Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Disease Progression

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Bone Density Conservation Agents

Antineoplastic Agents

Reproductive Control Agents

Estradiol

Tamoxifen

Hormones

Exemestane

Letrozole

Estrogens

Estradiol 17 beta-cypionate

Estradiol 3-benzoate

Polyestradiol phosphate

Estrogen Receptor Modulators

Anastrozole

Aromatase Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Enzyme Inhibitors

Antineoplastic Agents, Hormonal

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.

17B-estradiol

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.

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.

Mary Chamberlin, MD

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.

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.

ER Reactivation Therapy for Breast Cancer

Phase II Pre-emptive OsciLLation of ER activitY Levels Through Alternation of Estradiol/Anti-estrogen Therapies Prior to Disease Progression in ER+/HER2- Metastatic or Advanced Breast Cancer

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.

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.

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.

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.

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.

Dartmouth-Hitchcock Medical Center

Associate Professor of Medicine

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Participants receive 2 cycles of olaparib in combination with 17b-estradiol and then continue to be treated with single-agent 17b-estradiol until disease progression.

Participants will be treated with olaparib at the approved doses for the treatment of subtypes of breast cancer or at reduced dose/frequency for participants with moderate renal impairment.

17b-estradiol will be taken orally three times per day.

17b-estradiol

Research Nurse

Determine the safety and recommended Phase II dose of olaparib in combination with 17b-estradiol in post-menopausal patients with advanced ER+/HER2- breast cancer.

Patients with endocrine-resistant ER+/HER2- breast cancer are eligible. Patients will be treated with the combination of 17b-estradiol and olaparib for 2 cycles, and then treated with single-agent 17b-estradiol until disease progression. Clinical benefit, progression-free survival, objective response, tumor metabolic response, and toxicity will be determined.

Single-arm, 3+3 design with a dose-expansion cohort.

Estradiol Plus Olaparib for Breast Cancer (PHOEBE)

Phase 1b Study of Olaparib and Estradiol in Advanced ER+ Breast Cancer (PHOEBE)

The proportion of evaluable patients experiencing clinical benefit (stable disease at 24 weeks, complete or partial response per RECIST) will be measured.

The proportion of evaluable patients experiencing objective response (complete or partial response per RECIST) will be measured.

Progression-free survival will be measured by measuring the length of time between the start of study treatment until the time of cancer progression or death from any cause.

The concentration of Olaparib in plasma will be measured over 6 hours.

The concentration of 17b-Estradiol/Estrone in plasma will be measured over 6 hours.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
ER Reactivation Therapy for Breast Cancer	NCT02188745	Metastatic Brea...	17B-estradiol Letrozole Anastrozole Exemestane	18 Years -	Dartmouth-Hitchcock Medical Center
Estradiol Plus Olaparib for Breast Cancer (PHOEBE)	NCT05900895	Metastatic Brea...	Olaparib 17b-estradiol	18 Years -	Dartmouth-Hitchcock Medical Center
Estradiol Plus Olaparib for Breast Cancer (PHOEBE)	NCT05900895	Metastatic Brea...	Olaparib 17b-estradiol	18 Years -	Dartmouth-Hitchcock Medical Center

Spots Global Cancer Trial Database for estradiol therapy