Understanding the Microbiome and its Effect on Treatment of Patients with Colorectal Cancer

Benjamin Weinberg, MD

Benjamin Weinberg, MD

Of all the bacterial cells found in the human body, roughly 50 trillion live in the gut, and can have an effect on the immune system, leading to gastrointestinal (GI) malignancies, like colorectal cancer (CRC), said Benjamin Weinberg, MD, assistant professor of medicine and attending physician at MedStar Georgetown University Hospital, Washington, DC.

Many questions still exist as to which bacteria are good for the GI system, and which lead to diseases like CRC.¹However, Weinberg stated that one way of determining how gut bacteria cause CRC is by taking serial specimens of bile and stool and taking blood and tumor biopsies. Testing these samples could answer existing questions about how cancer, the microbiome, and the immune system connect and interact.

An important observation about the microbiome is that the type of bacteria found in a person’s gut can predict their resistance to certain drugs. In the case of treatment for CRC, there are some bacteria that are known to resist immunotherapy drugs especially.

In the treatment landscape for CRC, specifically for patients with metastatic disease, immunotherapy agents such as bevacizumab (Avastin), cetuximab (Erbitux) or panitumumab (Vectibix), are commonly used after a chemotherapy backbone. In later-line settings, oncologists also use immunotherapy drugs like regorafenib (Stivarga). Therefore, clearing certain gut bacteria is essential for cancer treatment to be effective.

In an interview withTargeted Oncologyat the 2019 Ruesch Center Symposium, Weinberg shared key points from his discussion on mining the microbiome in patients with CRC and summarized the treatment landscape for patients with metastatic disease. He also discussed an upcoming basket trial that uses liquid biopsies to place patients on treatment plans that will be most effective for their individual needs.

TARGETED ONCOLOGY: Can you give an overview of your discussion on the microbiome as it relates to CRC?

Weinberg: [During the symposium], we had a robust discussion on the microbiome. I learned that we may have as many as 50 trillion bacterial cells. We have a lot of bacteria cells in our body, most of which are located in the gut, and many of which we don't know exactly what they do. We know that some are good and help us to digest food, but we also know that some are bad, and they may play a role [in the development of] CRC.

The CRC discussion focused on how to best collect serial bile specimens, stool, tumors, and blood to figure out where these associations with microbiome, disease, and the immune system collide.

TARGETED ONCOLOGY: What is the key takeaway from your discussion?

Weinberg: The microbiome is complex. It's sort of a meeting place between the immune system, diet, environment, and genetics. It seems to play a stronger role in cancer, especially GI cancers both in terms of causative agents for cancers and to predict response to certain drugs, especially immunotherapy drugs.

                                                                                            

The field is very young, but it's growing quickly, and it's hard to stay on top of all the rapidly evolving data that are coming out of it. There is a role for doing some sort of research testing to figure out what bacteria are present in these tumors and try to figure what role they're playing.

TARGETED ONCOLOGY: Can you briefly summarize the treatment landscape for metastatic colorectal cancer (mCRC)?

Weinberg: There are a variety of treatment options for patients with mCRC. Most involve the backbone chemotherapy, a 5-fluorouracil type of therapy with either IV 5-FU, or oral capecitabine. Typically, we would also add a second chemotherapy agent such as oxaliplatin, or irinotecan. Then, we would add a biologic [agent] that targets the vascular endothelial growth factor (VEGF) pathway, like bevacizumab, or a biological [drug] that targets the epidermal growth factor receptor (EGFR) pathway, like cetuximab or panitumumab.

Those ladder drugs only work for patients that have KRAS-, NRAS-, BRAF-wildtype disease, especially in cancer that occurs on the left side of the colon. Those patients seem to benefit most, especially in the upfront setting.

In further line settings, access to drugs that haven't been used is appropriate. For example, if someone hasn't had prior VEGF therapy, you can use that, if they're still candidates for it. The other drugs available in later-line settings include trifluridine/tipiracil (Lonsurf), and regorafenib.

For rare subsets of patients with mCRC, for instance, those with MSI-high tumors, immune checkpoint inhibitors like pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy) are available. Lastly, the NTRK fusion tumors now have 2 drugs, larotrectinib (Vitrakvi) and entrectinib (Rozlytrek), which are both approved by the FDA for patients with rare subsets of CRC.

TARGETED ONCOLOGY:What are some promising novel combination being explored in this disease?

Weinberg: Another group of patients is those with HER2-amplified disease, which is something that we think about a lot in breast cancer, and also upper GI cancers. Some drugs target HER2 and are repurposed from breast cancer [treatment] and used in the treatment of colon cancer, especially rectal cancer that is HER-2 amplified. Those include drugs like trastuzumab, usually in combination with lapatinib (Tykerb), or trastuzumab (Herceptin) in combination with pertuzumab (Perjeta). There are also ongoing clinical trials looking at drugs such as tucatinib, which is a novel HER-2 targeted agent.

Other combinations that work well are chemotherapy with EGFR therapy. The VEGF drugs don't seem to work by themselves, so they have to be combined with chemotherapy. So, there's a whole landscape of potential combinations out there.

TARGETED ONCOLOGY: Is there a clinical trial that you can highlight around targeted therapies for mCRC?

Weinberg: The big trial that we are about to launch is the COLOMATE trial (NCT03765736), which is a large basket trial looking at liquid biopsies. Patients with mCRC who have already been exposed to most, if not all, of the standard treatment, would undergo a liquid biopsy blood test, and then based on that test, they could be assigned to specific substudies if they fit the profile. For example, if their liquid biopsy shows that they'reHER2amplified, they would be directed to enroll in the MOUNTAINEER study (NCT03043313), which is evaluating tucatinib in combination with trastuzumab.

Other studies are looking atEGFRre-challenging. If patients who've had prior disease progression on cetuximab or panitumumab don't acquire a resistance mutation in their liquid biopsy, they would be eligible for the PULSE study (NCT03992456), which is looking at how well retreatment with panitumumab works compared with standard of care in patients who've had prior disease progression.

The are other studies from the broader COLOMATE trial looking at when to give regorafenib. Should we give it before chemotherapy or after? There are also a variety of studies in the works that are using that backbone liquid biopsy screening protocol to design smaller subprotocols. The goal is to design targeted therapies for patients without an intrusive physical biopsy by using blood-based liquid biopsies.

Reference:

Dahmus JD, Kotler DL, Kastenberg DM, Kistler A. The gut microbiome and colorectal cancer: a review of bacterial pathogenesis. J Gastrointest Oncol. 2018; 9(4): 769