A Successful Multimodal Treatment for High-Grade Serous Ovarian Cancer with BRCA2 Heterozygous Deletion with Multiple Recurrences: A Case Report

Abstract

Introduction

Management of recurrent high-grade serous ovarian cancer (HGSOC) remains a challenge. This case presents a successful multimodal treatment plan in a BRCA-mutated patient with repeated recurrences.

Case Presentation

A 60-year-old woman diagnosed with FIGO stage III HGSOC received initial debulking surgery followed by chemotherapy at another hospital in December 2017. The patient presented to our institution in March 2019 for further management because of a suboptimal response to 2nd-line chemotherapy. A disseminated disease extent was identified. She progressed (new bone metastasis) during the 3rd- to 5th-line platinum-based chemotherapy, but achieved complete remission after changing to pembrolizumab and weekly paclitaxel. She had a 3rd relapse at the anterior mediastinum (proven by thoracoscopic resection in April 2020, and the tumor was found to harbor a BRCA2 heterozygous deletion), which was controlled by adjuvant radiotherapy combined with nivolumab and nab-paclitaxel, followed by maintenance therapy nivolumab plus olaparib, and eventually olaparib monotherapy. A 4th recurrence at the perigastric lymph nodes was found through periodic positron emission tomography surveillance with normal CA-125 in September 2021. Resection of metastasis and hyperthermic intraperitoneal chemotherapy (HIPEC) were performed, and maintenance therapy was again with olaparib. She has maintained remission since then.

Conclusion

A durable remission is possible by multimodality management, including the strategic use of chemo-immunotherapy, localized resection plus HIPEC/adjuvant radiotherapy, and poly (ADP-ribose) polymerase (PARP) inhibitor maintenance, in BRCAm-HGSOC with multiple recurrences.

Introduction

Among all epithelial ovarian cancers, high-grade serous ovarian cancer (HGSOC), frequently diagnosed at an advanced stage, accounts for a substantial portion of ovarian cancer-related mortality. According to the Cancer Genome Atlas, approximately 17% of patients with HGSOC possess germline BRCA mutations and 3% somatic [1], while a study from Taiwan showed germline and somatic BRCA1/2 mutation rates in HGSOC were 8/46 (17%) and 4/46 (8.7%), respectively [2]. These deleterious mutations enhance tumor susceptibility to poly (ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors (PARPi) exploit homologous recombination-deficient cancer cells, inducing cell death through synthetic lethality. Overall survival (OS) analysis of SOLO-1 trial (patients with BRCAm/HGSOC or HG endometrioid carcinoma) found that maintenance olaparib offered significant improvement of OS after 7 years of follow-up (hazard ratio 0.55, 95% confidence interval 0.4–0.76, p = 0.0004) in the 1st-line setting [3]. In patients with platinum-sensitive recurrent BRCAm ovarian cancer, OS analysis of SOLO-2 showed a marginal benefit adding olaparib as maintenance (median OS 51.7 months vs. 38.8 months, p = 0.054) [4].

In this case report, we present a patient with recurrent HGSOC harboring a somatic BRCA2 heterozygous deletion who received multimodal treatments, including surgery, chemoimmunotherapy, radiotherapy, hyperthermic intraperitoneal chemotherapy (HIPEC), and maintenance with PARPi. Despite experiencing disease progression/multiple recurrences, the patient achieved no evidence of disease (NED) >4 years from her last relapse, highlighting the potential for sustained disease control through an aggressive, multimodal treatment approach.

Case

The patient, a 60-year-old woman, had a history of triple-negative breast cancer in 2014, treated with breast-conserving surgery and adjuvant chemoradiation. There was no relevant family history of cancer. In 2017, she was diagnosed with FIGO stage III HGSOC of the left ovary. She underwent laparoscopic debulking surgery followed by 6 cycles of carboplatin and paclitaxel at Taipei Medical University Hospital (TMUH). Follow-up image in January 2019 suspected recurrence and an elevated CA-125 level were also noted at TMUH, and 2 cycles of lipo-doxorubicin as 2nd-line chemotherapy were given (Fig. 1). She came to our hospital for further management after suboptimal response to 2nd-line chemotherapy. A disseminated recurrence, with pelvic tumors, regional, inguinal, mediastinal nodal and splenic metastases, and probable tumor seeding in the pelvis was detected by positron emission tomography/computed tomography (PET/CT) (Fig. 2a). Blood BRCA test revealed no pathogenic or likely pathogenic variants.

