Cancers of Unknown Primary Site May Benefit From NGS Profiling

October 23, 2020
Allison Inserro
Allison Inserro

The study describes how RNA sequencing and DNA sequencing for selected genes were performed simultaneously to evaluate gene expression and alterations in order to predict tumor origin.

Unless patients with cancer of unknown primary site (CUP) have other factors working for them, many have poor survival time using platinum-taxane chemotherapeutics, with a median overall survival (OS) of just 6 to 12 months.

A recently published study describes how RNA sequencing and DNA sequencing for selected genes were performed simultaneously to evaluate gene expression and alterations in order to predict tumor origin. Based on the data, the researchers ran an algorithm they developed in an effort to predict the site of the tumor.

Then, per those results, patients received site-specific therapy according to the predicted site and detected gene alterations.

The current study built off of previous work by the authors, who tried to see if using a microarray analysis of gene expression and site-specific therapy might improve outcomes in another group of patients with previously untreated COP. There was no improvement in OS in patients receiving targeted therapy based on those results compared with those receiving empirical chemotherapy. In addition, the previous study predicted that 20% of patients would have lymphoma, which is not common in CUP research.

However, the current study, using NGS, forecast that just a single patient would have lymphoma. Adding more sensitive RNA sequencing analysis created more powerful results, and the different results seen in the earlier study may have been due to the "insufficient predictive ability of microarray-based expression profiling," the authors said.

They noted that to their knowledge this is the first prospective such trial using these methods. The phase 2 nonrandomized clinical trial was carried out at 19 centers in Japan and enrolled 111 previously untreated patients with CUP between March 2015 and January 2018.

The efficacy analysis included 97 patients who had undergone pathological evaluation by immunohistochemistry, CAT scans from the chest to pelvis, and a positron emission tomography scan.

Just over half (50.5%) of the participants were women, and the median (range) age was 64 (21-81) years.

By cancer type, the most commonly predicted ones were:

  • Lung, 21%
  • Liver, 15%
  • Kidney, 15%
  • Colorectal, 12%

One-year survival probability was 53.1% (95% CI, 42.6%-62.5%), median OS was 13.7 months (95% CI, 9.3-19.7), and median progression-free survival (PFS) was 5.2 months (95% CI, 3.3-7.1).

The most frequent gene alterations were in TP53 (46.4%), KRAS (19.6%), and CDKN2A (18.6%).

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.

“The results show that site-specific treatment, including guided targeted therapy based on next-generation sequencing, is a promising strategy for patients with cancer of unknown primary site and warrants further investigation in a randomized clinical trial,” the authors concluded.

Reference

Hayashi H, Takiguchi Y, Minami H, et al. Site-specific and targeted therapy based on molecular profiling by next-generation sequencing for cancer of unknown primary site: a nonrandomized phase 2 clinical trial. JAMA Oncol. Published online October 15, 2020. doi:10.1001/jamaoncol.2020.4643