|MOLECULAR TUMOR BOARD
|Year : 2021 | Volume
| Issue : 4 | Page : 737-746
FGFR alterations in head-and-neck cancer
Goutam Santosh Panda1, Vanita Noronha1, Omshree Shetty2, Asawari Patil2, Vijay Patil1, Pratik Chandrani1, Anuradha Chougule1, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
2 Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
|Date of Submission||19-Nov-2021|
|Date of Decision||27-Nov-2021|
|Date of Acceptance||10-Dec-2021|
|Date of Web Publication||29-Dec-2021|
Department of Medical Oncology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Panda GS, Noronha V, Shetty O, Patil A, Patil V, Chandrani P, Chougule A, Prabhash K. FGFR alterations in head-and-neck cancer. Cancer Res Stat Treat 2021;4:737-46
|How to cite this URL:|
Panda GS, Noronha V, Shetty O, Patil A, Patil V, Chandrani P, Chougule A, Prabhash K. FGFR alterations in head-and-neck cancer. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jan 20];4:737-46. Available from: https://www.crstonline.com/text.asp?2021/4/4/737/334228
| Case Summary|| |
History and examination
A 39-year-old man on prophylactic entecavir for hepatitis B surface antigen positivity with no history of substance abuse presented to us with a 3-month history of swelling on the right side of the face after a minor trauma. He also complained of right nasal discharge, nasal blockade associated with pain in the right orbit, decreased vision in the right eye, and swelling in the ipsilateral neck for 2 months. He had an Eastern Cooperative Oncology Group performance status of 1. Physical examination revealed a nontender swelling in the right maxillary region and palpable lymphadenopathy in the right levels Ib and Va. The right eye was laterally deviated. Visual acuity test revealed that the patient could only perceive hand motion in that eye.
Investigations and diagnosis
Magnetic resonance imaging showed a lesion in the right maxillary sinus extending to the high infratemporal fossa, superiorly involving the extraconal compartment of the right orbit, inferiorly involving the palate and alveolus, and posteriorly involving the pterygoid process with paracavernous extension.
A right maxillary sinus biopsy at our institute revealed that, histopathologically, the mass showed features characteristic of high-grade adenocarcinoma [Figure 1], androgen receptor positive in 40% of the cells with moderate nuclear staining; approximately 1% tumor cells showed membranous staining with weak-to-moderate intensity for programmed death-ligand 1 (PD-L1) using the Ventana SP263 antibody. Thus, the patient was diagnosed with unresectable adenocarcinoma of the maxillary sinus. Fluorodeoxyglucose-positron emission tomography-computed tomography (CT) revealed extensive lung metastases [Figure 2]. In-house targeted next-generation sequencing (NGS) for solid tumors was performed on the baseline biopsy specimen.
|Figure 1: (a and b): High grade sinonasal adenocarcinoma histology: Malignant tumor cells are seen in sheets and clusters, infiltrating the stroma. (a): H and E, ×100; (b): H and E, ×400|
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|Figure 2: Fluorodeoxyglucose-positron emission tomography-computed tomography showing multiple lung metastases|
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As per discussion in the multidisciplinary head-and-neck cancer tumor board, upfront palliative intent radiotherapy was deferred as the disease had extended into the ipsilateral orbit. The patient was planned for palliative-intent chemotherapy with once-a-week paclitaxel and carboplatin. He was also started on methylprednisolone, as per the suggestion of an ophthalmologist, for the left optic nerve compressive neuropathy. After 8 weeks of paclitaxel and carboplatin, there was local progression with partial response at the metastatic site (lungs). The optic neuropathy initially involving the right side progressed to involve the left side [Figure 3]. Hence, he was planned for combined androgen blockade (bicalutamide and leuprolide) along with palliative local radiotherapy. After 4 months of hormonal therapy, the disease progressed again with an increase in the number and size of metastatic lesions in the lung [Figure 4]. As a result of androgen receptor positivity and because immunotherapy was unaffordable, post-progression, he was continued on leuprolide and abiraterone was added. On subsequent progression, enzalutamide was considered because of the above reasons. After progression on enzalutamide, the next line of therapy was capecitabine and oxaliplatin. Post three cycles of capecitabine and oxaliplatin, the CT scan showed disease progression.
