Addition of Antiestrogen Treatment in Patients with Malignant PEComa Progressing to mTOR Inhibitors

Perivascular epitheliod cell tumors (PEComa) are rare mesenchymal neoplasms, a subset of which shows a malignant, aggressive clinical course (1). The standard treatment of localized disease is surgery and few systemic therapies are available for relapsed or advanced cases. We recently showed that standard soft-tissue sarcoma chemotherapy regimens are active only in a small proportion of patients with advanced PEComas, whereas mTOR inhibitors are the most active agents, with an objective response rate (ORR) of 40% and a median progression-free survival (PFS) of 10 months (2). Similar activity and efficacy results were reported from a preliminary analysis of an open-label, phase II study on nab-sirolimus (an albumin-bound intravenous mTOR inhibitor with high intratumoral drug accumulation; ref. 3), highlighting the central role of mTOR inhibition in advanced PEComa.

In case of acquired resistance to mTOR inhibitors, or in those patients with primary refractory tumors, other available therapies have limited benefit (2). Growing evidence supports a close interaction between the mTOR pathway and estrogen (ER) or androgen receptor signaling in a wide range of malignancies (4–6). The combination of mTOR inhibitors and antiestrogen treatment, such as the nonsteroidal aromatase inhibitor exemestane, has been deeply studied in breast cancer and represents the standard of care in a specific subset of patients with ER-positive breast cancer upon progression to hormonal therapy alone (7–9). Interestingly, cross-talk between estrogen and mTORC1 pathway was also demonstrated in PEComas using a patient-derived model of lymphangioleiomyomatosis (10). This provided a rationale for combining antiestrogens and mTOR inhibitors in consecutive patients with locally advanced or metastatic PEComa progressing to mTOR inhibitors alone.

Patients with locally advanced or metastatic PEComa in progression to mTOR inhibitors were treated with a combination of sirolimus and antiestrogen therapy. All patients signed an informed consent prior to the start of their treatment. All diagnoses were centrally reviewed at the Treviso General Hospital (Treviso, Italy), or at the Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Italy) according to the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone (1) by expert pathologists. RECIST v1.1 were used to assess tumor response (11). Patients' characteristics, treatment specifics, and clinical outcomes were retrospectively reviewed. The study was conducted according to the ethical principles for medical research involving human subjects adopted in the Declaration of Helsinki. Institutional approval was obtained for the retrospective analysis.

All patients proceeded directly from single-agent mTOR inhibitor to combination therapy with sirolimus and antiestrogen with no treatment gap after the failure of mTOR inhibitor alone. Sirolimus was given orally at a dose between 1 mg and 10 mg daily according to plasma drug level (optimal values were considered to be within the 14–20 ng/mL range). The plasmatic levels of sirolimus were checked every 14 days. Exemestane was given orally at a dose of 25 mg daily. The LHRH analogue triptorelin, was given intramuscularly at a dose of 3.75 mg every 28 days.

PFS was defined as the time between treatment initiation and disease progression (PD), or death for any cause, and was censored at the time of data cutoff (December 2019). Survival analyses were performed using the Kaplan–Meier method. Statistical analyses were performed using GraphPad Prism 8.3.1 (332) software and R software (v3.5.0). When relevant P values were below the 0.05 threshold, statistical tests were considered significant.

Since April 2018, a total of seven consecutive female patients, with a diagnosis of locally advanced or metastatic PEComa progressing to mTOR inhibitors were enrolled. In three out of seven patients (43%), the tumor showed immunohistochemical (IHC) staining for ER and progesterone receptor (PgR) at time of first diagnosis, whereas in one patient (14%), the tumor showed IHC staining only for PgR. In three patients (43%), the tumor was ER/PgR negative. Patients and disease characteristics are summarized in Table 1. Median age was 67 years (range, 47–76). Three patients (43%) received one prior line of treatment and four (57%) received two prior lines of treatment. Two patients received first-line hormonal treatment before starting second-line sirolimus alone: one patient (pt 4) received letrozole and one patient (pt 5) was treated with a combination of triptorelin and letrozole (Supplementary Table S1). Both patients experienced PD as their best response to the first-line hormonal treatment. In the previous line of treatment with mTOR inhibitor alone, all patients received sirolimus given orally at a dose between 1 and 10 mg daily according to plasma drug level, with an ORR of 43%, a disease control rate (DCR) of 71%, and a median PFS of 9.8 months [95% confidence interval (CI), 3.9–NA; Supplementary Table S1; Supplementary Fig. S1).

