Scientifically Speaking | Why a small rectal cancer trial is a big deal
The trial size was small. Larger trials will provide information on the efficacy of dostarlimab in larger groups. However, this is a shot in the arm for precision medicine, for we are getting better at treating cancers
Cells are supposed to live, divide, and die like clockwork according to a plan that is beneficial to the whole organism. There are over a hundred controls inside cells that keep them in check.
We talk about cancer as if it is a single disease, but really it is many different diseases. (Anna Tarazevich)
Some people are predisposed to certain cancers because of the genes they inherited. Mutations also accumulate in cells over time due to damage from the environment or lifestyle factors. Certain infections can also increase the risk for cancers. Cells become cancerous if they can wear down the internal machines that control growth and proliferation.
We talk about cancer as if it is a single disease, but really it is many different diseases. Cancer predates human existence and afflicts other animals. As long as cells can evolve, there will be a risk of developing cancer.
But that doesn’t mean that we can’t beat certain cancers. For example, the ability to treat rectal cancer has been getting better over the years. And results of a trial at Memorial Sloan Kettering Cancer Center that were recently presented at the American Society for Clinical Oncology meeting in Chicago and concurrently published in the New England Journal of Medicine show a new way to treat rectal cancer in some patients.
Treatment of advanced rectal cancers typically includes radiation therapy, chemotherapy, and surgery. This treatment method combining three approaches has resulted in high survival and cure rates for non-metastatic rectal cancer of up to 77% in three years.
But while a patient’s life may be saved, there is often a permanent toll that results in diminished quality of life. Many clinicians will, therefore, start with radiation and chemotherapy and assess how cancer is being managed, and then resort to surgery if needed.
I mentioned that cancers can arise from cells breaking down various checkpoints. Around 5 to 10% of patients with rectal cancers are deficient in one key cellular machine known as DNA-mismatch repair enzymes which are supposed to fix mutations. These patients don’t respond well to only radiation and chemotherapy, and so they often require surgery. And these are the patients who gave their consent to be a part of this experimental trial.
In the peer-reviewed medical article, results for 12 patients were reported, but in some media reports, there’s mention of up to 6 other patients who also benefited from this treatment. Patients received dostarlimab, a monoclonal antibody to treat the specific molecular defect (mismatch repair) implicated in their cancer. Immunotherapy (instead of the standard radiation and chemotherapy) proceeded for six months.
Patients were routinely assessed by imaging with the plan to start radiation and chemotherapy if cancer was detected. So far, those treatment options have not been needed. All of the patients had resolution of clinical signs: around a year later, cancer had not been found in a single patient who received dostarlimab.
Although these results have been presented as a “cure” it is still too early to say if cancer is gone in any of the patients who were treated with dostarlimab. Cancer is unpredictable and control of cancer after a year isn’t a guarantee that it won’t come back. Patients will need to be followed for much longer.
The trial size was also small. Larger trials with more diverse populations of patients will provide information on the efficacy of dostarlimab in larger groups. Patients responded well to immunotherapy, but long-term toxic effects in broader populations will also need to be documented.
The human gastrointestinal tract also contains diverse microbes, collectively called the gut microbiome. It is known that the gut microbiome influences the progression of rectal cancer, but it also might affect how well immunotherapy works. Not much is known about the interplay of gut microbes and biologics like monoclonal antibodies. More work on this front is needed.
Right now, there’s also the question of the cost of the treatment itself and the availability of the tools to diagnose mismatch-repair deficient rectal cancer outside of large cancer hospitals. This is certainly a concern in a country like India.
With these caveats in place, let me assure you that these results are significant. Cancers arise differently in different people and for decades they’ve been classified based on location, instead of individual features. When the human genome was sequenced two decades ago, it was supposed to herald the era of precision medicine, where precisely tailored drugs would be given to patients based on the molecular profile of their own disease. This was expected to result in faster and better recovery with fewer toxic effects.
Progress has been slow, but advances in diagnostics now make it possible to characterize cancers on a molecular level quickly and relatively cheaply. The frustration of clinicians who treat thousands of patients who need better treatments right now is valid, but the arc of drug discovery and adoption for cancer is long. Certainly, the costs of diagnostics and drugs will go down.
However, while greater accessibility might take a few years, there’s an immediate impact on how we should think about cancer. In my view, the most significant aspect of this study extends beyond the trial into the approach. At every cancer research and treatment conference, there are presentations on treating cancers based on molecular targets. This study adds a feather to the cap of immunotherapy, which has been yielding some great successes over the past decade.
Dostarlimab is a monoclonal antibody that is used to treat endometrial cancer with mismatch-repair deficient cells. In the current trial, it has shown effectiveness with the same deficiency in cells for cancer at another location. Mismatch repair deficiency has also been found in other kinds of gastrointestinal cancer, and also in some cancers of the prostate, bladder, breast, and thyroid. It’s tempting to speculate that we could use this drug for some cases of other cancers as well.
The take-home message is clear. We are getting better at treating cancers more effectively and with fewer adverse effects, based on their precise hallmarks. This is a shot in the arm for precision medicine.
Anirban Mahapatra is a scientist by training and the author of a book on COVID-19. He’s writing a second popular-science book
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