (HR) repair defects are of potential therapeutic relevance in a variety of different cancers. Numerous studies have investigated the rate of BRCA1/2 mutations in triple negative breast cancer, and current clinical studies are investigating the efficacy of agents targeting HR deficiency in this breast cancer subtype. A more comprehensive assay for HR defects might expand the number of patients likely to benefit from these therapies, and may expand their utility to other breast cancer subtypes. Recently three DNA-based measures of HR deficiency (HRD) have been developed based on whole genome tumor LOH profiles, telomeric allelic imbalance, or large-scale state transitions. These will be referred herein as HRD-LOH, HRD-TAI and HRD-LST respectively. All 3 scores are highly correlated with defects in BRCA1/2 and other pathway genes in breast or ovarian cancer, and are associated with sensitivity to platinum agents. 213 invasive breast tumor samples and matched normal tissue blocks were obtained from 3 commercial vendors. The samples were selected to contain approximately equal numbers of all subtypes of breast cancer as defined by IHC analysis of ER, PR, and HER2. BRCA1/2 mutation screening and BRCA1 promoter methylation analysis was performed, and genome wide SNP profiles were generated. These data were used to calculate HRD-LOH, HRD-TAI, and HRD-LST scores. Somatic and germline BRCA1/2 mutations were detected in all subtypes of breast cancer at significant levels with the total mutation frequency ranging from 7.8 – 16.4% depending on subtype. In contrast BRCA1 promoter methylation was confined almost exclusively to triple negative tumors (19.7%). Overall BRCA1/2 deficiency ranged from approximately 10% in ER+/Her2- tumors up to approximately 36% in triple negative tumors. HRD-LOH, HRD-TAI, and HRD- LST scores have previously been shown to be highly significantly associated with BRCA1/2 status in both breast and ovarian cancer. In this dataset all 3 scores showed significant association with BRCA1/2 status for the entire dataset, in addition significant association was observed between the scores and BRCA1/2 status in each of the individual tumor subtypes. The 3 scores were found to be highly correlated with one another, but all 3 were still significant in multivariate analysis. This dataset is not of sufficient size to determine which of these scores is best able to identify BRCA1/2 deficient tumors. It is likely that a combination of the 3 scores will prove to be the most robust predictor of HR deficiency. This study has demonstrated significant levels of BRCA1/2 deficiency across all subtypes of breast cancer. All 3 HR deficiency assays showed significant association with BRCA1/2 deficiency regardless of breast cancer subtype. The 3 scores are highly correlated, but also additive and a combination of all 3 is likely to provide the best predictor of HR deficiency. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-10.

Value of cell cycle progression (CCP) score to predict biochemical recurrence and definitive post-surgical pathology.

Abstract: 5043 Background: Prostate cancer (PCA) has a highly variable natural history and better tools are needed to more appropriately match treatment to a patient’s risk of progression. A prognostic mRNA ...

Understanding CYP2D6 and its role in tamoxifen metabolism.

Abstract: The gene CYP2D6 has an extremely important role in drug metabolism. "Cytochrome P450, family 2, subfamily D, polypeptide 6" is the official name of CYP2D6. The gene is located at position 13.1 on the long (q) arm of chromosome 21 and encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that are heavily involved in drug metabolism (Genetics Home Reference, 2013), and many drugs are activated into their biologically active compounds. Because of numerous polymorphisms, the gene also has significant person-to-person variability. To date, more than 80 distinct CYP2D6 alleles and specific types and frequencies have been associated with different ethnic groups. CYP2D6*4 is the most common variant allele in Caucasians and, in that population, has a frequency of about 25%. On the other hand, CYP2D6*10 is common in the Asian population (Stearns & Rae, 2008).

BRCA1/2 mutation prevalence among triple-negative breast cancer patients from a large commercial testing cohort.

Abstract: 1544 Background: BRCA1/2 deleterious mutation identification among triple-negative breast cancer (TNBC) patients has gained importance due to cancer-risk management implications for patients and th...

Abstract 1201: PTEN null expression is concordant in colorectal cancer primaries and metastases and associates with poor survival.

