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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:BackgroundCancer of unknown primary (CUP) describes patients with metastatic disease without an identified primary tumor site. Successful diagnosis and treatment of these patients remains difficult. Published guidelines on CUP have highlighted "favorable" subtype groups. We investigated a series of CUP patients to review adherence to guidelines, and identification of primary cancers or "favorable" subtypes.MethodsPatients with histologically confirmed CUP at an academic institution from 2012 to 2018 were identified. Patient demographics, tumor presentation, diagnostic work-up and treatment information were retrospectively collected from electronic data records for descriptive analysis and compared to published clinical guidelines. The primary endpoint was the proportion of patients where the primary site was identified. Multivariable logistic regression models were used to identify factors associated with primary site identification. Kaplan-Meier survival curves were used to determine factors associated with poorer OS.ResultsThree hundred and five patients were included with a median follow-up time of 4.3 months. Primary tumor sites were identified in 109 patients (37.5%), which was most commonly lung cancer (33%). Statistical analyses did not identify any demographic or initial presentation factors associated with identifying the primary or not. More diagnostic tests did not increase the likelihood of primary site identification (P=0.44). Patients with an identified primary did not have longer OS than other patients (median 5.2 months vs. 4.7 months, P=0.47). 57 patients (18.7%) who had a defined "favorable" subtype experienced superior OS (36.6 months vs. 3.8 months; P<0.0001). Further, patients with good prognostic status who followed published treatment guidelines had longer OS (17.6 months vs. 13.2 months; P=0.04).ConclusionsCUP remains a difficult cancer to diagnose and treat. These results suggest identifying the primary has less impact than anticipated, but particular efforts to identify patients with "favorable" subtypes of CUP is important prognostically.

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

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