Four-year recurrence-free survival in metastatic uterine adenosarcoma with somatic BRCA2 mutation on olaparib therapy: A case report

Graphical abstract

1. Introduction

Uterine sarcoma is a rare form of uterine cancer, accounting for approximately 3–7 % of all uterine malignancies (Nathenson et al., 2016). Uterine adenosarcoma is a subtype defined by the presence of malignant mesenchymal cells juxtaposed with benign glandular epithelial cells (Nathenson et al., 2016). The majority of uterine adenosarcoma cases (70 %–80 %) present at stage I (Nathenson et al., 2017); however, approximately one-third to one-half of patients experience recurrence within 10 years of diagnosis (Nathenson et al., 2016). Histological factors associated with an increased risk of recurrence include sarcomatous overgrowth, deep tumor infiltration, tumor cell necrosis, and myometrial invasion (Abeler et al., 2009, Clement and Scully, 1990). Sarcomatous overgrowth is diagnosed when more than 25 % of the tumor is made up of pure high-grade sarcoma, which has been linked with significantly shortened overall survival (Nathenson et al., 2016). A retrospective review of 554 patients who were treated for uterine adenosarcoma between 1988 and 2006 reported a 5-year survival rate of 79 % for stage I disease (n = 327) and 15 % for stage IV disease (n = 25) (Arend et al., 2010).

Recommended management for early-stage uterine adenosarcoma involves surgical resection with total hysterectomy and bilateral salpingo-oophorectomy. Lymphadenectomy is typically not recommended due to the low incidence of lymph node metastasis and lack of survival benefit (Nathenson et al., 2016). Adjuvant radiotherapy, either external beam radiotherapy or brachytherapy, is used in some cases, although retrospective studies have not shown overall survival benefit. (Carroll et al., 2014) Furthermore, data regarding the efficacy of neoadjuvant or adjuvant chemotherapy is limited to retrospective reviews and case reports. Some case series suggest chemotherapy (doxorubicin/ifosfamide or gemcitabine/docetaxel) may be beneficial for patients with myometrial invasion or sarcomatous overgrowth in reducing recurrence risk (Nathenson et al., 2016). Lastly, hormonal agents such as GnRH agonists, selective estrogen receptor modulators, aromatase inhibitors, and synthetic progesterones have shown some benefit in case studies, which may be correlated with the presence of estrogen and progesterone receptors (Carroll et al., 2014).

There is no established standard management for recurrent or metastatic uterine adenosarcoma. A retrospective review of 78 patients with recurrent or metastatic uterine adenosarcoma treated at MD Anderson Cancer Center reported a median survival of 1.8 years from time of recurrence (Nathenson et al., 2017). Histologic subtype influenced survival, with a median survival of 17.6 months for high-grade sarcoma and 33.5 months for tumors with a mixed epithelial and mesenchymal component (Nathenson et al., 2017). Surgical resection of recurrence led to an improved median overall survival (26.3 months vs. 15.1 months); however, chemotherapy, radiotherapy, or hormonal therapy did not significantly influence overall survival (Nathenson et al., 2017). Among patients who received chemotherapy, those treated with doxorubicin/ifosfamide had a median progression-free survival of 15.4 months, compared to 5.0 months for those treated with gemcitabine/docetaxel (Nathenson et al., 2017).

Targeted therapies are being explored for other subtypes of uterine sarcoma, particularly uterine leiomyosarcoma (uLMS)--which has been found to harbor mutations in the homologous recombination repair (HRR) pathway (Nasioudis et al., 2023, Seligson et al., 2019). BRCA1 and BRCA2 proteins play key roles in double-strand break repair within the HRR pathway, whereas the poly-ADP ribose polymerase (PARP) protein aids in single-strand break repair. Concomitant inactivation of both PARP, by use of a PARP inhibitor (PARPi), and BRCA 1/2 mutation leads to cancer cell apoptosis where the unrepaired single-strand breaks may degenerate into double-strand breaks, which in turn cannot be repaired in the absence of an intact HRR pathway. A retrospective review identified homozygous deletions of BRCA1/2 in 10 % of uLMS cases (6 of 61 patients), with some patients showing response to off-label PARPi use (Seligson et al., 2019).

Next-generation sequencing of uterine adenosarcoma tumor samples found HRR pathway mutations in 27 % of cases (17 of 63 patients) (Nasioudis et al., 2023) These findings suggest that targeted therapies for HRR pathway mutations could also be a potential treatment option for uterine adenosarcoma. We present a case of a patient with recurrent, metastatic, high-grade uterine adenosarcoma with a somatic BRCA2 mutation who has remained recurrence-free after starting olaparib over 4 years ago.

