Four-year complete remission with reduced-dose PARP inhibitor in advanced-stage epithelial ovarian cancer harboring a BRCA1 mutation: a case report of a chemotherapy-intolerant patient with idiopathic thrombocytopenic purpura

Abstract

Background

Ovarian cancer is a type of gynecological malignant tumor with high mortality rate, for which the standard primary treatment consists of cytoreductive surgery followed by platinum-based chemotherapy. However, a common adverse effect of carboplatin-paclitaxel regimen is thrombocytopenia due to bone marrow suppression. For ovarian cancer patients with preexisting idiopathic thrombocytopenic purpura (ITP), there exists a dilemma of balancing oncologic efficacy and hematologic safety. As a targeted therapy, poly ADP-ribose polymerase (PARP) inhibitor is more tolerable to platelet toxicity.

Case presentation

This report presents a 55-year-old woman with a 20-year history of ITP who was diagnosed with high-grade serous ovarian carcinoma (FIGO stage IIIC). Due to persistent thrombocytopenia, she was unable to tolerate postoperative carboplatin-paclitaxel chemotherapy. Molecular profiling revealed a breast cancer gene 1 (BRCA1) mutation, prompting initiation of olaparib alongside ITP-directed therapy. Over four years of follow-up, the patient achieved sustained tumor remission with stable platelet counts.

Conclusions

This case underscores the potential role of PARP inhibitors as a safe and effective alternative for ovarian cancer patients with concurrent ITP, maintaining both favorable oncologic result and hematologic stability.

Background

Epithelial ovarian cancer (EOC) is a highly aggressive gynecological malignancy, with serous carcinoma being the most prevalent subtype [1]. Approximately 80% of serous carcinomas are diagnosed at advanced stages (FIGO III or IV), leading to poor prognoses [2]. For advanced-stage EOC, surgery followed by postoperative carboplatin-based chemotherapy is the standard primary treatment. However, grade 3–4 thrombocytopenia was reported in 39% of EOC patients receiving first-line adjuvant chemotherapy [3]. In recent years, poly ADP-ribose polymerase (PARP) inhibitors have been demonstrated to bring significant improvements in progression-free survival to advanced-stage ovarian cancer patients with the effect of accumulation of DNA damage and synthetic lethality in BRCA-deficient tumor cells [4, 5]. Olaparib is now recommended as the maintenance treatment for patients with germline or somatic BRCA mutations who achieve a complete remission (CR) or partial remission (PR) following first-line platinum-based chemotherapy [6].

Idiopathic thrombocytopenic purpura (ITP), or immune thrombocytopenia, is an acquired autoimmune disorder characterized by antibody-mediated platelets destruction and impaired megakaryocyte maturation, resulting in thrombocytopenia. With an incidence of 2–5 per 100 000, ITP affects all age group with a female predominance [7]. Clinical presentations vary from asymptomatic thrombocytopenia to severe bleeding manifestations, including mucocutaneous bleeding (e.g., purpura, epistaxis, gingival bleeding and menorrhagia) and, in extreme cases (platelet count < 30 × 10⁹/L), intracranial hemorrhage. For patients with ITP, cytotoxic chemotherapy presents a significant therapeutic challenge due to their inherently low platelet counts and heightened bleeding risk.

Here we report a case of advanced EOC complicated with ITP, which successfully achieved sustained remission following cytoreductive surgery and olaparib maintenance therapy.

Case presentation

A 55-year-old woman, gravida 2, para 1, presented to our hospital following the incidental discovery of a lower abdominal mass during a routine examination. She denied any complaints such as abdominal distension. Physical examination revealed a cystic-solid mass measuring approximately 5 cm in diameter with reduced mobility in the left adnexal region. No ascites was detected either on physical examination or ultrasound. The patient had a history of untreated ITP for more than 20 years, with platelets fluctuating at 20–30 × 10⁹/L. Ultrasound guided needle biopsy of the lower abdominal mass was performed and indicated high grade serous carcinoma, supported by immunohistochemistry (positive staining for CK7 and PAX8). Magnetic resonance imaging (MRI) demonstrated two hyperenhancing lesions with high signal intensity in T2-weighted image and diffusion-weighted image: a 3.6 × 3.1 cm mass in the left pelvic cavity, considered as a tumor metastasis on omentum originated from ovary, and a 2.0 × 1.7 cm lesion adjacent to the right pelvic wall, considered as an enlarged retroperitoneal lymph node. No significant abnormalities were detected in the uterus, the bilateral adnexal regions, the rectus and the inguinal regions, and no ascites was demonstrated. Positron emission tomography/computed tomography (PET/CT) confirmed a pelvic mass on the left side (SUVmax 8.3) and multiple pelvic lymph nodes (the largest one SUVmax 7.6) with high fluorodeoxyglucose (FDG) uptake (Fig. 1). Laboratory results showed that CA125 level was markedly elevated at 366.0 U/ml, and CA199 (11.3 U/ml) and CEA (3.6 ng/ml) were normal. Given the patient’s baseline thrombocytopenia, intravenous immunoglobulin (IVIG) and recombinant human thrombopoietin (rhTPO) were administrated for 5 days and the platelet count increased to 145 × 10⁹/L, but dropped to 42 × 10⁹/L by day 9 post-treatment. Preoperatively, daily dose of 50 mg of eltrombopag and 1 unit platelet transfusion was administered, which raised the platelet count to 73 × 10⁹/L on the operative day.