|Figure 3: Computed tomography scan showing lesion in right maxilla encroaching onto the left side|
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|Figure 4: Computed tomography scan showing increased number of lung metastases|
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The patient was initially unwilling for an NGS due to financial constraints. However, as he was heavily pretreated and had exhausted almost all standard treatment options, he consented to undergo NGS testing to look for any targetable mutations. NGS analysis of the baseline right maxillary sinus biopsy was performed at the time of starting enzalutamide using SOPHiA Solid Tumor Plus Solution™, a hybrid-capture-based panel comprising targeted genes designed to identify single nucleotide variants (SNVs), insertions, and deletions in 42 genes, 137 RNA fusions, gene amplification events in 24 genes, and microsatellite instability (MSI) status (at 6 unique loci-BAT25, BAT26, CAT25, NR-21, NR-22, and NR-27). Barcoded DNA and RNA libraries were prepared from 100 ng of DNA and RNA. The final libraries (10 pM) were sequenced on the Illumina Miseq platform using the MiseqV2 reagent KIT. SOPHiA DDM, a platform for data analysis and clinical report generation, was used to evaluate the data. NGS revealed a tier II (likely pathogenic) missense mutation in exon 5 of the TP53 gene, amplification of the fibroblast growth factor receptor 1 (FGFR1) gene, and an SDC4-FGFR1 fusion. The copy number for FGFR1 amplification on chromosome 8 was 9.5 [Table 1].
|Table 1: Results of next-generation sequencing analysis of the baseline specimen|
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| Excerpts From the Discussion in the Molecular Tumor Board|| |
This case was discussed in the molecular tumor board of our institute. Various FGFR alterations are considered to play an important role in oncogenesis. SDC4 is not a usual fusion partner for FGFR and has not been reported in the literature thus far. However, SDC4 being the 5' partner of the fusion event was likely to not be significant, as a result of plurality. Therefore, the molecular tumor board recommended that FGFR inhibitors could be considered for off-label use in this patient with head-and-neck cancer. As the approved FGFR inhibitor, erdafitinib, was not available, the molecular tumor board recommended that lenvatinib or pazopanib, which also inhibit FGFR, be considered. Therapeutically, lenvatinib was chosen as it inhibits FGFR1 with half the maximal inhibitory concentration (IC50) of 61 nMol/L.
On the initial biopsy specimen, HER2/neu immunohistochemistry revealed a score of 2+ (equivocal), and the PD-L1 TPS was 1%. Since NGS did not detect any amplification of HER2, HER2/neu was considered to be nonamplified and hence was unlikely to be a driver event in this patient.
The patient was started on lenvatinib 14 mg orally once daily in September 2021. He was compliant to lenvatinib. The notable drug-attributable toxicities were Grade 1 hand–foot syndrome, diarrhea, and fatigue. Unfortunately, the patient developed progressive neurological symptoms and expired on October 15, 2021.
| Discussion|| |
Fibroblast growth factor receptor and mechanism of action
The epidermal growth factor receptor, FGFR, insulin receptor, RAR-related orphan receptor, and erythropoietin-producing hepatoma groups belong to the receptor tyrosine kinase (RTK) superfamily. The RTKs FGFR1–4 belong to the FGFR family, and each have three extracellular immunoglobulin-like domains, a transmembrane domain, and an intracellular domain.,,, Of the 22 known FGF ligands, only 18 bind to FGFR and lead to the activation of downstream signaling pathways. Cell survival, development, proliferation, angiogenesis, and differentiation are all aided by the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. The FGFR signaling pathway is depicted in [Figure 5]. SNVs, copy number amplifications (CNAs), and gene rearrangements or fusions are all common FGFR alterations in cancer. FGFR mutations are uncommon and observed in 5%–10% of all malignancies; however, a higher frequency of these mutations has been noted in a few malignancies such as urothelial cancer and intrahepatic cholangiocarcinoma (10%–30%).,,
Fibroblast growth factor receptor alteration in various malignancies
Single nucleotide variant
The several methods by which SNVs can cause the FGFR receptors to become constitutively active include enhanced dimerization, increased kinase activity, and greater affinity for the FGF ligands.
