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Clinical Trial Results Support Liquid Biopsy Monitoring to Predict Responders to Palbociclib

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NEW YORK (GenomeWeb) – A new study contributes to growing data indicating that liquid biopsy testing used in the early weeks or months of cancer treatment can help identify patients that are responding and will likely have better outcomes versus those that will not and might be better served by switching to another drug or other therapy.

Published last week in Nature Communications, the study followed patients in the PALOMA 3 trial of the CDK4/6 inhibitor palbociclib, testing them at the start of treatment, and then two to three weeks later using multiplex droplet digital PCR (ddPCR) to detect mutations in PIK3CA.

Investigators led by Nicholas Turner of the Institute of Cancer Research, London, observed that a large decrease in circulating PIK3CA mutations was associated with much better survival — about 11 months versus just 4 months — in women in the study who could be tested for the biomarker.

The results support the idea of longitudinal liquid biopsy testing for more accurate or more rapid assessment of patient response in clinical trials or other research. According to the study authors, the findings could also inform future testing strategies to help doctors detect, in clinical practice, whether this or other drugs are working in their patients.

The use of blood-based tests to monitor patients' response to ongoing therapy, or to measure the efficacy of curative treatments in early disease is an area of increasing focus for ctDNA researchers, Ben O’Leary, the study's first author and a clinical research fellow in the ICR's Molecular Oncology Team, said this week.

For example, a team from Denmark and the Netherlands recently reported on development of ddPCR assays to aid disease surveillance in patients with bladder cancer by picking up progression and metastasis earlier and more sensitively. And Resolution Biosciences has shared data from a study of a new assay for small-cell lung cancer aimed at monitoring the disease burden of patients in treatment as a way of assessing therapeutic effectiveness.

Investigators at Johns Hopkins have also been investigating whether tumor DNA lingers or disappears in the blood of triple negative breast cancer patients treated with neoadjuvant chemotherapy and whether this can predict which patients will go on to recur and which will not.

And another Hopkins group, in collaboration with the Institute of Medical Research in Melbourne, Australia, showed in 2016 that circulating tumor DNA can be used to identify colorectal cancer patients who are more likely to recur after surgical tumor resection.

In their study last week, the ICR-led team analyzed blood samples from women in the PALOMA-3 trial comparing palbociclib plus fulvestrant to fulvestrant plus placebo.

As part of the design of PALOMA-3, sequential plasma samples were collected at baseline, cycle 1 day 15, and at progression, with the specific aim of investigating the predictive power of ctDNA analysis.

"Having that built in, and then all the fantastic clinical annotation you get from a Phase III trial was [crucial] in giving us the ability to actually look at clinical outcome," O'Leary said.

Of the 521 patients recruited to the trial overall, 459 had baseline samples available for DNA extraction and 455 were successfully analyzed using the team's multiplex ddPCR assays running on the Bio-Rad QX200 platform.

Among these patients, 100 cases had a PIK3CA mutation, and 73 had matched day-15 samples. By comparing the amount of mutated PIK3CA detected in a blood test at the start of treatment with the amount detected 15 days after starting treatment, the investigators found that they could distinguish two groups of patients with very different outcomes.

Women who had a small decrease in PIK3CA circulating DNA at 15 days had a median progression-free survival of only 4.1 months, compared with women with a large decrease in PIK3CA, who had a median progression-free survival of 11.2 months.

Palbociclib, approved for use in women with metastatic HR+, HER2- breast cancer, is one of few therapies that can prolong the lives of women with advanced disease, but it doesn't work in everyone.

The potential illustrated by the study then, is that it could offer a method to catch non-responders faster than is possible using current imaging technology, funnel them to another treatment earlier, and thus improve their outcomes via that switch.

A caveat to this is the fact that there aren't great alternatives for women who don't respond to CDK4/6 inhibition. In other words, a patient finding out that she's not responding to palbociclib may not necessarily confer a significant benefit to her, at least right now. But that could change in the future as more drugs are developed, and different combination therapies move through clinical trials.

According to O'Leary this underscores the importance of investigating not only the validity of a testing method, but also the clinical utility.

"Our study is hopefully a first step on this route, but more hast to be done," he said. "First, we have to replicate this in an independent set, and then we have to take a second step, which is take this test, and do a clinical trial and see if … we can help people do better with a different treatment."

"It's laborious, but it had to be done to know that it works," he added.

While clinical researchers have largely said they view liquid biopsy recurrence and response monitoring as experimental, multiple companies have already begun to market tests that use circulating tumor DNA, circulating tumor cells, or other analytes to scan the blood of patients for signs of response, resistance, or cancer recurrence.

Cynvenio Biosystems, for example, launched a CTC- and protein-based monitoring service last year intended to track disease status or surveil for early signs of recurrence in breast cancer patients.

Other early movers in this area include CellMax Life, which offers liquid biopsy tests for both early detection of new colorectal cancers, and monitoring for resistance or recurrence in treated patients. And in the US, Pathway Genomics was at one point offering blood-based mutation testing both for early detection and recurrence monitoring. However, that CancerIntercept Monitor test is no longer listed on the company's website.

Whether in reaction to this or as a general reminder, the American Society of Clinical Oncology and College of American Pathologists issued a joint review earlier this week, stating, among other things, that "there is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection."

"I think that kind of guidance is important at this time," O'Leary said, "because what has been demonstrated is lots and lots of promise, but the next step — the next threshold that hasn't been met yet — is the evidence that demonstrates benefit."

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