Molecular test may prevent unnecessary surgery in patients with rectal cancer

A group of researchers led by Anamaria Aranha Camargo of the Ludwig Institute of Cancer Research and the Molecular Oncology Center of the Syrian-Lebanese Hospital look for genetic markers that may help physicians predict a response to treatment.

By Karina Toledo, in Salamanca

Agência FAPESP – The current standard treatment for rectal cancer involves what is known as neoadjuvant therapy – which consists of using chemotherapy and radiation therapy to reduce the size of the tumor – followed by invasive surgery that in most cases, has a major impact on the patient’s quality of life.

A significant portion of the patients responds so well to neoadjuvant therapy as to be able to completely dispense with any surgery. Scientists from the Ludwig Institute of Cancer Research, the Molecular Oncology Center of the Syrian-Lebanese Hospital and the Angelita & Joaquim Gama Institute are working together to develop a molecular test for the purpose of helping physicians identify those cases.

The preliminary results of the study, which has received FAPESP funding were presented by Anamaria Aranha Camargo, director of the Ludwig Institute, this Tuesday (12/11) during the “Frontiers of Science – Brazil and Spain in the 50 years of FAPESP” event.

The “Frontiers of Science” event includes the celebration of 50 years of FAPESP in the cities of Salamanca (12/10-12/12) and Madrid, 12/13-12/14), and brings together researchers from the state of São Paulo and from several academic and research institutions of Spain in a lively and varied program that is open to the public.

According to Camargo, approximately 3% of patients do not respond to neoadjuvant therapy and are unnecessarily subjected to the adverse effects of chemotherapy and radiation therapy. At the other extreme, however, 30% of patients respond so well that they do not even need surgery.

“That number could get up to 60% depending on the protocol used. We need more effective tools so that we can distinguish between these cases and provide a more personalized treatment,” Camargo told FAPESP Agência FAPESP.

Today, the assessment of the results of the neoadjuvant therapy is done by means of serological analyses, rectal exam and imaging tests like ultrasound and tomography. But none of these tests is enough to allow the physician to know with certainty that the tumor has disappeared. When in doubt, surgeons prefer to operate.

Depending on the area affected, the surgery could affect sexual function and cause urinary and fecal incontinence. The good news, though, is that advances in the area of genomics are allowing the identification of markers and the development of personalized tests that are able to free a good many of these patients from having to suffer.

In partnership with researchers Angelita Habr-Gama and Rodrigo Oliva Perez, of the Angelita & Joaquim Gama Institute, Camargo’s group sequenced the tumor genome of seven patients and identified all of the chromosomal rearrangements present in each case. They then developed molecular assays that allowed them to track the presence of these chromosome alterations in blood samples.

“If the molecular test detects the presence of the altered DNA, it’s a sign that there are still tumor cells producing and releasing this material into the bloodstream. If the results are negative, the patient can undergo the test from time to time in order to be certain that there is no recurrence,” Camargo explained.

Validation in a different group

The method has already been tested on two of the seven patients whose genome was sequenced. “As a positive control, we selected a case whose clinical examination had confirmed the continued presence of the tumor, and the molecular test in fact was able to track the tumor DNA in the blood,” Camargo reported.

As a negative control, the researchers used the molecular test on a patient who had already undergone surgery and whose biopsy had revealed no tumor cells. The molecular test results were also negative, reinforcing the hypothesis that the surgery was unnecessary.

“We began at the two extremes and we will now test the patients in cases where there is doubt. If we are able to gather evidence that the method does in fact have clinical use, the next step will be to test it on a larger sample,” Camargo said.

The biggest problem, according to Camargo, is that in the cases of rectal cancer, there is no recurrent pattern of chromosomal rearrangement. “Some patients may have ten rearrangements and others may have over one hundred. But with the sequencing technology available today at a relatively low cost, we are able to examine each of the tumors and design individualized molecular tests,” she said.

At the same time, the scientists analyzed the gene expression profile in another sample of 30 patients in an attempt to identify a set of genes that is able to indicate the response to the neoadjuvant therapy in advance.

“We have already found a gene signature capable of dividing the patients into two groups – those who respond completely to the treatment and those whose response is incomplete. But in order to be certain, we need to perform a validation on a different group of volunteers,” Camargo explained.

According to the researcher, it is estimated that by early 2013, the sequencing of a complete human genome will be able to be done at a cost of US$1,000.

“It is still an expensive methodology and it may take some time to become part of the National Health Care System. But it is an important advance and like all new technology, takes time to be absorbed and adapted by society,” she added.