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Keywords:

  • letrozole;
  • aromatase inhibitor;
  • leiomyosarcoma;
  • phase 2 clinical trial

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

Advanced uterine leiomyosarcoma (ULMS) is an incurable disease. A significant percentage of cases of ULMS express estrogen and/or progesterone receptors (ER and/or PR). To the authors' knowledge, the role of estrogen suppression in disease management is not known.

METHODS

The authors performed a single-arm phase 2 study of the aromatase inhibitor letrozole at a dose of 2.5 mg daily in patients with unresectable ULMS with ER and/or PR expression confirmed by immunohistochemistry. Tumor assessments were performed at baseline, 6 weeks, 12 weeks, and every 8 weeks thereafter. Toxicity was monitored throughout treatment. The primary endpoint was the progression-free survival at 12 weeks.

RESULTS

A total of 27 patients was accrued, with a median of 2 prior treatment regimens (range, 0-9 treatment regimens). The median duration of protocol treatment was 2.2 months (range, 0.4 months-9.9 months). The 12-week progression-free survival rate was 50% (90% confidence interval, 30%-67%). The best response was stable disease in 14 patients (54%; 90% CI, 36%-71%). Three patients, all of whom had tumors expressing ER and PR in > 90% of tumor cells, continued to receive letrozole for > 24 weeks. The most common reason for treatment discontinuation was disease progression (85%). Letrozole was found to be well tolerated.

CONCLUSIONS

Letrozole met protocol-defined criteria as an agent with activity in patients with advanced ULMS. Patients with the longest progression-free survival rate were those whose tumors strongly and diffusely expressed ER and PR. Cancer 2014;120:738–743. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Uterine leiomyosarcoma (ULMS) is an uncommon disease, accounting for approximately 2% of all invasive uterine cancers.[1] Although a small minority of patients with limited metastatic disease may experience prolonged disease-free survival after surgical metastasectomy, the vast majority of patients with metastatic ULMS will eventually die of their disease. Systemic therapies, including cytotoxic chemotherapies such as the combination of gemcitabine and docetaxel, doxorubicin-based regimens, and trabectedin, have all demonstrated benefit, but to the best of our knowledge none consistently led to long-term disease control in the majority of patients.[2-6] Similarly, pazopanib, a broad-spectrum kinase inhibitor, has been approved for the treatment of advanced soft tissue sarcoma, including LMS of any site; however, the median progression-free survival (PFS) is approximately 4.6 months in all soft tissue sarcomas.[7] Novel approaches to treatment are therefore needed.

In pathologic analysis of ULMS, estrogen receptors (ERs) and/or progesterone receptors (PRs) have been reported to be expressed in 40% to 80% of cases.[8-11] The biologic relevance of this expression as related to the underlying oncogenic mechanisms that lead to the initiation and maintenance of the neoplastic phenotype in ULMS is unknown. Aromatase inhibitors are a well-tolerated class of hormone-modulating agents approved for the management of postmenopausal women with breast cancer in the adjuvant and metastatic settings.[12-14] Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system, blocking the peripheral conversion of androgens to estrogens by competitively inhibiting the aromatase enzyme, binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues.

Anecdotal reports and a small retrospective series have reported mixed activity of aromatase inhibitors in patients with ULMS, although the extent and degree of ER/PR expression has not been reported consistently.[15-17] Despite these limited data, aromatase inhibitors are frequently used in the management of women with advanced ULMS. In the current study, we report the results of what to our knowledge is the first prospective clinical trial of an aromatase inhibitor, letrozole, in postmenopausal women with advanced ER-positive and/or PR-positive ULMS.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Design and Participants

The current study was a dual-institution, open-label, single-arm phase 2 clinical trial. Eligible patients were postmenopausal women with histologically or cytologically confirmed, ER-positive and/or PR-positive advanced (metastatic and/or unresectable) leiomyosarcoma of uterine origin. ER and/or PR positivity was confirmed on either primary or metastatic tumor tissue. Patients must have had measurable disease outside of a radiation field as per Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0), a life expectancy > 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. Patients may have received any number of prior regimens of chemotherapy for the treatment of ULMS. Patients who previously received prior hormonal therapy for the treatment of ULMS were excluded. In addition, all patients were required to have adequate renal, hepatic, and hematologic function.

All patients provided written informed consent before enrollment on the trial and the study protocol was approved by the Institutional Review Boards of both institutions.

Procedures

Eligible patients were treated on an outpatient basis. Patients received letrozole at a dose of 2.5 mg orally by continuous once-daily administration.

