Successful Treatment of Patients with Refractory High‐Grade Serous Ovarian Cancer with GOPC‐ROS1 Fusion Using Crizotinib: A Case Report

Abstract

Background

Recently, multiple poly (ADP‐ribose) polymerase (PARP) inhibitors have demonstrated excellent efficacy among patients with ovarian cancer with or without BRCA mutations. However, alternative therapeutic options are urgently required for patients who cannot benefit from conventional chemotherapy or PARP inhibitors.

Case Presentation

A patient with high‐grade serous ovarian carcinoma presented to our clinic after developing resistance to chemotherapy. Paired tumor‐normal next‐generation sequencing (NGS) was performed using peripheral blood to identify potential actionable mutations. NGS revealed the patient harboring a GOPC‐ROS1 fusion, which was subsequently verified using a reverse transcription polymerase chain reaction assay. No germline or somatic mutation in BRCA1/2 or mismatch repair genes was detected. Therefore, the patient received crizotinib treatment. A rapid, favorable clinical response (partial response at 1 month) was observed, with further pathological response monitored and evaluated in follow‐up interrogation.

Conclusion

This study suggested that crizotinib was an off‐the‐shelf, practical, and ostensibly effective treatment option for patients with ovarian cancer with ROS1 rearrangement. NGS‐based genetic testing may guide to plan therapeutic paradigms, and render precision medicine promising in ovarian cancer treatment.

Implications for Practice

Despite the previous report of ROS1 fusion in patients with ovarian cancer, it remains unknown whether patients can benefit from targeted therapeutic drugs. This study reports a GOPC‐ROS1 fusion identified by next‐generation sequencing in a patient with chemotherapy‐resistant ovarian cancer. The patient was administered crizotinib and showed rapid, remarkable response. This study suggests that comprehensive sequencing should be offered for patients with ovarian cancer without effective therapeutic strategies, and crizotinib can be used to treat ROS1‐rearranged ovarian carcinomas.

Short abstract

This case report describes the first known case of a patient with ovarian cancer with ROS1 rearrangement who experienced radiographic partial response after treatment with crizotinib.

Introduction

Ovarian cancer is the second‐most common cause of gynecological tumor death and is estimated to have caused approximately 22,500 deaths in China in 2015 [1]. Owing to a lag in early detection and screening methods, the 5‐year survival rate of ovarian cancer in China is much lower than that in the U.S. (2012–2015: 39.1% vs. 2009–2015: 47.6%) [2, 3]. To date, surgery and cytotoxic chemotherapy have been the mainstays of ovarian cancer treatment for decades. In recent years, multiple poly (ADP‐ribose) polymerase (PARP) inhibitors, including olaparib, niraparib, and rucaparib, have shown remarkable efficacy in the recurrent and maintenance settings for patients with advanced epithelial ovarian cancer with deleterious or likely deleterious BRCA gene mutations [4]. However, effective systemic therapy for patients who cannot benefit from PARP inhibitors or chemotherapy is still lacking. Despite several developing therapies with promising efficacy, such as folate receptor targeting and immunotherapy, it is also another highly potential strategy to unearth more targetable genetic aberrations and develop more effective drugs against them [5].

Paired tumor‐normal targeted next‐generation sequencing (NGS), providing abundant genetic information including both germline and somatic gene mutations, is increasingly used as a genetic sentinel for cancer treatment decision making, especially in cases of non‐small cell lung cancer (NSCLC). Drugs targeting multiple driver mutations, activating epidermal growth factor receptor mutations, ALK/ROS1 translocations, and BRAF V600E mutations for instance, have led to great survival benefits in selected patients with advanced NSCLC [6]. Results from multiple basket trials suggested that patients harboring the same molecular abnormalities may benefit from targeted therapy independent of tumor origin [7, 8]. Notwithstanding ROS1 rearrangement reported in patients with primary ovarian cancer [9], unequivocal clinical evidence on patient response to targeted therapies is warranted.

Crizotinib functions as a small‐molecule protein kinase inhibitor by competitively binding to the ATP‐binding pocket of target receptor tyrosine kinases [10]. Based on the dramatic response rates shown in PROFILE1005 and PROFILE1001, crizotinib was initially approved by the Food and Drug Administration (FDA) in 2011 for treatment of patients with ALK‐positive NSCLC [11, 12, 13]. Although ROS1 shares only 48.92% of amino acid sequence homology with ALK in the kinase domain, the three‐dimensional structures of the crizotinib binding sites of these two kinases are similar [14]. Probably due to the structural similarities, patients with NSCLC with ROS1 rearrangement also achieved remarkable tumor response to crizotinib treatment in multiple clinical trials [15, 16]. Currently, crizotinib is one of the most preferred first‐line targeted therapies for the treatment of advanced ROS1‐positive NSCLC.