Fig. 1.

Timeline of the patient treatment journey.

Fig. 2.

The maximum intensity projection PET image (a) in March 2019 illustrated recurrent pelvic tumors with regional, inguinal, mediastinal nodal and splenic (arrow) metastases. The PET image (b) in June 2019 indicated disease progression with multiple bone metastases.

Owing to serial disease progression, the patient’s chemotherapy regimen underwent several modifications. Initially, carboplatin (AUC = 4) combined with topotecan (0.75 mg/m²) was administered, but after 3 cycles, follow-up PET/CT indicated new bone metastases (Fig. 2b) accompanied by a rising CA-125 level (from 70.6 U/mL to 120 U/mL). The regimen was subsequently switched to carboplatin (AUC = 4) plus gemcitabine (600 mg/m²), but continued elevation of the tumor marker (CA-125: 357 U/mL) prompted a change to ifosfamide (3.75 gm/m², total dose over 3 days) and bevacizumab (15 mg/kg). Due to progression on platinum-based chemotherapy with topotecan, liposomal doxorubicin and gemcitabine (3rd to 5th-line), ifosfamide without platinum combined with bevacizumab was administered. Because serum CA-125 kept elevating on ifosfamide and bevacizumab, tumor BRCA testing revealing a BRCA2 heterozygous deletion as well as immunohistochemistry stain showing PD-L1 TPS <1% and CPS 40, treatment was changed to weekly paclitaxel (80 mg/m²) combined with pembrolizumab (total 200 mg), resulting in a radiologically confirmed complete remission (January 2020 CA-125: 5.7 U/mL and NED by PET/CT). Because PARPi was not reimbursed at the recurrent setting in Taiwan, the patient opted not to use PARPi for maintenance.

In June 2020, a PET/CT revealed mediastinal lymph node metastasis and mild elevation of CA-125 (from 5.7 U/mL to 15 U/mL). The patient underwent thoracoscopic mediastinal lymph node dissection followed by adjuvant radiotherapy for local recurrence control [5]. Given the remarkable clinical efficacy previously achieved with pembrolizumab plus weekly paclitaxel, subsequent recurrence occurred within 5 months, the chemoimmunotherapy regimen was transitioned to another immune checkpoint inhibitor (ICI), nivolumab (total 100 mg) and nab-paclitaxel (total 100 mg) to intensify the tumor control. Follow-up imaging and tumor markers showed NED. Maintenance therapy with nivolumab and olaparib (300 mg/day) was initiated then olaparib alone. Clinical evidence strongly substantiates the translational potential of this dual combination therapy. This ICI plus PARPi combination regimen achieved a remarkable objective response rate of 71.9%, accompanied by a median duration of response of 10.2 months [6]. The patient experienced elevated liver enzymes without associated symptoms.

In September 2021, a periodic PET/CT surveillance (CA-125: 5.0 U/mL) suggested left gastric lymph node metastasis (score 3). Laparoscopic cytoreductive surgery with HIPEC was performed, and the left gastric lymph node was proven to be the sole site of metastasis. Following surgery, the patient continued olaparib as maintenance therapy, and as of the latest follow-up, she remained NED for >4 years from the last relapse.

Discussion

Ovarian cancer is the second most lethal gynecological malignancy worldwide, behind cervical cancer, and the first in developed countries, with approximately 200,000 women dying globally in 2020 [7]. HGSOC is the most prevalent histologic type, and these patients usually undergo a combination of paclitaxel and carboplatin chemotherapy and surgical cytoreduction as part of frontline management. Up to 70% will achieve a state of clinical remission, but unfortunately, 80% will recur within 3 years of diagnosis. Once recurred, the disease is no longer curable but fortunately treatable for many years until resistance to further intervention and eventually dying of the disease [8]. The breakthrough impact of maintenance therapy with PARPi to prevent recurrence and death has been remarkable [3, 7, 8].

