Genomic testing aids precision therapy and tissue of origin identification for cancers whose primary site is unknown microbiologystudy

A new study highlights the potential of whole genome and transcriptome sequencing (WGTS) to improve precision treatment and identify the tissue of origin for cancers whose primary site is unknown, also called cancers of unknown primary (CUP).

The research is published in Nature Communications. The study was led by Associate Professor Richard Tothill of the Rare Disease Oncogenomics lab at the Collaborative Center for Genomic Cancer Medicine, a joint venture of the University of Melbourne and Peter MacCallum Cancer Center.

The research was also a collaboration with Professor Linda Mileshkin, Director of Medical Oncology and lead of the CUP clinic at the Peter Mac and clinical lead for this study. It compared the performance of WGTS to conventional gene panel testing in a retrospective cohort of 72 CUP patients.

Cancer of unknown primary (CUP) refers to the discovery of metastatic, or secondary, tumors for which the cancer’s original primary site, or tissue of origin, can’t be determined with standard diagnostic tests. Accounting for 1%–3% of new cancer cases, CUP patients often have a poor prognosis and limited treatment options.

Dr. Richard Rebello, study first author and post-doctoral scientist with the Rare Disease Oncogenomics lab, said the results demonstrated that WGTS detected all reportable mutations identified by panel testing and uncovered additional clinically relevant features in 76% of cases.

WGTS involves analyzing a biological sample to reveal the patient’s genome (their entire DNA) and their transcriptome (their RNA, which carries instructions from DNA)—information that can reveal known cancer-causing mutations for which there may already be targeted treatments.

“Although gene panel sequencing can detect many approved therapeutic targets, our findings show that WGTS increases the diagnostic yield and broadens treatment options for CUP patients,” said Dr. Rebello.

Crucially, the researchers found that WGTS suggested potential treatment options for 79% of patients, a significant improvement over panel testing—enabling 24% more patients to be potentially eligible for standard-of-care therapies and or phase I–II clinical trials.

“A major benefit to using WGTS testing is the ability to identify a likely tissue of origin of the CUP tumor,” said Associate Professor Tothill. “To resolve tissue of origin, we used deep curation to identify individual diagnostic features, as well as the CUP prediction algorithm (CUPPA) trained on WGTS data from known primary cancers—a method developed by Peter Priestley at the Hartwig Medical Foundation.

“When these combined strategies were used, 77% of CUP cases had a probable tissue of origin identified by WGTS, outperforming panel testing, which assisted tissue of origin diagnosis in only 34% of cases.”

Professor Mileshkin said, “We have shown that genomic tests that can help to resolve the primary cancer type diagnosis as well as guide targeted treatments are needed to improve outcomes for CUP patients. Currently, access to PBS-funded drug therapies as well as clinical trials is often restricted by cancer type rather than the molecular profile of the cancer, which can limit access to treatment for patients with CUP.”

Whereas previous studies have suggested that genomic testing only works well if done on fresh tumor samples, this study also demonstrated the feasibility of using WGTS on archived tissue samples and cell-free DNA or liquid biopsy, with a 97% success rate for WGTS using preserved (formalin-fixed paraffin-embedded—FFPE) samples and a 41% high likelihood tissue of origin predictions using cell-free DNA samples.

“Our findings could enable more equitable access to precision testing for CUP patients in the future, especially in regional areas where collecting fresh tissue samples is logistically challenging,” said Associate Professor Tothill.

“While wider acceptance of these genomic tests will require further validation, our work has importantly highlighted the potential of WGTS to improve precision treatment and tissue of origin diagnosis for CUP patients, offering hope for better outcomes in these challenging cancer cases.”