For cervical cancer patients, the post-treatment phase isn’t the finish line; it’s the start of a new chapter of careful observation. Even after a taxing therapeutic battle, enduring chemotherapy and radiation, and feeling the immense relief of treatment’s end, patients return for vital examinations every three to six months for traces of recurrence. Lurking beneath the surface of that relief is the persistent question: Is the cancer truly gone?
This uncertainty, shared by countless women and their dedicated medical teams, has long been a profound challenge in oncology. But a recent announcement at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting in Chicago has ignited a powerful spark of hope for a future without this lingering doubt. Researchers from the University of California, San Diego (UCSD) and Personalis demonstrated that the company’s NeXT Personal® blood test, designed to detect circulating tumor DNA (ctDNA) from cervical cancer, is capable of detecting cervical cancer recurrence months, even over a year, before traditional imaging.
The detection of cervical cancer ctDNA after chemoradiotherapy (CRT) by NeXT Personal was associated with a high subsequent risk of disease progression, with a median of ~5 months and up to ~16 months earlier than imaging scans. Just as importantly, the risk of progression and death was at least 95% lower for patients where ctDNA was not detected ~3 months after completing CRT. Results were published simultaneously in an Annals of Oncology study.
The quest for clarity
Cervical cancer remains a formidable adversary on the global health stage, with over 600,000 new cases diagnosed annually and 350,000 deaths among women. Jyoti Mayadev, MD, a prominent figure in gynecologic oncology at UCSD, is driven by the urgency to improve therapies and patient monitoring beyond initial treatment. The critical challenge, according to Mayadev, lies in identifying relapse as early as possible via minimal residual disease (MRD).
“To enhance treatment options for patients, improve survivorship rates, and investigate biomarkers that can help predict which patients will respond to standard therapy and which will not,” Mayadev told Inside Precision Medicine. “We are considering how to identify patients early if there are concerns about relapse or recurrence,” she noted, highlighting the crucial shift from reactive diagnosis to proactive detection.
Current preventative measures, such as the human papillomavirus (HPV) vaccination program, Pap smears, and primary HPV testing, are vital in reducing cervical cancer incidence. However, once a patient has been treated, the question of MRD comes to the forefront. “This MRD test is looking for early relapse detection for cervical cancer,” Mayadev said. “You’re looking at our patients after treatment cured them of their cervical cancer. Or are you able to detect the relapse earlier than you would by clinical examination or standard of care imaging? That’s where this comes into the forefront in terms of our discoveries.”
Underneath it all: the genesis of ultrasensitivity
The development of NeXT Personal stems from a recognition that existing ctDNA tests, while promising, weren’t sensitive enough to capture the earliest whispers of recurrence. Richard Chen, MD, Chief Medical Officer and EVP of R&D at Personalis, told Inside Precision Medicine, “When we started looking at this problem of detecting ctDNA at Personalis, what prompted the development of NeXT Personal and a more ultrasensitive approach was we looked at the first data, the first generation of tests and the data that was coming out and it was clear to us that this was going to be an incredibly powerful tool. But we also saw that patients who were testing negative, some of those patients or many of those, were still recurring over time.”
According to Chen, this observation, made approximately six years ago, spurred Personalis to embark on a mission to build a test “10–100 times more analytically sensitive than the first MRD tests.” Their audacious goal was a “one part per million sensitivity,” a level calculated to detect the absolute smallest traces of residual cancer. Achieving this required a paradigm shift in Personalis’ methodology.
“To achieve our target, we realized that we needed to move beyond exome-based approaches for tumor-informed MRD testing and utilize whole genome sequencing instead,” said Chen. “Initially, we tried using exome sequencing, but it was insufficient because we were limited by the number of mutations detected and could not capture a wide enough range to identify small traces of ctDNA. We were, I think, the first to go to whole-genome tumor-informed. Then, we also realized we needed to create a larger fingerprint. We calculated that 1,800 mutations could yield. That’s what we have created with Personalis’ NeXT Personal blood test. It’s whole genome, tumor-informed. We track up to 1,800 mutations that are unique to the tumor.”
The very idea of such extreme sensitivity was initially met with some skepticism. “Two or three years ago,” Chen said, “that was a legitimate question that people were asking, ‘Well, do you even need more sensitivity?’” The concern was whether detecting such minute traces would simply capture harmless cellular debris rather than clinically significant disease.
