Liquid Biopsy in Metastatic Breast Cancer Management: Where Does It Stand in Clinical Practice?

Victoria Stern, MA


November 04, 2021

Identifying the molecular features of metastatic breast cancer (MBC) offers a real-time window into a patient's treatment options as well as the potential to follow the disease as it evolves over time.

Tissue biopsy remains the gold standard for characterizing tumor biology and guiding therapeutic decisions, but liquid biopsies — blood analyses that allow oncologists to detect circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in the blood — are increasingly demonstrating their value. Last year, the US Food and Drug Administration (FDA) approved two liquid biopsy tests, Guardant360 CDx and FoundationOne Liquid CDx, that can identify more than 300 cancer-related genes in the blood. In 2019, the FDA also approved the first companion diagnostic test, therascreen, to pinpoint PIK3CA gene mutations in patients' ctDNA and determine whether patients should receive the PI3K inhibitor alpelisib along with fulvestrant.

Here's an overview of how liquid biopsy is being used in monitoring MBC progression and treatment — and what some oncologists think of it.

What We Do and Don't Know

"Identifying a patient's targetable mutations, most notably PIK3CA mutations, is currently the main use of liquid biopsy," said Pedram Razavi, MD, PhD, a medical oncologist who leads the liquid biopsy program for breast cancer at Memorial Sloan Kettering (MSK) Cancer Center in New York City. "Patients who come to MSK are offered a tumor and liquid biopsy at the time of metastatic diagnosis as part of the standard of care."

Liquid and tissue biopsy analyses can provide a more complete picture of a patient's condition. Whereas tissue biopsy allows oncologists to target a more saturated sample of the cancer ecosystem and a wider array of biomarkers, liquid biopsy offers important advantages as well, including a less invasive way to sequence a sample, monitor patients' treatment response, or track tumor evolution. Liquid biopsy also provides a bigger picture view of tumor heterogeneity by pooling information from many tumor locations as opposed to one.

But, cautioned Yuan Yuan, MD, PhD, liquid biopsy technology is not always sensitive enough to detect CTCs, ctDNA, or all relevant mutations. "When you collect a small tube of blood, you're essentially trying to catch a small fish in a big sea and wading through a lot of background noise," said Yuan, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County. "The results may be hard to interpret or come back inconclusive."

And although emerging data suggest that liquid biopsy provides important insights about tumor dynamics — including mapping disease progression, predicting survival, and even detecting signs of cancer recurrence before metastasis develops — the tool has limited utility in clinical practice outside of identifying sensitivity to various therapies or drugs.

"Right now, a lot of research is being done to understand how to use CTC and ctDNA in particular as a means of surveillance in breast cancer, but we're still in the beginning stages of applying that outside of clinical trials," said Joseph A. Sparano, MD, deputy director of the Tisch Cancer Institute and chief of the Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York City.

Personalizing Treatment

The companion diagnostic test therascreen marked the beginning stages of using liquid biopsy to match treatments to genetic abnormalities in MBC. The SOLAR-1 phase 3 trial, which led to the approval of alpelisib and therascreen, found that the PI3K inhibitor plus fulvestrant almost doubled progression-free survival (PFS) (11 months vs 5.7 months in placebo-fulvestrant group) in patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer.

More recent studies have shown that liquid biopsy tests can also identify ESR1 mutations and predict responses to inhibitors that target AKT1 and HER2. Investigators presenting at the 2021 American Society of Clinical Oncology meeting reported that next-generation sequencing of ctDNA in patients with HR-positive MBC, HER-positive MBC, or triple-negative breast cancer detected ESR1 mutations in 14% of patients (71 of 501). Moreover, ESR1 mutations were found only in HR-positive patients who had already received endocrine therapy. (The study also examined PIK3CA mutations, which occurred in about one third of patients). A more in-depth look revealed that ESR1 mutations were strongly associated with liver and bone metastases and that mutations along specific codons negatively affected overall survival (OS) and PFS: codons 537 and 538 for OS and codons 380 and 536 for PFS.

According to Debasish Tripathy, MD, professor and chairman of the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, in addition to tumor sequencing, "liquid biopsy has become a great research tool to track patients in real time and predict, for instance, who will respond to a treatment and identify emerging resistance."

