Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches
Abstract
:Simple Summary
Abstract
1. Introduction
2. Historical Perspective: Early Use of Estrogen and Estrogen-like Compounds
2.1. The Rise and Fall of DES
2.2. Transitioning to Tamoxifen (TAM) and Antiestrogens
Ethinylestradiol (EE); n = 82 | Tamoxifen (TAM); n = 184 | Diethylstilbestrol (DES) n = 117 | Estradiol (E2); n = 98 * Including E2V | |
---|---|---|---|---|
Adverse Events (All Grade) | % of Patients | % of Patients | % of Patients | % of Patients |
Gastrointestinal Issues | ||||
Gastrointestinal Effects | 13% | |||
Anorexia | 6% | 10% | 1% | |
Diarrhea | 4% | 7% | 3% | |
Nausea/Vomiting | 34% | 17% | 56% | 20% |
Musculoskeletal Issues | ||||
Increased Pain/Bone Pain | 17% | 1% | 10% | |
Reproductive and Breast Issues | ||||
Breast Pain | 7% | |||
Nipple/Areola Pigmentation | 16% | |||
Vaginal Discharge/Bleeding | 17% | 1% | 9% | 13% |
Vaginal Spotting | 9% | 1% | ||
Withdrawal Bleeding | 38% | 1% | ||
Cardiovascular Issues | ||||
Congestive Heart Failure | 5% | |||
Fatigue | 12% | 10% | ||
Skin, Hair, and Sensory Issues | ||||
Hot Flashes/Hot Flushes | 9% | 14% | 3% | |
Metabolic and Endocrine Issues | ||||
Hyponatremia | 7% | |||
Edema | 16% | 5% | 38% | |
Endometrial Thickening or Uterocervical Enormousness | 16% | |||
Liver Function Issues | ||||
Liver Dysfunction/Liver Function Impairment | 5% | 1% | 2% | |
Blood Disorders | ||||
Leukopenia | 5% | 1% |
Treatment (Dose, Number of Subjects, and Duration) | Eligible Patients/Prior Lines of Therapy | Population | Reported Outcomes | References |
---|---|---|---|---|
n = 12 Ethinylestradiol: 1 mg daily for 7 to 36 months. | Treated with ≥2 estrogen-depriving therapies and other endocrine therapies. | Aged 49–85 (Mdn 75) ER+ postmenopausal women | ORR = 3/12(25) CBR = 4/12(33) | [30] |
n = 32 Estradiol: 30 mg daily for evaluation at 24 weeks | Treated with AI and/or one line of chemotherapy. | Aged 39.4–77.7 (Mdn 59.5) ER+ and/or PgR+ clinically postmenopausal women | ORR = 1/32(3) CBR = 9/32(28) | [26] NCT00324259 |
n = 34 Estradiol: 6 mg daily | Treated with AI and/or one line of chemotherapy. | Aged 36.3–83.8 (Mdn 54.7 yrs.) ER+ and/or PgR+ clinically postmenopausal women | ORR = 3/34 (9) CBR = 10/34(29) | [26] NCT00324259 |
n = 18 Ethinylestradiol: 3 mg per day for 3–12 months | Treated with AI and/or endocrine therapies including chemotherapy. | Aged 51–83 (Mdn 63) ER+ clinically postmenopausal women | ORR = 9/18 (50) CBR = 10/18 (56) | [29] UMIN000002831 |
n = 13 Estradiol: 6 mg per day for 3 months. | Treated with ≥1 prior endocrine therapy and progressed thereafter. | Aged 49–85 (Mdn 68) ER+ postmenopausal women | ORR = 3/13(23) CBR = 6/13(46) | [31] NCT01385280 |
n = 19 2 mg estradiol valerate daily for evaluation at 24-weeks. | Treated with a third-generation AI and responded or had stable disease for ≥6 months prior to disease progression. | Aged 49–90(Mdn 67) ER+ clinically postmenopausal women | ORR = 0/19(0) CBR = 5/19(26) | [27] Eudract 2004-000595-14 |
n = 15 TTC-352: 15, 30, 60, 120, 180 mg twice a day for 28-day cycles of treatment until disease progression. | Progressed on two prior lines of hormonal therapy including chemotherapy and mTOR inhibitors. All received a CDK4/6 inhibitor. | Aged 40–62 (Mdn 51) ER+ postmenopausal for ≥1 year or surgically sterile | ORR = 0/12(0) CBR = 2/12(16) | [32] NCT03201913 |
n = 12 Fetal E4; 20 mg, 40 mg or 60 mg per day for 12 weeks. | Treatment failure with tamoxifen and/or AI(s) due to resistance or side effects. Most received prior endocrine, targeted and chemotherapies. | Aged 56–79 (Mdn 70) ER+ postmenopausal women (Natural or surgical) for ≥5 years | ORR = 1/9(11) CBR = 5/9(66) | [25] NCT02718144 |
n = 19 Estradiol 6mg per day for 7–14 days prior to surgery. | Newly diagnosed low-grade, breast cancer without exogenous estrogen exposure | Aged 55.4–75.5(Mdn 67) ER+/HER2- clinically postmenopausal women for ≥ 5 years | ORR = 6/19(32) | [33] NCT02238808 |
n = 19 Alternating estradiol 2 mg orally three times a day for 8 weeks followed by AI for 16 weeks for evaluation at 24-weeks. | Progression on ≥1 antiestrogen or AI-based therapy | Aged 45–80 (Mdn 61) Postmenopausal women with ER+/HER2- breast cancer | ORR = 3/19 (15.8) CBR = 8/19 (42.1) | [34] NCT02188745 |
3. Optimal Placement of Estrogens in Therapy: Women’s Health Initiative (WHI) and the Million Women Study (MWS)
3.1. Women’s Health Initiative (WHI)
3.2. Million Women Study (MWS)
4. Molecular Mechanisms of Estrogen-Induced Tumor Regression
4.1. ER+ Breast Cancer Models
4.2. Activation of Extrinsic Death-Receptor Pathway and Unfolded Protein Response (UPR)
4.3. Involvement of the Intrinsic-Mitochondrial Pathway in E2-Induced Apoptosis
4.4. Estrogen Induces Receptor-Dependent DNA Damage in ER-Positive Breast Cancer Models
5. Predictive Biomarkers for Response to Estrogens
5.1. Single Predictive Biomarkers
5.2. Multigene Predictive Biomarkers
6. Novel Estrogenic Therapeutic Approaches on the Horizon
7. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Shete, N.; Calabrese, J.; Tonetti, D.A. Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches. Cancers 2023, 15, 3647. https://doi.org/10.3390/cancers15143647
Shete N, Calabrese J, Tonetti DA. Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches. Cancers. 2023; 15(14):3647. https://doi.org/10.3390/cancers15143647
Chicago/Turabian StyleShete, Nivida, Jordan Calabrese, and Debra A. Tonetti. 2023. "Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches" Cancers 15, no. 14: 3647. https://doi.org/10.3390/cancers15143647