Tumor assessments according to RECIST (version 1.0) were performed by computed tomography/magnetic resonance imaging at baseline, week 6, week 12, and then every 8 weeks thereafter. Patients remained on protocol until disease progression or unacceptable toxicity, which every occurred first. Adverse events were monitored and recorded throughout the study according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Pathologic Analysis

All cases were reviewed by a dedicated gynecologic or soft tissue pathologist at the participating institutions (Dana-Farber Cancer Institute/Brigham and Women's Hospital Cancer Center or Massachusetts General Hospital) to confirm the diagnosis of leiomyosarcoma. ER/PR expression was determined by the diagnostic pathologist as per institutional standard immunohistochemical staining and may have been performed either at the participating center (Dana-Farber Cancer Institute/Brigham and Women's Hospital Cancer Center or Massachusetts General Hospital) or at the hospital that rendered the initial diagnosis of ULMS. Reported expression of ER and/or PR was required for inclusion. When available, tumor tissue was reviewed for the extent of ER/PR expression as reported by the percentage of lesional material expressing each marker as determined by a single pathologist (M.N.).

Cases were considered to have positive expression of ER and/or PR if any staining of tumor cells was identified. If positive, then the percentage of positive nuclei was recorded.

Statistical Analysis

The primary objectives of the current study were to evaluate the clinical activity of letrozole in postmenopausal women with advanced ER-positive and/or PR-positive ULMS and to evaluate the safety of letrozole in this patient population.

The primary endpoint was the progression-free survival (PFS) rate, defined as the percentage of patients who were free of objective disease progression (as per RECIST version 1.0) at 12 weeks. The study was designed to distinguish a favorable true PFS rate of 40% from a null rate of 20% using a conventional 2-step phase 2 study design model. The 40% PFS rate was chosen based on European Organization for Research and Treatment of Cancer criteria.[18] If at least 4 of the first 17 patients enrolled were free of disease progression at 12 weeks, an additional 20 patients would be enrolled, for a total accrual goal of 37 patients. If ≥ 11 patients among 37 eligible patients were free of disease progression at 12 weeks, letrozole was to be considered effective and worthy of further study in patients with uterine leiomyosarcoma. This statistical model provided 10% type I error and 90% power. There was a 54.9% probability of stopping early if the drug was ineffective, a 9.5% probability of rejecting the treatment if it was effective (true rate of 40%), and a 90.3% probability of rejecting the treatment if it was ineffective (true rate of 20%). Descriptive statistics were used to characterize patients at baseline. PFS curves were obtained using the Kaplan-Meier method, with 90% confidence intervals (90%CI) calculated using the Greenwood formula. The associations between PR, ER, ECOG performance status, body mass index, mitotic rate, and PFS were explored using Cox regression models.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Enrollment

A total of 19 eligible patients were enrolled in the first stage between March 4, 2009 and February 4, 2010, 17 of whom received at least 1 dose of letrozole. Two patients were deemed to be ineligible after enrollment and before receiving first dose of study drug. After 7 patients were observed to be free of disease progression at 12 weeks, an additional 9 patients were accrued, for a total of 28 patients enrolled and 26 treated patients. The study was closed due to a decline in accrual and the concurrent observation of at least 11 patients being free of disease progression at 12 weeks, which was the protocol criterion for efficacy.

Patient and Tumor Characteristics

Table 1 summarizes patient characteristics at the time of study entry for all 26 eligible and treated patients. The median age at study entry was 56 years (range, 44 years-74 years). The majority of patients were white (86%) and postmenopausal (77%), with an ECOG performance status of 0 (65%). All patients had histologically confirmed LMS of the uterus. Before study enrollment, patients had received a median of 2 previous chemotherapeutic regimens (range, 0 regimens-9 regimens). Tumor characteristics are summarized in Table 2.The median mitotic rate was 23 per 10 high-power fields, with a range of 3 to 100 per 10 high-power fields. Four cases expressed ER only and 22 cases expressed both ER and PR.

Table 1. Baseline Patient Characteristics
CharacteristicNo. (%)
  1. Abbreviations: BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; ULMS, uterine leiomyosarcoma.

  2. Tumor Characteristics

No. of treated patients26
Median age (range), y56 (44-74)
ECOG performance status 
017 (65)
18 (31)
21 (4)
Menopausal status at time of diagnosis of ULMS 
Premenopausal5 (19)
Postmenopausal20 (77)
Unknown1 (4)
Median BMI (range)28 (21-41)
Median no. of prior therapies (range)2 (0-9)
Table 2. Tumor Characteristics
CharacteristicNo. (%)
  1. Abbreviations: ER, estrogen receptor; HPF, high-power fields; PR, progesterone receptor.