In terms of predicting responses to treatment, the plasmaMATCH trial assessed ctDNA in 1034 patients with advanced breast cancer for mutations in ESR1, HER2, and AKT1 using digital droplet polymerase chain reaction (PCR) and Guardant360. Results showed that 357 (34.5%) of these patients had potentially targetable aberrations, including 222 patients with ESR1 mutations, 36 patients with HER2 mutations, and 30 patients with AKT1 mutations.

Agreement between digital droplet PCR and Guardant360 testing was 96%-99%, and liquid biopsy showed 93% sensitivity compared with tumor samples. The investigators also used liquid biopsy findings to match patients' mutations to targeted treatments: fulvestrant for those with ESR1 mutations, neratinib for HER2 (ERBB2) mutations, and the selective AKT inhibitor capivasertib for estrogen receptor–positive tumors with AKT1 mutations.

Overall, the investigators concluded that ctDNA testing offers "accurate tumor genotyping" in line with tissue-based testing and is ready for routine clinical practice to identify common as well as rare genetic alterations, such as HER2 and AKT1 mutations, that affect only about 5% of patients with advanced disease.

Predicting Survival and Recurrence

A particularly promising area for liquid biopsy is its usefulness in helping to predict survival outcomes and monitor patients for early signs of recurrence before metastasis occurs. But the data to support this are still in their infancy.

A highly cited study, published over 15 years ago in the New England Journal of Medicine, found that patients with MBC who had five or more CTCs per 7.5 mL of whole blood before receiving first-line therapy exhibited significantly shorter median PFS (2.7 vs 7.0 months) and OS (10 vs > 18 months) compared with patients with fewer than five CTCs. Subsequent analyses performed more than a decade later, including a meta-analysis published last year, helped validate these early findings that levels of CTCs detected in the blood independently and strongly predicted PFS and OS in patients with MBC.

In addition, ctDNA can provide important information about patients' survival odds. In a retrospective study published last year, investigators tracked changes in ctDNA in 291 plasma samples from 84 patients with locally advanced breast cancer who participated in the I-SPY trial. Patients who remained ctDNA-positive after 3 weeks of neoadjuvant chemotherapy were significantly more likely to have residual disease after completing their treatment compared with patients who cleared ctDNA at that early stage (83% for those with nonpathologic complete response vs 52%). Notably, the presence of ctDNA between therapy initiation and completion was associated with a significantly greater risk for metastatic recurrence, whereas clearance of ctDNA after neoadjuvant therapy was linked to improved survival.

"The study is important because it highlights how tracking circulating ctDNA status in neoadjuvant-treated breast cancer can expose a patient's risk for distant metastasis," said Yuan. But, she added, "I think the biggest attraction of liquid biopsy will be the ability to detect molecular disease even before imaging can, and identify who has a high risk for recurrence."

Razavi agreed that the potential to prevent metastasis by finding minimal residual disease (MRD) is the most exciting area of liquid biopsy research. "If we can find tumor DNA early before tumors have a chance to establish themselves, we could potentially change the trajectory of the disease for patients," he said.

Several studies suggest that monitoring patients' ctDNA levels after neoadjuvant treatment and surgery may help predict their risk for relapse and progression to metastatic disease. A 2015 analysis, which followed 20 patients with breast cancer after surgery, found that ctDNA monitoring accurately differentiated those who ultimately developed metastatic disease from those who didn't (sensitivity, 93%; specificity, 100%) and detected metastatic disease 11 months earlier, on average, than imaging did. Another 2015 study found that the presence of ctDNA in plasma after neoadjuvant chemotherapy and surgery predicted metastatic relapse a median of almost 8 months before clinical detection. Other recent data show the power of ultrasensitive blood tests to detect MRD and potentially find metastatic disease early.

Although an increasing number of studies show that ctDNA and CTCs are prognostic for breast cancer recurrence, a major question remains: For patients with ctDNA or CTCs but no overt disease after imaging, will initiating therapy prevent or delay the development of metastatic disease?

"We still have to do those clinical trials to determine whether detecting MRD and treating patients early actually positively affects their survival and quality of life," Razavi said.

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