A groundbreaking study published in Clinical Cancer Research has revealed that nearly half of ovarian cancer patients who appear cancer-free on conventional scans still harbor hidden cancer cells that could drive recurrence. The research, led by Break Through Cancer's Targeting Minimal Residual Disease (MRD) in Ovarian Cancer TeamLab, found that 42.1% of patients in clinical remission had detectable minimal residual disease when examined through minimally invasive second-look laparoscopy.
Surgical Detection Reveals Hidden Disease Burden
The study analyzed 95 patients who completed frontline therapy for high-grade epithelial ovarian cancer. Using second-look laparoscopy (SLL) performed 6 to 8 weeks after the last cycle of adjuvant chemotherapy, researchers detected surgical MRD in 40 of 95 evaluable patients. Each case involved a median of 9.0 biopsies (range, 3-18) to comprehensively assess for residual disease.
"This work shows that what we see on a scan does not always tell the whole story," said Dr. Amir Anthony Jazaeri, senior study author and professor in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. "With SLL, we've been able to uncover disease that was otherwise invisible, and more importantly, study how to target it."
Clinical Factors Predict MRD Risk
Multivariate analysis identified key predictors of surgical MRD presence. Patients who received neoadjuvant chemotherapy versus primary cytoreductive surgery showed a significantly higher likelihood of SLL-positive status (OR, 4.53; 95% CI, 1.65-12.44; P = .003). Additionally, patients with homologous recombination deficiency (HRD)-negative disease had a higher probability of experiencing SLL positivity (OR, 3.55; 95% CI, 1.23-10.24; P = .019).
The study population was predominantly White (82.1%) and non-Hispanic (90.5%), with high-grade serous disease comprising 87.4% of cases. Most patients had stage III disease (67.4%), with 56.8% receiving neoadjuvant chemotherapy as frontline treatment and 73.7% achieving R0 cytoreduction status.
Survival Impact Demonstrates Clinical Significance
The presence of surgical MRD carried profound prognostic implications. Across the overall SLL cohort, detectable surgical MRD correlated with significantly worse progression-free survival (HR, 2.9; 95% CI, 1.7-4.9; P <.001) and overall survival (HR, 7.7; 95% CI, 2.8-20.9; P <.001). Multivariate analysis revealed that HRD-positive status favorably correlated with progression-free survival (HR, 0.27; 95% CI, 0.13-0.56; P <.001), while receipt of neoadjuvant chemotherapy correlated with worse progression-free survival (HR, 2.62; 95% CI, 1.34-5.13; P = .005).
Blood-Based Detection Shows Promise
Among 44 patients with evaluable circulating tumor DNA (ctDNA) results, both surgical and molecular MRD detection methods demonstrated strong prognostic value. Surgical MRD presence conferred worse progression-free survival (HR, 3.1; 95% CI, 1.4-6.9; P = .003) and shorter overall survival (HR, 9.9; 95% CI, 2.2-44.7; P <.001). Molecular MRD per ctDNA-positive status correlated with inferior progression-free survival (HR, 5.3; 95% CI, 2.3-12.4; P <.001) and overall survival (HR, 3.6; 95% CI, 1.3-10.0; P = .008).
Advanced Profiling Reveals Therapeutic Targets
The research team conducted unprecedented analysis of MRD samples using advanced spatial transcriptomic and proteomic profiling. This detailed examination identified specific druggable targets and revealed key biological features including hypoxia signaling, immune evasion, and epithelial-mesenchymal transition—factors that may explain why some cancer cells survive treatment and point to new drug combinations that could specifically target MRD.
Safety Profile and Clinical Implementation
The minimally invasive SLL procedure demonstrated an acceptable safety profile, with intraoperative complications occurring in only 2.1% of cases. Two patients experienced bowel injuries necessitating conversion to laparotomy, while another required conversion for small bowel resection due to gross disease identified during laparoscopy.
Implications for Future Treatment Strategies
"Using MRD offers two key advantages over current approaches for advanced ovarian cancer," Dr. Jazaeri explained. "First, it can show early whether a treatment is working, allowing for quicker, smaller trials and faster access to new therapies. Second, by studying MRD's biology, we can uncover ovarian cancer's weaknesses and develop more effective, potentially curative treatments."
The findings support ongoing clinical trials using MRD detection through SLL as a primary endpoint to evaluate novel immunotherapies. Tyler Jacks, PhD, president of Break Through Cancer, emphasized the broader implications: "These findings do not just answer long-standing questions; they open the door to smarter trials, understanding where recurrence comes from, and blocking it from occurring."
This study represents a significant advancement in understanding ovarian cancer recurrence mechanisms and provides a foundation for developing more effective interventional strategies targeting minimal residual disease.
