Pathologic complete response to immune checkpoint inhibitor in a stage IIIB ovarian clear cell carcinoma patient with POLE mutation resistant to platinum-based chemotherapy: a case report.

Background: Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian cancer with unique features at histological and molecular levels. The prevalence of OCCC is higher in east Asia than in Western countries. As cases are usually chemo-resistant, treatment effects of platinum-based chemotherapy are not satisfactory, especially for patients with stage III or IV disease. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with advanced-stage cancers. However, whether advanced OCCC patients benefit from ICIs remains elusive. Case Description: Herein, we report a Chinese patient with stage IIIB inoperable OCCC who was resistant to platinum-based chemotherapy and anlotinib. Next-generation sequencing (NGS) revealed a pathogenic polymerase epsilon (POLE) P286R mutation and a high level of tumor mutation burden (TMB) in tissue and plasma samples. The ICI sintilimab was then used with bevacizumab as third-line treatment. Tumor reduction was observed, and the patient underwent surgical resection which indicated a pathologic complete response (pCR). Maintenance therapy with sintilimab and bevacizumab was applied, and the patient has achieved overall survival (OS) of 35 months since the diagnosis. They have also achieved a progression-free survival (PFS) of 29 months since commencing ICI treatment and have been disease-free for 24 months after surgical resection. Conclusions: The treatment effect of ICI in POLE-mutant OCCC patients has been rarely reported. The treatment benefits observed in the stage IIIB OCCC patient who was resistant to platinum-based chemotherapy may be associated with the presence of POLE mutation and a high level of TMB. Comprehensive genomic profiling could contribute to appropriate treatment decisions for OCCC. 2022 Gland Surgery. All rights reserved.

Introduction

Ovarian cancer is a common and life-threatening gynecological disease with different subtypes, including high-grade serous carcinoma, low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, and clear cell carcinoma (1). Ovarian clear cell carcinoma (OCCC) has a high prevalence in East Asia and is as high as 25% in Japan, but appears less frequently in Western populations, where the prevalence is estimated to be between 5% and 12% (2). The treatment strategies for OCCC include surgery and platinum-based chemotherapy, while the chemo-resistant nature of the disease means the effect of these therapies is unsatisfactory, especially for patients with stage III or IV disease (3). A previous study has revealed that advanced OCCC is associated with a poor prognosis that the 3-year overall survival (OS) rate is less than 45% (4).

Mutations in ARID1A and PIK3CA occur in approximately 50% of OCCC patients, while their co-occurrence occurs in up to 70% of patients (5). Numerous efforts in developing novel targeted therapies for OCCC have been made, but most studies were in-vitro and none of the regimens have yet been approved. To date, treatment options for inoperable OCCC patients are still limited to platinum-based chemotherapies.

Immune checkpoint inhibitors (ICIs) including antibodies targeting programmed cell death protein 1 (PD-1) or programmed cell death ligand-1 (PD-L1) have been approved for the treatment of various advanced cancers (6). While the efficacies of ICIs in advanced OCCC remain elusive. DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors present increased tumor mutation burden (TMB) and the benefit of immune-combined therapy for advanced patients with solid cancers, such as non-small cell lung cancer (7). To date, the treatment effect of ICIs in POLE-mutant OCCC patients has been rarely documented.

Herein, we report a Chinese patient with stage IIIB POLE-mutant OCCC who was resistant to platinum-based chemotherapy and subsequent anlotinib. Next-generation sequencing (NGS) revealed the high levels of TMB in tissue and plasma, and in addition to frequent OCCC mutations such as TP53, ARID1A, and PIK3CA, the patient harbored a pathogenic mutation of POLE rarely reported in OCCC. A ICI sintilimab was used with bevacizumab as the third-line treatment, and tumor reduction was observed. Surgical resection indicated the patient achieved pathologic complete response (pCR). The presence of POLE mutation and high level of TMB might explain the remarkable treatment effect of ICI in our case. We present the following article in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-22-420/rc).

Case presentation

The patient was a 37-year-old Chinese woman. Before coming to our hospital, she underwent a gynecological ultrasound in September 2018 which detected the presence of ovarian masses. The patient then received positron emission tomography-computed tomography (PET-CT) in October 2018, and the results indicated bilateral ovarian masses with activated fluorodeoxyglucose (FGD) metabolism in both ovaries and the abdominal aorta. In November 2018, she attended our hospital and underwent percutaneous biopsy of the suspected tumor lesion, and the immunohistochemistry (IHC) results showed CK (+), CK7 (+), P63 (−), Ki-67 (60%), Pax-8 (+), WT-1 (−), P16 (+), NapsinA (+), ER (−), PR (−), Vim (partial+), and CA125 (partial+). Pathological evaluation of the tumor indicated a poorly differentiated adenocarcinoma, and combined with the results of imaging and IHC, the patient was diagnosed with stage IIIB (T3N1M0) bilateral ovarian cancer with multiple lymph node metastases.

