evidencia de terapias en segunda línea en hr+/her2- abc, inhibidores de mtor
TRANSCRIPT
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Evidencia de terapias en segunda línea en aBC, inhibidores mTOR
Mauricio Lema Medina MDClínica de Oncología Astorga / Clínica SOMA, Medellín
Medellín, 9 de noviembre, 2016 – La Provincia@Onconerd
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E?F?
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E? F?
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YOUR LOGO
Scientific rationale…
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Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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LTED cells exhibit PI3K/mTOR pathway hyperactivation and variable response to E2.
ER+ cell-lines: MCF-7, ZR75-1, MDA-361LTED: Long-term estrogen deprivedControls: Actin / AKTER expression: ERPI3k/mTOR expression: p-S6K/p-AKT https://doi.org/10.1172/JCI41680Miller TW, JCI, 2010
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PI3K pathway inhibition suppresses hormone-independent cell growth
ER+ cell-lines: MCF-7, ZR75-1, MDA-361LTED: Long-term estrogen deprivedBEZ235 (Dactolisib): PI3k/mTOR inhibitorRAD0001 (Everolimus): mTOR inhibitorAEW541: IGR-1R inhibitorLapatinib: EGFR/Her2 inhibitor https://doi.org/10.1172/JCI41680Miller TW, JCI, 2010
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Anti ER treatment with Fulvestrant induces PI3k pathway activation
Fox EM, Arteaga CL, Miller TW. Frontiers in Oncology, 2012
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Adapted from Atkins MB et al. Nat Rev Drug Discov 2009;8(7):535-6.
Mechanism of Action of mTOR Inhibitors
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Crosstalk between ER and mTOR Signaling
Adapted from Di Cosimo S, Baselga J. Nat Rev Clin Oncol 2010;7(3):139-47.
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In the clinic…
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Everolimus is an mTOR inhibitor shown to increase the antitumor activity of letrozole in the neoadjuvant setting (JCO 2009;27:2630).
Randomized trials of first-line hormone therapy with mTOR inhibition in metastatic breast cancer (mBC) have been disappointing (Proc SABCS 2006;Abstract 6091).
Selection of patients with aromatase inhibitor-pretreated mBC may enrich the study population for tumors that are driven by activation of the PI3K/AKT/mTOR pathway.
Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Bachelot T et al. Proc SABCS 2010;Abstract S1-6.
TAMRAD Phase II Study Schema
Primary endpoint: Clinical benefit rate (CBR) at 6 months; a gain of 20% in CBR required to warrant further study of tamoxifen/everolimus combination.Secondary endpoints: Time to progression (TTP), overall survival, objective response rate, toxicity.
Tamoxifen + everolimus
(n = 54)
Tamoxifen(n = 57)
Eligibility
Metastatic breast cancerMenopausal conditionHormone receptor-positive; HER2-negativePrior exposure to aromatase inhibitor (AI)
R
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Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
“Patients with primary hormone resistance had only a slightly higher CBR with tamoxifen plus everolimus (12 of 26 patients; 46%) than tamoxifen alone (10 of 28 patients; 36%).”
Patients with primary resistance were those relapsing during or within 6 months of stopping adjuvant AI treatment or progressing within 6 months of starting AI treatment in the metastatic setting
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Tamoxifen Tamoxifen + Everolimus
Hazard Ratio (95% CI) p-value
CBR (n = 57; 54) 42.1% 61.1% — —
Median TTP (n = 57; 54) 4.5 mos 8.6 mos 0.53(0.35-0.81) 0.0026
TTP, all pts with primary hormone resistance1 (n = 54) 3.9 mos 5.4 mos 0.74
(0.42-1.3) —
TTP, all pts with secondary hormone resistance2 (n = 56) 5.0 mos 17.4 mos 0.38
(0.21-0.71) —
Overall survival (n = 57; 54) — — 0.32(0.15-0.68) 0.0019
1 Patients who received no benefit from hormone therapy, experiencing either relapse during adjuvant AI or progression within six months of starting AI in the metastatic setting2 Patients who relapsed later, either after AI discontinuation in the adjuvant setting or after responding, experiencing progression later in the metastatic setting
Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Adverse event (AE)Tamoxifen (n = 57) Tamoxifen + everolimus (n = 54)
Any grade Grade 3/4 Any grade Grade 3/4
Fatigue 52.6% 10.5% 74.1% 5.6%
Stomatitis 7.0% 0 51.9% 11.1%
Rash 5.3% 1.8% 38.9% 5.6%
Anorexia 17.5% 3.5% 44.4% 9.3%Diarrhea 8.8% 0 38.9% 1.9%Dose reduction due to AE 0 28%Treatment discontinuation due to AE 7.0% 5.6%
Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Everolimus combined with tamoxifen allowed for a 61% CBR compared to 42% with tamoxifen alone.
