Monitoring ctDNA Predicts HER2+ Cancer Treatment Response

SAN DIEGO — Monitoring a patient’s circulating tumor DNA (ctDNA) can provide valuable insights on early response to targeted therapies among patients with HER2-positive cancers.

This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.

“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.

Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.

“Such monitoring may be useful in clinical trials and eventually in practice,” she added.

Need for New Methods to Predict Early Tumor Response

Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.

During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.

“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.

Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.

“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.

In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.

Design of Patient-Specific ctDNA Assays

In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).

By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).

During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.

Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.

Changes in ctDNA Levels Predict Patient Survival

The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = .04).

Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).

“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.

Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”

The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.

In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”

Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.

Implementation of ctDNA Monitoring in Clinical Trials

Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.

“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.

He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.

“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.

Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.