Here, we report a fusion of ROS1 to the Golgi‐associated PDZ and coiled‐coil motif‐containing (GOPC) gene accidentally identified in a patient with refractory high‐grade serous ovarian cancer. The patient was administered crizotinib and showed radiographic partial response after 1 month of treatment and normalization of serum CA‐125 after 2 months of treatment.

Case Presentation

A 69‐year‐old female underwent total abdominal hysterectomy plus comprehensive staging and debulking in October 2018. Postoperative findings confirmed the diagnosis of phase IIIC high‐grade serous ovarian carcinoma. Because of accidental supply shortage of paclitaxel liposome, the patient was administered one cycle of liposomal doxorubicin plus lobaplatin with relatively less neurotoxicity [17] and then switched to two cycles of paclitaxel liposome plus carboplatin from October 2018 to January 2019. The patient experienced aggravating abdominal distension, lower back pain, and vaginal bleeding in February 2019. Subsequent pelvic enhanced computed tomography (CT) scanning revealed disease progression, including thickening of the omentum along with increasing of multiple nodules around it, enlargement of lymph nodes on both groins and cardiophrenic angle, expansion of the irregular soft tissue mass in the vesicorectal space to 5.3 × 4.2 cm, and a newly emerging soft tissue mass in the subcutaneous region of the lower abdomen. In addition, the patient lost the ability to eat and defecate, experiencing incomplete intestinal obstruction and swelling pain on the left hypochondrial region with the pain numerical rating scale score of 8.

To identify potentially actionable mutations, paired NGS‐based genetic testing of 1,021 cancer‐related genes was performed using both circulating free DNA and DNA extracted from the leukocytes (Geneplus‐Beijing Ltd., Beijing, China). As a result, seven somatic mutations were identified and summarized in Table 1. No pathogenic or likely pathogenic germline mutations in BRCA1, BRCA2, ATM, MLH1, MSH2, MSH6, PMS2, and PALB2 were found. Of great interest, a ROS1 rearrangement (GOPC‐ROS1) was detected with the mutant allele frequency of 1.0% and was verified using a reverse transcription polymerase chain reaction (RT‐PCR)‐based AmoyDx assay (Amoy Diagnostics, Xiamen, China; Table 1; Fig. 1). Based on these results, crizotinib was given in a dose of 250 mg twice a day. The patient reported that the pain and intestinal obstruction completely disappeared and abdominal distension was significantly improved within 3 days. After 24 days, the patient was basically rehabilitated to normal activities with the Karnofsky Performance Score of 80. After 1 month of treatment, pelvic CT scanning showed decrease of nodules around the omentum, shrinkage of lymph nodes in the subcutaneous region of the lower abdomen, obvious narrowing and decrease of lymph nodes on both groins and cardiophrenic angle, and significant reduction of the mass in the vesicorectal space to 3.2 × 1.7 cm (Fig. 2A, 2B). According to RECIST v1.1, partial response was achieved. In addition, the normalization of serum CA‐125 was observed after 2 months of treatment (Fig. 2C). The treatment has lasted more than 2 months, and a long‐term pathological surveillance will be further carried out within follow‐up interrogation.

Table 1.

Somatic mutations detected by next‐generation sequencing

Gene	Transcript	c.HGVS	p.HGVS	Allele frequency
Single‐nucleotide variants and small insertions/deletions (gene)
MLL2	NM_003482.3	c.6520C>A	p.Q2174K	1.70%
BRD3	NM_007371.3	c.499 + 1G>C		1.40%
MTOR	NM_004958.3	c.1822G>A	p.D608N	1.00%
SOX9	NM_000346.3	c.166G>T	p.G56C	1.00%
HIST1H4I	NM_003495.2	c.185T>A	p.F62Y	0.90%
CBL	NM_005188.3	c.486_487delGGinsC	p.A163Qfs*3	0.50%
Fusions (gene)
GOPC‐ROS1	NM_002944.2;NM_020399.3 (Functional region: EX8:EX35)			1.00%

Abbreviation: HGVS, Human Genome Variation Society.

Figure 1.