Fig. 1.

Axial MRI and PET/CT images of pelvis taken at the time of diagnosis. Two lesions in left part of the pelvic cavity (arrowheads) and near the right pelvic wall (arrows), measuring 3.6 × 3.1 cm and 2.0 × 1.7 cm respectively, were shown with high intensity in both T2-weighted image without contrast (a) and diffusion-weighted image (b). PET/CT revealed high fluorodeoxyglucose (FDG) uptake of these lesions (the left one SUVmax 8.3, the right one SUVmax 7.6) (c, d)

The patient underwent exploratory laparotomy, and intraoperative finding revealed a metastatic tumor on the omentum (Fig. 2) and enlarged right obturator and common iliac lymph nodes (the largest one about 3 cm). Peritoneal carcinomatosis index of this patient was evaluated as 3, which supported primary debulking surgery. Therefore, we performed omentectomy, total hysterectomy, bilateral salpingo-oophorectomy, appendectomy and pelvic lymphadenectomy with complete macroscopic resection (CC0). Definitive histopathologic examination confirmed high-grade serous ovarian carcinoma, staged as IIIC according to the International Federation of Gynecology and Obstetrics (FIGO) system. An additional 1-unit platelet transfusion was administered intraoperatively.

Fig. 2.

Intraoperative finding of a metastatic tumor on the omentum

After the surgery, the patient’s platelet count rose to 107 × 10⁹/L. Taking into account her comorbid status and individual preference, we initiated dose-modified chemotherapy with paclitaxel (135 mg/m²) and carboplatin (area under the blood concentration = 4) on postoperative day 21. However, by day 8 of chemotherapy, the platelet count had declined to 32 × 10⁹/L, reaching a nadir of 8 × 10⁹/L on day 13, accompanied by lower limb and conjunctival bleeding. Severe thrombocytopenia and concurrent grade 3 leukopenia and grade 4 granulocytopenia necessitated discontinuation of cytotoxic chemotherapy due to intolerable toxicity. Hematologic support with rhTPO for 14 days and an increased dose of eltrombopag successfully restore platelets to 114 × 10⁹/L. Molecular profiling identified a breast cancer gene 1 (BRCA1) germline mutation, so we prescribed her with olaparib 300 mg bid. Over the subsequent years, the hemogram was closely monitored and the dose of olaparib was adjusted as needed. Mycophenolate mofetil was added for ITP management under hematology specialist guidance. At 48-month follow-up, the patient now remained in complete radiologic remission and normal range of tumor marker (CA 125) on a stable maintenance regimen (olaparib 150 mg bid, eltrombopag 50–75 mg qd and mycophenolate mofetil 0.5–0.75 g bid), with platelet counts stable at 40–60 × 10⁹/L (Fig. 3).

Fig. 3.

Changes in platelet count and CA125 during diagnosis, treatment and follow-up

Discussion and conclusions

High-grade serous ovarian carcinoma, as shown in this case, is typically managed with cytoreductive surgery followed by platinum-based chemotherapy. Complete cytoreduction of tumor lesions has been proved to be one of the most important prognostic factors with a significantly improved survival rate in patients with no gross residual disease [8]. Adjuvant platinum-based chemotherapy is suggested for patients with advanced stage epithelial ovarian cancer.

