3 days ago
Could Liquid Biopsy Guide Treatment in Cervical Cancer?
Circulating tumor DNA (ctDNA) levels in patients with cervical cancer before and during treatment were prognostic of disease progression and survival in a post hoc analysis of the phase 3 CALLA trial.
The findings 'support the future utility of…ctDNA analysis to help guide treatment decisions for locally advanced cervical cancer,' said lead study author Jyoti Mayadev, MD, a radiation oncologist at Moores NCI-Designated Comprehensive Cancer Center and professor of radiation medicine and applied sciences at the University of California, San Diego School of Medicine in La Jolla, California.
Mayadev reported the results at the American Society of Clinical Oncology (ASCO) 2025 annual meeting. They were published simultaneously in the Annals of Oncology .
The previously published CALLA trial showed that patients receiving adjuvant chemoradiotherapy (CRT) for locally advanced cervical cancer did not have improved progression-free survival (PFS) with the addition of concurrent durvalumab compared with placebo.
The trial included 770 patients with previously untreated stage IB2-IIB node-positive or IIIA-IVA any node-status locally advanced cervical cancer who were randomly assigned to receive durvalumab (1500 mg intravenously once every 4 weeks) plus CRT (n = 385) or CRT alone (n = 385).
CRT, consisting of external beam radiotherapy with intravenous cisplatin or carboplatin, was delivered once weekly for 5 weeks, followed by image-guided brachytherapy.
Exploratory Analysis Methods and Results
A preplanned exploratory analysis sampled ctDNA levels in a subset of 186 patients to determine if ctDNA could serve as a biomarker for treatment response.
The study used an ultrasensitive tumor-informed ctDNA assay, personalized for each patient, to test plasma at baseline, cycle 3 day 1 (immediately post-CRT), and cycle 6 day 1 (3 months post-CRT), explained Mayadev during her presentation at the meeting.
ctDNA was detected in 99% of baseline samples, with no difference across the treatment arms, she reported. Immediately after treatment, detectable levels decreased to 35.5% in the durvalumab/CRT arm and 39.8% in the CRT-only arm.
By 3 months after treatment, levels declined further to 23.4% and 36.4%, respectively, demonstrating a 13% lower rate of detectable ctDNA in the durvalumab/CRT arm at this timepoint.
The study showed that ctDNA levels were prognostic of both PFS and overall survival (OS), regardless of treatment arm.
Among patients in whom ctDNA was detectable immediately posttreatment, 68% subsequently progressed, and among those without detectable ctDNA, 83% had not progressed by the time of data cutoff, for a positive predictive value of 61%, a negative predictive value of 83%, and a sensitivity and specificity of 68% and 78%, respectively.
ctDNA Detected 5.5 Months Before Radiographic Progression
The median lead time from ctDNA detection on the ultrasensitive assay until radiographic or clinical evidence of progression was 5.5 months, ranging from 1.5 to 16.5 months.
Looking specifically at PFS and OS, patients with ctDNA levels were prognostic of PFS and OS for patients in both treatment arms at all timepoints measured.
In the durvalumab/CRT arm, low vs high ctDNA at baseline conferred a hazard ratio of 0.60 for PFS and of 0.63 for OS. In the CRT-only arm, low vs high ctDNA conferred hazard ratios of 0.62 and 0.85 for PFS and OS, respectively.
Similarly, detectable ctDNA levels immediately posttreatment compared with undetectable levels identified patients at a higher risk for progression and death, regardless of treatment arm. With detectable ctDNA as the reference, PFS and OS hazard ratios were 0.23 and 0.20 in the durvalumab/CRT arm and 0.15 and 0.18 in the CRT-only arm, respectively.
Having no ctDNA detected 3 months after treatment cessation reduced the risks for progression and death by at least 95% for patients in both treatment arms, Mayadev said during her presentation.
Multivariate analysis showed that detection of ctDNA immediately posttreatment conferred a hazard ratio of 5.27 ( P < .001) for PFS, independent of disease stage at baseline or treatment allocation, she said.
'Our study found that persistent ctDNA levels posttreatment strongly correlated with an increased risk of relapse and were likely reflective of residual disease that, in some instances, went undetected by other means,' wrote Mayadev and co-authors in their paper. 'On average, ctDNA was detected 5.5 months before radiographic progression. In clinical practice, this could allow for proactive treatment management to potentially improve patient outcomes — for example, earlier consideration of adjuvant therapies, such as immunotherapy or systemic therapy, or a switch to a novel therapeutic regimen. In cases of recurrence, tracking ctDNA levels in real-time could also help assess response to salvage therapy, providing a dynamic tool for optimizing therapeutic decisions.'
'This really is a good analysis showing how ctDNA is definitely a better prognostic marker than standard poor prognostic clinical factors such as nodal status and even updated FIGO staging for cervical cancer,' said Mark Einstein, MD, the discussant for the paper, who is professor and chair of the Department of Obstetrics and Gynecology and Women's Health at Montefiore Medical Center/Albert Einstein College of Medicine, New York City.
However, he said the positive predictive value and sensitivity 'are good, but they're not great. The negative predictive value, though, is excellent, and this would reveal that the test might have some value as a negative predictive marker of recurrence rather than a positive predictive marker of recurrence.'
But, the bigger question, he said, is 'what are we going to do with that information? If we actually do know that someone has a positive ctDNA, are we going to get into the situation that we are in with ovary cancer, with CA125 without measurable disease, where it just creates a lot of anxiety without necessarily restarting treatment? This could identify central disease before it actually becomes distant, which could lead to potentially curative surgical options, and it might put someone on increased surveillance in imaging, but I think we need to really look at this prospectively.'
Also commenting on the study, Sarah Kim, MD, a gynecologic surgeon specializing in the treatment of ovarian, endometrial, cervical, vulvar, and vaginal cancer at the Memorial Sloan Kettering Cancer Center in New York City, pointed out what she found useful and what additional questions need to be answered.
'Further studies need to be done to validate these results and determine the clinical utility in the setting of adjuvant therapy or recurrence,' she said in an interview with Medscape Medical News .
'I think these are important findings and potentially clinically impactful for patients with locally advanced cervical cancer,' said Kim. 'They support the use of ctDNA to detect minimal residual disease and/or the use of ctDNA as a prognostic marker, which is lacking in cervical cancer. We have seen similar results in patients with endometrial cancer, where the ctDNA increases prior to any detection of disease on imaging.'
The trial was sponsored by AstraZeneca.
Mayadev disclosed leadership roles with the American Brachytherapy Society and NRG Oncology; honoraria from AstraZeneca; consulting or advisory roles with Agenus, AstraZeneca/MedImmune, Merck, Primmune Therapeutics, and Varian Medical Systems; research funding from Varian Medical Systems; and travel, accommodations, and other expenses from Merck.
Einstein disclosed a consulting or advisory role with Antiva Biosciences, Asieris Pharmaceuticals, and Merck, and research funding from Johnson & Johnson, Merck, and PapiVax Biotech, Inc.
Kim had no disclosures.
