Dual Fulvestrant‐Trametinib Therapy in Recurrent Low‐Grade Serous Ovarian Cancer

Abstract

Low‐grade serous ovarian carcinoma (LGSOC) is known to exhibit chemoresistance. Effective treatment options for recurrent disease are few and often limited to hormone antagonism. Combination of endocrine therapies with MEK‐inhibitors displays synergism in preclinical ovarian cancer models, however. This brief communication presents the use of combination anti‐estrogenic and MEK‐inhibitor therapies, fulvestrant and trametinib, as treatment in a heavily pretreated patient with estrogen receptor‐positive, recurrent LGSOC. The dual‐therapy regimen was well tolerated and appeared to confer 9 months of progression‐free survival. Further investigation is warranted to explore this effect.

Short abstract

This case report describes a patient with low‐grade serous ovarian cancer who was treated with combination MEK‐inhibitor and estrogen antagonist therapy with good results.

Introduction

Low‐grade serous ovarian carcinoma (LGSOC) is known to exhibit chemoresistance 1. Effective treatment options for recurrent disease are few and often limited to hormone antagonism. MEK inhibitors have been shown to be of clinical benefit in LGSOC 2. Preclinical data have suggested that MEK inhibitors, particularly in combination with endocrine therapies, have potentiated tumor response 3, 4. Here we present the case of a patient with heavily pretreated, recurrent LGSOC who was treated with combination MEK‐inhibitor and estrogen antagonist therapy.

Case Presentation

The patient is a 62‐year‐old female with recurrent LGSOC. She was initially diagnosed in 1977, at which point she underwent total abdominal hysterectomy with bilateral salpingo‐ oophorectomy followed by treatment with doxorubicin, cyclophosphamide, and cisplatin. She recurred in 2004 and received an additional nine lines of hormone and chemotherapy through March of 2018 (Table 1). Sequelae of her prior treatments included chronic diarrhea, osteopenia, and chronic hypomagnesemia. In 2017, she had a pulmonary drainage catheter placed secondary to a recurrent malignant left pleural effusion.

Table 1.

Patient treatment course

Year	Chemotherapy	Radiation	Surgery	Outcome
1977	Doxorubicin, cyclophosphamide, cisplatin		TAH/BSO + debulking	Positive second look surgery
2004	Carboplatin + paclitaxel	EBRT + VBT		Complete response
2012–2013	Carboplatin + gemcitabine			Progression
2013	Pegylated liposomal doxorubicin			Progression; Treatment holiday
2015–2016	Letrozole (intermittent)			Progression
2017	Tamoxifen			Progression
2017	Lupron			Progression
2017	Bevacizumab			Adverse reaction
2017–2018	Anastrozole			Progression
2018	Fulvestrant
2018–2019	Fulvestrant + trametinib

Abbreviations: ERBT, external beam radiation therapy; TAH/BSO, total abdominal hysterectomy/bilateral salpingo‐oophorectomy; VBT, vaginal brachytherapy.

In April 2018, a positron emission tomography/computed tomography (PET/CT) indicated progression of disease on her most recent regimen. Next‐generation sequencing performed on a repeat biopsy revealed an estrogen receptor (ER)‐positive, progesterone receptor–negative, KRAS‐mutated, microsatellite‐stable tumor. CA‐125 was 865 U/mL. The patient was started on intramuscular fulvestrant at this time. Her CA‐125 responded initially to the fulvestrant with additional reductions following the addition of trametinib 3 months later (Fig. 1).

Figure 1.

CA125 levels in units/mL as a function of time. The first arrow (left) corresponds with initiation date of fulvestrant therapy. The second arrow (right) corresponds with initiation date of fulvestrant/trametinib combination therapy.

Within the first month of combined therapy, the patient reported complete resolution of her pleuritic chest pain. She required an initial treatment holiday of 1 week for grade 2 diarrhea, which resolved with treatment discontinuation. Upon reinitiation, her diarrhea remained at baseline. She also developed a grade 1 nonpainful, papulopustular rash limited to the nose and skin around the lips, which was treated with doxycycline and completely resolved. She had no further dermatologic issues. Her CA‐125 dropped to 167 U/mL 3 months after combined treatment initiation and her PET/CT noted partial response, consistent with her biochemical improvement.