Abstract: Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a negative regulator of the phosphoinositide-3-kinase (PI3K) survival pathway. In colorectal cancer, the method of detection is relevant in determining the frequency of loss of PTEN and the association of PTEN status with outcome. Earlier studies reported discordant PTEN expression in an average of 1 in 3 matched colorectal primaries and metastases. Ours is the first investigation of PTEN concordance using a standardized immunohistochemistry assay. Objectives: Our primary aim was to determine the level of concordant PTEN expression in matched human colorectal primaries and liver metastases using a robust assay. Secondary aims were to relate PTEN status to oncogenic mutations in the RAS and PI3K pathways, and to overall survival. Experimental Design: We used a standardized immunohistochemistry assay and a reproducible method of interpretation to characterize PTEN expression in paired colorectal primaries and liver metastases collected from 70 patients. Mutational hotspots in KRAS, NRAS, BRAF and PIK3CA were sequenced. Results: 7 patients were excluded due to insufficient primary tumor. PTEN null expression was found in 7 of 62 assessable colorectal primaries (12.3%) and 6 of 58 assessable liver metastases (10.3%). PTEN expression (positive or null) was concordant in 98% of matched primaries and liver metastases. There was no significant association between PTEN status and RAS family or PIK3CA mutations. The median overall survival of patients with PTEN null tumors was 9 months, compared to 49 months with PTEN expressing tumors (HR=6.25, 95% CI (1.98, 15.42), p = 0.0017). The association of increased risk of death with PTEN null expression remained significant in multivariate analysis (HR=6.31, 95% CI (2.03, 17.93), p = 0.0023). Conclusion: PTEN status was highly concordant in matched colorectal primaries and liver metastases. Loss of PTEN expression predicted poor overall survival. | | | | PRIMARIES | | | | |:----------- | ----------------- | ---------------------------- | ---------------- | ------- | ------------------ | -------- | | | | PTEN | | PIK3CA | | RAS/BRAF | | | | (−),(+),equivocal | | WT, Mut | | WT, Mut | | METASTASES | PTEN null (−) | 6, 0, 0 | PIK3CA wild-type | 54, 0 | RAS/BRAF wild-type | 29, 1 | | | PTEN positive (+) | 1, 43, 5 | PIK3CA mutant | 2, 5 | RAS/BRAF mutant | 0, 31 | | | PTEN equivocal | 0, 2, 0 | | | | | | CONCORDANCE | | 98%(86% including equivocal) | | 96.7% | | 98.4% | Concordance of PTEN, PIK3CA, RAS, and BRAF in paired colorectal primaries and liver metastases Citation Format: Chloe E. Atreya, Zaina Sangale, Nafei Xu, Mary R. Matli, Eliso Tikishvili, William Welbourn, Steve Stone, Kevan M. Shokat, Robert S. Warren. PTEN null expression is concordant in colorectal cancer primaries and metastases and associates with poor survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1201. doi:10.1158/1538-7445.AM2013-1201

Hereditary cancer genes

Abstract: The invention generally relates to a molecular classification of disease predisposition and particularly to molecular markers for cancer predisposition and methods of use thereof

Response to article: Langford et al. racial and ethnic differences in direct-to-consumer genetic tests awareness in HINTS 2007: sociodemographic and numeracy correlates. J Genet Counsel (2012) 21:440-447.

Abstract: The intention of this letter is to clarify the distinction between direct to consumer testing versus direct to consumer advertising. The introduction of this article used the definition from the Genetics Home Reference 2011 to define direct-to-consumer (DTC) genetic tests. This definition specifically states that \" …genetic tests…..Allow a person to obtain genetic information without involving a doctor or insurance company in the process and provides an estimate of an individual's statistical risk for developing a specific health condition \". The intro-duction's second paragraph immediately after this definition states, \" Myriad Genetics launched the first major DTC publicity campaign for its BRCA1/BRCA2 tests… \" This unfortunately and inaccurately implies that Myriad's products, as supported by public awareness campaigns, are DTC genetic tests. Myriad's products are not DTC genetic tests because they must be ordered by a licensed health care professional. Patients cannot directly order these tests. Myriad's public awareness campaigns that have taken place in various parts of the country are, as the name implies, meant to raise awareness about the importance of family history as it relates to cancer risk. Each geographical location was carefully selected after evaluating that there were qualified healthcare personnel in those areas to address patient concerns after seeing the public awareness campaign. Consumers who saw these commercials or advertisements could not simply order a test and then get medical information back without involving a healthcare provider. If a consumer called Myriad directly, they were encouraged to talk to their own physician or directed to a healthcare provider near them who could discuss their family history with them. Specifically and to the point, Myriad's operations, including its public awareness campaign, do not \" allow a person to get genetic information without involving a doctor. \" Thus, Myriad's products by definition are not DTC products. Conflating DTC advertising and DTC testing as the authors have done introduces unhelpful ambiguity and potential confusion into an important debate over the appropriateness of offering genetic testing directly to the general public. There are important differences between raising public and provider awareness about the importance of family history (DTC advertising) and enabling a consumer to directly order a genetic test (DTC genetic testing). In fact, public awareness campaigns such as Myriad's and the Surgeon General's Family Health History Initiative, which is \" to encourage all American families to learn more about their family health history, \" (Surgeon General's Family Health …