Despite good responsiveness to debulking surgery and adjuvant chemotherapy, more than 70% of patients with advanced EOC will experience recurrence. Therefore, maintenance therapy is emphasized with the goal of effectively killing residual slowly dividing cells and inhibiting progression or recurrence. With a reported median progression-free survival of 56.0 months and a 7-year overall survival rate of 67.0%, PARP inhibitors such as olaparib have been established as the optimal maintenance therapy in BRCA-mutated ovarian cancer [5, 9]. For patients with stage II–IV disease, the National Comprehensive Cancer Network (NCCN) Guidelines recommend early screening for BRCA1/2 mutations in the course of workup and primary treatment and recommend olaparib as a maintenance therapy for patients who have a BRAC1/2 mutation and have a complete remission after completion of initial therapy [6].

What distinguishes this patient from other ovarian cancer patients is that she was complicated with ITP. The co-occurrence of ITP and solid malignancies represents an exceptionally rare clinical scenario, with only scattered case reports documented in medical literature. Available evidence from systemic analyses indicates that lung cancer and breast cancer are the predominant types among patients with ITP who develop solid tumors [10]. Gastrointestinal cancer (including gastric, hepatic, esophageal, colonic or rectal, duodenal papillary, and pancreatic cancer) has also been reported to be common in this dual-diagnosis population [11]. In contrast, gynecological malignancies show substantially less association and a very few cases of ovarian cancer coexisting with ITP have been reported prior to this case [10–13]. In this patient, the 20-year interval between ITP onset and newly diagnosis of ovarian cancer, along with the persistence of thrombocytopenia following complete tumor resection, may suggest independent processes of these two diseases.

For ITP patients with persisting thrombocytopenia, myelosuppression induced by conventional carboplatin-based chemotherapy poses significant challenge on safety. Previous reported cases of ITP complicated with ovarian cancer either response well to prednisone therapy or recover spontaneously to normal platelet level after tumor excision, leading to favorable tolerance to chemotherapy and uninterrupted adjuvant therapy with platinum [10–13]. In this case, adjuvant paclitaxel-carboplatin was initiated postoperatively but terminated due to severe thrombocytopenia (minimum platelet count of 8 × 10⁹/L) and hemorrhagic complications, in spite of the administration of a dose-modified regimen. This highlights the dilemma of balancing oncologic efficacy with hematologic safety in ITP patients, especially those with persistently low platelet level.

In contrast to carboplatin-based chemotherapy regimens, which carries a rather high risk of thrombocytopenia due to bone marrow suppression, olaparib primarily induces nausea, fatigue, vomiting and anemia, with minimal platelet toxicity (1% grade 3–4 thrombocytopenia) [5]. This pharmacologic distinction made olaparib a rational alternative for our patient, whose thrombocytopenia originated from ITP was exacerbated by chemotherapy to a life-threatening level and treatment discontinuation was necessitated. Over four years, olaparib was adjusted according to the patient’s platelet count and finally stabilized at a reduced dose of 150 mg bid. Its maintenance achieved sustained remission (CA125 normalization and imaging-confirmed tumor-free status) with stable platelet count, demonstrating its efficacy and tolerability in this high-risk situation.

To our knowledge, this represents the first report case of BRCA-mutated advanced EOC with comorbid ITP successfully treated with PARP inhibitors monotherapy following surgery, without standard adjuvant chemotherapy. The success of this strategy highlights that PARP inhibitors may serve as a viable alternative for ovarian cancer patients with preexisting platelet disorders (e.g., ITP) and BRCA mutation when conventional chemotherapy is intolerant. Precise and individualized management for diverse ovarian cancer patients is also stressed in this case report.

Abbreviations

ITP

Idiopathic thrombocytopenic purpura

PARP

Poly ADP-ribose polymerase

BRCA1

Breast cancer gene 1

EOC

Epithelial ovarian cancer

CR

Complete remission

PR

Partial remission

MRI

Magnetic resonance imaging

PET/CT

Positron emission tomography/computed tomography

FDG

Fluorodeoxyglucose

IVIG

Intravenous immunoglobulin

rhTPO

Recombinant human thrombopoietin

FIGO

International federation of gynecology and obstetrics

NCCN

National comprehensive cancer network

Author contributions

DW, HW, TZ and XW were responsible for clinical diagnosis and treatment. DW and XW were involved in the study conceptualization and design. PL, DW and XW took part in the acquisition, analysis and interpretation of data. PL drafted the original manuscript. XB, DW and XW critically reviewed and edited the paper. XW provided supervision throughout the project. All authors read, critically revised and approved the manuscript.

Funding

This work was funded by grants from the National Key Clinical Specialty Construction Project (Nos. U114000).

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.