“Four years of remission with fulvestrant monotherapy in advanced endometrioid adenocarcinoma of the endometrium Harboring an ESR1 Mutation: A case Report”

Research highlights

• •Progestin therapy is the preferred hormonal treatment for advanced endometrioid carcinoma.
• •Next-generation sequencing can aid decision-making in advanced disease.
• •ESR1 and CTNNB1 mutations are poor molecular prognostic factors.
• •Fulvestrant may be an option to treat patients with ESR1 mutations.

1. Background

Uterine body cancer is the most prevalent gynecological malignancy among women in the United States. In 2024, an estimated 67,880 new cases and 13,250 deaths are expected. While many patients receive an early diagnosis, those with advanced disease face a poor prognosis, with a 5-year survival rate of only 18 %, according to the American Cancer Society. Endometrial cancer accounts for over 80 % of uterine body carcinomas, with 80–85 % of these cases presenting as the endometrioid subtype. This subtype is commonly characterized by a low histological grade, indolent behavior, and generally good prognosis. However, despite declines in incidence and mortality rates throughout the 20th century, both have risen over the past decade, largely due to factors such as obesity, estrogen replacement therapy without progesterone antagonism, delayed childbearing, and an aging population. This highlights the need for greater awareness and continued dialogue about endometrial cancer (SEER*Explorer, 2024).

The no specific molecular profile subtype (NSMP), identified by The Cancer Genome Atlas (TCGA), represents about 50 % of all cases and typically manifests as endometrioid adenocarcinoma, marked by estrogen receptor (ER) expression, a key prognostic biomarker. Although no standardized cut-off for ER expression exists, its presence can help guide endocrine therapy decisions and aid in differentiating between low- and high-risk cases (Kuhn et al., 2024). Hormonal therapy decisions are complex, depending on factors such as histological grade, disease burden, thromboembolic history (especially with tamoxifen use), and the presence of resistance mutations like the estrogen receptor alpha mutation (ESR1), which can affect the efficacy of aromatase inhibitors. Despite ESR1 mutations occurring in 3.2 % of patients, selective estrogen receptor degraders (SERDs) remain a treatment option, though early studies indicate limited responses in advanced disease, suggesting a need for better patient selection criteria. These findings imply that ESR1 alone is insufficient to guide treatment decisions.

This article presents a case of metastatic endometrial endometrioid adenocarcinoma with squamous component and an ESR1 mutation where the patient achieved complete and sustained remission with fulvestrant, despite facing challenging clinical circumstances. To the best of our knowledge, this is one of the earliest documented examples of such a remarkable response to fulvestrant in this patient profile.

2. Case report

A 64-year-old woman with a history of obesity, dyslipidemia, and glucose intolerance was diagnosed with endometrial carcinoma in November 2013, following hysteroscopy and biopsy due to postmenopausal bleeding. She underwent a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy. Pathology confirmed FIGO stage Ia (2009) grade 1 endometrial endometrioid adenocarcinoma with lymphovascular invasion. She was referred to adjuvant brachytherapy, and four insertions were recommended and completed in January 2014.

In July 2017, follow-up exams revealed suspicious implants in the pelvic lymph nodes and peritoneum, with disease progression confirmed by biopsy. Due to peritoneal recurrence, she underwent optimal cytoreductive surgery, which included pelvic peritonectomy, omentectomy, systematic pelvic lymphadenectomy, and removal of suspicious implants. The surgical specimen was identified as grade 2 endometrioid adenocarcinoma with squamous differentiation. Immunohistochemistry showed mismatch repair proficiency (pMMR) and p53 wild type, categorizing the tumor as NSMP. First-line chemotherapy with carboplatin and paclitaxel was initiated. During treatment, the patient developed deep vein thrombosis and pulmonary thromboembolism, which were managed with anticoagulants. She completed six cycles of chemotherapy and subsequently entered surveillance in complete response.