Given the patient was not suitable for surgical treatment at the time of diagnosis, intrapelvic injection with cis-platinum (90 mg) and postoperative venoclysis with albumin-bound paclitaxel (nab-paclitaxel) were administered. In December 2018, she was readmitted to our hospital with low-grade fever, and a CT scan observed increased tumor lesion and the presence of pelvic effusion. The patient was then discharged after intratumoral injection with lobaplatin (40 mg). In January 2019, she experienced symptoms of neoplastic fever, and treatment was changed to gemcitabine (1,400 mg at day 1 and 8) with cis-platinum (30 mg at day 1 to 3, 25 mg at day 4). However, as the patient was intolerant due to anemia and hyponatremia, treatment was discontinued at day 8 and she was discharged. In February 2019, the tumor lesion had increased in size, and the patient received anlotinib (12 mg qd, day 1–14). However, during platinum-based chemotherapy and anlotinib treatment, the tumor continued to grow, and pelvic effusion was observed by enhanced CT scan.

Progressive disease (PD) was evident in April 2019 () and the patient underwent a second biopsy of the tumor lesion. The IHC results were: Pax-8 (+), P53 (40%+), WT-1 (−), ER (−), PR (−), CK (+), and Ki-67 (70%+), and pathological evaluation of the tumor indicated a poorly differentiated adenocarcinoma. Given positive PAX-8 in the IHC and the presence of transparent cytoplasm, the tumor was diagnosed as OCCC. Tissue and plasma samples of the patient were also analyzed by NGS with the former showing mutations with potential clinical significance in several genes related to ovarian cancer such as TP53, PIK3CA, ARID1A, and POLE (). In the plasma sample, PIK3CA p.E81K, and POLE p.P286R mutations were also identified (). Notably, high levels of TMB were observed in tissue (188.9 mutations/Mb) and plasma samples (65.9 mutations/Mb), while the microsatellite stability (MSS) was present in tissue. The patient then received bevacizumab (300 mg) and sintilimab (100 mg) for four treatment cycles from May to August 2019. At the end of August 2019, adverse events were observed, including infection (grade 3), and thrombocytopenia (grade 3) which were controlled by administration of meropenem, prednisone, and levothyroxine. In September 2019, the patient continued with the fifth treatment cycle of bevacizumab and sintilimab, during which a decrease in tumor lesion size was seen along with absorption of pelvic effusion ().

Figure 1

Treatment evaluation by CT scans. (A) Before ICI treatment; (B) before surgical resection; (C) 12 months after surgery; (D) 24 months after surgery. ICI, immune checkpoint inhibitor; CT, computed tomography.

Table 1

Mutations with potential clinical significance identified by sequencing

Gene	Mutation description				Allelic frequency
	The change at the DNA level	The change at the protein level	Mutation type		Tissue	Plasma
TP53	c.637C>T	p.Arg213*	Nonsense		13.69%	N/A
ARID1A	c.5965C>T	p.Arg1989*	Nonsense		11.96%	N/A
ARID1A	c.4381C>T	p.Arg1461*	Nonsense		10.63%	N/A
ATM	c.46G>T	p.Glu16*	Nonsense		18.51%	N/A
ATRX	c.988A>T	p.Lys330*	Nonsense		14.77%	N/A
FGFR2	c.1646A>C	p.Asn549Thr	Missense		14,72%	N/A
IDH1	c.394C>T	p.Arg132Cys	Missense		16.96%	N/A
PIK3CA	c.241G>A	p.Glu81Lys*	Missense		14.61%	0.51%
POLE	c.857C>G	p.Pro286Arg	Missense		14.41%	0.46%
PTEN	c.1021T>G	p.Phe341Val	Missense		21.07%	N/A
RB1	c.967G>T	p.Glu323*	Nonsense		14.47%	N/A
RB1	c.2501C>A	p.Ser834*	Nonsense		12.40%	N/A
SETD2	c.871G>T	p.Glu291*	Nonsense		16.81%	N/A

*, indicates a stop codon. N/A, not available.