The majority of SNVs are observed in FGFR2 and are highly sensitive to FGFR inhibitors. These FGFR2 SNVs are seen at higher frequencies in endometrial cancer, non-small-cell lung cancer, and stomach cancers., Approximately 10%–60% of all urothelial carcinomas harbor FGFR3 SNVs. FGFR4 SNVs are known for their higher frequencies in rhabdomyosarcomas (7%–8%).
It is unclear why FGFR1–3 interacts with certain genes or why some gene partners appear to be more common than others. According to Singh et al., a fusion of FGFR3 with TACC3 in glioblastoma resulted in oncogenic transformation. As per Helsten et al., fusions involving FGFR2/3 and TACC3 were the most common FGFR fusions, followed by those involving NPM1, TACC2, and BICC1. FGFR2 fusions with partners such as CASP7, CCDC6, and AFF3 have been observed in triple-negative breast cancer, while FGFR3–TACC3 and FGFR2–CIT fusions have been detected in lung cancer. Katoh have reported that only 2% of patients with glioblastoma and cervical squamous cell carcinoma harbor the FGFR3–TACC3 fusion. FGFR fusions and amplifications have been reported in gastric cancers as well.
Copy number amplifications
Helsten et al. have reported that CNAs are the most common type of genomic modification in the FGFR family, with their frequencies being the highest in FGFR1 and FGFR4. The rate of FGFR1 amplification ranges from 7% to 27% in breast cancer and has been linked to a poor prognosis and disease recurrence. In addition to breast cancer, amplification of FGFR1 has been seen in small-cell lung carcinoma (6%), non-small-cell lung cancer (17%), and urothelial cancer (7%)., Until now, CNAs have not been proven to be good predictive markers, particularly when involving FGFR1. Hence, using CNAs without regard for mRNA or protein expression as a marker for FGFR-targeted treatment selection is a matter of concern. In the European Society for Medical Oncology precision medicine working group, FGFR2 amplification in metastatic gastric cancer has been considered as a level IIIA biomarker.
Poor agreement between FGFR1 gene amplification and mRNA (and therefore protein) expression has been shown by Ng et al. They reported that FGFR1 gene amplification and protein overexpression were likely to be unrelated in lung cancer and possibly in other cancers as well. Future trials may explore the levels of FGFR mRNA and protein as potential biomarkers in patients without fusion.
Targeting fibroblast growth factor receptor
The biological activities of FGFR1 (FGFR1-TACC1, R189C, and K656E), FGFR2 (FGFR2-AHCYL1, FGFR2-CCDC6, FGFR2-KIAA1598, FGFR2-PPHLN1, KLK2-FGFR2, C62Y, D101Y, R203C, G227E, S252W, P253R, W290C, G305R, Y375C, N549H/K/S, G613S, K659E, and R664W), and FGFR3 (FGFR3-TACC3, G66fs*, R248C, S249C, R248_S249insC, G370C, S371C, Y373C, G380E/R, A391E, K403fs*, K650E/M/N/Q/T, E686T, and G691R) mutations have been shown to be the most significant transforming alterations,,,,,, and hence, are potential targets for therapeutic exploitation. We have therefore detailed the importance of various FGFR inhibitors in the following sections.
Multi-target tyrosine kinase inhibitors
As a result of the similarities between the kinase domains of FGFR and other RTKs, certain non-selective tyrosine kinase inhibitors (TKIs) meant to target other RTKs such as vascular endothelial growth factor receptors, for example, ponatinib, dovitinib, and nintedanib also have some inhibitory action against FGFR, as shown by in vitro studies. However, non-selectivity has become a significant hurdle in their use in clinical practice. Toxicity remains a major deterrent to incorporating non-selective FGFR inhibitors in day-to-day clinical practice. These non-selective inhibitors might be useful in overcoming acquired resistance to treatment, for example, the use of ponatinib against BCR–ABL T315I mutation. Non-selective TKIs include nintedanib, regorafenib, anlotinib, MAX40279, pazopanib, and lenvatinib.,,,,,
Selective tyrosine kinase inhibitors
Rogaratinib (BAY1163877), CPL-304-110, pemigatinib, infigratinib (BGJ398), debio1347, and erdafitinib (JNJ-42756493) are pan-FGFR inhibitors and considered to be first-generation TKIs. However, because of the structural differences between FGFR4 and FGFR1-3, the first-generation TKIs, except erdafitinib and LY287445, do not inhibit FGFR4., Another pan-FGFR inhibitor, futibatinib (TAS-120), is under evaluation in a Phase I/II clinical trial. Few TKIs that target FGFR4 exclusively include PRN1371, INCB062079, roblitinib (FGF401), and fisogatinib (BLU-554).
