Interview: The winding road to curing metastatic colorectal cancer

Dr Eduard Batlle (Institute for Research in Biomedicine Barcelona, Spain) works on the molecular biology of metastatic colorectal cancer (CRC). Medicom Medical Publishers asked him how the emerging understanding of the tumour biology and tumour microenvironment of metastatic CRC could transform the treatment landscape of this highly prevalent cancer.

Could you describe your current research projects and what potential impact they might have on colorectal cancer treatments?

“My lab investigates CRC, with a focus on mechanisms,” replied Dr Batlle. “Currently we cannot cure late-stage CRC, because we do not understand how metastases work. Therefore, we’ve seen very few developments in terms of therapies for these patients over the last 30 to 40 years.” Dr Batlle further outlined that the current management of patients with CRC is largely based on surgery. “While this is a curative strategy for many patients with early disease, in patients with advanced disease the management is still mostly based on chemotherapy, which is not a curative treatment in the majority of cases.” According to Dr Batlle, the status quo with regard to treating patients with advanced CRC is caused by the lack of understanding of metastatic disease. “In my lab, we are investigating metastases, which is the cause of death in these types of cancers. Currently, we're looking at 2 different problems.”

First, Dr Batlle described that many patients with localised disease receive surgery during which the primary tumour is removed effectively. Some of these patients, particularly patients with stage 3 disease, receive adjuvant chemotherapy. Nonetheless, about 30% of these patients relapse over the next months or years. “We hypothesise that the primary tumour has shed cells into the circulation, perhaps weeks, months, or years before surgery and adjuvant chemotherapy is administered,” explained Dr Batlle. “These cells are hidden in our organs. At some point, these cells resume growth and regenerate the disease at different locations. These metastases are tremendously difficult to cure. One of the focus points of my lab is trying to understand this invisible phase of the disease, when patients are virtually cured but at risk of relapse.” Dr Batlle said that this phase cannot be studied in human patients because it is unknown where these residual cells are. “Therefore, we use mouse models that reproduce metastatic relapse. With this research, we are trying to understand the genetic make-up of these residual cells, and investigate why some of these cells migrate, escape the immune system, and colonise organs. Next, we are looking for the weaknesses of these cells in order to manipulate them with novel or existing therapies, to prevent the formation of metastases.”

The other focus of Dr Batlle’s research is directed at the 25% of patients who already have metastases at the time of diagnosis. “Patients with metastases have a very bad prognosis and we are looking at how to cure these patients. We aim our efforts largely at the immune system, because we know that these metastases can potentially be recognised by the immune system. However, the tumour has developed mechanisms to prevent the attack or to become invisible to the immune system. Manipulating the signals that the cancers utilise to evade the immune system could be a potent therapeutic target.”

What are some of the advances in genomics and molecular biology that we can use to understand these processes?

“A lot is known about CRC,” stated Dr Batlle. “We know the mutations, its different subtypes, and we understand some of the immunology of CRC. However, one of the problems is that genomic and transcriptomic research has largely focused on primary disease. This is paradoxical, because we can cure the primary disease with surgery. Now, we are beginning to realise that metastases are quite different from the primary tumours.” Dr Batlle explained that metastases are different from primary tumours for various reasons. “First, metastases are clonal expansions; maybe of 1, 2, or 3 cells. We are still debating on whether they are monoclonal or polyclonal. A few cells come from the primary tumour and regenerate. Therefore, these cells do not represent the entire population of cells, but only a subset of cells. Second, these cells suffer major adaptations because they are residing in different organs; the liver and the lungs have very different environments compared with the primary site. Third, these metastatic cells are often immune-edited, meaning that these cancer cells have lost the antigens that would make them visible to the immune system.”

“Another level of complexity comes from the fact that a patient may have more than one metastasis and each of these metastases might behave differently. They are heterogeneous and respond differently to therapy.” Dr Batlle emphasised that it is therefore important to first understand the heterogeneity and complexity of metastatic disease in patients with CRC.

The final problem Dr Batlle mentioned is tumour access. “The primary tumour is very easy to access, but it is much more complicated for metastases. For example, taking biopsies of the liver or the lungs is ethically difficult, imposing limitations and biases.”

Would you agree that combination therapies might be the best approach to target the problem at hand?

