Plasma Tumor DNA in Breast Oncology

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Plasma tumor DNA is superior to serum for analyzing the DNA shed by tumors into the bloodstream.
Plasma tumor DNA is superior to serum for analyzing the DNA shed by tumors into the bloodstream.

Plasma tumor DNA (ptDNA), the plasma component of circulating tumor DNA, is superior to serum for analyzing the DNA shed by tumors into the bloodstream, and could dramatically change future treatment algorithms for breast cancer, according to a plenary presentation at the 2016 San Antonio Breast Cancer Symposium.

“ptDNA detection can change the paradigm and rationale for how we administer systemic therapies in early-stage breast cancers,” said Ben Ho Park, MD, PhD, of the department of oncology, Johns Hopkins University, Baltimore, Maryland. “In metastatic breast cancer, mutations can be reliably detected within ptDNA.”

It is not currently possible to predict ahead of time who needs surgery, Dr Park said.

“The notion is that in the future we might be able to offer some patients a no-surgery option,” he said. “If this works, we can avoid unnecessary treatment.”

But to get there will require the same evidence required for new drug approvals: prospective randomized trials that demonstrate clinical utility.

Analyzing ptDNA involves technical challenges; the fraction of ptDNA in total plasma DNA is “often small,” Dr Park noted. “A big problem in the past was that the quality of plasma DNA is highly dependent on how it is processed. Within a few hours it can begin to lyse.”

Assays for detecting rare mutations in ptDNA are “akin to looking for needles in a haystack,” he said. ptDNA can be measured using digital PCR or “deep” (high-coverage) next generation sequencing (NGS) using any of a variety of techniques, but NGS can involve artifacts. Barcoding and other techniques can “cancel out the noise,” Dr Park said.

ptDNA can now be used to measure somatic tumor point mutations, rearrangements (such as fusion mutations), or both.

“Second-generation automated droplet digital PCR and ptDNA detection tools make it a very easy process,” he said.

Dr Park reviewed recent work to validate analytical methods at his lab, including retrospective and prospective concordance research in patients with metastatic breast cancer, comparing tumor tissue and ptDNA mutation testing.

“Timing matters,” he noted. “Discordant results were found only in patients with greater than 3 years between archival tissue and blood draw.” In contrast, paired samples of concurrently-collected biopsy and blood draw yielded 100% tumor ESR1 mutation concurrence.

Accumulating evidence shows that ESR1 mutations “may be prognostic for worse outcomes,” he noted.

Dr Park and colleagues have undertaken validation studies for the use of ptDNA to monitor tumor responses to therapy in small numbers of patients. The hope is that, 1 day, such monitoring will guide adaptive treatment strategies that quickly spot tumor evolution and respond appropriately.

The goal of systemic therapies in pre-metastatic settings is to eliminate micrometastatic disease and improve cure rates. Next must come validation and demonstration of clinical utility, Dr Park said.

RELATED: Large-scale Analysis of Sequencing Data Confirms Genes That Increase Breast Cancer Risk

“Even if you can show that an assay separates out distinct groups, can you do anything about it?,” he asked.

Clinical validation studies like the prospective Translational Breast Cancer Research Consortium (TBCRC)-040 (ClinicalTrials.gov Identifier: NCT02743910) trial are now under way to find out. Five patients at Johns Hopkins have enrolled since this summer.

Reference

  1. Park BH. PL2 Cell free plasma tumor DNA in breast oncology. Paper presented at: 39th San Antonio Breast Cancer Symposium; Dec 2016; San Antonio, TX.

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