In December 2019, CT and FDG PET/CT scans revealed new lesions in the peritoneum and at the rectosigmoid junction, with biopsy-confirmed progressive disease (Fig. 1). Immunohistochemistry of the recurrent tumor showed high ER expression (98 %) and HER-2 negativity. Re-exposure to six cycles of carboplatin and paclitaxel was attempted but yielded a poor clinical response, resulting in stable disease. Another surgical resection was performed in May 2020, which showed endometrioid carcinoma with squamous differentiation, histological grade 2 (FIGO), with transmural infiltration into the intestinal mucosa and the presence of implants in the peri-intestinal adipose tissue (Fig. 2). Concurrently, Next Generation Sequencing (NGS) testing revealed a tumor mutation burden (TMB) of 1 mutation per megabase, as well as CTNNB1 S37F and ESR1 L536P mutations.

Fig. 1.

FDG PET-CT showing increased uptake in a metastatic peritoneal lesion (A) and a metastatic rectosigmoid lesion (B), respectively.

Fig. 2.

A: adenocarcinoma infiltrating the intestinal wall and pericolic adipose tissue (HE, 20x). B: endometrioid adenocarcinoma with squamous differentiation (HE, 200x).

Given the suboptimal response to chemotherapy and the presence of an ESR1 mutation, fulvestrant monotherapy was introduced in June 2020. The patient received fulvestrant 500 mg on Days 1, 15, and 29, and then once monthly thereafter, administered intramuscularly. As of August 2024, four years after starting fulvestrant, the patient continues to exhibit a complete and sustained response with no signs of disease activity (Fig. 3). She remains asymptomatic with an ECOG performance status of 0. The treatment will be continued for a total of at least 5 years due to the outstanding response.

Fig. 3.

Abdomen and pelvis MRI with gadolinium from 06/08/2024. A: sagittal T2 cut compatible with hysterectomy, oophorectomy, and rectosigmoidectomy, with no signs of recurrence in the surgical site or thickening of the remaining colonic segment. B: axial T2 cut at the level of the psoas muscle, showing a regular and homogeneous peritoneal surface.

3. Discussion

In this case report, we describe a case of advanced endometrioid adenocarcinoma of the endometrium with metastases to the peritoneum and lymph nodes, in which fulvestrant monotherapy achieved a complete and sustained response lasting over four years. Although hormonal therapy is included in the management guidelines for endometrioid adenocarcinoma, its modest and often brief response in clinical practice usually limits its use to patients with low-grade tumors and indolent recurrences. Despite poor prognostic features, such as the presence of ESR1 and CTNNB1 mutations, and prior chemotherapy, this case suggests there is still a potential role for this treatment modality. This case report aims to provide valuable insights into the role of hormonal therapy in metastatic endometrial carcinoma and to highlight areas for improvement in patient selection criteria.

Historically, progestin therapy has been the standard choice for first-line hormonal treatment. Other options include anti-estrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors, sometimes used in combination (Ethier et al., 2017). However, data on hormonal therapy for endometrial carcinoma is limited and derived from small, heterogeneous studies. A meta-analysis reported a mean overall response rate (ORR) of 21.6 % for first-line treatment and 18.5 % for second-line treatment. The median progression-free survival (PFS) and overall survival (OS) were 2.8 and 10.2 months, respectively. Subgroup analysis revealed variations in ORR, with a reduction in older patients, those with adenosquamous histology, and high-grade tumors, but increased ORR in ER-positive cases (Ethier et al., 2017).

The role of fulvestrant in advanced or recurrent endometrial cancer, unlike in breast cancer, remains uncertain and largely unproven. Emons et al.'s Phase II study of 250 mg of fulvestrant administered intramuscularly (IM) monthly to a cohort, 71 % of whom had endometrioid adenocarcinoma, reported a median PFS of 2.3 months and a median OS of 13.2 months, with no complete responses observed (Emons et al., 2013). Similarly, a Gynecologic Oncology Group study found minimal efficacy, reporting only one complete response among 31 ER-positive patients (Covens et al., 2011). Although the FUCHsia trial, which used fulvestrant in patients with low-grade gynecological neoplasms and positive ER, reported disease progression in all patients with endometrial carcinoma, the combination of fulvestrant and abemaciclib showed promising results (Trozzi et al., 2024). A recently published study on this combination, used in a predominantly endometrioid population after chemotherapy, reported a median PFS of 9.0 months and a median OS of 37.8 months (Green et al., 2024). In contrast, fulvestrant monotherapy in this case produced a remarkable complete and sustained response lasting over four years, with no signs of disease activity. The patient remains asymptomatic, maintains optimal functional status, and continues to have an excellent quality of life.