“I'm not a very strong believer of combination therapies,” answered Dr Batlle. “We’ve seen thousands of clinical trials with combination therapies with very little success over the past 20 years. One of the reasons is that plasticity is a key aspect of CRC. Every time we hit a pathway, the cells adapt, change, and persist.” Dr Batlle further explained that each therapy targets a particular cell state. “These cancers are heterogeneous, and the different cells, even though they have the same mutations, adopt different cell states. If you hit with one drug you usually kill one particular cell state, but you spare the other. Chemotherapy is a classic example of this. You administer chemotherapy, removing the proliferating cells, but the non-proliferating cells survive; and only 15–20% of CRC cells are proliferating cells! The moment you stop the therapy, the other, resistant cells just regenerate the disease. The same thing happens with all the combination therapies that we currently have. However, the treatment landscape may change in the coming years, because the development of KRAS inhibitors offers promise, demonstrating significant results in research. Since more than 50% of CRCs carry an active KRAS mutation, I’m positive that this may be a powerful tool in the treatment of CRC.”

“On the other hand there is immunotherapy,” continued Dr Batlle. “Approximately 15% of CRCs have mutations in the DNA repair genes, with many mutations and many antigens. Patients with this disease type have a better prognosis because the immune system can recognise and eliminate metastatic cells. Therefore, these patients often react very well to checkpoint blockade immunotherapy. However, for the majority of patients, immunotherapy does not work well in the adjuvant setting.” Still, Dr Batlle reasoned that there might be an important role for immunotherapy in the treatment of CRC. “Perhaps all of these combination therapies have a curative effect on a subset of patients with CRC. It comes down to patient selection. We have to choose the right patients with the right tumour burden. This implies that we need a better understanding of metastatic disease. That's part of the road ahead, selecting the right immunotherapy for the right patient.”

Have there been improvements with regard to detecting micro-metastases?

“One development in that area is the emergence of cell-free DNA tests,” said Dr Batlle. “The results of the clinical trials are very impressive and these tests will probably be implemented as a standard-of-care procedure. Essentially, a patient receives surgery of the primary tumour and a blood test looking for the mutations of that particular tumour. If, after surgery, cell-free DNA is gone, a patient’s probability of relapsing is very low. If cell-free DNA is detected in the blood, there is an increased risk of relapse. Those are the patients that probably benefit from chemotherapy or other types of adjuvant therapy to prevent relapse.”

Hereafter, Dr Batlle referred to a paper in Nature in which he and his research team showed that the tumour microenvironments of metastases evolve [1]. “Initially there is residual disease or micro-metastases, and the tumour microenvironment of these micro-metastases is still very immature,” he explained. “If you treat these types of lesions in mice models in the neoadjuvant setting it's sufficient to give checkpoint blockade immunotherapy. That activates the immune system and will eliminate residual disease during that particular therapeutic window. Thereafter we performed surgery and our mice became disease-free and did not relapse. However, if we wait until after surgery, the tumour microbiome is mature and checkpoint blockade immunotherapy does nothing.”

Dr Batlle explained that this research was performed in models with microsatellite stable (MSS) CRC, thus holding a low mutational burden. It implies that some patients may benefit from checkpoint blockade immunotherapy in the period between diagnosis and surgery. A study by Chalabi et al. showed that neoadjuvant therapy in a small sample of patients with MSS CRC was indeed efficacious [2]. Other studies investigating neo-adjuvant therapies in patients with MSS or MSI CRC are ongoing [3]. “The prediction is that up to 30% of patients may benefit from neoadjuvant therapy as a preventive treatment for relapse,” added Dr Batlle.

Do you have a final message for our readers?

“It's important to realise that there has been little progress despite all the investments,” replied Dr Batlle. “CRC is the second most frequent cancer in the world, meaning that there are millions of patients diagnosed with CRC every year. In my view, we need to refocus the question. Going through the same group of combination therapies is not the answer. There is something we do not yet understand and we have to make progress there, in order to produce a therapy that really works.”

1. Canellas-Socias A, et al. Nature. 2022;611(7936):603-613.
2. Chalabi M, et al. Nat Med. 2020;26(4):566-576.
3. Verschoor YL, et al. Nat Med. 2024;30:519-530.

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Posted on 23 February 202417 May 2024