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Liquid Biopsy May Aid Treatment Decisions in Solid Tumors

Fuerst, Mark L.

doi: 10.1097/01.COT.0000489502.40733.c6
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CHICAGO—A liquid biopsy may offer a non-invasive alternative to tissue biopsy to help guide treatment decisions for patients with advanced solid tumors, according to a new study.

Interest is growing in utilizing comprehensive tumor genetic profiling to guide patients toward appropriate targeted therapies. “Advanced cancers shed tumor DNA into the bloodstream. This circulating tumor DNA (ctDNA) harbors cancer-associated mutations of potential use in diagnostics,” said Philip Mack, PhD, Professor and Director of Molecular Pharmacology at the University of California Davis Comprehensive Cancer Center, Sacramento, at a press briefing at the 2016 American Society of Clinical Oncology Annual Meeting.

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Next-Generation Sequencing

The study (Abstract LBA11501) assessed the accuracy and clinical utility of a highly sensitive next-generation sequencing technique for cancer mutation testing conducted exclusively in blood. The study included 17,628 blood samples from 15,191 patients, including those with advanced lung cancer (37%), breast cancer (14%), colorectal cancer (10%), and other cancers (39%). Each patient provided one or more blood samples for analysis of ctDNA.

A comprehensive, commercially available liquid biopsy assay (Guardant360) was used to profile four major classes of gene alterations from over 50 types of cancer. The clinical utility and accuracy of this test was assessed for tumor alterations detected at very low frequencies in blood.

Results were compared to publicly available, population-scale tumor sequencing projects, including The Cancer Genome Atlas. The new study is one of the largest cancer genomics studies ever, according to Mack.

When ctDNA was positive for key abnormalities in EGFR, BRAF, KRAS, ALK, RET, and ROS1 that drive tumor growth, the same mutations were reported in tissue 94-100 percent of the time. “ctDNA mutation patterns were highly consistent with distribution in tissue. ctDNA analysis additionally detected resistance alterations, such as T790M, not present at the time of initial tissue biopsy,” he explained.

The study showed the clinical utility of comprehensive liquid biopsy. “ctDNA analysis identified cancer mutations useful as biomarkers for an FDA-approved targeted drug in 49 percent of patient cases. For patients with tumors that have acquired resistance to an effective treatment, ctDNA analysis detected the presence of resistance mutations that can guide the choice of new therapy.”

The detection of key cancer mutation in plasma ctDNA occurred at expected frequencies and distribution. “This remained true for mutations detected at very low levels. Alterations observed at ctDNA fractions as low as 0.06 percent responded to treatment, highlighting the importance of assay sensitivity,” said Mack.

Plasma testing has several advantages. “Detection of tumor-specific mutations in a blood draw is an attractive alternative when tissue biopsies are not feasible. It is easy to do in any clinic and avoids biopsy-related complications,” he said.

In addition, “physicians can monitor changes in disease over time. They can potentially identify mutations in metastatic lesions not observed in the original tumor biopsy. This provides an opportunity to identify treatment-induced resistance mechanisms.”

Based on the genetic changes the blood test revealed, the researchers provided the study participants' physicians with lists of possible treatment options, including FDA-approved drugs and/or clinical trials. Overall, ctDNA testing revealed a possible treatment option for nearly two-thirds of patients tested (63.6%), which included FDA-approved drugs as well as eligibility for clinical trials.

Clinical utility was evident among lung cancer patients. In 362 lung cancer cases, tissue was insufficient for testing or partially tested in 63 percent. Among these cases, the ctDNA test identified key genetic mutations at frequencies consistent with their prevalence in the published literature, providing these patients with their only source of an actionable target.

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Precision Medicine

Another study (Abstract LBA11511) presented at the press briefing showed that a precision medicine approach may expand therapeutic options for patients. An increasing number of targeted agents are approved for use in specific cancer types based on the presence of critical molecular alterations, with similar molecular alterations occasionally found in a variety of other cancer types, said lead author John D. Hainsworth, MD, senior investigator at Sarah Cannon Research Institute in Nashville, Tenn.

He reported on MyPathway, an ongoing non-randomized, open-label trial to evaluate agents targeting HER2, BRAF, Hedgehog, or EGFR pathways in non-indicated tumor types harboring these molecular alterations.

Patients were matched with drugs targeting those abnormalities. Patients received a combination of trastuzumab (Herceptin) and pertuzumab (Perjeta) if they had HER2 abnormalities (amplification, overexpression, or mutation); vemurafenib (Zelboraf) for BRAF mutations; vismodegib (Erivedge) for Hedgehog pathway mutations; and erlotinib (Tarceva) for EGFR mutations.

Among the first 129 patients, 82 patients had alterations in HER2, 33 patients in BRAF, eight patients in Hedgehog and six patients in EGFR. All patients had an advanced solid tumor and had received a mean of three prior therapies.

Some 29 patients with 12 different types of cancer responded to targeted treatment. Fourteen responders have progressed after a median of 6 months of treatment; 15 responses are ongoing at 3 to more than 11 months.

The most promising efficacy was seen among patients with HER2 abnormalities. Seven of 20 patients with colorectal cancer, three of eight patients with bladder cancer, and three of six patients with biliary cancer experienced objective responses (tumor shrinkage of 30% or more). Based on these results, recruitment to each of these groups has been expanded, Hainsworth said.

The group of patients with lung cancer and BRAF mutations will also be expanded. Among the first 15 patients in that group, three had objective responses and two had stable disease lasting for at least 4 months.

“Clinical trials enrolling patients based on identified tumor molecular alterations, independent of tumor type, are feasible and important to benefit unmet medical needs,” concluded Hainsworth.

Mark L. Fuerst is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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