Six patients (86%) received a combination of sirolimus and exemestane, whereas one patient (pt5; 14%) received a combination of sirolimus, exemestane, and triptorelin since in premenopausal status. All the patients started combined treatment with the same sirolimus dose as in the previous line with mTOR inhibitor alone. Median dose of sirolimus in the combined treatment was 6 mg (range, 2–10 mg). In six out of seven patients (86%), we did not observe a modification of sirolimus plasmatic levels after the addition of exemestane, thus no dose adjustments were required for sirolimus. One patient (pt 5; 14%) required a dose reduction from 5 to 2 mg after the addition of exemestane and triptorelin because of an increase in the plasmatic levels of sirolimus beyond the upper limit of optimal range. At the time of data cutoff (December 2019), four PFS events were recorded and all patients were alive. After a median follow-up of 13.1 months, three patients (43%) experienced a partial response (PR), three patients (43%) experienced stabilization of disease (SD), and one patient (14%) had a PD as best response, with an ORR of 43% (95% CI, 16–75) and a DCR of 86% (95% CI, 49–97). The swimmer plot in Fig. 1A shows the pattern of response to the combined treatment for each patient. For responding patients, median time to response was 2.1 months (range, 1–2.9) and median response duration was 11.1 months (range, 4.8–16.9). Median PFS was 7 months (95% CI, 3.7–NA) with a 1-year PFS rate of 43% (95% CI, 18–100; Fig. 1B). Interestingly, one patient with abdominal PEComa (pt 5) was treated in first-line with letrozole and triptorelin with PD as best response. Then the hormonal treatment was discontinued and the patient received sirolimus with a PR lasting 4 months. Upon progression on sirolimus, the patient continued sirolimus and exemestane and triptorelin were added leading to a new PR (Fig. 2). At the time of this analysis, the patient was still responding to the combination treatment with a PFS of 13 months. Whereas ER and PgR expression were positive in the tumor specimen of this patient, the tumors of the two other patients who obtained a PR were negative for hormonal receptor expression (Fig. 1A). No serious adverse events occurred during the combined treatment.

The PEComa family of tumors include angiomyolipoma, clear cell sugar tumor of the lung, and lymphangioleiomyomatosis. Both lymphangioleiomyomatosis and malignant PEComa harbor mutations and LOH affecting the TSC2 gene or, more rarely, the TSC1 gene. TSC1 and TSC2 gene products contribute to a molecular complex that negatively regulates mTORC1. As a consequence of TSC1 or TSC2 alterations, the mTOR pathway is constitutively activated (6). This molecular insight constituted the rationale for the use of mTOR inhibitors (e.g., sirolimus) in patients with PEComa. Currently, mTOR inhibitors are the most active agents available for advanced PEComa, despite still not being approved by any regulatory agency for such indication. Unfortunately, chemotherapy is active in less than 10%–20% of patients with a limited PFS (2) and no other reports on valid treatments are published until now.

In this retrospective study of seven patients with locally advanced or metastatic PEComa progressing while on sirolimus, we observed three PR and three SD with the combination of exemestane and sirolimus. Median PFS was 7 months and median response duration was 11.1 months. In our series, therefore, the addition of exemestane to sirolimus achieved a reversion of sirolimus resistance in 86% of patients and resulted in a new, long-lasting response in a subgroup of them (43%).