Identification of GOPC‐ROS1 fusion. (A): Sequencing reads of GOPC and ROS1 are shown by the Integrative Genomics Viewer. (B): Schematic representation of the fusion involving GOPC and ROS1. (C): Verification of this fusion using the reverse transcription polymerase chain reaction method.

Figure 2.

Changes of tumor lesions and CA125 before and after crizotinib treatment. (A): Computed tomography before crizotinib treatment. (B): One month after crizotinib treatment. (C): Rapid decrease of CA125 after crizotinib treatment.

Discussion

Ovarian cancer refractory to conventional surgery and chemotherapy is still an incurable disease. Multiple clinical studies confirmed the promising efficacy of PARP inhibitors for advanced ovarian cancer, which served as a novel tool in the therapeutic arsenal to treat ovarian cancer. With cutting‐edge theoretical and technical advances in precision medicine, genetic aberrations–directed targeted therapies are becoming more and more popular in the systemic treatment of ovarian cancer. Here, we reported a case of a 69‐year‐old female who was diagnosed with refractory high‐grade serous ovarian cancer. Circulating free DNA–based comprehensive genetic profiling indicated that the patient harbored GOPC‐ROS1 fusion (exon8:exon35) with the mutant allele frequency of 1%, which was further verified using an RT‐PCR assay. The patient achieved dramatic tumor remission following crizotinib treatment with significant symptomatic relief.

ROS1 gene encodes a receptor tyrosine kinase of the insulin receptor family. Since the first demonstration of ROS1 fusion with the FIG (also known as GOPC) gene in glioblastoma in 2003, ROS1 has been reported to undergo gene rearrangement in a variety of tumors, including glioblastoma, NSCLC, cholangiocarcinoma, and ovarian cancer [9, 18]. The prevalence of ROS1 fusion in ovarian cancer varied largely among studies, ranging from 0.5% to 3.9% [19, 20]. Known ROS1 fusion partners include CD74, SLC34A2, SDC4, TPM3, GOPC, and so on. The fusion breakpoints of ROS1 are commonly located at exon 32, 34, and 35. Importantly, all fused proteins retained the ROS1 kinase domain, which stimulated the oncogenic cellular signaling pathways essentially involved in cell growth and proliferation [21]. The GOPC gene is located on chromosome 6q22.1. It encodes a Golgi protein with a PDZ domain that interacts with many other proteins, and it plays a key role in vesicular trafficking in secretory and endocytic pathways [22]. A deletion of approximately 240 kb in chromosome 6q22 has been suggested to result in the formation of GOPC‐ROS1 fusion [23].

ROS1 inhibition is an effective state‐of‐the‐art strategy for treating patients with ROS1‐rearranged NSCLC. Multiple clinical studies confirmed the promising efficacy of crizotinib, a ROS1 tyrosine kinase inhibitor approved by the FDA and China National Medical Product Administration, in patients with NSCLC harboring ROS1 rearrangement [15, 16]. Among 127 East Asian patients with ROS1‐positive NSCLC, the objective response rate (ORR) evaluated by independent radiology review was 71.7%, and the median progression‐free survival (PFS) was 15.9 months [16]. The efficacy of crizotinib in patients with different types of ROS1 partners was also investigated in 49 patients. This study found that the CD74‐ROS1 group had a higher rate of brain metastasis, lower ORR, and shorter PFS and overall survival. ROS1 fusion partner may influence the prognosis and treatment outcomes of patients with ROS1‐positive NSCLC who receive crizotinib treatment [24].

Conclusion

To our knowledge, this represents the first study reporting radiographic partial response following crizotinib treatment in a patient with ovarian cancer with ROS1 rearrangement. This case provides unequivocal clinical evidence for targeted therapy effectiveness in treating patients with ovarian cancer harboring ROS1 rearrangement.

Author Contributions

Conception/design: Dapeng Dong, Ge Shen

Provision of study material or patients: Yong Da, Ming Zhou, Gang Yang

Collection and/or assembly of data: Mingming Yuan, Rongrong Chen

Data analysis and interpretation: Ming Zhou, Gang Yang

Manuscript writing: Dapeng Dong, Ge Shen, Yong Da

Final approval of manuscript: Dapeng Dong, Ge Shen, Yong Da, Ming Zhou, Gang Yang, Mingming Yuan, Rongrong Chen

Disclosures

Mingming Yuan: Geneplus‐Beijing Ltd. (E). Rongrong Chen: Geneplus‐Beijing Ltd. (E). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board