Colorectal cancer incidence is increasing worldwide, particularly in people younger than 50 years, but the reason remains a mystery. In addition, the effectiveness of treatments inexplicably varies within the same patients over time, among patients and geographically. Could the microbiome be responsible?
A new cohort study, spearheaded by the team of researchers and people affected by colorectal cancer taking on our Microbiome challenge, seeks to find out.
The microbiome – the trillions of bacteria, viruses and fungi residing in the body – is emerging as a key player in human health, by shaping immunity, nutrition and overall well-being. The extent to which perturbations in the microbiome underpin the development and epidemiology of certain cancers is only beginning to be understood. Shedding light on this link in colorectal cancer, which is diagnosed in 1.8 million people worldwide each year, may lead to the development of new ways to detect, screen and prevent the disease. The Cancer Grand Challenges OPTIMISTICC team aims to pinpoint how the microbiome affects colorectal cancer initiation and development, as well as patient outcomes, and to translate their findings into novel preventive, diagnostic and treatment strategies.
Because the gut microbiome lies at the intersection of lifestyle and colorectal cancer development, research in this nascent area has the potential to transform understanding of this disease. “The amazing thing about the microbiome is how it’s influenced and shaped by the diet and various lifestyle factors – many of which also seem to influence colorectal cancer risk and outcomes,” explains Kimmie Ng, OPTIMISTICC co-investigator and a medical oncologist specialising in gastrointestinal cancers as the director of the Young-Onset Colorectal Cancer Center at Harvard’s Dana-Farber Cancer Institute.
A major component of the team’s programme is MICROCOSM*, a first-of-its-kind clinical cohort study collecting stool and blood samples, and long-term clinical information from more than 2,500 people with colorectal cancer. The study’s ambitious design could deepen understanding of the microbiome and subsequently improve quality of life and survival in people with colorectal cancer. “We need to identify the interactions between the microbiome and the diet and lifestyle factors that influence risk and outcomes in these patients, so we can make informed recommendations about diet and lifestyle and treatment, then move beyond observations to understand the underpinning biological mechanisms,” says Kimmie. The study has grown since it first opened and is now enrolling patients from multiple sites across the US, Spain and Brazil.
Tapping the microbiome to guide individualised treatment
Through the cohort study, the team’s first goal is investigating how lifestyle factors influence the microbiome and subsequently colorectal cancer outcomes in three patient subgroups: those with early-onset colorectal cancer (diagnosed before the age of 50), those receiving chemotherapy and those receiving immunotherapy. Serial samples from before, during and after treatment are being analysed to understand how the microbiome changes as patients’ tumours evolve or their treatments progress. Participants also fill out a comprehensive questionnaire on their diet and lifestyle so that these factors can be evaluated and incorporated.
The team hopes that these data will reveal whether the microbiome might be responsible for the dramatic increase in colorectal cancer cases in young adults – a worrying trend that has yet to be explained. “What we are asking is: are there differences in the composition and diversity of the microbiome in younger colorectal cancer patients compared with older people?” Kimmie explains. “That would give important clues as to why early-onset colorectal cancer is on the rise, so that we can make informed recommendations about diet and lifestyle and identify high-risk individuals.”
The OPTIMSTICC team’s second major goal is to understand how the microbiome influences individuals’ responses to treatment. For example, patients across geographical areas have considerably different responses to the chemotherapy drug capecitabine: patients with colorectal cancer in North America experience significantly more severe adverse effects than those in Europe. Similarly, checkpoint-inhibitor immunotherapies are powerful treatment options for a small proportion of people with colorectal cancer but have very little effect in others. The team suspects that the reason for these interindividual differences may lie in the unique microbiomes resulting from differing diets and lifestyles. By tapping into the shared or differing features between these groups, the team’s cohort study might enable clinicians to work with the microbiome to enhance the stratification of patients to treatment, alleviate toxicity to chemotherapy and overcome the resistance that many people currently experience to immunotherapies.
