Prior Neoadjuvant Therapy Research Articles

The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer patients using ColoPrint.

TPS10632 Background: An 18-gene expression profile, ColoPrint, has been developed for identifying colon cancer patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature was validated in public datasets and independent patient cohorts (stage II and III patients). Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) (median follow-up 70 months). ColoPrint classifies 65% of stage II patients as Low Risk. The 3-year RFS was 91% for Low Risk and 74% for High Risk patients with a HR of 2.9 (p=0.001). ColoPrint was the only significant prognostic marker in the subgroup of patients with T3-MSS phenotype (Tabernero, ASCO GI 2012). Methods: A blinded prospective trial, PARSC (Prospective study for the Assessment of Recurrence risk in Stage II colon cancer patients) using ColoPrint has been initiated. Objectives are: (1)To validate the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage II colon cancer. (2) To compare the risk assessment in stage II patients using the ColoPrint profile vs a clinical risk assessment based on Investigator’s assessment of risk and ASCO high-risk recommendations. (3) To investigate therapy as a potential confounding factor for ColoPrint results. (4) To assess the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage III colon cancer. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II and III, no prior neo-adjuvant therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician adhering to National Comprehensive Cancer Network (NCCN)-approved regimens or a recognized alternative (blinded for ColoPrint result). The trial started in Sept. 2008 with currently 32 participating sites in 11 countries. Thus far, 340 eligible stage II and 280 stage III patients have been enrolled. The aim is to enroll 575 stage II patients. Clinical trial registry number: NCT00903565.

The PARSC trial, a prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.

678 Background: An 18-gene expression profile, ColoPrint, has been developed for identifying CC patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature was validated in in-silico datasets and independent patient cohorts of stage II and III patients. Uni-and multivariate analysis was performed on the pooled stage II patient set (n=320) who had a median follow-up of 70 months. ColoPrint identified two-third of the stage II patients (209/320) as low risk. The 3-year relapse-free survival was 94% for Low Risk patients and 79% for High Risk patients with a HR of 2.74 (95% CI 1.54 - 4.88; p=0.006). Moreover, the profile stratified patients independent of ASCO clinical risk factors. Methods: A prospective trial, PARSC (Prospective study for the Assessment of Recurrence risk in Stage II CC patients) using ColoPrint has been initiated. Objectives are: (1) to validate the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage II colon cancer; (2) to compare the risk assessment in stage II patients using the ColoPrint profile vs. a clinical risk assessment based on Investigator’s assessment of risk and ASCO high-risk recommendations; (3) to investigate therapy as a potential confounding factor for ColoPrint results; and (4) to assess the performance of ColoPrint in estimating the 3-year relapse rate in patients with stage III colon cancer. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II and III, no prior neo-adjuvant therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician adhering to National Comprehensive Cancer Network (NCCN)-approved regimens or a recognized alternative. Results: The trial started in Sept. 2008 with currently 30 participating sites in 11 countries. Thus far, 288 eligible stage 2 and 251 stage 3 patients have been enrolled. Conclusions: The aim is to enroll 575 stage II patients to differentiate between 3 year RFS predicted by ColoPrint and clinical factors.

Prediction of gemcitabine benefit after curative-intent resection of pancreatic adenocarcinoma using HENT1 and dCK protein expression.

4024 Background: In resected pancreatic adenocarcinoma (PA), gemcitabine was shown to improve both DFS and OS, equally to 5FU. In vitro, gemcitabine efficacy is linked to expression of the human equilibrative nucleoside transporter 1(hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit1 (RRM1) proteins. This study evaluated association of these three proteins with efficacy of gemcitabine in resected PA. Methods: Patients with resected PA and no prior neoadjuvant therapy were accrued in 5 university hospitals. hENT1, dCK and RRM1 protein expression were semi-quantitatively assessed by immunohistochemistry using tissue microarray analysis and applying scoring systems as previously reported. The primary clinical end-point was overall survival (OS). The association of clinico-pathological parameters and protein expression with OS was evaluated by log-rank testing and Cox proportional regression. For statistical analysis, biomarkers expression was dichotomized as followed: hENT1 high vslow, dCK high vs low, RRM1 positive vs negative. Results: 434 patients with resected PA were analysed with a median OS of 30.4 months (95% CI: 26.0-34.8); 142 patients (32.7%) did not receive any adjuvant treatment; 243 (56%) were treated with an adjuvant gemcitabine-based therapy (Gem), and 49 (11.3%) with an adjuvant non gemcitabine-based therapy. In patients who did not received Gem (n=191), hENT1, RRM1 and dCK expression were not associated with OS in univariate and multivariate analysis. There was a significant interaction for OS between Gem and hENT1 (p=0.001), and Gem and dCK (p=0.001). In multivariate models adjusted for center, tumor grade, maximum tumor size, lymph nodes, and resection margins, Gem was associated with better OS in hENT1 high (n=163; HR: 0.44, 95%CI: 0.28-0.69, p<0.001) and in dCK high tumors (n=302; HR: 0.57, 95% CI:0.41-0.78, p=0.001). By contrast, in dCK low (n= 114, p=0.73) and in hENT1 low (n=249, p=0.66) tumors, patients derived no benefit from gemcitabine. Conclusions: In this multicenter study, hENT1 and dCK high expressions may predict benefit from gem-based chemotherapy after curative-intent surgery in PA.

