Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy
Abstract
:1. Introduction
2. Estrogen and Lung Cancer
2.1. Estrogen in Normal Lung Physiology
2.2. Estrogen Receptor Expression in Lung Cancer
ERα | ERβ | PR | n | Ref | |||
---|---|---|---|---|---|---|---|
Antibody | % | Antibody | % | Antibody | % | ||
HC20 | 49 | H150 | 49 | -- | -- | 447 | [23] |
HC20 | 36 | -- | -- | SP2 | 45 | 316 | [26] |
HC20 | 52 | -- | -- | -- | -- | 122 | [36] |
HC20 | 79 | MCA1974S | 97 | MAB429 | 91 | 183 | [44] |
HC20 | 0–48 | H150 | 54–98 | SP2 | 58–70 | 317 | [24] |
1D5 | 17–40 | 14C8 | 16–48 | ||||
6F11 | 0–45 | ||||||
Biogenex | 0 | BioGenex | 46 | -- | 301 | [28] | |
1D5 | 19 | -- | -- | AR441 | 8 | 64 | [32] |
1D5 | 0 | -- | -- | hPRa3 | 0 | 248 | [39] |
-- | 0 | 14C8 | 50 | Ncl-PgR | 0 | 127 | [45] |
-- | -- | 14C8 | 86 | -- | -- | 262 | [42] |
1D5 | 0 | Cosmobio | 67 | -- | -- | 30 | [38] |
-- | 0 | 14C8 | 50 | -- | 0 | 127 | [31] |
1D5 | 14 | PPG5/10 | 9 | PgR, Dako | 12 | 109 | [27] |
1D5 | 9 | Biogenex | 38 | PgR, Dako | 11 | 100 | [25] |
1D5 | 0 | -- | -- | -- | 0 | 45 | [37] |
6F11 | 55 | ||||||
1D5 | 0 | MCA1974S | 61 | -- | -- | 278 | [29] |
6F11 | 0 | ||||||
6F11 | 78 | -- | 76 | sc543 | 12 | 58 | [33] |
6F11 | <1 | 14C8 | 71 | MAB429 | 13 | 105 | [34] |
6F11 | 54 | MS-ERβ13-PX1 | 90 | -- | -- | 59 | [35] |
6F11 | 38 | 14C8 | 33 | MAB429 | 47 | 228 | [46] |
Scoring method | Positivity | Ref |
---|---|---|
Scoring formula = [(3x) + (2y) + (1z)]/100 where x, y, and z are % staining at intensity 3, 2 and 1, respectively | High versus low expression defined by dichotomizing at the median value | [45] |
Staining intensity: 0 (none), 1 (weak), 2 (moderate), 3 (strong) | ||
Percentage of cells staining at each intensity level (0–100%) | ||
Proportion and intensity score added together to obtain a total score ranging 0–8 (Allred score) | Negative expression: 0 | [23,44] |
Proportional score for positive staining: | Weak: 2–4 | |
0 (none), 1 (≤1% positive tumor cells), 2 (2–10%), 3 (11–33%), 4 (34–66%), 5 (>67%) | Strong: 5–8 | |
Intensity score: 0 (none), 1 (weak), 2(intermediate), 3 (strong) | ||
Percentage of staining cells: (<10%, 11–50%, 51–100%) | >10% tumor cells with at least 1+ staining | [29] |
Staining intensity: 1 (weak), 2 (moderate), 3 (strong) | ||
Scoring formula = intensity × percentage of positive cells (overall IHC score 0–300) | IHC score equivalent or greater than the median | [31] |
Intensity (0, 1, 2, 3+) | ||
Percentage of positive cells (0–100%) | ||
Scoring formula = intensity × percentage of positive cells (overall IHC score 0–300) | Any expression score >0 | [24] |
Intensity (0, 1, 2, 3+) | ||
Percentage of positive cells (0–100%) |
2.3. Estrogen Receptor and EGFR Mutation
2.4. Mechanism of Estrogen in Lung Carcinogenesis
2.5. Other Associated Hormones in Lung Cancer
3. Prognostic Implications of Estrogen Receptor Expression in Lung Cancer
4. Hormone Receptors as Predictive Markers of Lung Cancer Therapy
Name | Class | Mechanism | Route of administration | Studies in NSCLC |
---|---|---|---|---|
Exemestane | Aromatase inhibitor, steroidal | Inhibits aromatase, irreversible | Oral | Tumor reduction in lung cancer xenografts [61] |
