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.
Inclusion Criteria:
1. 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.
2. Most recent treatment must have been with Tamoxifen, Raloxifene, Toremifene, or an
Aromatase Inhibitor (letrozole, anastrozole, or exemestane), and patient must have
been on-treatment at time of recurrence/progression and undergo tumor biopsy, which
will be performed as standard of care.
- Treatment with Exemestane plus Everolimus (Afinitor®), or with hormonal therapy
in combination with a CDK inhibitor, or with any experimental therapeutic, as
prior or most recent therapy is allowed.
- Any number of prior lines of anti-estrogen therapy is permissible.
- One line of prior chemotherapy for advanced/metastatic disease is permissible.
3. Histologic documentation of ER-high/HER2-negative breast cancer by core needle, fine
needle aspiration, or incisional biopsy of ≥1 site(s) of metastatic or locally
advanced disease performed as standard of care within 2 months prior to assessment of
eligibility for study participation (except, as noted below, in patients with
bone-only metastatic breast cancer).
1. ER-high 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.
2. HER2-low 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.
3. Excess tumor tissue from biopsy must be available for molecular analysis. This
will include tumor tissue sufficient to make ≥10 five-micron sections; more tumor
tissue is preferred.
4. Frozen tumor tissue (acquired during clinically indicated tumor biopsy) is
strongly preferred for research analysis (if available). Tumor tissue procured
after 12-14 days of 17b estradiol therapy as part of a repeat research biopsy
(optional) should be processed (FFPE or frozen) in the same manner as tissue
acquired at baseline.
5. Patients with bone-only metastatic disease with a history of ER+/HER2- primary
breast cancer are eligible, and bone biopsy is not required, providing their
primary cancer is consistent with the above-described ER and HER2 criteria.
4. Patient must be a candidate for treatment with 17b-estradiol and an aromatase
inhibitor.
5. If most recent therapy was in adjuvant setting, recurrence-free interval (time from
initiation of adjuvant anti-estrogen therapy to clinical evidence of disease
recurrence) must have been at least 2 years. If most recent therapy was in
advanced/metastatic setting, progression-free interval must have been at least 4
months.
6. Patient must be post-menopausal based on either a history of an oophorectomy, or at
least one year of amenorrhea. An elevated serum gonadotropin level can be used to
confirm menopausal status in a subject with <1 year of amenorrhea.
7. Routine clinical staging, including either PET/CT, or CT (CAP) and bone scan.
8. Patient must be capable and willing to provide informed written consent for study
participation.
9. The following laboratory values must be confirmed for eligibility, and be within 28
days prior to initiation of study therapy:
Hematology panel
- hemoglobin > 9 g/dL
- white blood cell (WBC) count (≥ 2,000/UL)
- platelet count ≥ 75,000/UL
Serum biochemistry/metabolic panel
- creatinine ≤ 1.5 x upper limits of normal (ULN)
- total bilirubin ≤ 1.5 x upper limits of normal (ULN)
- 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:
1. Treatment with fulvestrant within 4 months prior to study enrollment.
2. Any other concurrent systemic anti-cancer treatments, including conventional
chemotherapeutic agents and biological agents, during the study period.
Agents to ameliorate bone turnover (e.g., bisphosphonates, denosumab) are permitted.
3. Any investigational cancer therapy in the last 28 days.
4. Known CNS disease, unless clinically stable for ≥ 3 months.
5. History of any of the following:
- deep venous thrombosis
- pulmonary embolism
- stroke
- acute myocardial infarction
- congestive heart failure
- previous malignancy not treated with curative intent, or with an estimated
*recurrence risk ≥30%
