Manisit Das
In earlier OncoBites articles, we discussed how genetic testing is increasingly used to guide cancer management. Cancer arises due to changes in our DNA sequences that make up our genes, which we refer to as gene mutations. By analyzing the genetic signatures within the tumor, clinicians can make better-informed choices to streamline the patient to a treatment plan that is specific to the patient’s tumor. This genetic profiling approach is like trying to find a shoe that fits comfortably. Having the right shoe can make a strenuous hike smoother by reducing the pain while increasing the probability of a positive outcome of such a hike.
While precision medicine is a ray of hope for the future, unfortunately, its benefits haven’t reached every patient yet. Not all genetic changes driving cancer have an approved targeted therapy, and hence there is a lower likelihood of conducting genetic analyses for some cancers over others. Pancreatic ductal adenocarcinoma (PDAC), a major subtype of pancreatic cancer is a great example of one such cancer. Pancreatic cancer is a deadly disease, and the 5-year survival rate of the disease is still less than 10% in the US. So far RAS, a gene mutated in about 95% of patients, the major player in pancreatic cancer, is undruggable. Surgery is the most effective treatment strategy; however, most patients at diagnosis do not qualify for surgical removal of the tumor. This is because the cancer has spread beyond the primary site, making it so surgery is no longer an option. These patients are now treated with a combination of non-targeted chemotherapy drugs, which often come with high toxicities. Thus, rarely patients are genetically tested in pancreatic cancer, with a limited arsenal of drugs available to serve targeted clusters of patients.
Two recent studies explored the potential of genetic sequencing in patients with advanced pancreatic cancer. Advanced cancer means the disease had metastasized to distant locations of the body beyond the pancreas, a scenario commonly seen at diagnosis with this aggressive disease. The studies aimed at answering two primary questions:
- Feasibility: If genetic profiling can be performed in patients with PDAC?
- Clinical management: If genetic profiling should be performed in patients with PDAC?
For a long time, PDAC tumors were thought to be crime maps dominated by a few big bad guys like KRAS, a gene of the RAS family, with little else of significance. However, one of the two studies mentioned above showed that it is possible to utilize the information from genetic sequencing to target the tumors which do not express the mutated KRAS. This is critical as any changes in treatment protocols at the clinic is guided by a simple premise: Will this affect the management of the disease? The authors highlighted instances where the sequencing results were successful in guiding therapy. A patient who was being treated with chemotherapy drugs without any success was found to have a mutation in a gene called BRAF. It was known from preclinical studies that cells with a BRAF mutation could be sensitive to a class of drugs called MEK inhibitors. After treatment with a MEK inhibitor drug, the patient showed a partial response to the therapy, living for about 16.5 months past diagnosis. While the outcome is unfortunate, it must be noted that median survival for patients with locally advanced pancreatic cancer with chemotherapy is somewhere between 6 to 12 months, so the survival, in this case, was a significant improvement.
The other study published in the same issue went on to perform an in-depth analysis of organoids, which are tiny three-dimensional structures grown in the lab, crafted to mimic many aspects of the original tumor, and are derived from the patient tissue. Like the first study we discussed, this study also found potentially targetable mutations in the small proportion of patients who do not express a mutation in KRAS. Further, the authors compared the RNA expression profiles in the organoids with the sequencing data obtained from clinical trials and found good correlations between the signatures that predicted success for some of the standard of care chemotherapy drugs. While analyzing the DNA is essential to identify the genetic drivers of cancer, it is also valuable to take a snapshot of the RNA signatures in the tumor and other tissues, as it allows us to look at the genes being actively expressed at a given time.
In cancer, especially pancreatic cancer, time is critical. Thus, to establish a framework of molecular analysis requires the ability to characterize the information rapidly, so that the information obtained can be useful clinically. Further, the window available for treatment is often not long enough, making the design of clinical trials to test strategies that may affect a small subset of patients extremely difficult. Not to mention, recruiting enough patients to the trial will be challenging. Last but not the least, we still haven’t gotten far in our quest to target the undruggable gene, which affects the majority of patients with PDAC. Nevertheless, these studies bring some hope to patients who do not express the common RAS mutation. Hopefully soon, we will be able to clinically translate the genetic profiling approach to offer better treatment options for these small subsets of patients who may have a better outcome if they receive an appropriate first-line therapy after diagnosis.
Works Discussed
Collisson, E. A. (2018). Bringing Pancreas Cancer into the Lab. Cancer Discovery, 8(9), 1062-1063. doi: 10.1158/2159-8290.cd-18-0811
Aguirre, A. J., Nowak, J. A., Camarda, N. D., Moffitt, R. A., Ghazani, A. A., Hazar-Rethinam, M., . . . Wolpin, B. M. (2018). Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discovery. doi: 10.1158/2159-8290.cd-18-0275
Tiriac, H., Belleau, P., Engle, D. D., Plenker, D., Deschênes, A., Somerville, T. D. D., . . . Tuveson, D. A. (2018). Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discovery, 8(9), 1112-1129. doi: 10.1158/2159-8290.cd-18-0349
Image Credits
Featured Image: Cancerous cells forming a lump in the pancreatic tissue.
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