2. Case description

A 60-year-old woman presented to her gynecologist in July 2016 with abnormal uterine bleeding. Ultrasound with doppler revealed a heterogenous mass measuring 2.5 × 1.9 cm with minimal associated vascularity. Subsequent hysteroscopy and dilation and curettage revealed fragments of atypical adenofibromatous endometrial polyp(s), suspicious for mullerian adenosarcoma (Fig. 1A) and fragments of smooth muscle tumor of uncertain malignant potential (STUMP). She then underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy (in 2016 the role of lymphadenectomy was still undetermined) (Carroll et al., 2014). Surgical pathology identified uterine adenosarcoma without myometrial invasion (Fig. 1B), stage 1A. Bilateral fallopian tubes, ovaries, omental biopsy, and all lymph nodes (inguinal and para-aortic) were negative for disease. She was placed on Megace and entered surveillance with computed tomography (CT) imaging every 3–6 months.

Fig. 1.

Small tissue fragments from the endometrial curettings showed a suggestion of periglandular cuffing by atypical stromal cells with rare mitotic figures, suggestive of adenosarcoma (A, H&E, 200x). The subsequent hysterectomy showed focal residual adenosarcoma without myoinvasion (B, H&E, 80x). Three years later, small bowel resection showed transmural invasion by high-grade sarcoma with smooth muscle differentiation, consistent with recurrence of the sarcoma component of the adenosarcoma (C, H&E, 20x; D, H&E, 200x).

In July 2019, three years after surgery, she presented to the emergency department with abdominal pain and bladder pressure. Imaging with CT revealed a lobulated, septated, low-density pelvic mass measuring 8.5 × 7 × 5 cm, and surgery was planned for August 2019. Before the planned operation, she returned to the emergency department with four days of worsening, severe abdominal pain, and new bloating and nausea. A repeat CT scan showed an increase in mass size to 14 × 12 × 13 cm, with encasement of the distal ileum causing small bowel obstruction (Fig. 2). She underwent urgent resection of the abdominopelvic mass and small bowel (30 cm) with functional end-to-end anastomosis. Pathology confirmed high-grade sarcoma with smooth muscle differentiation that morphologically resembled the adenosarcoma from the 2016 surgical pathology. The tumor transmurally invaded the small bowel, and the omentum was found to have scattered atypical cells in a myxoid background suspicious for sarcoma involvement (Fig. 1C & D).

Fig. 2.

CT from primary recurrence on 07/28/2019. Coronal contrast-enhanced CT (A) shows a malignant small bowel obstruction secondary to encasement of distal ileum (white arrow) by a large pelvic recurrence (yellow arrows). There is also trace ascites (perihepatic, mesenteric denoted by yellow asterisks). Not shown was a large right pleural effusion. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

After recovering from surgery, the patient was recommended to undergo six cycles of ifosfamide/doxorubicin adjuvant therapy. Given the limited treatment options for metastatic uterine adenosarcoma, the tumor was sent for whole genome sequencing to explore potential targeted therapies. Foundation One testing identified somatic loss of BRCA2; subsequent germline testing was negative.

She began chemotherapy in September 2019 and completed six cycles of ifosfamide/doxorubicin by January 2020. An interval CT scan after completion of three chemotherapy cycles showed marked reduction in abdominal disease burden, with previously enlarged lymph nodes returning to normal size. However, a residual mass in the pelvic mesentery measured 2.8 × 1.2 cm, and mild thickening in the left paracolic gutter remained. After completing six cycles of chemotherapy, follow-up CT imaging revealed new, ill-defined disease in the right hepatic lobe measuring 1.8 × 1.0 cm, while the pelvic mesenteric mass slightly decreased to 2.3 × 1.5 cm (Fig. 3a).

Fig. 3.

Axial contrast-enhanced CT images following treatment for recurrence and while on maintenance olaparib. A: CT from Jan 2020 after the completion of six cycles of chemotherapy, showing a small residual pelvic mesenteric mass measuring 2.3 × 1.5 cm (yellow arrow). B: CT from October 2020, after six months of olaparib therapy, shows subtle residual tissue (1.3 cm) in the left pelvis (white arrow), inseparable from the left vaginal cuff. C: CT from December 2024 shows no evidence of residual disease. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Given the tumor's aggressive nature with progression documented during conventional therapy, BRCA2-targeted maintenance therapy with olaparib was recommended given the lack of salvage therapy options. Initially, her insurance denied coverage for the medication, but after multiple appeals highlighting the lack of other options, olaparib was approved for compassionate care use and treatment was started in March 2020 at a dose of 300 mg twice daily. Six months later, a CT scan showed a reduction in the size of pelvic mass to 1.3 cm (Fig. 3B) and resolution of peritoneal and hepatic lesions. Over the following four years and 8 months, the pelvic mass has remained stable, and no new metastatic lesions have been detected. The patient continued on olaparib maintenance without adverse effects or need for dose reduction. Surveillance imaging was performed every six months (Fig. 3C), and CA-125 levels were monitored every three months, consistently remaining below 9.0.