According to TCGA’s molecular classification, approximately half of patients fall into the NSMP subtype, with endometrioid adenocarcinoma as the prototype. In this subtype, ER is a key prognostic marker. An ER cutoff of ≥ 10 % has been associated with lower recurrence rates in high-risk patients, helping to define a more favorable prognosis group. Exon 3 mutations in CTNNB1, initially thought to reduce hormonal therapy efficacy, did not show significant clinical effects. Interestingly, a study of 22 patients with advanced endometrial carcinoma treated with aromatase inhibitors or progestin found only one circulating ESR1 mutation (Y537C) before hormone therapy, while two mutations (Y537C and Y537S) emerged during disease progression. Although the ESR1 L436P mutation found in our patient was not covered by the droplet digital PCR kit used in the study performed by Drouyer et al., they concluded that ESR1 mutations do not appear to contribute to resistance mechanisms, and their clinical relevance is not yet fully established. (Drouyer et al., 2023).

The squamous component is another factor that warrants consideration. Found in 12.8–25 % of endometrioid adenocarcinoma cases, it was hypothesized that squamous differentiation might increase the risk of early recurrence and metastases to unusual sites, even in low-grade tumors (Ruhul Quddus et al., 2024). However, like the other previously mentioned factors, it has not proven sufficient to independently alter the disease's natural course (Aslan et al., 2021).

This case exemplifies the complexity of managing endometrioid adenocarcinoma of the endometrium, owing to a combination of both positive and negative prognostic factors. Furthermore, it raises questions about the current criteria for selecting patients for hormonal therapy, as well as the use of histopathological, immunohistochemical, and molecular biomarkers. Notably, this article is one of the pioneering reports documenting a significant and durable clinical response to fulvestrant monotherapy. However, the findings should be interpreted with caution, given the involvement of only one patient and the retrospective design. Additionally, it could be argued that this patient experienced a prolonged response to fulvestrant because she underwent cytoreduction before receiving this agent. However, considering that she presented a recurrence two years following a secondary cytoreduction, fulvestrant may have contributed to sustaining her disease-free survival after her tertiary cytoreductive surgery. Furthermore, the possibility of selection bias due to the monocentric nature of the study should be taken into account. Larger studies are essential to validate these findings and improve treatment strategies for similar patient populations.

CRediT authorship contribution statement

João Felipe Feldmann: Writing – original draft, Visualization, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Karoline Duarte: Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. João Henrique Feldmann: Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Mariana Carvalho Gouveia: Writing – review & editing, Visualization, Validation, Supervision. Romulo Loss Mattedi: Writing – review & editing, Visualization, Validation, Supervision. Fabio Payao Pereira: Writing – review & editing, Visualization, Validation, Supervision. Mariana Scaranti: Writing – review & editing, Visualization, Validation, Supervision, Resources, Project administration, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Mariana Gouveia reports a relationship with Novartis Pharmaceuticals Corporation, Knight Therapeutics, GSK, AstraZeneca that includes: speaking and lecture fees. Mariana Gouveia reports a relationship with GSK, Pfizer, Abbvie that includes: travel reimbursement. Mariana Scaranti reports a relationship with MSD, AstraZeneca, Libbs, GSK, Zodiac, Roche, Orentt, MDHealth, Sanofi, Gilead, and Abbvie that includes: consulting or advisory and speaking and lecture fees. Mariana Scaranti reports a relationship with GSK, AstraZeneca, MSD, Daiichi-Sankyo that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.].

Data availability

The data supporting the findings of this case report are available from the corresponding author upon reasonable request. Due to privacy and ethical considerations, the data are not publicly available. Access to the data will require approval from the institution’s ethical review board and may necessitate additional patient consent.