A new exploratory study has shed light on the potential role of the gut microbiome in predicting outcomes for cervical and endometrial cancer patients treated with immunotherapy. The phase II PRIMMO trial, conducted at multiple centers in Belgium, examined associations between gut bacterial composition and clinical outcomes in patients receiving a pembrolizumab-based regimen.
Published in October 2024 in the journal Gynecologic Oncology, this investigator-initiated study was funded by grants from Kom op Tegen Kanker, de Nationale Loterij, and the Anticancer Fund. The pharmaceutical companies MSD and Nutrisan provided the study drugs pembrolizumab and curcumin, respectively, free of charge.
The PRIMMO trial enrolled 35 patients (15 with cervical cancer and 20 with endometrial cancer) who had received at least one prior line of systemic therapy for recurrent and/or metastatic disease. The study treatment included an immunomodulatory five-drug cocktail along with intravenous pembrolizumab and radiation therapy to a single tumor lesion.
Researchers collected fecal samples from patients at screening, day 15, and day 99 to characterize the gut microbiome using 16S rRNA gene sequencing. They then analyzed associations between bacterial taxa and clinical outcomes, including treatment efficacy and toxicity.
The results revealed several interesting findings. Certain bacterial taxa were associated with the occurrence or resistance to severe treatment-related adverse events. For example, enrichment of Lactobacillus fermentum before treatment was linked to severe gastrointestinal toxicity. In terms of efficacy, the Blautia genus and its Lachnospiraceae family were consistently associated with favorable outcomes when present before pembrolizumab initiation. Conversely, the Enterobacteriaceae family and Clostridium genus were linked to poor efficacy.
Perhaps most intriguingly, the researchers identified two distinct gut microbiome clusters with dramatically different survival outcomes. Patients in one cluster had more than four times the risk of death compared to the other (hazard ratio 4.4, 95% confidence interval 1.9 to 10.3, P < 0.001). These clusters also showed interesting trends in peripheral immune monitoring data, though these were not statistically significant.
The study had several limitations, including its small sample size and lack of a comparator arm or validation cohort. The researchers pooled data from both cervical and endometrial cancer patients due to limited numbers. Additionally, the 16S rRNA sequencing method used precludes species or strain-level taxonomic assignments and functional characterization of the microbiome.
Despite these limitations, the authors concluded that their exploratory study offers initial insights into the complex interplay between the gut microbiome and clinical outcomes in cervical and endometrial cancer patients treated with immunotherapy. They suggest that the gut microbiome may aid in risk-benefit assessment for immune checkpoint inhibitors in these patients.
The potential clinical impacts of this research are significant. If validated in larger studies, gut microbiome profiling could become a valuable tool for personalizing immunotherapy in gynecologic cancers. It may help identify patients most likely to benefit from treatment or those at higher risk of severe side effects. Furthermore, the identification of beneficial bacteria opens the door to potential therapeutic modulation of the gut microbiome to enhance treatment efficacy.
However, the authors caution that more research is needed before these findings can be translated into clinical practice. They call for well-designed, sufficiently powered, and geographically diverse studies to independently validate their results and explore them in the context of various tumor subtypes and treatments.
This study adds to a growing body of evidence suggesting that the gut microbiome plays a crucial role in modulating responses to cancer immunotherapy. While still in its early stages, this line of research holds promise for improving outcomes in difficult-to-treat gynecologic cancers. As our understanding of the microbiome-immune system interaction deepens, it may lead to novel strategies for enhancing the efficacy of cancer immunotherapies while mitigating their toxicities.
References
De Jaeghere EA, Hamerlinck H, Tuyaerts S, et al. Associations of the gut microbiome with outcomes in cervical and endometrial cancer patients treated with pembrolizumab: Insights from the phase II PRIMMO trial. Gynecol Oncol. 2024;191:275-286. doi:10.1016/j.ygyno.2024.10.020
