William Welbourn

Prognostic Utility of the Cell Cycle Progression Score Generated from Biopsy in Men Treated with Prostatectomy

PURPOSE The cell cycle progression score is associated with prostate cancer outcomes in various clinical settings. However, previous studies of men treated with radical prostatectomy evaluated cell cycle progression scores generated from resected tumor tissue. We evaluated the prognostic usefulness of the score derived from biopsy specimens in men treated with radical prostatectomy. MATERIALS AND METHODS We evaluated the cell cycle progression score in cohorts of patients from the Martini Clinic (283), Durham Veterans Affairs Medical Center (176) and Intermountain Healthcare (123). The score was derived from simulated biopsy (Martini Clinic) or diagnostic biopsy (Durham Veterans Affairs Medical Center and Intermountain Healthcare) and evaluated for an association with biochemical recurrence and metastatic disease. RESULTS In all 3 cohorts the cell cycle progression score was associated with biochemical recurrence and metastatic disease. The association with biochemical recurrence remained significant after adjusting for other prognostic clinical variables. On combined analysis of all cohorts (total 582 patients) the score was a strong predictor of biochemical recurrence on univariate analysis (HR per score unit 1.60, 95% CI 1.35-1.90, p=2.4×10(-7)) and multivariate analysis (HR per score unit 1.47, 95% CI 1.23-1.76, p=4.7×10(-5)). Although there were few events (12), the cell cycle progression score was the strongest predictor of metastatic disease on univariate analysis (HR per score unit 5.35, 95% CI 2.89-9.92, p=2.1×10(-8)) and after adjusting for clinical variables (HR per score unit 4.19, 95% CI 2.08-8.45, p=8.2×10(-6)). CONCLUSIONS The cell cycle progression score derived from a biopsy sample was associated with adverse outcomes after surgery. These results indicate that the score can be used at disease diagnosis to better define patient prognosis and enable more appropriate clinical care.

Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy.

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.

PTEN loss in biopsy tissue predicts poor clinical outcomes in prostate cancer

To determine whether PTEN status in prostate biopsy represents a predictor of intermediate and long‐term oncological outcomes after radical prostatectomy, and whether PTEN status predicts response to androgen deprivation therapy.

Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer

Abstract Objective: The CCP signature test (Prolaris) quantifies a patient’s risk of disease progression and prostate cancer specific mortality using a gene-expression-based cell cycle progression (CCP) score. This study evaluated the potential clinical utility of the CCP test in a US-based clinical setting. Methods: Urologists who participated in a prospective clinical study were sent a retrospective questionnaire to assess the value of the CCP test result. Fifteen board-certified urologists participated in the study, representing 15 distinct community urology group practices. Questionnaires were received for 294 evaluable patients. All patients had localized prostate cancer (T1–T3b, N0, M0). Results: Physicians found the CCP score valuable and indicated that 55% of tests generated a mortality risk that was either higher or lower than expected. Physicians also indicated that 32% of test results would lead to a definite or possible change in treatment. The data suggest that the test would have the net effect of shifting patients from more aggressive treatment to more conservative treatment. This was evidenced by the significant association between change in treatment and lower CCP scores (p < 0.002) and by the fact that 62% of tests likely to lead to a definite or possible change in treatment had mortality risks lower than the physician expected versus only 10% with risks higher than expected. Study limitations: This study measured the retrospectively assessed likelihood of change in treatment as estimated by the physician, not the actual change in treatment. Conclusions: The CCP score adds meaningful new information to risk assessment for localized prostate cancer patients. Real-world use of the test is likely to lead to a change in treatment in a significant portion of tested patients, particularly by shifting patients towards more conservative management. This could reduce overtreatment of patients with less aggressive disease, decreasing patient morbidity and costs for payers and the healthcare system.

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

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.

Use of the cell cycle progression (CCP) score for predicting systemic disease and response to radiation of biochemical recurrence.

BACKGROUND Determining the optimal treatment for biochemical recurrence (BCR) after radical prostatectomy (RP) is challenging. OBJECTIVE We evaluated the ability of CCP score (a prognostic RNA expression signature) to discriminate between systemic disease and local recurrence in patients with BCR after RP. METHODS Sixty patients with BCR after RP were selected for analysis based on: 1) metastatic disease, 2) non-response to salvage external beam radiotherapy (EBRT), and 3) durable response to salvage EBRT. CCP scores were generated from the RNA expression of 46 genes. Logistic regression assessed the association between CCP score and patient group. RESULTS Passing CCP scores were generated for 47 patients with complete clinical and pathologic data. CCP score predicted clinical status when comparing patients with metastatic disease or non-responders to salvage therapy to patients with durable response (p = 0.006). CCP score remained significantly predictive of clinical status after accounting for time to BCR, PSA level at BCR, and Gleason score (p = 0.0031). CONCLUSIONS Elevated CCP score was associated with increased risk of systemic disease, indicating that CCP score may be useful in identifying patients with BCR who are most likely to benefit from salvage radiation therapy.

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

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

Prognostic utility of CCP score in men with prostate cancer after primary external beam radiation therapy.

47 Background: Accurate risk stratification improves decision making in localized prostate cancer. The CCP score, a prognostic RNA signature based on the average expression level of 31 cell cycle progression (CCP) genes, was developed to aid in this task. Previously, the CCP score was shown to be predictive of biochemical recurrence (BCR) after prostatectomy, and prostate cancer specific mortality in men undergoing observation. However, the value of CCP score in men undergoing primary electron beam radiation therapy (EBRT) was untested. METHODS The CCP score was derived retrospectively from the diagnostic biopsy of 141 patients treated with EBRT at the Durham VA medical Center. Inclusion criteria were disease diagnosis from 1991 to 2006 and available biopsy tissue. Approximately half of the cohort was African-American. Outcome was time from EBRT to BCR using Phoenix definition, and median follow-up for patients without BCR was 4.8 years. Association with outcome was evaluated by CoxPH survival analysis and likelihood ratio tests. RESULTS Patient data were censored at 5-years of follow-up and 19 patients (13%) had BCR. The median CCP score was 0.12(IQR -0.43 to 0.66). In univariable analysis, CCP score was a significant prognostic variable (p-value = 0.0017). The hazard ratio (HR) for BCR was 2.55 (95% CI (1.43, 4.55)) for a one-unit increase in CCP score (equivalent to a doubling of gene expression). In a predefined multivariable analysis that included Gleason score, PSA, and percent positive cores, the HR for CCP changed only marginally and remained significant (HR per CCP unit 2.09 (95% CI (1.05, 4.18), p-value = 0.035), indicating that CCP provides prognostic information that is not provided by standard clinical parameters. Further adjustment for hormonal therapy or radiation dose did not materially alter this association. The score was also associated with prostate cancer specific mortality. There was no evidence for interaction between CCP and any clinical variable, including ethnicity. CONCLUSIONS In a cohort of men treated with EBRT, the CCP score was significantly associated with outcome and provided prognostic information beyond what was available from clinical parameters. If validated in a larger cohort, CCP score could be used to select high-risk men undergoing EBRT who may need combination therapy for their clinically localized prostate cancer.