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Molecular driver alterations and their clinical relevance in cancer of unknown primary site.

ABSTRACT: Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable.

SUBMITTER: Loffler H

PROVIDER: S-EPMC5190099 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceAlthough profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach.ObjectiveTo assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.Design, setting, and participantsThis phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan.InterventionsRNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations.Main outcomes and measuresThe primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations.ResultsOf 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months.Conclusions and relevanceThis study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP.Trial registrationUMIN Identifier: UMIN000016794.

Project description:BackgroundLiver metastases from cancer of unknown primary (CUPL) constitute a rare disease, particularly among individuals younger than 50 years old. This paper aims to investigate the clinical characteristics of patients with CUPL and analyze prognostic differences across distinct age groups.MethodsData pertaining to patients with CUPL were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was employed to adjust for clinical variables. Cox regression analysis identified risk factors influencing overall survival (OS), while competing-risk analyses were conducted to determine prognostic factors for cancer-specific survival (CSS). Survival differences were compared using the Kaplan-Meier method and cumulative incidence function (CIF).ResultsThe study encompassed 4,691 patients, with 319 (6.8%) in the age <50 years group and 4,372 (93.2%) in the age ≥50 years group. Individuals with unexplained liver metastases exhibited a 1-year OS rate of 14.7% and a 1-year CSS rate of 23%. Following matching, age, histology, brain metastases, and chemotherapy were identified as independent prognostic factors affecting OS. Additionally, race, grade, histology, brain metastases, and chemotherapy were recognized as independent prognostic factors influencing CSS. Notably, the age <50 years group demonstrated superior OS and CSS compared to the age ≥50 years group before and after PSM. Among patients undergoing chemotherapy, the age <50 years group exhibited enhanced OS and CSS compared to their age ≥50 years counterparts. Furthermore, in individuals subjected to radiotherapy, the age <50 years group demonstrated superior OS, although no significant difference in CSS was observed.ConclusionsThe survival prognosis of patients with CUPL was found to be poor. However, both OS and CSS were more favorable in the age <50 years group compared to the age ≥50 years group. Additionally, radiotherapy and chemotherapy were associated with an OS benefit for patients in the age <50 years group.

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Molecular driver alterations and their clinical relevance in cancer of unknown primary site.

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