In October 2019, the patient underwent surgical resection of the uterus, bilateral adnexa, omentum majus, and pelvic lesions, and postoperative evaluation indicated pCR without residual cancerous tissue. Bevacizumab and sintilimab were used as maintenance therapy from November 2019 to May 2020, and no recurrence was observed. CT scans also revealed no recurrence in October 2020 (). Until the most recent follow-up in October 2021 (), the patient had a disease-free survival of 24 months after surgical resection, a progression-free survival (PFS) of 29 months since ICI treatment, and an OS of 35 months since diagnosis. The treatment timeline of the patient is summarized in .

Figure 2

Summary of treatment timeline. PD, progressive disease; NGS, next-generation sequencing; ICI, immune checkpoint inhibitor; pCR, pathologic complete response; PFS, progression-free survival; OS, overall survival.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The primary treatment strategy for OCCC includes standard staging surgery and optimal cytoreduction combined with post-operative chemotherapy. Some patients with stage III or IV disease may not be eligible for surgical treatment, and platinum-based chemotherapy is usually used to reduce tumor burden. However, OCCC seems to be less sensitive to conventional platinum-based chemotherapy, with the response rate of paclitaxel plus carboplatin in OCCC ranging from 22% to 56% (8). In one study more than 50% of patients with stage III or IV OCCC had chemotherapy refractory or resistant disease (9). In our case, the patient with stage IIIB OCCC commenced with platinum-based chemotherapy, while adverse effects and tumor increase were observed until PD. Very low response rates (<10%) of chemotherapy were reported in patients with recurrent OCCC and development of novel therapeutic strategies has been an unmet clinical need.

Previous molecular profiling revealed unique features of OCCC compared with other subtypes of ovarian cancer. In OCCC, ARID1A and PIK3CA mutations occur frequently and usually coexist, while BRCA1/2 mutations are less common (2). In our study, 171 mutations were identified in tissue sample including 13 with potential clinical significance. Consistent with previous studies, mutations in our case involved the PI3K/AKT/mTOR pathway (PIK3CA and PTEN) and the SWI/SNF chromatin remodeling complex (ARID1A and ATRX). In addition, we identified POLE p.Pro286Arg mutation in tissue and plasma samples of the patient. The POLE gene encodes the catalytic subunit of DNA polymerase ε. The exonuclease domain mutations (EDMs) of POLE such as p.P268R, p.S297F,p.V411L, and p.S459F have been reported in endometrioid and serous carcinomas of ovarian cancer and colorectal cancer (10,11). The presence of POLE EDMs in cancer patients is usually concurrent with an extremely high TMB level, which has been recognized as a positive predictor of cancer immunotherapy. In OCCC, no pathogenic POLE mutations were identified as previously reported. Our study first reported an OCCC patient harboring POLE EDM p.P286R and showed high levels of TMB in tissue and plasma. The use of ICIs in OCCC is limited due to the rarity of the disease. A phase II trial evaluated the use of nivolumab in patients with platinum-resistant ovarian cancer, and complete response was observed in one of two OCCC patients. In our case, the patient achieved pCR after ICI treatment. The treatment effect of ICI might be explained by the presence of POLE mutation and high level of TMB.

In addition to ICI, other potential therapeutic targets for OCCC such as PIK3CA and ARID1A have been investigated. The PI3K/AKT/mTOR pathway is involved in various cellular functions, and several inhibitors targeting it showed antitumor activity in-vitro and have been evaluated in ongoing clinical studies (12,13). The mTOR inhibitor everolimus showed treatment benefits in a 36-year-old relapsed OCCC patient harboring mutations in PTEN and PIK3CA (14). In a phase II trial, another mTOR inhibitor, temsirolimus, was used in combination with carboplatin and paclitaxel as first-line treatment for stage III-IV OCCC but failed to show treatment benefit compared with controls (15). The ARID1A encoding a key component of the SWI/SNF chromatin remodeling complex is another candidate target for OCCC, and the rationale of this target is based on synthetic-lethal approaches which have been validated in-vitro (12).

There are some limitations associated with our study. Only 1 patient was included in this work. Large cohorts or clinical trials are needed to explore the treatment effects of ICIs as late-line treatment of OCCC patients who carry POLE mutations.

In conclusion, our study reported that a patient with stage IIIB OCCC who was resistant to platinum-based chemotherapy benefited from ICI, and the treatment effects may be associated with the presence of pathogenic POLE mutation and high TMB level. As a distinct subtype of ovarian cancer, OCCC has unique molecular features which may act as actionable therapeutic targets. Comprehensive genomic profiling could contribute to identifying and understanding these emerging targets of OCCC.

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