POLLY: ER Reactivation Therapy for Breast Cancer
Study Details
Study Description
Brief Summary
Before anti-estrogens such as tamoxifen were developed to treat estrogen receptor (ER)-positive breast cancer, high-dose estrogen therapies were used. This seems counterintuitive since anti-estrogens block ER function, while estrogens increase ER function, but these therapies are effective to similar extents for the treatment of metastatic ER+ breast cancer. Estrogen therapies are most effective against cancers that develop resistance to anti-estrogens, likely because such cancers have adapted to grow without ER function, and restoring ER function (with estrogen) is damaging to the cancer cells. In some patients with ER+ breast cancer that becomes resistant to anti-estrogens, treatment with the estrogen 17B-estradiol induces tumor response. Furthermore, when 17B-estradiol-sensitive tumors eventually become resistant to 17B-estradiol, switching back to anti-estrogen therapy is often effective. These observations suggest that cancers can alternate between anti-estrogen-sensitive and 17B-estradiol-sensitive states. The investigators hypothesize that treatment with alternating 17B-estradiol / anti-estrogen therapies on a defined 8-week / 16-week schedule will more effectively prevent cancer growth than continuous treatment with either type of therapy in patients with metastatic anti-estrogen-resistant ER+ breast cancer.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
Metastatic breast cancer is rarely cured by current therapies. ER+ breast cancers ultimately become resistant to all available anti-estrogens. Response rates to estrogens are similar to those of anti-estrogens in the metastatic setting. Given that ER+ breast cancers are often responsive to anti-estrogens and estrogens, alternating anti-estrogen/estrogen therapies may be more effective than continuous treatment with either type of agent. Anecdotal evidence indicates that such a strategy of alternating therapies is effective in some patients. Preclinical evidence suggests that anti-estrogen-resistant ER+ breast cancers are sensitized to the anti-tumor effects of estrogens. Such cells harbor subpopulations that can ultimately regain the ability to grow in the presence of estrogens, and revert to their anti-estrogen-sensitive state. The investigators will formally test whether alternating 17B-estradiol/anti-estrogen therapies is effective for the management of anti-estrogen-resistant metastatic ER+/HER2- breast cancer, and to identify molecular biomarkers that predict tumor response to 1) 17B-estradiol and 2) alternating 17B-estradiol/anti-estrogen therapies. If successful, this study would present a novel strategy to manage metastatic ER+/HER2- breast cancer by pre-emptively switching therapies prior to disease progression.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Alternating Therapy Study will use an 8-week/16-week alternating regimen of 17B-estradiol/AI (aromatase inhibitor) therapy. Use of only one Aromatase inhibitor throughout the study is preferred. 17B-estradiol: One tablet containing 2 mg 17B-estradiol will be taken orally three times daily, for a total dose of 6 mg/day. Letrozole: One tablet containing 2.5 mg letrozole will be taken orally once per day. Anastrozole: One tablet containing 1 mg anastrozole will be taken orally once per day. Exemestane: One tablet containing 25 mg exemestane will be taken orally once per day. |
Drug: 17B-estradiol
Anti-estrogen
Other Names:
Drug: Letrozole
Aromatase inhibitors work by blocking estrogen receptors; they stop a key enzyme (called aromatase) from changing other hormones into estrogen. This lowers estrogen levels in the body, taking away the fuel that estrogen receptor-positive breast cancers need to grow.
Other Names:
Drug: Anastrozole
Aromatase inhibitors work differently from tamoxifen and raloxifene. Instead of blocking the estrogen receptors, they stop a key enzyme (called aromatase) from changing other hormones into estrogen. This lowers estrogen levels in the body, taking away the fuel that estrogen receptor-positive breast cancers need to grow.
Other Names:
Drug: Exemestane
Aromatase inhibitors work differently from tamoxifen and raloxifene. Instead of blocking the estrogen receptors, they stop a key enzyme (called aromatase) from changing other hormones into estrogen. This lowers estrogen levels in the body, taking away the fuel that estrogen receptor-positive breast cancers need to grow.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Clinical benefit [12 Months]
Determine the rate of clinical benefit from alternating 17B-estradiol/aromatase. Clinical benefit is defined as complete response, partial response or stable disease at 24 weeks per RECIST criteria.
Secondary Outcome Measures
- Objective response rate [8 weeks]
Determine the objective response rate of patients treated with 17B-estradiol therapy for 8 weeks. Objective Response is defined as complete response + partial response as per RECIST criteria; the proportion of patients experiencing objective response on 17B-estradiol will be calculated to determine objective response rate.
- Progression-free survival [12 Months]
Determine the progression-free survival from alternating 17B-estradiol/aromatase inhibitor therapy in patients with advanced ER+ breast cancer. Progression-free survival is defined as the time period from the start of a treatment until the time of cancer progression or death from any cause. Cancer progression will be determined as per RECIST criteria.