Following two years of treatment, she was counseled on several occasions regarding the risk vs. benefit ratio for continuation of olaparib in the context of limited alternative treatment options and the risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The patient and her provider agreed that the risk of cancer recurrence outweighed the potential risk of developing MDS or AML from prolonged use of olaparib. She opted to continue the therapy with full understanding of the associated risks and continues this therapy at present.

3. Discussion

This case highlights the novel use of PARP inhibition for the management of recurrent metastatic uterine adenosarcoma. Following initiation of olaparib, the patient’s tumor burden underwent a partial response followed by stable, asymptomatic disease for over four years. Although a previous case report demonstrated two years of recurrence-free survival with olaparib for management of uLMS, this case is unique in its extended progression-free survival and is the only case report highlighting the use of PARP-i in high grade, metastatic, recurrent uterine adenosarcoma to the best of our knowledge (Shammas et al., 2022).

There are several clinical trials underway investigating the use of PARPi (NCT05174455) and PARPi plus Nivolumab (NCT04624178) in uLMS. A phase II clinical trial of olaparib in combination with temozolomide, an alkylating agent that induces DNA damage (and is thought to work synergistically with PARPi), reported an objective response rate of 27 % (6 of 22) and a median progression-free survival of 6.9 months in patients with uLMS (Ingham et al., 2023). Five of the patients in this trial had deleterious alterations in the HRR pathway, and those specifically with alterations of RAD51B, PALB2, and ATR achieved the longest progression-free survival of 31.5, 27.3, and 7.1 months, respectively (Ingham et al., 2023). To our knowledge, there has yet to be any preclinical or clinical studies investigating the use of PARPi for uterine adenosarcoma.

The SOLO1 clinical trial found that olaparib maintenance therapy improved overall survival (67.0 % vs 46.5 % alive at 7 years follow up) of patients with advanced ovarian cancer (stage III or IV) and a BRCA1/2 mutation (DiSilvestro et al., 2023). Treatment with olaparib for more than two years has been documented to increase the risk of developing MDS/AML, however, in this trial 26 patients (10 %) in the olaparib group chose to continue therapy beyond two years (DiSilvestro et al., 2023). At 7 years of follow-up, 4 (1.5 %) cases of MDS/AML were reported in the olaparib group, compared to 1 (0.8 %) case in the placebo group (DiSilvestro et al., 2023). Higher rates of MDS/AML associated with PARPi use have been observed in patients with history of prior DNA-damaging chemotherapy, such as carboplatin. A single institution retrospective review of patients with ovarian cancer treated with PARPi found that those who developed MDS/AML had an average of 12.6 prior lines (n = 32) of chemotherapy, including carboplatin, compared to 4.1 prior lines (n = 201) in patients who did not develop MDS/AML (Asare et al., 2024). We feel that the relatively low incidence of MDS/AML development in the setting of stable disease with no other favorable treatment option supports the likely safety and efficacy of extended therapy for the patient reported in this case report.

It is possible that PARPi could be an effective therapy for tumors that are BRCA wild-type but contain other mutations in the HRR pathway. A study that investigated the molecular genetics of tumors for patients with high-grade recurrent ovarian cancer that responded to rucarparib, a PARPi, revealed that 28.9 % (11 of 38) of long-term responders (>1 year) and 33.3 % (13 of 39) of intermediate responders (6–12 months) did not have a BRCA mutation (Swisher et al., 2021). Rather, most of these BRCA wild-type patients had high genome-wide loss of heterozygosity of the HRR pathway (9 of 11 long-term responders and 10 of 13 intermediate responders), including 7 patients with RAD51C, RAD51D, or CDK12 mutations (Swisher et al., 2021). The 2024 National Cancer Comprehensive Network guidelines for uterine cancer recommend molecular genomic profiling for metastatic uterine sarcoma and specify that molecular profiling should at least include testing for NTRK, MSI, and TMB (Abu-Rustum et al., 2024). However, given that 28.2 % of patients with uterine sarcoma harbor an HRR pathway mutation (Nasioudis et al., 2023), it would be prudent to consider including HRR pathway testing as well.

This case demonstrates that PARPi may be a potentially beneficial therapy for the management of uterine adenosarcoma. We advocate tumor molecular profiling for patients with recurrent and metastatic uterine adenosarcoma to identify BRCA 1/2 somatic mutations and other alterations in the HRR pathway that may benefit from targeted therapy.

CRediT authorship contribution statement

Katie Foug: Writing – review & editing, Writing – original draft, Conceptualization. Stephanie L. Skala: Writing – review & editing, Visualization. Erica Stien: Writing – review & editing, Validation. Kevin Reynolds: Writing – review & editing. Jean Siedel: Supervision. Shitanshu Uppal: Writing – review & editing, Supervision, Conceptualization.

Informed consent

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 Editor-in-Chief of this journal on request.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.