Abstract P1-01-05: Clinical Significance of Tumor Burden in the Sentinel Nodes after Neoadjuvant Therapy Differs from Sentinel Nodes in the Adjuvant Setting and This May Influence the Management of the Axilla

Abstract Background. Lymph node metastases are the most significant prognostic factor for breast cancer patients. The use of sentinel node biopsy (SLN) has generated an increased detection of positive nodes through the identification of isolated tumor cells (ITC) and micrometastasis. The objective of this study is to evaluate the significance of SLN micrometastasis and ITC for patients undergoing neoadjuvant chemotherapy versus patients undergoing surgery first. Material and Methods. A total of 571 patients with clinically node negative T1-T3 breast cancer underwent SLN surgery from 2004 to 2008. Clinicopathological data were reviewed and comparison was made between results in the adjuvant and neoadjuvant setting. Results. Of the 571 patients, 71 patients (12.5%) underwent SLN biopsy after neoadjuvant chemotherapy and 500 (87.5%) underwent surgery first. The SLN identification rate in the adjuvant and neoadjuvant therapy groups were similar (96.2% vs 95.8%). Mean number of sentinel nodes removed were 2,2 (range 1-15) in the adjuvant group and 2.2 (range 1-7) in the neoadjuvant group. The SLN was positive in the adjuvant group in 151 patients (30%) while in 27 patients (37.5%) in the neoadjuvant group. The SLN was the only positive node in 106 patients (70.1%) in the adjuvant group and in 6(26%) in the neoadjuvant group. Micrometastasis in the SLN was found in 39 patients (7.8%) in the adjuvant group and in 7 (9.8%) patients in the neoadjuvant group. In the adjuvant group, 7 patients (17.9%) had additional non SLN positive in the axillary dissection (ALND), while 3 (49%) in the neoadjuvant group. ALND was performed in all patients with ITC in the SLN in the neoadjuvant setting and 50% of them had additional nonSLN. Discussion. The significance of micrometastasis or ITC in the sentinel node seems to differ in patients with neoadjuvant therapy or surgery first. Micrometastsis or ITC in patients with prior neoadjuvant therapy may reflect residual disease in the axilla, as 50% of patients will have additional positive nodes. Completion axillary node dissection should be considered in this group of patients. Even more, the majority of patients with a positive SLN in the neoadjuvant group harbored additional positive axillary nodes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-05.

Are there differences in zonal distribution and tumor volume of prostate cancer in patients with a positive family history?

To determine if there are any differences in the zonal distribution and tumor volumes of familial and sporadic prostate cancers (PC) in men undergoing radical prostatectomy. 839 patients underwent a radical prostatectomy in the absence of prior neoadjuvant therapy between 1987 and 1996. Telephone interviews were conducted to obtain an updated family history. A positive family history was defined as the diagnosis of PC in at least one first degree relative. Prostatectomy specimens were examined to determine the number of tumor foci, zonal origin of the dominant tumor focus, tumor volume of the largest cancer focus, total tumor volume, Gleason score and stage, and the surgical margin status. Results were stratified according to family history and ethnicity. We successfully contacted 437 patients (52%). Prostatectomy specimens from 55 patients were excluded from review due to a history of prior transurethral resection of the prostate (n = 26) or uncertain pathological stage (n = 29). Of the remaining 382 patients, 76 (20%) reported having a first-degree relative with PC. Statistical analysis revealed no significant differences in the pathologic variables between the two groups of patients with or without a family history of PC. Familial and sporadic PC share similar characteristics. No histopathological differences account for the increased positive predictive value of PC screening tests among patients with a family history of PC.

