A phase II study to evaluate the efficacy and toxicity of oxaliplatin in combination with gemcitabine in carcinoma of unknown primary.

BACKGROUND: Preclinical and clinical data suggest synergy for gemcitabine and oxaliplatin. These agents were tested in several known cancers that also comprise the common carcinoma of unknown primary (CUP) subtypes; namely, lung and pancreaticobiliary profiles. METHODS: The study enrolled 29 patients of whom 28 patients were eligible for treatment. Gemcitabine was given at 1,000 mg/m(2) as a fixed dose rate infusion and oxaliplatin was infused at 100 mg/m(2) every 2 weeks with restaging performed after 3 cycles at 6 weeks. RESULTS: The study reported one complete response (CR) (4%), 6 patients with a partial response (PR) (25%), and 13 with stable disease (SD) (54%); and 4 patients had progressive disease (PD) (17%) on restaging. Median overall survival (OS) and progression-free survival were 12.8 months (95% confidence interval [CI] 8.5-18.5) and 3.1 months (95% CI 1.7-6), respectively. The 1-year OS was 54%. The most common grade 3 toxicities were nausea (22%), vomiting (15%), and fatigue (11%). There were no grade 4 toxicities. This study was closed early as we moved from an empiric therapy platform to a more individualized approach. CONCLUSIONS: Gemcitabine and oxaliplatin is a well-tolerated regimen in CUP with similar outcomes to previously documented CUP studies. In selected good performance status patients this combination may serve as a first-line doublet chemotherapy option for CUP patients.

Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary.

PURPOSE: Accurate identification of tissue of origin (ToO) for patients with carcinoma of unknown primary (CUP) may help customize therapy to the putative primary and thereby improve the clinical outcome. We prospectively studied the performance of a microRNA-based assay to identify the ToO in CUP patients. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded (FFPE) metastatic tissue from 104 patients was reviewed and 87 of these contained sufficient tumor for testing. The assay quantitates 48 microRNAs and assigns one of 25 tumor diagnoses by using a biologically motivated binary decision tree and a K-nearest neighbors (KNN). The assay predictions were compared with clinicopathologic features and, where suitable, to therapeutic response. RESULTS: Seventy-four of the 87 cases were processed successfully. The assay result was consistent or compatible with the clinicopathologic features in 84% of cases processed successfully (71% of all samples attempted). In 65 patients, pathology and immunohistochemistry (IHC) suggested a diagnosis or (more often) a differential diagnosis. Out of those, the assay was consistent or compatible with the clinicopathologic presentation in 55 (85%) cases. Of the 9 patients with noncontributory IHC, the assay provided a ToO prediction that was compatible with the clinical presentation in 7 cases. CONCLUSIONS: In this prospective study, the microRNA diagnosis was compatible with the clinicopathologic picture in the majority of cases. Comparative effectiveness research trials evaluating the added benefit of molecular profiling in appropriate CUP subsets are warranted. MicroRNA profiling may be particularly helpful in patients in whom the IHC profile of the metastasis is nondiagnostic or leaves a large differential diagnosis.

Emerging techniques for determining the tissue of origin in patients with unknown primary carcinoma.

New molecular tests to assign a putative tissue of origin in patients with carcinoma of unknown primary (CUP) have recently become commercially available. This editorial addresses this new technology in terms of our current understanding of CUP, and how these tests may affect its management.

Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation.

PURPOSE: To evaluate the feasibility of a 10-gene reverse transcriptase polymerase chain reaction assay to identify the tissue of origin in patients with carcinoma of unknown primary (CUP) site. PATIENTS AND METHODS: Diagnostic biopsy formalin-fixed, paraffin-embedded (FFPE) specimens from 120 patients with CUP were collected retrospectively from Sarah Cannon Research Institute, Nashville, TN, and prospectively from The University of Texas M. D. Anderson Cancer Center, Houston, TX. Tissue of origin assignments by the assay were correlated with clinical and pathologic features and with response to therapy. RESULTS: The assay was successfully performed in 104 patients (87%), and a tissue of origin was assigned in 63 patients (61%). In the remaining 41 patients (39%), the molecular profiles were not specific for the six tumor types detectable by this assay. The tissues of origin most commonly identified were lung, pancreas, and colon; most of these patients had clinical and pathologic features consistent with these diagnoses. Patients with lung and pancreas profiles had poor response to treatment. Patients with colon cancer profiles had better response to colon cancer-specific therapies than they did to empiric CUP therapy with taxane/platinum regimens. Patients with ovarian cancer profiles were atypical, with widespread visceral metastases and a paucity of overt peritoneal involvement. CONCLUSION: This gene expression profiling assay was feasible using FFPE biopsy specimens and identified a putative tissue of origin in 61% of patients with CUP. In most patients, the assigned tissue of origin was compatible with clinicopathologic features and response to treatment. Prospective studies in which assay results are used to direct therapy are indicated.

Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions.

Carcinoma of unknown primary (CUP), which accounts for about 3-5% of all new cancers, is a challenging heterogeneous entity with an unmet research need. Traditionally, CUP has been managed with broad-spectrum chemotherapy, but with the increasing availability of sophisticated diagnostic techniques and the emergence of new treatments that have been shown to be effective in specific cancers the one-treatment-fits-all approach to CUP might eventually no longer be valid. CUP in association with a colon-cancer profile (CCP-CUP) is an example of an emerging, specific CUP subset that seems to benefit from a tailored approach. CCP-CUP is identified by CK20 and CDX2-positive and CK7-negative immunohistochemistry and a clinical course consistent with that of patients known to have metastatic colon cancer. Our findings suggest that patients with CCP-CUP derive substantial benefit from the use of specific treatments developed for colon cancer and larger clinical trials are warranted to more definitely test this finding. In the era of molecular profiling, we expect that additional work with CCP-CUP and other CUP subsets will provide attractive tailored treatment alternatives, with efficacies that exceed the current one-treatment-fits-all approach.

Metastatic patterns in adenocarcinoma.

BACKGROUND: Unique metastatic patterns cited in the literature often arise from anecdotal clinical observations and autopsy reports. The authors analyzed clinical data from a large number of patients with histologically confirmed, distant-stage adenocarcinoma to evaluate metastatic patterns. METHODS: Tumor registry data were collected between 1994-1996 on 11 primary tumor sites and 15 metastatic sites from 4399 patients. The primary and metastatic sites were cross-tabulated in various ways to identify patterns, and the authors developed algorithms by using multinomial logistic regression analysis to predict the locations of primary tumors based on metastatic patterns. RESULTS: Three primary tumors had single, dominant metastatic sites: ovary to abdominal cavity (91%), prostate to bone (90%), and pancreas to liver (85%). The liver was the dominant metastatic site for gastrointestinal (GI) primary tumors (71% of patients), whereas bone and lung metastases were noted most frequently in non-GI primary tumors (43% and 29%, respectively). In a study of combinations of liver, abdominal cavity, and bone metastases, 86% of prostate primary tumors had only bone metastases, 80% of ovarian primary tumors had only abdominal cavity metastases, and 74% of pancreas primary tumors had only liver metastases. A single organ was the dominant source of metastases in 7 sites: axillary lymph node from the breast (97%), intestinal lymph node from the colon (84%), thoracic lymph node from the lung (66%), brain from the lung (64%), mediastinal lymph node from the lung (62%), supraclavicular lymph node from the breast (51%), and adrenal gland from the lung (51%). CONCLUSIONS: The algorithms that the authors developed achieved a cross-validated accuracy of 64% and an accuracy of 64% on an 1851-patient independent test set, compared with 9% accuracy when a random classifier was used.