  2. a

    Material was unavailable for ER/PR quantitation.

ER expression only4 (15)
ER and PR coexpression22 (85)
% ER staining 
>50%8 (31)
10%-50%8 (31)
Unknowna10 (38)
% PR staining 
>50%7 (27)
10%-50%7 (27)
Unknowna12 (46)
Median mitotic count per 10 HPF (range)23 (3-100)

Treatment and Best Response

The median duration of letrozole treatment for the entire cohort was 10 weeks (range, 2 weeks-45 weeks). Best response was stable disease in 14 patients (54%; 90% CI, 36%-71%). The 12-week PFS rate was 46% (90% CI, 29%-64%). This CI excluded the null rate of 20%. The median duration of treatment was 2.2 months. The most common reason for treatment discontinuation was disease progression, which ultimately occurred in 22 of 26 patients (85%)

Toxicity

Table 3 summarizes the most common treatment-related toxicities observed. Side effects were generally manageable, with hot flashes, musculoskeletal symptoms, fatigue, and nausea being the most common adverse events. Three patients (12%) experienced grade 3 adverse events. One patient died of progressive disease within 30 days of treatment and another patient developed colon cancer and was removed from the study.

Table 3. Most Commonly Observed Treatment-Emergent Toxicitiesa
ToxicityGrade 1Grade 2Grade 3
  1. a

    Adverse events were monitored and recorded throughout the study according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Hot flashes1700
Muscle pain800
Joint pain410
Fatigue410
Nausea410
Abdominal pain320
Diarrhea310
Pain, other300
Constipation201

Progression-Free Survival

Figure 1 shows the Kaplan-Meier PFS curve. The median PFS was 12 weeks (90% CI, 6.6 weeks-13.6 weeks). The actuarial 12-week PFS rate was 50% (90% CI, 30%-67%) and the actuarial 24-week PFS rate was 17% (90% CI, 4%-37%). Three patients were free of disease progression after 24 weeks on study. The tumor characteristics of these cases are summarized in Table 4. Two of the 3 patients who remained free of disease progression at 24 weeks received letrozole as first-line systemic therapy. The third patient had received 3 prior therapies (doxorubicin in combination with ifosfamide, single-agent ifosfamide, and gemcitabine in combination with docetaxel), with treatment durations ranging from 1 month to 8 months. In addition, 2 of the patients in this cohort had demonstrated disease progression within the 3 months before study enrollment.

image

Figure 1. The Kaplan-Meier progression-free survival curve is shown. 90% CI indicates 90% confidence interval.

Download figure to PowerPoint

Table 4. Characteristics of Patients Free of Disease Progression at 24 Weeks
Age, Years% ER Expression% PR ExpressionMitotic Rate per 10 HPFNo. of Prior TherapiesDisease Progression Prior to Enrollment
  1. Abbreviations: ER, estrogen receptor; HPF, high-power fields; PR, progesterone receptor.

4710010033Yes, 3 mo
19>95>95300Yes, 12 mo
65100100400Yes, 3 mo

There was no statistically significant relationship noted between the mitotic rate and PFS (P = .65 using the Cox regression model with the mitotic rate as a continuous variable, and log-rank P values of .46 and .74, respectively, using a cutoff value of 20 or 10).

However, there was a significant association noted between higher ER status, using a cutoff of 90% to divide patients into 2 groups, and prolonged PFS (log-rank P = .04). There was also a significant relationship noted between PR status, similarly using a cutoff of 90%, and PFS (log-rank P = .01). Although there was a trend toward improved PFS noted when using lower cutoffs of 50% and 80%, respectively, for ER and PR expression, this difference was not statistically significant in this small cohort. There was no significant relationship noted between ECOG performance status, body mass index (using a cutoff at the median of 32), or menopausal status and PFS (log-rank P > .05).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

To the best of our knowledge, the current study is the first prospective phase 2 trial of an aromatase inhibitor in patients with metastatic ULMS. ULMs is the most common mesenchymal malignancy of the uterus. Despite complete resection of disease localized to the uterus, metastases occur in approximately 50% of patients within 3 years.[19]

Although systemic therapies can lead to disease control in a subset of patients, the duration of benefit may be limited, and cure is typically not possible. Therefore, addition therapeutic options that balance disease control with toxicity are needed. The progression free survival at 12 weeks (PFS12) is sufficient to justify this regimen as a relatively nontoxic control arm for further studies and there has been discussion within the National Cancer Institute Gynecologic Cancer Steering Committee of using this regimen as a treatment arm in adjuvant studies.

