Patient case: 73-year-old female with breast cancer; genetic feature: CDKN2A

Clinical trial: ER Reactivation Therapy for Breast Cancer

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.

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.

Eligibility: 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%

Relevance to patient case: not relevant