At the time of writing, the team has enrolled more than 500 patients, collected more than 800 stool samples and 600 blood samples, and begun to analyse the preliminary data – making progress despite the setbacks of the COVID-19 pandemic, which initially hindered participant enrolment, sample collection and face-to-face meetings.
Putting patients at the heart of the research
Patient advocates – people with a personal experience of cancer – play a vital role in all Cancer Grand Challenges teams. In taking on the microbiota challenge, “the patient advocates have been absolutely critical in the design and implementation of the cohort study,” Kimmie says. This process includes ensuring that some of the study’s most important elements – such as the diet-and-lifestyle questionnaire – are relatable and understandable to participants. “A person undergoing treatment for advanced colorectal cancer will already be going through so much – the advocates have made taking part in the cohort study as accessible and the least burdensome as possible for our participants,” Kimmie elaborates.
Chicago-based Candace Henley is one of the study’s patient advocates and a survivor of colon cancer. “We want to make sure that treatment options, clinical trials, everything about the cancer continuum for those after us is better than what we've experienced in our own journeys,” she says. “I’m an 18-year survivor, and I’m still experiencing challenges from my treatment. We’re advocating for early detection, the patient voice and the betterment of the patients who come after us. If our work could lead to more targeted, less harsh treatments for people, that would be amazing.”
The recruitment of patient advocates from multiple countries has facilitated enrolment of the large, diverse cohort of participants necessary for understanding the connection between colorectal cancer and the microbiome, and factors of geography or ancestry that may affect risk or outcomes. Similarly, “if we can find a common signal in the microbiome in different geographical areas that associates with early-onset colorectal cancer or poorer immunotherapy response, for example, despite otherwise different lifestyles, we can be confident that the result is robust,” explains co-investigator Josep Tabernero, director of the Vall d’Hebron Institute of Oncology in Barcelona. The team is beginning to work with more centres across Europe and North and South America. “As the cohort study continues to grow, ensuring the people recruited to take part represent the diversity of the population remains an important aim for the team going forward,” Josep says.
Transcending collaborative boundaries
Taking on the Microbiota challenge and assembling a large international cohort critically relies on collaborative international efforts that transcend institutional and geographical boundaries. Researchers with diverse expertise and patient advocates from the UK, US, the Netherlands, Canada and Spain have united through the Microbiota challenge by connecting, exchanging ideas and sharing knowledge. The rich sample library collected through the cohort study is used to examine host-microbe interactions throughout the entire challenge, informing preclinical work through the isolation of organisms and their metabolites, and the generation of organoids and other model systems.
“The Cancer Grand Challenges mechanism is just perfect for compiling the right team and recruiting the right patients,” says Kimmie. “It's opened my eyes to all the innovative ways that we can target the microbiome.”
Although the effects of the pandemic on the study are ongoing (for example, by limiting the supply of stool kits), this enormous collaborative effort is already fruitful. The team’s cohort study is generating encouraging data, including preliminary results on the effects of the microbiome on patients’ responses to immunotherapy and chemotherapy toxicity. Over the next year, the team hopes to perform deep sequencing of stool samples, increase patient enrolment across all study regions and begin to share their results more widely so that they can ultimately be translated to clinical interventions for patients.
“This is a huge undertaking, so I have huge admiration for the work they’re doing,” says Candace. “I’m so excited about where this ends up, and I feel privileged to be a part of it.”
“It really is about scientists coming together with clinicians, advocates and disciplines beyond their own. That melding of worlds is really important for advancing the science,” adds Kimmie. “I think our team is a perfect model of how that has worked well.”
Written by Gege Li
* Microbiome of Colorectal Cancer: Longitudinal Study of Mechanism (MICROCOSM) is a global, first-of-its-kind clinical cohort study seeking to understand the role of the microbiome in treatment response and early-onset colorectal cancer.
The OPTIMISTICC team is funded by Cancer Research UK with generous support from Nick and Annette Razey.
This article was originally included in our annual progress magazine Discover: A year of scientific creativity.