Time to progression and overall survival increased with the addition of everolimus to tamoxifen compared to tamoxifen alone.
Toxicity was manageable and consistent with previous studies. Clinical benefit may favor patients with secondary hormone resistance. Based on these promising results, this combination warrants further study in hormone-
receptor positive/HER2-negative mBC after progression on aromatase inhibitors.
Randomized Phase II Trial of Everolimus in CombinationWith Tamoxifen in Patients With Hormone
Receptor–Positive, Human Epidermal Growth FactorReceptor 2–Negative Metastatic Breast Cancer With Prior
Exposure to Aromatase Inhibitors: A GINECO Study
10.1200/JCO.2011.39.0708Bachelot T, JCO, 2012
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Investigator Commentary: Combining Biologic and Endocrine Therapy in Advanced ER-Positive Breast CancerThe TAMRAD study was interesting in that the outcome was better than expected with the addition of everolimus to tamoxifen. The caveat is that this is a Phase II trial with approximately 100 patients, but the investigators demonstrated an improvement in clinical benefit rate, time to disease progression and survival with the addition of everolimus. The suggestion also arose that patients with secondary, as opposed to primary, endocrine resistance may have derived the most benefit from the combination. Of course, more side effects — fatigue, stomatitis, rash, et cetera — were observed with the doublet. The presenters’ conclusion was appropriately cautious in stating that the doublet should not be considered as standard treatment and further research is warranted.
Interview with William J Gradishar, MD, January 4, 2011
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Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in
advanced breast cancer
Treilleux I, Ann Oncol, 2015
Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells).
Results A total of 55 primary tumor samples from the TAMRAD trial—25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group—were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6–34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient.
10.1093/annonc/mdu497
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Forest plot of time to progression with tamoxifen/everolimus versus tamoxifen alone for each biomarker tested.
I. Treilleux et al. Ann Oncol 2015;26:120-125
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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TTP with tamoxifen/everolimus and tamoxifen alone.
I. Treilleux et al. Ann Oncol 2015;26:120-125
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in
advanced breast cancer
Treilleux I, Ann Oncol, 2015
Conclusions A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.
10.1093/annonc/mdu497
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A phase II study of combined fulvestrant and everolimusin patients with metastatic estrogen receptor (ER)-positive breast
cancer after aromatase inhibitor (AI) failure
Massarweh S, Breast Cancer Res Treat, 2014 10.1007/s10549-013-2810-9
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A phase II study of combined fulvestrant and everolimusin patients with metastatic estrogen receptor (ER)-positive breast
cancer after aromatase inhibitor (AI) failure
Massarweh S, Breast Cancer Res Treat, 2014 10.1007/s10549-013-2810-9
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A phase II study of combined fulvestrant and everolimusin patients with metastatic estrogen receptor (ER)-positive breast
cancer after aromatase inhibitor (AI) failure
Massarweh S, Breast Cancer Res Treat, 2014 10.1007/s10549-013-2810-9
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A phase II study of combined fulvestrant and everolimusin patients with metastatic estrogen receptor (ER)-positive breast
cancer after aromatase inhibitor (AI) failure
Massarweh S, Breast Cancer Res Treat, 2014 10.1007/s10549-013-2810-9
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A phase II study of combined fulvestrant and everolimusin patients with metastatic estrogen receptor (ER)-positive breast
cancer after aromatase inhibitor (AI) failure
Massarweh S, Breast Cancer Res Treat, 2014 10.1007/s10549-013-2810-9
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Hortobagyi GN et al. SABCS 2011;Abstract S3.7. Baselga J et al. N Engl J Med 2011;[Epub ahead of print].
Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial
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Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
Postmenopausal, ER-positive locally advanced or metastatic breast cancerProgression on letrozole or anastrozole(n = 724)
R
Everolimus – 10 mg daily+
Exemestane – 25 mg daily
(n = 485)
Placebo+
Exemestane – 25 mg daily
(n = 239)
Stratification: Sensitivity to prior hormonal therapy and presence of visceral metastases
Endpoints:• Primary: Progression-free survival (PFS) by local assessment• Secondary: Overall survival, overall response rate, quality of life,
safety, bone markers, pharmacokinetics
BOLERO-2 Study Design
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Response and Clinical Benefit
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
Everolimus + Exemestane
Placebo + Exemestane
Response Clinical Benefit
Perc
ent
12.0%
1.3%
50.5%
25.5%
P < 0.0001
P < 0.0001
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BOLERO-2: Everolimus + Exemestane Improves PFS in HR+ MBC
Baselga J, et al. N Engl J Med. 2012;366:520-529.
