Circulating clues to conquering stomach cancer

The evolving landscape of oncology forces payers and providers alike to search for tools that sharpen prognostic accuracy while guiding treatment decisions. A recent phase 2 randomized trial conducted in Brazil, published in Scientific Reports, offers compelling evidence that circulating tumor cells (CTCs) may serve as a practical biomarker in advanced gastric cancer. The study examined patients treated with standard XELOX chemotherapy (capecitabine plus oxaliplatin) versus XELOX combined with menadione, a CDC25B phosphatase inhibitor. The findings suggest that tracking CTC response could help stratify risk, tailor therapy and, ultimately, improve survival outcomes.

Gastric cancer remains a formidable challenge in oncology, claiming lives with alarming frequency despite advances in treatment. Globally, it's the fifth most common cancer and a leading cause of mortality, with five-year survival rates hovering around 30% in the U.S. and even lower elsewhere. For patients with advanced disease, standard chemotherapy regimens like XELOX, combining capecitabine and oxaliplatin, offer some extension of life, but outcomes are often limited, with median survival stretching to just 6-14 months. Traditional markers such as carcinoembryonic antigen (CEA) and CA19-9 have limited utility in monitoring disease progression. CTCs, however, represent a malignant phenotype detectable in peripheral blood, offering a minimally invasive way to assess tumor biology in real time.

Menadione, a vitamin K3 analog, targets CDC25B phosphatase, an enzyme implicated in cell cycle progression and overexpressed in many gastric tumors. It is not approved or available for human use in the United States as a prescription medication or dietary supplement, however. The FDA has not sanctioned it for therapeutic purposes due to documented safety risks, including potential liver toxicity, hemolytic anemia, and other adverse effects.

Nevertheless, researchers have long eyed it for its potential to halt cancer growth, based on preclinical work showing tumor shrinkage in animal models. Franciso Cezar Aquino de Moraes, from the Oncology Research Center, University Hospital João de Barros de Barreto in Brazil, and team randomized 107 patients with metastatic gastric adenocarcinoma. Half received XELOX alone, while the other half got the combination with menadione dosed orally at 2.5 g/m² on the first two days of each three-week cycle.

The trial's focus wasn't solely on survival metrics. It also focused on CTCs. Using a detection method called SET-iFISH, the team tracked CTC counts at baseline and follow-up points up to 15 months. Patients were dubbed "CTC responders" if counts dropped by at least 50% post-treatment, a threshold borrowed from validated criteria in other cancers.

In the menadione group, CTC responders showed markedly better overall survival (OS). Hazard ratios for death were significantly lower at six, nine, and twelve months compared to non-responders. Progression-free survival also demonstrated benefit, with non-responders facing up to a 10.5-fold higher risk of cancer progression by 15 months. Even in the XELOX-only arm, CTC response correlated with improved outcomes, though the effect was less pronounced. Across both groups, CTC levels trended downward over time, but correlations strengthened more in the menadione cohort, hinting at the drug's role in amplifying chemotherapy's effectiveness.

CTC monitoring offers a noninvasive, liquid biopsy alternative to traditional imaging or tumor markers like CEA, which often fall short in sensitivity. Integrating CTC assessments could enable earlier identification of non-responders, allowing timely switches to alternative therapies or enrollment in trials. Ideally, CTC testing could eventually optimize resource allocation for cancer treatment through risk stratification.

The authors noted the limitations of the study, saying that this was a small, open-label trial, and “while menadione appeared well-tolerated, larger phase 3 studies are needed to confirm survival benefits and CTC's predictive power.” Morphological changes in CTCs post-menadione, with cells appearing more rounded with dimmer epithelial markers, suggested a shift toward less aggressive phenotypes, but molecular underpinnings remained unexplored.