Related Experiment Video
Updated: Dec 5, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown
Hidetoshi Hayashi1, Yuichi Takiguchi2, Hironobu Minami3
1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Importance:
Although 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.
Objective:
To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.
Design, Setting, And Participants:
This 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.
Interventions:
RNA 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 Measures:
The 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.
Results:
Of 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 Relevance:
This 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 Registration:
UMIN Identifier: UMIN000016794.
Insights
Next-generation sequencing (NGS) profiling and targeted therapies show promise for treating cancer of unknown primary site (CUP). This approach aids in predicting tumor origin and guiding personalized treatment for better patient outcomes.
Area of Science:
- Oncology
- Genomics
- Clinical Trials
Background:
- Cancer of unknown primary site (CUP) presents a diagnostic and therapeutic challenge.
- Next-generation sequencing (NGS) offers potential for molecular profiling to guide treatment.
- Previous clinical trials have not evaluated NGS-based site prediction and targeted therapy for CUP.
Purpose of the Study:
- To assess the clinical utility of site-specific treatment for CUP patients.
- To evaluate molecularly targeted therapy guided by NGS results.
- To determine the efficacy of an NGS-based algorithm for predicting tumor origin.
Main Methods:
- Phase 2 clinical trial involving 97 patients with unfavorable CUP.
- Simultaneous RNA and DNA sequencing for gene expression and alterations.
- Application of a novel algorithm to predict tumor origin and guide therapy.
Main Results:
- The 1-year survival probability was 53.1%.
- Median overall survival (OS) was 13.7 months, and median progression-free survival (PFS) was 5.2 months.
- Targetable EGFR mutations were identified in 5.2% of patients, with 2 achieving durable PFS with afatinib.
Conclusions:
- NGS-based profiling and site-specific therapy, including molecularly targeted therapy, show potential for treating the unfavorable subset of CUP.
- This approach may improve clinical outcomes for CUP patients.
- Further research is warranted to optimize NGS-guided treatment strategies for CUP.
More Related Videos
07:59Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
13:24Integration of Wet and Dry Bench Processes Optimizes Targeted Next-generation Sequencing of Low-quality and Low-quantity Tumor Biopsies
Published on: April 11, 2016
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...