Our data about the promising activity of sirolimus and antiestrogen treatment in patients with sirolimus-resistant advanced PEComa are consistent with preclinical evidences showing an interaction between the estrogen pathway and the PI3K/AKT/mTOR pathway in PEComa (10). Even if a subset of PEComa is characterized by the expression of ER and PgR, the response to hormone therapy alone in patients with aggressive PEComa is only anecdotally reported (12). Indeed, two of the patients included in this case series were previously treated with first-line hormone therapy and experienced a PD as best response. Interestingly, both patients had a clinical benefit from the combination of sirolimus and exemestane after progressing to sirolimus alone: one patient (pt 5) experienced a PR (Fig. 2) and the other (pt 4) experienced an SD. Furthermore, in two out of three patients experiencing a response to the combination of sirolimus plus hormonal therapy, the tumors were ER/PgR negative at time of first diagnosis. These observations suggest that further translational investigations are needed to deeply understand the interplay between estrogen pathway and the PI3K/AKT/mTOR pathway in aggressive PEComa.

In conclusion, this is the first report on the activity of sirolimus plus antiestrogen therapy in patients with advanced PEComa upon progression to sirolimus alone. If our preliminary data will be confirmed, new regimens, in which mTORC1/2 and estrogen signaling are targeted, may be used in the clinical practice to improve the prognosis of patients with malignant PEComas.

R. Sanfilippo reports grants and personal fees from Eli Lilly (financial support to clinical studies at institution and personal fees for advisory role, speaker's role, and travel coverage for medical meetings) and PharmaMar (financial support to clinical studies at institution and personal fees for advisory role, speaker's role, and travel coverage for medical meetings), and grants from Amgen Dompé (financial support to clinical studies at institution), Bayer (financial support to clinical studies at institution), Daiichi Sankyo Pharma (financial support to clinical studies at institution), Epizyme Inc. (financial support to clinical studies at institution), and Novartis (financial support to clinical studies at my institution) outside the submitted work. P.G. Casali reports grants and personal fees from Bayer (financial support to clinical studies at institution and personal fees for speaker, consultancy, or advisory role), Deciphera (financial support to clinical studies at institution and personal fees for speaker, consultancy, or advisory role), Eisai (financial support to clinical studies at my institution and personal fees for speaker, consultancy, or advisory role), Eli Lilly (financial support to clinical studies at institution and personal fees for speaker, consultancy, or advisory role), and Pfizer (financial support to clinical studies at institution and personal fees for speaker, consultancy, or advisory role outside the submitted work), personal fees from Nektar Therapeutics (for speaker, consultancy, or advisory role), and grants from Advenchen Laboratories (financial support to clinical studies at institution), Amgen Dompé (financial support to clinical studies at institution), AROG Pharmaceuticals (financial support to clinical studies at institution), Blueprint Medicines (financial support to clinical studies at institution), Daiichi Sankyo (financial support to clinical studies at institution), Epizyme Inc, (financial support to clinical studies at institution), GlaxoSmithKline (financial support to clinical studies at institution), Karyopharm Pharmaceuticals (financial support to clinical studies at institution), Novartis (financial support to clinical studies at institution), and PharmaMar (financial support to clinical studies at institution) outside the submitted work. No potential conflicts of interest were disclosed by the other authors.

R. Sanfilippo: Conceptualization, data curation, supervision, investigation, writing–original draft, project administration, writing–review and editing. C. Fabbroni: Data curation, investigation, writing–original draft, writing–review and editing. G. Fucà: Conceptualization, data curation, formal analysis, investigation, writing–original draft, writing–review and editing. E. Fumagalli: Investigation, writing–review and editing. C. Morosi: Investigation, writing–review and editing. M. Sbaraglia: Investigation, writing–review and editing. A. Gronchi: Investigation, writing–review and editing. P. Collini: Investigation, writing–review and editing. A.P. Dei Tos: Investigation, writing–review and editing. P.G. Casali: Conceptualization, supervision, writing–original draft, writing–review and editing.

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