Monoclonal antibodies and antibody-drug conjugates
Bemarituzumab (FPA144), a monoclonal antibody that selectively targets FGFR2-IIIb, is the most therapeutically exciting FGFR2 monoclonal antibody currently under development. Vofatamab (B-701) and LY3076226 are among the other medications that are being studied for therapeutic use.
Fibroblast growth factor ligand traps
Another method for suppressing FGF/FGFR signaling is to use FGF “traps” to prevent the binding of FGF ligands to their receptors. Preclinical research has shown the efficacy of FP-1039 in endometrial malignancy with FGFR2 mutations and lung cancer with FGFR1 amplification. A Phase I study has demonstrated that FP-1039 is well tolerated in unselected patients with cancer with some typical side effects of FGFR TKIs such as hyperphosphatemia and retinal changes.
Fibroblast growth factor receptor inhibitors in clinical practice
The most convincing data on the antitumor activity of FGFR inhibitors have come from studies that used pan-FGFR inhibitors, especially in FGFR-mutant urothelial malignancies and cholangiocarcinoma with FGFR2 fusions [Table 2].
|Table 2: Approved tyrosine kinase inhibitors targeting the fibroblast growth factor receptor pathway|
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Erdafitinib is approved for use in patients with locally advanced or metastatic urothelial cancers harboring a susceptible FGFR2/3 alteration upon progression during or post first-line platinum-based chemotherapy including within 12 months of platinum-based chemotherapy in the neoadjuvant and adjuvant settings.
Pemigatinib is recommended for adult patients with cholangiocarcinoma with previously treated, unresectable, locally advanced or metastatic disease harboring alteration in FGFR2.
Fibroblast growth factor receptor inhibitors in head-and-neck cancer
There are no data from Phase III trials for FGFR inhibitors in head-and-neck cancer. Approximately 10%–17% of patients with head-and-neck cancer have recurrent FGFR1 amplifications, and overexpression of FGFR1 has been seen in more than 75% of both human papilloma virus (HPV)-positive and -negative head-and-neck squamous cell carcinoma (HNSCC) where it confers poor prognosis. HPV-positive cancers have been shown to exhibit amplifications of FGFR1-3 and FGFR3-TACC3 fusion. Higher level of FGFR1–3 expression is known to promote tumor initiation and progression in HNSCC.
Furthermore, in HNSCC cell lines, reduced expression of FGFR3 has been associated with a 35% reduction in cell proliferation and increased sensitivity to radiation. Resistance to bevacizumab has also been attributed to altered FGFR signaling.
McDermott et al., through their study in HNSCC cell lines, have shown that FGFR signaling may play a significant role in mediating cisplatin resistance in head-and-neck cancer stem cells and concluded that some patients may benefit from FGFR-targeted therapy.
Baschnagel et al. have shown the radiosensitizing property of AZD4547, a selective FGFR inhibitor, in FGFR2-expressing cell lines and HNSCC xenograft model. SenthilKumar et al. also investigated the use of AZD4547, as a radiosensitizer in HNSCCs that express FGFR.
Dumbrava et al. reported a complete response to an FGFR inhibitor in a patient with metastatic head-and-neck cancer with FGF amplification. Although conducted in a small cohort (10 patients), another Phase I study has shown a disease control rate of 80% with rogaratinib, an oral FGFR inhibitor.
