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Institute of Pathology
Institute of Pathology
University Clinic Erlangen
Professor Arndt Hartmann has disclosed that he has received consulting fees from Agilent, AstraZeneca, Bristol-Myers Squibb, Diaceutics, Janssen, MSD, Pfizer, and Roche.
Alterations in FGFRs and Tumor Types
The fibroblast growth factor receptor (FGFR) family is part of the larger tyrosine kinase signaling pathway responsible for cellular proliferation and differentiation.
The FGF family includes approximately 22 members that are divided into 7 subfamilies. These subfamilies can be further divided into 3 groups based on their mechanism of action: canonical FGF, endocrine FGF, and intracellular FGF. It is important to understand the first 2 groups, canonical and endocrine, because they produce their biologic actions by signaling through the receptor FGFR.
Genetic alterations in FGFRs can be found across various tumor types and can lead to different mechanisms of oncogenesis. Some alterations cause constitutive activation of the receptor, which results in an oncogenic signal and activation of different downstream signaling pathways. Other FGFR mutations can allow for dimerization with other alternate receptor tyrosine kinases, such as MAP or ErbB, and result in constitutive phosphorylation and downstream signaling.
The most frequent alteration across tumor types, including in breast or ovarian cancer, is amplification of FGFR1 and, less frequently, amplification of FGFR2 and FGFR3. However, it is not clearly understood how well these FGFR amplifications can respond to anti-FGFR–targeted treatment. Activating point mutations in FGFR3 and FGFR2 are frequent in urothelial carcinoma of the bladder as well as in non-small-cell lung cancer, endometrial carcinomas, and gastric cancer.
In urothelial cancer, for example, FGFR3 mutations occur mainly in low-grade noninvasive papillary tumors, which have a relatively stable genome with few other alterations. FGFR3 alterations are detected in 60% to 70% of these non-muscle-invasive carcinomas, but FGFR3 alterations are also detected in approximately 15% to 20% of more advanced, invasive urothelial carcinoma as well.
Translocations that lead to activating fusion proteins are another mechanism important in both FGFR3 and FGFR2 pathogenesis. These activating translocations are found in urothelial carcinoma and in other cancer types, such as intrahepatic cholangiocarcinoma developing from the cholangiocellular cells within the liver and on the liver hilus. FGFR2 fusions are detected in 10% to 15% of cholangiocellular carcinomas, whereas fusions that involve other members of the FGFR family are rare.
Many tumor types such as urothelial cancer, endometrial carcinoma, gastric carcinoma, and non-small-cell lung cancer (adenocarcinoma seen frequently in nonsmokers) harbor FGFR alterations that could potentially be targeted for treatment.
Importance of Testing for FGFR Alterations
Why do we want to detect these alterations? Several inhibitors of FGFR are in clinical trials and 2 inhibitors have already been granted accelerated FDA approval—one for urothelial carcinoma and one for intrahepatic cholangiocellular carcinoma. Erdafitinib is currently approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma who have a susceptible FGFR3 or FGFR2 genetic alteration and whose disease has progressed during or following platinum-containing chemotherapy. Pemigatinib is approved for the treatment of previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. Infigratinib is currently being assessed in both cholangiocarcinoma with FGFR gene fusions or rearrangements and in advanced or metastatic urothelial carcinoma with FGFR3 alterations.
For each of these treatments, molecular pathology testing of formalin-fixed, paraffin-embedded specimens can be used to detect specific mutations or translocations within the tumor. For erdafitinib, the FDA approved the therascreen FGFR RGQ RT-PCR kit as a companion diagnostic for detection of specific point mutations and fusions in FGFR3/FGFR2. For pemigatinib, the FDA approved FoundationOne CDX as a companion diagnostic to detect certain FGFR2 fusions and select rearrangements.
In the last few years, we have also learned that in bladder cancer, FGFR3 mutations and translocations occur in specific subtypes of this cancer. We now know that bladder cancer, like other cancer types, is not one disease but several transcriptionally different diseases (eg, basal layer―like bladder cancer and several luminal bladder cancer subtypes) and these subtypes have differences in FGFR3 mutation frequency. In specific luminal subtypes and specific histopathologic patterns of bladder cancer, FGFR3 mutations are very frequent, and pathologists can often predict which patients will have a very high likelihood for FGFR3 alterations using morphology and/or immunohistochemical or molecular typing and, therefore, which patients would be very good candidates for anti-FGFR–targeted treatment.
Methods of Testing for FGFR Alterations
The specific point mutations and translocations associated with effective treatment can be detected using reverse transcriptase polymerase chain reaction (RT-PCR) methods or next-generation sequencing (NGS). Since the point mutations and translocations being detected by RT-PCR are always in the same gene locations, the entire gene does not need to be sequenced, facilitating development of mutation specific RT-PCR kits that have the advantage of detecting both mutations and/or translocations in 1 test. These kits are available at most commercial laboratories for easy patient sample testing. The alternative to RT-PCR is to use NGS to detect either DNA mutations or RNA translocations or fusions.
The use of NGS panels for comprehensive genomic profiling in clinical diagnostics allowed for significant improvements in the detection of FGFR alterations. However, although NGS panels can easily detect point mutations, detection of FGFR fusions using NGS is more challenging. Whole genome sequencing can identify fusions and has been used to identify new fusion, but this technique is expensive and not used in the diagnostic setting. There are now other methods such as targeted sequencing, hybrid capture, amplicon, and anchored multiplex PCR testing that can be used for detecting fusions for clinical diagnostics.
In Germany, the first-round robin trials in bladder cancer, lung cancer, and cholangiocellular carcinoma are in development to validate the current FGFR alteration testing modalities, with detection method validation carried out by the molecular pathology department testing facility. Overall, the molecular pathologic detection of these FGFR alterations have been performing well. For example, bridging studies comparing the results from the assay used in the pivotal trials leading to the FDA approval of erdafitinib showed high concordance in the FDA-approved companion diagnostic RT-PCR test.
During the past 10 years, we have learned much about how FGFR alterations can be targeted with systemic therapy, resulting in the accelerated FDA approval of 2 FGFR inhibitors. FGFR inhibitors have been under investigation for many years, so it is exciting to see their development and use now in clinical practice.