The characteristics of ULMS can vary widely, both with regard to pathologic features and natural history. Approximately 40% to 80% of ULMS express some degree of ER and/or PR positivity. However, to the best of our knowledge, the precise role of hormonal receptors in the disease biology of ULMS remains unclear. One single-institution retrospective study suggested that the expression of ER and/or PR in LMS confined to the uterus was associated with superior outcomes when compared with cases that did not express ER/PR.[11] To the best of our knowledge, the current study is the first prospective evaluation of aromatase inhibition in patients with ULMS expressing ER and/or PR by immunohistochemistry. It is interesting to note that our overall patient population had a median PFS of 12 weeks; however, the 3 patients whose tumors demonstrated > 90% expression of both ER and PR had significantly longer disease control in the current study: > 24 weeks. In addition, 2 of 3 of these patients had high mitotic rates (30 mitoses and 40 mitoses per 10 high-power fields, respectively), suggesting that traditional features that may be related to more aggressive behavior may not apply to tumors that retain high expression of ER and PR.

Two of the 3 patients in this latter group experienced clear disease progression within the 3 months before study enrollment, suggesting that a subset of ULMS may indeed be reliant on pathways related to ER/PR and that suppression of estrogen may impact disease progression in this subset of patients.

Previous reports evaluating the role of hormone suppression in patients with ULMS are primarily retrospective anecdotal case reports that have described unique patients who experience disease control while receiving aromatase inihibitors.[15-20] These reports were limited by the highly selective nature of case reports and often lacked detailed additional pathologic details regarding tumor characteristics, such as mitotic rate or degree of ER/PR expression.

A retrospective series of aromatase inhibition in 40 patients with advanced ULMS reported an objective response rate of 9%.[17] All patients who achieved response had tumors that expressed ER, which was defined as ER staining in > 10% of tumor cells. Further detail on the degree of ER expression or the mitotic rate was not described.

Letrozole met our protocol definition as a potentially active agent in patients with advanced ULMS that expresses ER and/or PR. The European Organization for Research and Treatment of Cancer criteria of a PFS rate of 40% at 12 weeks is based on second-line therapy in patients with soft tissue sarcoma. It is interesting to note that the median number of prior therapies in the current study cohort was 2, suggesting that this population was more heavily pretreated, although 2 of the 3 patients with longer disease control received letrozole as first-line therapy. The current study data also suggest that the potential benefit is somewhat limited in an unselected cohort of patients with ER-positive/PR-positive metastatic ULMS. We did observe a nonstatistically significant trend toward longer PFS in patients with tumors that more strongly expressed ER/PR, which may be related to the underlying more favorable biology of these tumors. However, in patients with very high expression of both ER and PR, defined as > 90% of tumor cells, there was significantly longer PFS, including among patients with active disease progression at the time of study entry, suggesting that aromatase inhibition may play a role in disease control in this highly selected population of patients with advanced ULMS that strongly expresses ER and PR.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Dr. George received consulting fees from Novartis and Pfizer for content related to gastrointestinal stromal tumors as well as drug support for a separate investigator-initiated trial and financial support to the Dana-Farber Cancer Institute for Novartis- and Pfizer-sponsored clinical trials. She also received consulting fees for content related to gastrointestinal stromal tumors as well as financial support to the Dana-Farber Cancer Institute from Ariad Pharmaceuticals for an Ariad-sponsored clinical trial; consulting fees including travel support for content related to gastrointestinal stromal tumors and financial support and drug support to the Dana-Farber Cancer Institute for an investigator-initiated clinical trial from Bayer as well as support for a Bayer-sponsored clinical trial; and consulting fees including travel support from GlaxoSmithKline. Dr. Quek has received grants from Novartis and Janssen. Dr. Wagner has received a grant and personal fees from Novartis. Dr. Demetri has received grants and consulting fees from Novartis, GlaxoSmithKline, Johnson & Johnson, and Merck as well as research support to the Dana-Farber Cancer Institute for specific clinical trial agreements in the sarcoma unit. He has also provided unpaid expert regulatory testimony for GlaxoSmithKline, Johnson & Johnson, and Merck and has acted as a paid member of the Scientific Advisory Board for ZioPharm Oncology Inc.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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