0 6 12 18 24 30 36 42 48 54 60 66 72 78Wks
Prob
abili
ty o
f Eve
nt (%
)Everolimus + exemestane(median PFS: 10.6 mos)Placebo + exemestane(median PFS: 4.1 mos)
HR: 0.36 (95% CI: 0.27-0.47;log-rank P < .001)
Patients at Risk, nEverolimusPlacebo
485239
385168
28194
20155
13233
10220
6711
4311
286
183
93
31
20
00
100908070605040302010
0
Central Assessment
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BOLERO-2: Final PFS Analysis (18-Mo Follow-up)PFS, Mos EVE + EXE PBO + EXE HR (95% CI) P ValueLocal review 7.8 3.2 0.45
(0.38-0.54)< .0001
Central review 11.0 4.1 0.38(0.31-0.48)
< .0001
With visceral mets 6.83 2.76 0.47(0.37-0.60)
--
Without visceral mets 9.86 4.21 0.41(0.31-0.55)
--
Bone-only mets 12.88 5.29 0.33(0.21-0.53)
--
Progression after neo/adj therapy
11.50 4.07 0.39(0.25-0.62)
--
OS data still not mature (HR: 0.77; 95% CI: 0.57-1.04) Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia (5%), fatigue (4%)
Piccart, M, et al. SABCS 2012. Abstract P6-04-02.
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Common Adverse Events
Everolimus + Exemestane(n = 482)
Placebo + Exemestane(n = 238)
All Grades Grade 3/4 All Grades Grade 3/4Stomatitis 59% 8% 11% <1%Rash 39% 1% 6% 0Fatigue 36% <5% 27% 1%Diarrhea 33% <3% 19% <1%Decreased appetite 30% 1% 12% <1%Nausea 29% <2% 28% 1%
Noninfectious pneumonitis 15% 3% 0 0
Hyperglycemia 14% <6% 2% <1%
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
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Bolero-2: OS of Exemestane + Everolimus in mBC
Piccert M, et al. Ann Oncol 2014
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Wolff AC. JCO, 2013
Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal
Women With Locally Advanced or Metastatic Breast Cancer
Primary endpoint: Progression-free survival (PFS) of the intent-to-treat population as assessed by independent review.progression-free survival (PFS) of the intent-to-treat population as assessed by independent review.
Letrozole + Oral temsirolimus
(n = 54)
Letrozole + Placebo(n = 57)
EligibilityMetastatic breast cancer or Locally-advances breast cancerMenopausal conditionHormone receptor-positive; HER2-negative
Patients were ineligible if they had prior adjuvant AI within 12 months before study day 1, if disease recurrence occurred during the first 6 months of adjuvant endocrine therapy, or if prior endocrine therapy (including AIs) was administered for locally advanced/MBC
R
10.1200%2FJCO.2011.38.3331
Letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks)
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Wolff AC. JCO, 2013
Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal
Women With Locally Advanced or Metastatic Breast Cancer
10.1200%2FJCO.2011.38.3331
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Wolff AC. JCO, 2013
Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal
Women With Locally Advanced or Metastatic Breast Cancer
10.1200%2FJCO.2011.38.3331
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Wolff AC. JCO, 2013
Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal
Women With Locally Advanced or Metastatic Breast Cancer
10.1200%2FJCO.2011.38.3331
“Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer.”
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Before hormone-resistance…
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Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor
receptor 2–negative (HER2−) advanced breast cancer (BC)
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Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor
receptor 2–negative (HER2−) advanced breast cancer (BC)
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Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor
receptor 2–negative (HER2−) advanced breast cancer (BC)
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Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor
receptor 2–negative (HER2−) advanced breast cancer (BC)
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In relation to other options in aBC
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Generali D, Breast Cancer Res Treat, 2015
A network meta-analysis of everolimus plus exemestane versus chemotherapy in the first- and second-line treatment
of estrogen receptor-positive metastatic breast cancer
10.1007/s10549-015-3453-9
PFS/TTP
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Generali D, Breast Cancer Res Treat, 2015
A network meta-analysis of everolimus plus exemestane versus chemotherapy in the first- and second-line treatment
of estrogen receptor-positive metastatic breast cancer
10.1007/s10549-015-3453-9
RR
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Generali D, Breast Cancer Res Treat, 2015
A network meta-analysis of everolimus plus exemestane versus chemotherapy in the first- and second-line treatment
of estrogen receptor-positive metastatic breast cancer
10.1007/s10549-015-3453-9
HR
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Conclusions
Upregulation of PI3k/AKT/mTOR pathway is found after long-term estrogen deprivation
Co-inhibition of ER and mTOR overcomes (to some extent) endocrine resistance in aBC
Short (or no) prior endocrine exposure may not be preclude synergism of anti-ER/anti-mTOR. But further studies are needed.
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E/F
@Onconerd