Randomized Phase II Trial Comparing Site-Specific Treatment Based on Gene Expression Profiling With Carboplatin and Paclitaxel for Patients With Cancer of Unknown Primary Site

Abstract

PURPOSE Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types. CONCLUSION Site-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.

Integrated clinicomolecular characterization identifies RAS activation and CDKN2A deletion as independent adverse prognostic factors in cancer of unknown primary

“…In principle, there are two strategies to improve outcome in unfavorable CUP based on molecular profiling of cancer tissue. One strategy aims to predict the putative primary based on gene expression or methylation profiling and to tailor treatment accordingly . However, this putative primary based treatment approach did not prove superior over empiric standard chemotherapy in both randomized clinical trials conducted so far .…”

“…One strategy aims to predict the putative primary based on gene expression or methylation profiling and to tailor treatment accordingly . However, this putative primary based treatment approach did not prove superior over empiric standard chemotherapy in both randomized clinical trials conducted so far . The other strategy to improve prognosis based on molecular profiling aims to identify clinically actionable mutations for targeted therapy.…”

Molecular Profiles of Brain and Pulmonary Metastatic Disease in Cancer of Unknown Primary

“…Excellent response to crizotinib in a ROS1 rearranged CUP has been reported [17]. Although the treatment benefits of genomic profiling remain hopeful, there is no randomized data to support precisionbased treatment based on targeted mutations [18,19].…”

“…A recent multicenter phase II trial with gene expression profiling (GEP) performed by microarray analysis guided treatment versus empiric carboplatin and paclitaxel in CUP had nonstatistically significant inferior outcomes for 1-year survival at 44% in the guided treatment group versus 54.9% for 1-year empiric [18]. The most common cancer types predicted included pancreatic cancer (21%), gastric cancer (21%), and lymphoma (20%).…”

“…Although workup for this patient was complicated by discontinuity with care, genomic profiling shortly after routine workup failed to reveal a primary would have allowed for identification of ICI targets earlier in the clinical course. Although previous studies have shown presence of biomarkers able to be targeted with immune checkpoint blockade [18], there is no randomized control trials to date assessing efficacy of these treatments compared with empiric chemotherapy. Further research is needed both to address optimal timing of GEP as well as evaluate efficacy of ICIs on CUP.…”