A new interventional study shows that a blood test can reveal who still has microscopic traces of bladder cancer after surgery – and may therefore benefit from immunotherapy. The approach is more precise than current guidelines, and for 60% of those treated, cancer DNA disappeared from the blood and scans showed no signs of disease.
When people with muscle-invasive bladder cancer have had their bladder removed after chemotherapy, the disease is not necessarily gone. Around half relapse within two years.
The question is therefore who should receive immunotherapy afterwards – and who may be able to avoid it. Today, the decision is based mainly on the tissue removed during surgery and on the programmed death-ligand 1 (PD-L1) marker. But these criteria can both miss hidden disease and lead to treating people who might otherwise have been spared.
With the TOMBOLA study, the researchers therefore shifted the focus from risk assessment to molecular traces in the blood. Small remnants of the cancer’s DNA can reveal hidden disease and help doctors decide whether to start immunotherapy.
“For many years, we have been working on measuring cancer DNA in the blood of patients with bladder cancer, and we have demonstrated that this is a very strong prognostic marker. In the TOMBOLA study, we now show that we can actually use this marker to guide treatment. The majority of patients among whom the marker can be measured become cancer DNA-negative when they receive immunotherapy, and this strongly suggests that the treatment has a real effect,” explains Lars Dyrskjøt, Professor at the Department of Molecular Medicine of Aarhus University Hospital in Denmark.
The research has been published in Annals of Oncology.
Risk assessment gave way to molecular traces
Adjuvant immunotherapy – that is, immunotherapy after surgery – is currently offered to patients who, after surgery, are assessed as being at high clinical risk and who also test positive for the PD-L1 marker. This is risk assessment – not a direct sign that disease remains.
The criteria therefore do not necessarily reveal the crucial point: whether microscopic disease is in fact still present in the body.
The researchers therefore investigated whether measuring cancer DNA in the blood, known as circulating tumour DNA (ctDNA), could move the decision closer to the disease itself. The test was tailored to each patient’s cancer so that the researchers could look for precisely the DNA changes found in that tumour.
The study involved 178 patients who, after chemotherapy and surgery, were followed with repeated blood samples so that the researchers could determine who still had measurable traces of cancer in their blood.
The blood test showed the next step
The result determined what happened next. Patients with ctDNA-positive samples were offered immunotherapy with atezolizumab for up to one year, regardless of whether a scan had already shown relapse. Patients without measurable ctDNA were instead monitored with scans.
Among those treated, 60% achieved a complete response: cancer DNA could no longer be detected, and scans showed no signs of disease at the end of the treatment course. In addition, 97% of the ctDNA-negative patients had not relapsed after one year.
The analysis first identified a group of patients who may have needed further treatment. Some 76% of ctDNA-positive patients would not have been eligible for immunotherapy under current European criteria and could therefore easily have been overlooked.
It also showed who might be able to avoid treatment. Some 15% of ctDNA-negative patients were both clinically high risk and PD-L1 positive and would therefore normally be candidates for immunotherapy, but none developed metastatic relapse during the follow-up period.
“This is molecular analysis of whether there is hidden spread of the disease rather than clinical assessment. If we detect cancer DNA in the blood, the patient most likely has metastatic disease and therefore needs immunotherapy. We simply identify patients based on traces of the disease itself,” says Lars Dyrskjøt.
Relapse could be seen earlier in the blood
The researchers also investigated how early ctDNA could warn of relapse. For 63% of those who became ctDNA-positive, the first positive sample was taken within four months.
Typically, around 90 days passed from the first blood test showing measurable traces of cancer until the relapse could be confirmed on a scan. In some cases, several years elapsed before the disease could be seen on a scan. This underlines that ctDNA can reveal microscopic disease earlier than imaging.
The amount of ctDNA was also linked to patient survival and, possibly, to the effect of immunotherapy.
High levels were associated with a significantly shorter time to relapse than low levels. This suggests that the test also indicates how aggressive the disease is.
TOMBOLA shows how the strategy can be used to guide treatment, but the trial was not randomised. It is therefore important that IMvigor011 points in the same direction. In that trial, the same strategy was investigated in a randomised setting among patients with high-risk bladder cancer, and the treatment was compared with placebo.
The researchers saw a significant survival benefit among ctDNA-positive patients who received atezolizumab compared with patients who received placebo. In addition, patients who continued to have no detectable ctDNA had a one-year disease-free survival rate of 95%.
The test needs to find its place in clinical practice
The United States Food and Drug Administration has already approved a ctDNA-based companion diagnostic for use with atezolizumab, enabling immunotherapy to be targeted based on cancer DNA in the blood. In Europe, guidelines will typically need to be amended, and approved CE-marked tests must be available before the analysis can play the same role in clinical practice.
“Together with IMvigor011, we now have quite clear clinical evidence that we can use tumour DNA in the blood to guide immunotherapy after surgery for both high-risk and low-risk patients. I am myself a member of the Danish guideline group for bladder cancer, DaBlaCa, and we are currently updating the official recommendations so that they include ctDNA analysis,” says Lars Dyrskjøt.
If the strategy proves viable in clinical practice, it could extend beyond bladder cancer. The idea is the same: to use the cancer’s own DNA traces to determine who still has residual disease after treatment. Similar studies are underway in areas such as bowel cancer and kidney cancer.
In addition, bladder cancer treatment is changing rapidly. New combination therapies are moving from the time after surgery to the time before surgery. The next question is therefore not whether ctDNA can be used but where in the treatment pathway the measurement is most useful: before surgery, after surgery or when doctors need to decide whether to step treatment up or down.
“This whole field is developing very rapidly at the moment, and this is good news for cancer patients, because it means that they will receive more effective treatment than they do today. But it also means that we must continually reassess how best to use ctDNA measurements in these new treatment contexts,” says Lars Dyrskjøt.