Anastrozole | Aromatase inhibitor, nonsteroidal | Inhibits aromatase, reversible | Oral | Ongoing phase II clinical trial [67] |
Letrozole | Aromatase inhibitor, nonsteroidal | Inhibits aromatase, revesible | Oral | Decreased cell proliferation in ER expressing cell lines [35] |
Letrozole | Aromatase inhibitor, nonsteroidal | Inhibits aromatase, revesible | Oral | Decreased cell proliferation in ER expressing cell lines [35] |
Fulvestrant | Estrogen receptor antagonist | Competitively binds to estrogen receptors, antagonistic effect only | Intramuscular | Decreased cell proliferation in vitro and tumor reduction in lung cancer xenografts [8,61,65], ongoing phase II clinical trials [ 67] |
Tamoxifen | Selective estrogen receptor modulator, nonsteroidal | Competitively binds estrogen receptors; exhibits mixed agonist and antagonist effects | Oral | Anti-tumor effect in vitro [66] but increased tumor growth in xenografts [10 ]. Phase II trials showed activity in combination with platinum-based chemotherapy but this was not confirmed in phase III trials [68,69,70] |
Toremifene | Selective estrogen receptor modulator, nonsteroidal | Competitively binds estrogen receptors; exhibits mixed agonist and antagonist effects | Oral | Phase II trials showed activity in combination with platinum-based chemotherapy but this was not confirmed in phase III trials [71,72] |
Patient population | Allowed prior therapy | Preselected biomarker | Treatment | ER/PR assessment | ClinicalTrials.gov Identifier |
---|---|---|---|---|---|
Stage III or IV NSCLC, postmenopausal women, EGFR mutation positive | 0–1 prior chemotherapy | EGFR mutation | Gefitinib + fulvestrant versus gefitinib | Not defined | NCT01556191 |
Stage III or IV NSCLC, postmenopausal women, EGFR wildtype | 1–2 prior chemotherapy | EGFR wildtype | Erlotinib + fulvestrant versus erlotinib | Not defined | NCT01556191 |
Stage IIIB or IV NSCLC, both gender, ER or PR positive | Stable disease on erlotinib >2 months, prior chemotherapy not defined | ER and PR expression | Erlotinib + fulvestrant (single arm) | Evaluation prior to trial entry | NCT00592007 |
Stage IIIB or IV NSCLC, both gender | ≥1 prior chemotherapy | None | Erlotinib + fulvestrant versus erlotinib | Correlative tissue analysis | NCT00100854 |
Stage IIIB or IV, postmenopausal women | Completed 6 cycles of first line platinum based chemotherapy | None | Maintenance therapy: (1) Best supportive care versus ; (2) Bevacizumab versus ; (3) Fulvestrant + anastrozole versus; (4) Fulvestrant + anastrazole + bevacizumab | Correlative tissue analysis | NCT00932152 |
5. Conclusions
References
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Baik, C.S.; Eaton, K.D. Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy. Cancers 2012, 4, 969-988. https://doi.org/10.3390/cancers4040969
Baik CS, Eaton KD. Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy. Cancers. 2012; 4(4):969-988. https://doi.org/10.3390/cancers4040969
Chicago/Turabian StyleBaik, Christina S., and Keith D. Eaton. 2012. "Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy" Cancers 4, no. 4: 969-988. https://doi.org/10.3390/cancers4040969