Liquid Biopsies Could Help Guide Therapy in Carcinoma of Unknown Primary
A recent study suggests that next-generation sequencing of circulating tumor DNA is feasible in carcinoma of unknown primary, which could facilitate targeted therapy for this hard-to-treat disease.
It may be possible to guide therapy through liquid biopsies in patients who have carcinoma of unknown primary (CUP), a rare and difficult-to-treat malignancy. A new study published in Cancer Research is suggesting next-generation sequencing of circulating tumor DNA (ctDNA) is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations. The researchers contend there is enough evidence to support the inclusion of noninvasive liquid biopsies in next-generation clinical trials.
Using ctDNA, the team identified distinct genomic profiles with potentially targetable alterations in 99.7% of CUP patients who had detectable alterations. Razelle Kurzrock, MD, chief of the division of hematology and oncology at the University of California San Diego School of Medicine and director of the Center for Personalized Cancer Therapy at UC San Diego Moores Cancer Center in San Diego, California, said these findings could greatly impact how CUP patients are managed in the future.
“Overall, we found that circulating tumor DNA derived from a blood sample yields useful genomic information in many patients with CUP. This information can be used to choose genomically targeted therapy and also to choose immunotherapy, if for instance the patient has a mismatch repair gene alteration,” said Dr. Kurzrock.
CUP is a rare metastatic disease with an incidence of 7 to12 cases per 100,000 per year. Using liquid biopsies from 442 CUP patients, Dr. Kurzrock and colleagues interrogated 54 to 70 genes in ctDNA using next-generation sequencing. They found that 80% of CUP patients had detectable ctDNA alterations and 66% had at least one characterized alteration.
The study showed that 43.9% of the patients harbored two or more alterations. The most prevalent variants were found in the genes TP53, KRAS, PIK3CA, BRAF, and MYC. The study showed that 99.7% of patients with at least one characterized alteration had theoretically actionable genetic mutations, either with off-label use of U.S. Food and Drug Administration–approved agents or agents currently under investigation.
“The most important take-home message is that the majority of patients with CUP have potentially actionable genomic alterations detectable by a simple blood test. This is particularly important because CUP is almost the ideal cancer in which to apply genomics, since we don’t have an organ-of-origin diagnosis for these patients,” Dr. Kurzrock told OncoTherapy Network.
The researchers conducted two case studies to demonstrate the clinical relevance of their findings. In the first case, they analyzed a series of five liquid biopsies from a woman with metastatic CUP and identified dynamic changes in ctDNA that corresponded to therapeutic interventions. In the second case, the investigators matched a patient with adenocarcinoma of unknown primary with liver and abdominal lymph node metastases harboring KRAS and MLH1 mutations to combination treatment with trametinib and nivolumab, an anti-PD1 checkpoint inhibitor. Within 8 weeks, the patient had a partial response (36.4% tumor reduction) and a rapid decline in tumor marker CA-19-9, an antigen used to monitor treatment response.