Approximately 9 months after initiation of dual therapy, her CA‐125 rose above her baseline at initiation of dual therapy and a PET/CT showed progression of disease. In total, our heavily pretreated patient remained on combined therapy for 11 months.

Discussion

LGSOC exhibits higher expression of estrogen and progesterone receptors than high‐grade serous ovarian tumors, suggesting that low‐grade disease may especially benefit from hormonal therapy 5. This is consistent with previous work showing a significant extension of progression‐free survival (PFS; and trend toward improved overall survival) in patients with LGSOC treated with maintenance hormone therapy (MHT, primarily letrozole and tamoxifen) following primary chemotherapy and cytoreductive surgery compared with those who underwent observation alone 6.

Fulvestrant is a direct antiestrogen agent that, unlike tamoxifen, has no known agonist effects. Work with BG‐1 ovarian cancer cell lines found that long‐term (>3 months) fulvestrant exposure confers an irreversible inhibition of ERα expression and subsequent loss of estrogen‐induced cell proliferation, which is not observed in cells exposed to other antiestrogen agents 7. Prior clinical investigation of fulvestrant's efficacy on ER‐positive recurrent ovarian cancer has demonstrated a median PFS of 86 days with minimal toxicity 8. Although not limited to LGSOC, it shows the utility of estrogen antagonism in patients with recurrent disease. Our patient experienced a similar length of time for her biologic response prior to addition of trametinib.

Inhibition of the MAP‐Kinase pathway with MEK inhibitors is a novel treatment approach for recurrent LGSOC. A phase II trial performed by the Gynecology Oncology Group (GOG239) found selumetinib, an inhibitor of MEK1/2, to confer a median PFS of 11 months 2. Eight patients had a complete or partial response. As with our patient, 41/52 patients experienced drug‐induced diarrhea and 31/52 developed rash. In contrast to our patient, only 1 of the 126 regimens previously received by the enrolled patients was a hormone antagonist (Lupron Depot [leuprolide acetate]; AbbVie, North Chicago, IL). GOG281's initial results showed trametinib to confer a PFS of 13.0 months in women with LCSOC 9. Like GOG239, however, it is limited in application to our patient's case as only 41.8% of their 260‐patient cohort had received >3 prior treatments.

Hormone therapy and MEK inhibitors appear to exhibit synergy when used in combination on ER‐positive ovarian cancer in preclinical models. Animal studies have found significantly reduced tumor sizes in SKOV3 xenograft‐bearing mice treated with MEK‐inhibitor (CI‐1040) and fulvestrant dual therapy, for example, compared with those treated with MEK‐I (p = .02) or fulvestrant (p = .002) alone 3. MEK inhibitors induced overexpression of ERα, rendering cancer cells sensitive to antiestrogen therapies. This synergism has similarly been observed in human ER‐positive, high‐grade serous ovarian cancer cell lines 4. Interestingly, one in vivo trial of combination therapy on estrogen‐sensitive breast cancer found it to elicit a worse PFS than fulvestrant plus placebo alone 10, suggesting the dual‐therapy effect may be somewhat specific to ovarian cancer.

In our patient, combination fulvestrant and trametinib was well tolerated, but it is difficult to ascertain the exact clinical additive or synergistic effect of the regimen. Combination therapy trials using these two drugs have not yet been performed. Understanding that she derived benefit from single‐agent fulvestrant prior to the addition of trametinib, delineating whether tumor response would vary between concurrent dual therapy versus sequenced therapy requires further study.

Conclusion

Here we present the use of combination antiestrogenic and MEK‐inhibitor therapies, fulvestrant and trametinib, in a heavily pretreated patient with ER‐positive, recurrent LGSOC. Although her PFS paralleled that demonstrated by GOG239 and GOG281, suggesting it may be attributed to MEK‐inhibitor effect alone, she cannot be properly compared with these cohorts given her heavily pretreated history and established resistance to both platinum and non‐fulvestrant antihormonal agents. Recognizing the limited treatment options for recurrent LGSOC, and biologic plausibility to suggest synergy of these two agents, consideration should be given to clinical trials evaluating the safety, efficacy, and cost‐effectiveness of this dual‐modality approach.

Disclosures

The authors indicated no financial relationships.