‘Outstanding’ Cancer Patients Give Clues to Better Drug Treatments | Science

By Jocelyn KaiserNov 19, 2020 @ 11:50 am

While even the best cancer drugs don’t give most people a long time to have their cancer spread, there are rare exceptions: patients whose multiple tumors melt and who stay healthy years later. Researchers have long dismissed these “exceptional players” as inexplicable outliers. Now, an effort to systematically study them is yielding data that could help improve cancer treatments.

The project, led by the US National Cancer Institute (NCI), examined the DNA of tumors and immune cells found around or in these cancers in 111 exceptional responders. In 26 of the patients, scientists found genomic changes in tumors or immune cues that may explain why a drug that didn’t work for most people shrank responder tumors for months or years. Some cases suggest that combining certain drugs may give better results. The results show that examining these lucky few is worth it, says Dale Garsed of the Peter MacCallum Cancer Center in Australia. The study “opens new avenues for treating comparable cancers in a larger population,” he says.

Equally enthusiastic is the former NCI director who launched the initiative in 2014. “It is gratifying to see so much new information from this initial survey of cancer patients who have unexpectedly done well with existing therapies,” says cancer biologist Harold Varmus of Weill Cornell Medicine, who does did not work on the study itself. The results are “complex”, he notes, but they “promote unique hypotheses” and underscore the value of conducting genomic tests on patients’ tumors in order to personalize treatments.

Varmus was inspired in part by a patient with bladder cancer who responded to a drug that was generally lackluster due to certain mutations in her tumor. From more than 500 cases submitted by clinical researchers, the NCI selected those that match specific criteria: the patient’s tumors shrank or disappeared in response to a drug that worked for less than 10% of patients in the whole clinical trial. Or the patient had a response that lasted at least three times as long as a typical patient.

A team led by Louis Staudt and Percy Ivy of NCI narrowed down the patient list to those with enough medical data and tumor samples with intact DNA. Their team analyzed these 111 cases using a battery of genomic analyzes and tests for immune cells in and near tumors.

In 26 cases, the data seem to explain the patient’s exceptional response. For example, a patient with brain cancer who was still alive after more than 10 years was given a chemotherapy drug called temozolomide which kills tumor cells by damaging their DNA. The patient’s tumor had genomic changes that crippled two DNA repair pathways that cells use to counter the drug’s attack, the NCI team reports today in Cancer cell.

A patient with colon cancer in remission for almost 4 years after treatment with temozolomide had two changes that paralyzed DNA repair pathways and was given a second investigational drug that blocked a third. “Any backup system that would have reversed the damage has been inactivated,” said this person. These results suggest that treating some patients with a cocktail of drugs, each blocking different DNA repair pathways, may be helpful, says Ivy.

Two patients who had received chemotherapy for rectal cancer and bile duct cancer had unexpected tumor mutations – they were in the BRCA genes, best known to cause breast cancer. BRCA mutations also weaken DNA repair, making tumors vulnerable to chemotherapy.

In other cases, the tumors have shrunk after patients are given a drug that blocks a protein that stimulates cell growth. The tumors exhibited DNA modifications which stimulated high activity of the protein gene, which made the tumor cells highly dependent on the growth signal; as a result, the drug worked exceptionally well.

In other exceptional responders, their tumors were infiltrated with unusually high levels of certain immune cells. This suggests that their immune system was ready to enter and destroy tumors once an anti-cancer drug began to kill certain cells, Staudt says.

The results suggest that more patients should have their tumors analyzed with genomic tests so that doctors can select appropriate drugs. But the results can still be difficult to interpret – many tumors had combinations of mutations and changes in immune cells, the NCI authors found.

As for the 85 cases the NCI team couldn’t resolve, Staudt says the molecular evidence was not strong enough to draw any conclusions. His team is uploading the data from the 111 patients to an NCI database so that other researchers can study them and look for similar cases. “Maybe we missed something,” he says.

Researchers from North America, Europe and Australia have started similar outstanding stakeholder projects, and NCI researchers are hoping some of those efforts can pool their data. Staudt would like to see a study of at least 1000 patients. “These are puzzles to be solved,” he says. “I think they are teaching us something.”