Vall d’Hebron identifies a prognostic marker of rectal cancer based on gut microbiome

Paolo Nuciforo
  • Persistency of Fusobacterium nucleatum, an intestinal bacterium, in rectal tumors after chemotherapy is associated with high risk of relapse in patients with locally advanced rectal cancer.
  • This is the first study to investigate the microbiome as a biokarmer of rectal cancer. The study was conducted by the Vall d’Hebron Institute of Oncology (VHIO).
  • VHIO also takes part in the MICROCOSM trial under the auspice of the OPTIMISTICC Consortium and leads a study to assess the relationship between immunotherapy and the microbiome.

Barcelona, June 23, 2020.- The studies carried out in the last decade have revealed that the microbiome plays a major role in intestinal health and other aspects associated with human health. The first studies that documented the influence of the microbiota in cancer in general, and colorectal cancer in particular appeared in 2012. A study published in November 2017 in Science led by the Dana-Farber Cancer Institute –in which the Vall d’Hebron Institute of Oncology (VHIO) was actively involved– demonstrated the persistency of Fusobacterium in liver metastases in patients with colorectal cancer and the effectiveness of antimicrobial therapy. Now Dr. Paolo Nuciforo has led a study to investigate the role of this bacterium in locally advanced rectal cancer. The study was published in the prestigious journal Annals of Oncology last Saturday, June 20th.

“From our previous studies, we learned that Fusobacterium is a relevant pathogenic intestinal bacterium of the microbiota which is associated with colorectal cancer. However, there was scarcity of data on the role of this bacterium in advanced rectal cancer. To bridge this gap of knowledge, we studied its association with response to treatment and survival”, explains Dr. Paolo Nuciforo, principal investigator of the VHIO’s Molecular Oncology Group. The author also points out that this is the first study to identify a prognostic marker of rectal cancer based on the gut microbiome.  The results of this study revealed that persistency of Fusobacterium nucleatum after neoadjuvant chemo-radiotherapy (nCRT) was associated with higher rates of relapse in patients with locally advanced rectal cancer.

Research for clinical solutions: The role of the microbiota in rectal cancer
To date, nCRT followed by surgery is the gold standard treatment for patients with locally advanced rectal cancer. The patients who receive nCRT and achieve a complete pathological response (i.e. absence of residual tumor in surgical biopsies) have a favorable prognosis, with a reduction in local relapse and an improvement of survival. In patients with partial or no response, the approach that yields the best outcomes in the long term is unknown. “There isn’t any marker that helps us predict the patients who will relapse or not, so treatments cannot be adjusted or reinforced in patients at a higher risk, or not initiated in those who won’t relapse”, says Dr. Nuciforo.

The urge to meet this clinical need and previous experience with Fusobacterium nucleatum led Dr. Paolo Nuciforo and his team to postulate the hypothesis that this bacterium could have a prognostic value in patients with advanced rectal cancer. To undertake this study, a total of 254 samples of 143 patients with rectal adenocarcinoma were analyzed. This analysis involved assessing the presence and count of Fusobacterium nucleatum. To such purpose, in situ RNA hybridization assays and digital image analyses were performed. The presence of the bacterium in samples before and after nCRT therapy was determined.

The first finding of this study was that the presence of Fusobacterium nucleatum in the tumours of untreated patients did not have any prognostic value and could not be used as a marker to predict a complete pathological response or not in patients who received preoperative therapy. “In contrast, although the presence of Fusobacterium nucleatum does not predict response, it can help identify a higher risk of relapse or metastasis in patients who did not show complete response to treatment”, explains Dr. Paolo Nuciforo.

This finding led the authors coin the concept of “tumor microbiotype”. This way, Dr. Nuciforo and his team categorized rectal cancer into two micriobiotypes: positive or negative to Fusobacterium. “Patients with negative residual tumors after surgery showed a favorable course. In contrast, if residual tumors were positive, the risk of relapse at 2-3 years was seven times higher than in negative tumors, which was associated with a poor prognosis. In clinical practice, these findings may support risk management decision-making”, says Dr. Paolo Nuciforo.

Tumor microenvironment and immune response
The behavior of tumors determined by the presence of the bacterium in the microbiota is associated with tumor microenvironment and immunologic response. “When Fusobacterium nucleatum persists after treatment, an immunosuppressive microenvironment is created to prevent that immune cells attack the tumor effectively”, says Dr. Nuciforo. The authors found that when the presence of these bacteria was not detected, CD8T + cells increased sharply, and inflammatory response was stronger.

This finding opens an avenue for future research on therapies targeted against Fusobacterium nuc., which may help improve response in patients. “When this bacterium is suppressed, an antitumoral microenvironment is created, which is a promising avenue for future research on new treatments that help reduce the risk that the tumor escapes the immune system”, concludes Dr. Nuciforo.

OPTIMISTICC: How does the microbiome affect the treatment of cancer?
The VHIO study led by Dr. Paolo Nuciforo is one of the projects conducted under the auspice of the OPTIMISTICC consortium and was granted a Cancer Grand Challenges award by Cancer Research UK.  There is cumulative evidence of the role that the microbiome plays in numerous aspects of human health. However, many questions remain unanswered. The relationship between the microbiome and oncologic therapies is not fully understood. To address this question, a number of institutions, VHIO included, created the OPTIMISTICC consortium. Synergic studies seek to identify the microbial that are associated with cancer, the moment at which the microbiome becomes key in cancer, and the patients at a higher risk of developing cancer. This study, led by Dr. Paolo Nuciforo, forms part of this research project.

Although there is evidence that the microbiome may play a role in many types of cancer, the OPTMISTICC study is focused on colon cancer. Several workgroups have been created to address different issues. Dr. Josep Tabernero at VHIO, and Dr. Kimmie Ng at the Danna Farber Cancer Institute co-lead the workgroup set up to investigate how the microbiome modulates response to the treatments currently available.

MICROCOSM was launched to answer this question. “Three large cohorts were established for a longitudinal follow-up.  On the one hand are patients who develop cancer at an early age, before 50.  Another cohort will be used to assess how chemotherapy relates to the microbiome. The third cohort will be used to assess how immunotherapy relates to the microbiome. This cohort will be coordinated by VHIO, whereas the other cohorts will be coordinated by the Danna Farber Cancer Institute and the California-San Francisco University”, explains Dr. Elena Élez, a researcher at the VHIO Workgroup on Gastrointestinal and Endocrine Tumors.

DNA, RNA and metabolomic profiling and culture analysis of fecal samples are being performed in the three cohorts. VHIO is responsible for the processing and storage of samples in a specific biobank. Apart from collecting samples, comprehensive diet and lifestyle questionnaires are being distributed among patients to collect information such as the frequency of intake of some foods, presence of diseases, use of supplements, or frequency of physical exercise, among others. Apart from samples of oncologic patients, young patients are being used as controls.

“Although the MICROCOSM trial is focused on intestinal cancer, we’re taking fecal samples from patients receiving immunotherapy. We hope that these data will help us identify biomarkers that predict response to a particular treatment and find new targets that improve response”, says Dr. Paolo Nuciforo.