In an illustration of how whole-genome sequencing can provide critical information to guide the care of cancer patients and reveal the intrinsic complexities of cancer itself, researchers from the Translational Genomics Research Institute sequenced the whole genome of a patient with a rare and very aggressive type of thyroid cancer, and identified a target for which there is an approved drug available.
Led by Michael Demeure, an endocrine surgeon as well as the director and a clinical professor within the Rare Cancer Unit of TGen's Rare Cancer Program, the researchers detailed the case study in the World Journal of Surgery this month.
According to Demeure, whole-genome sequencing is especially useful for such rare tumor types because they often do not have an effective standard of treatment and little is known about their genomic profile.
"Our likelihood of finding something that explains why we get the tumor or that is a potential therapeutic target is higher than with more common cancers," Demeure told Clinical Sequencing News. More common cancers such as colon and breast are well studied and, as such, physicians typically have both a standard protocol for treatment and even second- and third-line therapies available.
For rare tumor types, there are fewer options, and if a patient progresses on standard chemotherapy, the oncologist is often left to essentially pick a drug at random, Demeure said. "That's why these types of tumors are ideal for the genomic sequencing approach," he said.
In the World Journal of Surgery study, the authors describe a 62-year-old male patient with the tall cell variant of papillary thyroid cancer, a rare and unusually aggressive form, who had undergone multiple operations, radioiodine therapy — radiation treatment that concentrates the radiation in the thyroid glands — and treatment with the drug sorafenib, which is approved for use in radioiodine-resistant thyroid cancer.
Despite all these treatments, the patient's cancer continued to progress and metastasize.
The patient was a "good candidate for sequencing," said Demeure, who was also his surgeon. Aside from having a rare and highly aggressive form of cancer, mutational profiling of BRAF and NRAS — genes commonly mutated in thyroid cancer — turned up negative.
"We thought, 'there's got to be something unique and different going on,'" Demeure said.
Whole-genome sequencing of the patient's tumor and matched normal sample uncovered 57 somatic mutations in 55 genes in the cancer genome. It confirmed the absence of mutations to NRAS and BRAF and also found no rearrangements between the RET and PTC genes, another common genetic alteration in thyroid cancer.
Somewhat surprisingly, the researchers found a translocation between ALK and EML4, which has been reported in about 5 percent of lung cancers, as well as in pediatric neuroblastoma. Additionally, there is an approved compound that targets that fusion.
The EML4-ALK fusion is "known to be a driver and also a therapeutic target" for the drug crizotinib, marketed by Pfizer as Xalkori, and is effective in about 70 percent of ALK+ lung cancers, Demeure said. The fusion was confirmed in a CLIA setting.
Since the drug is only approved for lung cancers, the patient's oncologist had to get approval to use the drug off-label and was also able to convince the patient's insurance company to cover payment.
After starting treatment, the patient "had stable disease for about six months," Demeure said, but due to other medical issues stopped treatment after six months.
The case represents both the utility of sequencing rare cancer types as well as the complexities of acting on that data. Even if a druggable mutation is identified, a potential therapeutic can only be used off-label, so there is no guarantee that a patient's insurance company will cover the drug.
Nevertheless, TGen hopes to make the case that sequencing patients with rare and/or advanced cancer is both cost-effective and has clinical utility.
Previously, TGen told CSN that it was validating a cancer sequencing protocol that involves low-pass whole-genome sequencing, deep exome sequencing, and whole-transcriptome sequencing to be run in its CLIA laboratory with one of its goals to demonstrate the cost benefits and clinical utility for guiding cancer treatment.
One challenge TGen has already made significant progress on is reducing turnaround time. At the time it completed the current study, turnaround time was around three to four months, Demeure said.
Now, however, TGen has CLIA certification for whole-genome sequencing and is in the midst of implementing a cancer sequencing protocol that would reduce the time frame significantly, to several weeks.
Last year, it published the results of a nine-patient pilot study for implementing whole-genome and transcriptome sequencing for patients with rare and/or advanced cancer.
Establishing utility in rare cancers makes sense as a first step, said Demeure, since these cancers have few treatment options. Even if sequencing identifies an off-label treatment or clinical trial, the case can be made to the insurance company that either the oncologist can "treat the patient with a drug that we have no idea it works," or can "treat the patient with this [off-label] drug, which at least has a chance of working because the therapeutic target is there," he said.
Nevertheless, Demeure cautioned that the presence of a therapeutic target does not guarantee the respective drug will work. For instance, he said, in the case crizotinib, even in patients that are ALK+, it is effective in about 70 percent patients, meaning that for 30 percent of patients, even though they have the drug target, it is still ineffective.
Moving forward, Demeure thinks it will be important to study patients that have these markers but still do not respond to the drug.
Additionally, he said that since finding the ALK-EML4 fusion in his patient with thyroid cancer, he has heard anecdotal evidence that other researchers have also found the same mutation in other patients with thyroid cancer. "It may be a low-frequency recurring event," he said, that could open up a new treatment avenue, although he stressed that studies would have to be done to see whether the fusion was in fact recurrent and whether crizotinib would be effective in these patients.