However, Personalis’ subsequent data, including findings in lung and breast cancer and now colorectal and cervical cancer, have consistently demonstrated the profound clinical value of this heightened sensitivity. “The entire field is now shifting toward more sensitive tests, and we are at the forefront of this advancement,” Chen said. Their research shows that even the lowest traces detected by NeXT Personal are indicative of cancer that will eventually progress and cause problems for the patient, dispelling the “too sensitive” myth.
Rock steady: the CALLA study
The pivotal data validating NeXT Personal’s potential came from a new analysis of the CALLA Phase 3 study. This large global trial, involving 770 patients, initially aimed to improve progression-free survival in high-risk, node-positive patients with locally advanced cervical cancer. While the primary objective of the original trial was not met, it provided an invaluable cohort for investigating novel biomarkers.
Mayadev’s team, utilizing NeXT Personal, analyzed blood samples from 186 patients within the CALLA cohort. The results, presented at ASCO 2025, were striking: overall ctDNA levels after CRT were strongly predictive of the risk of cervical cancer progression. For the first time, this ultrasensitive test detected cervical cancer progression up to 16 months ahead of imaging, with a median lead time of approximately five months. This lead time offers an unprecedented opportunity for earlier intervention.
The power of an ultrasensitive test like NeXT Personal lies not just in identifying positive cases earlier but also in providing meaningful reassurance when results are negative. As Chen explained, a key frustration for clinicians with less sensitive tests is that “when the test is negative, doctors can’t reassure the patient by saying, ‘Look, rest easy because it’s not that sensitive.’” NeXT Personal aims to provide clarity on both ends.
For patients, this clarity is paramount. Underscoring the emotional toll of the “watchful waiting” period, Mayadev said, “Uncertainty about your cure can be extremely anxiety-provoking. Having a liquid biomarker, like the one Personalis is working hard on, to reassure patients with real data is huge.”
The implications for clinical practice are profound. If a patient is ctDNA-negative after treatment, the data suggest a remarkably high probability—even 95% at three months post-CRT—that they will remain negative. “So, potentially those patients may not need further therapy,” Chen said, envisioning a future where some patients might safely forego additional, potentially burdensome treatments like long-term immunotherapy. This potential de-escalation of therapy could significantly improve patients’ quality of life.
Conversely, for the 68% of patients in the study who were ctDNA positive three months after CRT and later diagnosed with relapse, the early detection provides a critical window. This lead time is crucial, as less sensitive ctDNA methods have often detected cancer only when it has become metastatic, limiting treatment options. The field, Chen asserts, has now widely recognized that increasing sensitivity in our tests, as well as in those being developed by others, is crucial for patient care. This empowers clinicians to consider earlier, potentially more effective interventions.
Future collaboration and clinical trials
The success of NeXT Personal in predicting cervical cancer recurrence marks an important turning point, but it is just the beginning. The next crucial steps involve integrating this powerful tool into routine clinical practice and conducting further high-level evidence trials to define its optimal use.
“Even if the stars align and you have the best tests, if they’re not available to patients or the data isn’t out there, uptake is low,” Mayadev said. “We have to come together as a scientific community and work with partners like Personalis to decide on the next steps.” This includes designing thoughtful clinical trials to optimize the utilization of this early detection capability and inform treatment decisions.
Both Mayadev and Chen stressed the importance of these forthcoming trials. “The next wave of trials,” Chen said, “will focus on the enriched biomarker population and aim to offer them a better treatment option.” This meticulous process, although time-consuming and resource-intensive, is essential to ensure that patients receive the right treatment at the right time. Furthermore, accessibility and reimbursement for these advanced assays are vital to ensure broad patient access.
The dedication to patients drives this entire endeavor. Mayadev’s personal motto, “We want to treat patients, cure patients, and get them back to their lives,” encapsulates the profound human impact of this research. The anxiety of recurrence can profoundly affect a patient’s productivity, family life, and ability to return to normalcy. Providing concrete data that assures patients of their cure or allows for earlier intervention is invaluable.
The tragic reality that HPV contracted at a young age can lead to death decades later fuels the passion of researchers like Mayadev. “I see so many sad cases every year. I cannot even recount it, and it keeps us up at night,” she shared, a poignant reminder of the human cost of this disease. But now, thanks to the tireless work of individuals like Chen and the innovative technology of NeXT Personal, Mayadev said, “We have these great windows of opportunity, and we will not waste them.”
In the waiting room, the echoes of doubt may finally begin to dissipate, giving way to resounding certainty and hope.