- Adverse event profiles [12 Months]
Determine the adverse event profiles of 17B-estradiol and aromatase inhibitors in this patient population. Adverse events will be recorded as Grade 1, 2, 3, or 4. Incidences will be compared within patients over time.
- Predictive tumor genetic lesions [12 Months]
Determine whether specific tumor genetic lesions in ESR1 are predictive of response to 17B-estradiol and/or subsequent aromatase inhibitor therapies. The rates of clinical benefit from 17B-estradiol and/or subsequent AI therapy will be compared between patients with tumors with vs. without genetic lesions in ESR1.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Women ≥18 years of age with clinical stage IV ER+/HER2- breast cancer, or with locally recurrent ER+/HER2- disease not amenable to therapy for curative intent.
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Patient must have been treated with an anti-estrogen at any time in their disease history. Combination regimens that include an anti-estrogen and any biologic, or targeted therapy, are permitted (e.g., any CDK inhibitor, everolimus, or any other novel biologics), and are considered to be a single hormonal therapy based regimen.
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Any number of prior lines of anti-estrogen (i.e., hormonal) therapy is permissible.
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One line of prior chemotherapy for advanced/metastatic disease is permissible.
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Histologic documentation of ER strongly+/HER2- breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of ≥1 site(s) of metastatic or locally advanced disease performed as standard of care within the past 4 months for assessment of eligibility for study participation (except as noted below in c/d/e).
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ER strongly+ status defined as ER staining by immunohistochemistry in ≥50% of malignant cell nuclei with an intensity ≥2+ on a scale of 0-3+. These criteria are equivalent to an Allred score ≥6.
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HER2-negative status is defined as immunohistochemistry score of 0-1+, or with a FISH ratio of <2 if IHC is 2+ or if IHC has not been done (as per ASCO/CAP definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the PI.
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Archived tumor specimens: Excess tumor tissue must be available for research purposes. This will include tumor tissue sufficient to make ≥10 five-micron sections; more tumor tissue is preferred.
Freshly acquired tumor specimens: As part of a clinically indicated biopsy procedure, an additional 1-3 cores or tissue fragments will be obtained by core needle or surgical biopsy for research purposes and FFPE.
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Patients with bone-only metastatic disease with a history of ER+/HER2- breast cancer are eligible, and bone biopsy is not required, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
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Patients with non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained are also eligible, providing their primary cancer is consistent with the above-described ER and HER2 criteria.
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Patient must be a candidate for treatment with 17B-estradiol and an aromatase inhibitor.
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If the most recent therapy was in the adjuvant setting, the recurrence-free interval (time from initiation of adjuvant anti-estrogen therapy to clinical evidence of disease recurrence) must have been ≥2 years.
If the most recent therapy was in the advanced/metastatic setting, the progression-free interval must have been ≥3 months (except in the case of investigational hormonal therapies).
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Patient must be post-menopausal based on either a history of an oophorectomy, or ≥1 year of amenorrhea. An elevated serum gonadotropin level and estradiol level in the postmenopausal range (as locally defined) can be used to confirm menopausal status in a subject with <1 year of amenorrhea.
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Baseline radiographic staging, including specifically either PET/CT, or CT (CAP) and bone scan.
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Patient must be capable and willing to provide informed written consent for study participation.
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The following laboratory values must be confirmed for eligibility within 28 days prior to initiation of study therapy:
Hematology panel
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hemoglobin > 9 g/dL
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white blood cell (WBC) count (≥ 2,000/uL)
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platelet count ≥ 75,000/uL Serum biochemistry/metabolic panel
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creatinine ≤ 1.5 x upper limits of normal (ULN)
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total bilirubin ≤ 1.5 x upper limits of normal (ULN)
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ALT and AST ≤ 3.0 x upper limits of normal (ULN) For patients with liver metastasis: < 5 x upper limits of normal (ULN)
Exclusion Criteria:
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Treatment with fulvestrant within 16 weeks prior to study enrollment.
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Any other concurrent systemic anti-cancer treatments, including conventional chemotherapeutic agents and biological agents, during the study period.
Anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted.
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Any investigational cancer therapy in the last 3 weeks.
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Known CNS disease, unless clinically stable for ≥ 3 months.
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History of any of the following:
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deep venous thrombosis
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pulmonary embolism
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stroke
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acute myocardial infarction
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congestive heart failure
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previous malignancy not treated with curative intent, or with an estimated recurrence risk ≥30%
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Baystate Medical Center | Springfield | Massachusetts | United States | 01199 |
| 2 | Mayo Clinic Cancer Center | Rochester | Minnesota | United States | 55905 |
| 3 | Dartmouth Hitchcock Medical Center | Lebanon | New Hampshire | United States | 03756 |
Sponsors and Collaborators
- Dartmouth-Hitchcock Medical Center
Investigators
- Principal Investigator: Gary N Schwartz, MD, Dartmouth-Hitchcock Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D14122