Beyond PARPi, immunotherapy may offer potential benefits in BRCAm HGSOC due to the high tumor mutation burden and increased tumor-specific neoantigen load observed in these tumors. This is evidenced by a significantly higher median tumor mutation burden in BRCA1/2-altered tumors relative to wild-type tumors (24.59 vs. 5.90; p < 0.001) [9]. High mutation burden is associated with elevated neoantigen levels, which may enhance ICI efficacy by recruiting tumor-infiltrating T lymphocytes and triggering the PD-1 pathway upregulation to evade immune response [10]. Although adding ICI to chemotherapy, either in the front-line setting or at recurrence has historically been disappointing, the recent ENGOT-ov65/KEYNOTE-B96 trial (NCT05116189), a randomized, double-blind phase 3 study, investigating pembrolizumab versus placebo plus weekly paclitaxel (with or without bevacizumab) for platinum-resistant recurrent ovarian cancer has changed the paradigm. This trial demonstrated statistically significant and clinically meaningful improvements in progression-free survival and, importantly, OS in participants with PD-L1-expressing tumors. With a hazard ratio of 0.76 (95% CI: 0.62–0.94; p = 0.0053), KEYNOTE-B96 became the first phase 3 study to report a statistically significant OS benefit with pembrolizumab and chemotherapy in platinum-resistant recurrent ovarian cancer [11]. While our patient was BRCA2-mutated and her tumor PD-L1 showed a low TPS (<1%) but high CPS 40, her CR to ICI and chemotherapy regimen aligns with the results observed in the KEYNOTE-B96 study [11].

In the present case, the patient exhibited resistance to multiple chemotherapy regimens on her first recurrence and developed new bone metastasis but achieved disease control upon transition to pembrolizumab and weekly paclitaxel. Although 3rd relapse occurred shortly, it was controlled with surgery and radiotherapy, nivolumab and abraxane followed by maintenance nivolumab and olaparib then olaparib alone. Although OS benefit from olaparib as maintenance therapy after salvage chemotherapy is marginal [4], maintenance olaparib rechallenge is beneficial in patients with platinum-sensitive recurrent ovarian cancer [12].

The role of HIPEC in the recurrent setting is controversial [10, 13, 14]. This case underscores the potential role of HIPEC in managing occult peritoneal disease during the excision of a metastatic gastric lymph node. One more important point is that the 3rd and 4th recurrences were detected by PET/CT with normal CA-125 (Fig. 1, 3). PET was found to provide a positive impact in 85% who had documented relapse for restaging prior to or after curative salvage therapy [15]. This highlights the importance of periodical imaging surveillance in the setting of recurrent disease to detect subsequent isolated recurrences for long-term disease control.

Fig. 3.

The patient achieved complete remission after multimodal therapies. However, a left gastric nodal recurrence was noted in September 2021, with the lesion demonstrated on the maximum intensity projection PET image (a) (arrow), transaxial PET/CT fusion image (b), CT image (c), and PET image (d).

Conclusion

This case highlights the therapeutic challenges of managing recurrent HGSOC, particularly in the context of disseminated disease and progression during salvage therapy. However, the patient’s successful outcome, achieving sustained CR (>4 years) after the 4th relapse, reflects the advantages of periodical molecular imaging for surveillance, immunotherapy, surgical interventions, with/without HIPEC and/or adjuvant radiotherapy, and rechallenging with maintenance PARPi, especially for patients with BRCA mutations. This article adheres to the CARE Guidelines to ensure a comprehensive and transparent report, with the CARE checklist attached as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000553170).

Statement of Ethics

The case report was approved by the Chang Gung Medical Foundation Institutional Review Board (IRB Number: 202401717B0). Written informed consent was obtained from the patient for the publication of the details of the medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest relevant to this article.

Funding Sources

The authors report no external funding source for this study.

Author Contributions

H.H.C. and C.H.L. conceived and designed the study. H.H.C. was responsible for data collection, literature search, and drafting the initial manuscript. C.H.L. provided the clinical case, performed the literature review, and was responsible for the critical revision and final approval of the manuscript. F.Y.L. and C.C.W. contributed to the clinical management of the patient and data interpretation. M.C.L. contributed to the literature review. All authors have read and agreed to the final version of the manuscript.

Funding Statement

The authors report no external funding source for this study.

Data Availability Statement

The data supporting the findings of this case report are included within the article. Any additional clinical data are not publicly available to protect patient privacy but may be made available from the corresponding author.