FGFR2 fusions are common in a subset of cholangiocarcinoma and lung, breast, thyroid, and prostate adenocarcinoma (1–3) and rare in ovarian adenocarcinomas, while FGFR2 point mutations or gene amplification is more common (4, 5). To date, there is only one other case report of FGFR2 fusion-positive ovarian neoplasm (6). The vast majority of FGFR2 breakpoints result in the truncation of the C-terminal domain of FGFR2, which has well-supported in vitro evidence to activate FGFR2, seemingly with or without fusing with a dimerization domain provided by its partner (7–13). The Food and Drug Administration (FDA) has approved uses of futibatinib and pemigatinib for FGFR2 fusion-positive cholangiocarcinoma and an additional use of pemigatinib for myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA/PDGFRB or FGFR1 or with PCM1::JAK2 (14–16). Although their effects vary by cancer type, they are the most effective on intrahepatic cholangiocarcinoma, which is also the most well-represented in this fusion-positive group (17).

We present a case of high-grade serous carcinoma of Mullerian primary with a novel FGFR2::IQCG fusion an exceedingly rare combination of tumor type and fusion class, which progressed through multiple lines of therapy before and after a brief period on futibatinib. We illustrate the accompanying molecular findings over time to serve as a starting point in better characterizing the contexts surrounding targetable molecular alterations and affecting therapeutic choices.

The patient is a 62-year-old woman initially diagnosed with a primary International Federation of Gynecology and Obstetrics (FIGO) stage IIIC high-grade serous tubo-ovarian carcinoma. The patient had undergone an exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and optimal cytoreductive surgery, followed by six cycles of intraperitoneal and intravenous chemotherapy with cisplatin and paclitaxel. The pre-therapeutic specimen was unavailable for molecular studies. Three years later, the patient presented with elevated CA125 values and a peritoneal recurrence. The molecular panel (FoundationOne CDx) reported that the recurrent tumor sample was homologous recombination deficient (HRD) with 20.3% loss of heterozygosity (LoH; cutoff >16%), microsatellite stable (MSS), and low tumor mutational burden (TMB; 1 mutation/Mb). This was also the first report of an FGFR2::IQCG fusion in this patient. Concurrent molecular changes included amplification of BCL2L1 at chromosome 20q11.21, C11orf30 (EMSY) at 11q13.5, PIK3CA/PRKCI/TERC at 3q26, and a TP53 p.F341fs*4 mutation ( Table 1 ).

She completed six cycles of second-line chemotherapy with carboplatin and liposomal doxorubicin. One year after its completion, she experienced a second relapse and received a third regimen of six cycles of carboplatin in combination with bevacizumab followed by maintenance therapy with the PARP inhibitor olaparib for 4 months until she experienced a third relapse. Her disease was now deemed platinum-resistant, and two circumscribed lesions were treated with radiation therapy. Six months later, she had a hepatosplenic and pelvic relapse and was enrolled in a clinical trial assessing the folate receptor-targeting antibody–drug conjugate mirvetuximab soravtansine. After treatment of eight cycles over 5 months, she experienced progression of the pelvic disease and was enrolled in another clinical trial assessing the PD-L1 inhibitor atezolizumab in combination with an anti-TIGIT antibody and bevacizumab.

Six months into that clinical trial, her peritoneal disease progressed, and she was subsequently enrolled in a clinical trial assessing futibatinib, a selective, irreversible inhibitor of FGFR 1, 2, 3, and 4. Two cycles (1 month) into the trial, she experienced small bowel obstruction due to interval growths of small bowel serosal implantation. She was taken off the trial and started her seventh regimen of eighth cycles of pemetrexed and bevacizumab. Upon renewed progression, she received an eighth regimen of paclitaxel/gemcitabine and bevacizumab. At that time, a second FoundationOne CDx panel was performed on a new tissue biopsy. HRD was positive again (LoH 25.3%), the microsatellite was stable (MSS), and TMB was low (4 mutations/Mb). FGFR2::IQCG fusion and the TP53 mutation were redemonstrated while previously reported gene amplifications were negative, and two new mutations, NF1 c.7458-1G>A and RB1 p.N290fs*11, were detected ( Table 1 ).

Following a partial response to the later chemotherapy, imaging demonstrated new progression 3 months after completion of her last chemotherapy. Weekly chemotherapy with topotecan was initiated, which had to be discontinued after 1 month due to rapid progression. The tumor tissue from the second molecular panel had a HER2/neu expression level of +1 on immunohistochemistry, and she received 11 cycles of the HER2-targeting antibody–drug conjugate, fam-trastuzumab deruxtecan-nxki. After this regimen, she was enrolled in a clinical trial assessing the novel second-generation folate receptor-targeting antibody–drug conjugate IMGN151. Following renewed progression, the patient received single-agent weekly paclitaxel but finally opted for palliative/hospice care 9 years after her initial diagnosis of FIGO stage IIIc tubo-ovarian carcinoma.

Clinical history, histopathology results, and molecular pathology results were retrieved from the electronic health record system at University of California, Los Angeles.

The tumor tissue tested using FoundationOne^® CDx followed the methods detailed in their method validation report (18). Of note, this assay targeted full coding exonic regions and selected intronic regions of FGFR2 for rearrangement detection.

Non-overlapping curated studies on cBioPortal (https://www.cbioportal.org/) were queried with FGFR2 as the gene keyword on March 28, 2024. The results were downloaded into a tab-separated text file. All analyses were carried out in Microsoft Excel and are available as Supplementary Tables .

FGFR2::IQCG is a novel fusion with the FGFR2 breakpoint at chr10:121480398 (hg38)/10:123239912 (hg19) and IQCG at chr3:197946881 (hg38)/3:197673752 (hg19). The FGFR2 breakpoint is 337 bases upstream of exon 18 of its canonical transcript NM_000141 and preserves all except the last amino acid of the FGFR2 protein tyrosine kinase domain (TKD), which spans AA 456–768 according to GenBank, accessed 11/1/2023 ( Figure 1A ). The IQCG breakpoint is 1,194 bases upstream of exon 3, which contains 59 bases in its 5′ untranslated region (5′UTR) ( Figure 1B ). Assuming splicing is not affected, the fusion protein adds five amino acids, VTALL, to the truncated FGFR2 before reaching a stop codon ( Figures 1C, D ).

We present a case of FGFR2 fusion to a novel 3′ partner at a common breakpoint near the FGFR2 C-terminus in a high-grade serous Mullerian primary adenocarcinoma, an unusual neoplasm type to harbor this fusion. A review of the literature about its breakpoint and the proposed translation product, which resembles an early truncation of the C-terminal inhibitory domain, supports a likely activation of oncogenic pathways downstream of FGFR2 even in the absence of an extra dimerizer domain provided by the fusion partner. Although activating changes in FGFR family receptor tyrosine kinases are known to respond to FGFR inhibitors, the present case terminated her futibatinib trial after two cycles due to small bowel obstruction, which prevented the continuation of this oral medication. The interval growth of serosal implantation is consistent with the limited trial outcomes on ovarian cancer cases. The effects of FGFR inhibitors may be affected by the tumor developmental timeline, subclonality, and precise driving potential of the co-occurring oncogenic drivers such as gain of oncogene-containing chromosomal regions. More cases of similar cancer types harboring FGFR fusions will be necessary to shed light on the mechanism of limited efficacy of target therapies.