False positive endoscopic ultrasound fine needle aspiration cytology: incidence and risk factors

ObjectiveIt is broadly accepted that the false positive (FP) rate for endoscopic ultrasound fine needle aspiration (EUS FNA) is 0–1%. It was hypothesised that the FP and false suspicious (FS)...

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1α and HIF-2α expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1α and HIF-2α, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1α and -2α were expressed in >50% of rectal cancers (HIF-1α, 54%, 48/90; HIF-2α, 64%, 58/90). HIF-1α positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were shown between HIF-2α expression and any pathological features, and HIF-1α positivity had no effect on outcome. The study showed an independent association between HIF-1α expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1α, but not HIF-2α, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.

Pre-operative estimation of esophageal tumor metabolic length in FDG-PET images with surgical pathology confirmation

The aim of this study was to evaluate a 3D tumor segmentation method for fluorodeoxyglucose positron emission tomography (FDG-PET) in the context of noninvasive estimation of tumor metabolic length (Lm), as it correlates with surgical pathology and phantom results. Thirty-four patients (7 women, 27 men) with esophageal cancer were retrospectively evaluated. All patients underwent FDG-PET-computed tomography (CT) imaging following endoscopic ultrasound (EUS). Seventeen patients had esophagectomy after PET/CT, without prior neoadjuvant therapy. Tumor length was assessed by EUS (Le, n=31) and histopathology (Lp, n=17). Images were evaluated quantitatively with a 3D threshold-based region-growing program (Medical Image Processing Analysis and Visualization). Lm, total metabolic volume (Vm), maximum standardized uptake value (SUVmax), and average SUV (SUVa) over the entire tumor were obtained for several threshold values (mean activity in the liver plus 0-, 1-, 2-, 3-, and 4-SD of the activity in the liver). Lm showed a good correlation with Lp for all thresholds (best correlation for Lm(2-SD), r=0.74, P<0.001). A positive nonsignificant correlation was observed between Lp and Le (r=0.30, P=0.29). Lm(2-SD) correlated well with Le (r=0.71, P<0.001). Good correlations were also observed between Lm(2-SD) and Vm(2-SD) (r=0.89, P<0.001) and SUVa(2-SD) (r=0.38, P<0.05). Vm(2-SD) also had a significant correlation with Lp (r=0.61, P<0.05) and Le (r=0.57, P<0.001). FDG-PET-derived tumor metabolic length of untreated esophageal carcinomas correlates well with surgical pathology results, and provides preliminary evidence that noninvasive delineation of the superior and inferior extent of viable tumor involvement might be feasible using computer-generated metabolic length measurements.

Efficacy of Radical Retropubic Prostatectomy as the Primary Treatment for Patients with Clinically Localized Prostate Cancer and a Serum PSA Level ≥0ng/ml

Purpose: We retrospectively reviewed the clinicopathological characteristics ofpatients who underwent radical retropubic prostatectomy (RRP), and these patients had clinically localized prostate cancer and a preoperative serum prostate-specific antigen (PSA) level ≥20ng/ml. Materials and Methods: Among the 266 patients who underwent RRP without any prior neoadjuvant therapy between March 2004 and March 2006, 29 patients had clinically localized prostate cancer and a preoperative serum PSA level ≥20ng/ml. We analyzed several clinicopathologic factors that might predict organ-confined disease. Results: Of the 29 patients, 11 (37.9%) had organ-confined cancer. The level of serum PSA, the PSA density (PSAD), the Gleason score (3+4 or less), the prostate volume, tumor volume and the tumor percentage were significant factors for predicting organ-confined cancer (p<0.05). The number of the positive cores, the percentage of the core material that was positive, the sum of the tumor length of the positive core, tumor percent of the total core length and tumor percent of the positive core length were also significantly higher in the group with an extraprostatic extension of disease compared tothe organ-confined cancer group (p<0.05). Conclusions: For the patients with clinically localized prostate cancer and a serum PSA level ≥20ng/ml, radical prostatectomy can be considered as the primary treatment for some cases that have a relatively lower PSA and PSAD, a biopsy Gleason score of 3+4 or less and low predictive volume of the tumor from the biopsy results. (Korean J Urol 2007;48: 945-950)