Currently, at least 109 studies (7 Phase III studies) are actively recruiting patients to evaluate the effect of FGFR-targeted therapy in various cancers (clinicaltrials.gov.in) as depicted in [Table 3].
|Table 3: Genomically driven trials of fibroblast growth factor receptor inhibitors in head and neck cancer|
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Off-label use of drugs
An off-label use of a drug refers to the unapproved use of a drug that has been approved for a different indication. Off-label drug use is not uncommon in oncology, as some drugs are found to act against many tumors and sometimes cancer progression occurs after exhausting all the recommended treatment options. The increased application of molecular testing has led to the identification of many actionable targets. Conducting a randomized trial in patients with particular histology having a particular genetic aberration is not an easy task, as hundreds of patients have to be screened in order to find one eligible patient. Despite the fact that a particular molecular aberration can be found in various cancer types, therapeutic approval is mostly dependent on the primary tumor type rather than the molecular aberration. Pembrolizumab, one of the exceptions to this rule, is approved for use in any solid tumor, regardless of its origin, as long as it shows high MSI, deficiency in mismatch repair or high tumor mutational burden. Some of the recent trials evaluating the role of off-label drugs have created a ripple in the field of oncology. Conventional therapy was compared to targeted therapy according to the molecular profile in patients with any refractory cancer in the SHIVA01 Phase II study. Although this study did not demonstrate a higher efficacy of targeted therapies, it did show that the off-label use of targeted therapies might be a reasonable option in patients with MEK/RAF signaling pathway alterations. The American Society of Clinical Oncology's Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a Phase II non-randomized multibasket trial that attempts to describe the effectiveness and safety of targeted anticancer drugs in patients harboring potentially actionable mutations. Similarly, the recently published Lung Cancer Master Protocol (Lung-MAP; S1400) was designed to screen and treat patients with platinum pre-treated squamous non-small-cell lung cancer with the primary objective of developing an infrastructure that could be utilized to effectively test the targeted therapies in biomarker defined subgroups. This study established that comprehensive genomic testing was feasible, and biomarker-driven studies could be carried out in rare genotypes to test the drug activity. In a systematic review of the literature for the use of off-label drugs in oncology, Saiyed et al. concluded that the use of off-label drugs was common in cancer, particularly in the palliative setting, and greater scrutiny should be exercised to weigh the risks and benefits of these drugs. A single-center study from Spain has reported a high-quality evidence backing the off-label use of antineoplastic drugs. Since the field of oncology is rapidly evolving, we may consider the off-label use of medications if the patient consents or has progressed on all standard treatment options. The use of lenvatinib as an FGFR inhibitor in our patient was also off-label use as there is no approval in this setting. He was offered lenvatinib, a non-selective FGFR inhibitor, after multiple lines of therapy and after exhausting all standard treatment options.
Toxicities of fibroblast growth factor receptor inhibitors
FGFR inhibitors disturb the phosphate homeostasis, a mechanism typically controlled by FGF23, resulting in hyperphosphatemia shortly after the start of therapy. Ocular events such as central serous retinopathy, gastrointestinal problems, hand–foot syndrome, fatigue, and stomatitis/mucositis, are some of the typical adverse effects. Nail problems such as onycholysis and onychodystrophy have been documented with both infigratinib and erdafitinib but not with other FGFR inhibitors such as pemigatinib and rogaratinib. Fatigue, nail problems, and stomatitis are the most common dose-limiting toxicities reported worldwide, prompting dosage reduction, stoppage, and/or supportive therapy [Table 4].
|Table 4: Important adverse events of fibroblast growth factor receptor inhibitors|
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Resistance to fibroblast growth factor receptor inhibitors
FGFR inhibitors are in limited use as a standard of care at present, and reports of resistance to FGFR inhibitors are limited too. A few early reports suggest the development of resistance to FGFR inhibitors by means of gatekeeper mutations, activation of alternative kinase pathways, or epithelial to mesenchymal transition.,, Thus, just like any other kinase inhibitor, monitoring for the development of resistance and countering it with advanced line therapies becomes an important aspect with the wider utilization of FGFR inhibitors.
| Conclusion|| |
Targeting the FGFR signaling pathway is an example of precision oncology and biomarker-driven therapy. Several FGFR mutations have been linked to oncogenesis. Clinical investigations have demonstrated that persons with non-urothelial tumors with FGFR2/3 gene fusions can benefit from FGFR inhibitors and that patients with urothelial cancer respond better to TKI due to a greater incidence of FGFR3 point mutations. Since initial studies have shown improved clinical outcomes with the use of FGFR-targeted therapy, we anticipate that research in these areas will lead to a better understanding of the FGFR biology, which can then be used to improve patient care and survival.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]