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TRANSCRIPT
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#SEOM20
Cáncer de endometrio: del conocimiento molecular a la práctica clínica.
¿Podemos personalizar el tratamiento? César Gómez Raposo
Oncología Médica, Hospital Universitario Infanta Sofía San Sebastián de los Reyes, Madrid
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❑ Consultant or Advisory Role: Tesaro-GSK, PharmaMar
❑ Speaking: Roche, Astra Zeneca, MSD
Disclosure Information
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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Introduction Endometrial cancer: histological clasification
Endometrioid Serous Clear Cels Carcinosarc.
grade 1-2 grade 3
80% 10% 3%
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#SEOM20 TCGA, Nature 2013. Talhouk, Br J Cancer 2015.
ProMisE
Introduction Endometrial cancer: molecular clasification
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Endometrioid Serous Clear Cels Carcinosarc.
grade 1-2 grade 3
Urick, Nature Rev 2019.
Introduction Endometrial cancer: histological & molecular clasification
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Introduction Endometrial cancer: histological & molecular clasification
1. How to grade endometrial EC? - Recommend moving toward a binary scheme to grade endometrial EC:
“low grade”; grades 1 and 2 “high grade”; grade 3
2. How to incorporate the 4 genomic subcategories identified through TCGA? - Proposed a multimodality classification system of HGECs using POLE mutational analysis and
IHC for p53, PMS2 and MSH6. - Terminology: reporting the genomic classifier as well as the analysis used (for example;
endometrial EC, FIGO grade 3. Genomic classifier group: Copy number high (p53 abnormal IHC) - Provisionally propose to classify CCC on the same multimodality system.
McCluggage et al. Int J Gynecol Pathol 2019. Soslow et al. Int J Gynecol Pathol 2019.
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#SEOM20
Introduction Endometrial cancer: histological & molecular clasification
1. How to grade endometrial EC? - Recommend moving toward a binary scheme to grade endometrial EC:
“low grade”; grades 1 and 2 “high grade”; grade 3
2. How to incorporate the 4 genomic subcategories identified through TCGA? - Proposed a multimodality classification system of HGECs using POLE mutational analysis and
IHC for p53, PMS2 and MSH6. - Terminology: reporting the genomic classifier as well as the analysis used (for example;
endometrial EC, FIGO grade 3. Genomic classifier group: Copy number high (p53 abnormal IHC) - Provisionally propose to classify CCC on the same multimodality system.
McCluggage et al. Int J Gynecol Pathol 2019. Soslow et al. Int J Gynecol Pathol 2019.
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Endometrioid Serous Clear Cels Carcinosarc.
grade 1-2 grade 3
Introduction Endometrial cancer: histological & molecular clasification
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Carcinosarc.
Cherniack et al, Cancer Cell 2017.
Introduction Uterine carcinosarcomas (UCS)
UCSs most closely resemble SECs molecularly Frequent TP53 mutations
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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Título de la diapositiva
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Título de la diapositiva
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POLEmut & MMRd EC
Eggink et al, Oncoinmunology 2017. Pilulats et al, Clin Cancer Res 2016.
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AntiPD-(L)1 therapy in MMRd EC
Drug Phase Patients N ORR Outcomes
Pembrolizumab 1 II MSI-H/MMRd 49 57.1% mPFS 25,7 (4.9-NR) mOS NR (27.2-NR) DOR NR (2,9-27.0+)
Nivolumab2 II MMRd 13 46.15% NR
Durvalumab3 II MMRd 35 dMMR 43%
Avelumab 4 II MMRd 16 dMMR 27% PFS6m 33.3%
Atezolizumab 5 Ia 15 13 %
Dostarlimab6, I/II MMRd 103 44.7 % DOR: NR PFS18m 79.2%
ORR: overall response rate. PFS: progression free-survival. OS: overall survival. DOR: duration of response. NR: not reported.
1.Marabelle, J Clin Oncol 2019. 2.Azad, J Clin Oncol 2019. 3. Antill, ASCO 2019. 4. Konstantinopoulos, ASCO 2019.
5. Liu, Gynecol Oncol 2019. 6. Oaknin, ESMO 2020.
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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Título de la diapositiva
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Anti-PD1 therapy in MMRp
Drug Phase Patients N ORR Outcomes
Dostarlimab1 I/II MMRd 142 13.4% DOR: not reached mPFS at 18m: 61.3
Durvalumab2 II pMMR 35 3%
Avelumab3 II pMMR 16 6.25%
ORR: overall response rate. PFS: progression free-survival. OS: overall survival. DOR: duration of response. CR: complete responses. SD: stable disease.
1.Oaknin, ESMO 2020. 2. Antill, ASCO 2019. 3. Konstantinopoulos, ASCO 2019.
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Anti-PD1 therapy in MMRp
Predicting tumor response to PD-1 blockade
Molecular subtype not immune response drives outcomes in EC
Talhouk, Clin Cancer Res, 2019.
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Anti-PD1 therapy in MMRp
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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Título de la diapositiva
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Recurrent mutations in EC
Recurrently mutated genes are different between four subgroups
TCGA, Nature 2013.
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Somatic aberration frequencies for major diver genes in EC
EEC SEC CCEC UCS
grade 3 grade 1-2
PTEN PI3K-AKT inhibitors PARP inhibitors CDK4/6 inhibitors
52-82% 62-90% 2-3% 0-21% 11-33%
PI3KCA Pi3K-AKT-mTOR inhibitors 38-54% 45-59% 15-35% 24-36% 22-40%
PIK3R1 Pi3K-AKT-mTOR inhibitors 19-38% 31-41% 5-8% 7-18% 6-20%
KRAS MEK inhibitors 17-23% 7-33% 2-6% 2-14% 10-17%
FGFR2 FGFR inhibitors 11-13% 14-16% 8 % 0 % 0-2%
ARID1A Synthetic lethal interactions
39-47% 39-60% 7-11% 14-21% 10-24%
TP53 G2/M checkpoint inhibition Synthetic lethal interact?
6-10% 21-35% 59-93% 28-46% 44-91%
ERBB2 amplification
ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %
Mutation Potential actionability
Adaptado de Urick, Nat Rewiew 2019.
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Título de la diapositiva
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Serous EC (p53mut) Chemotherapy
PORTEC 3 Updated results
De Boer, Lancet Oncol 2019.
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Serous EC (p53mut)
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Lenvatinib + Pembrolizumab Phase II open-label, single-arm trial
Makker, SGO 2020.
Tumor response by histology
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Somatic aberration frequencies for major diver genes in EC
EEC SEC CCEC UCS
grade 3 grade 1-2
PTEN PI3K-AKT inhibitors PARP inhibitors CDK4/6 inhibitors
52-82% 62-90% 2-3% 0-21% 11-33%
PI3KCA Pi3K-AKT-mTOR inhibitors 38-54% 45-59% 15-35% 24-36% 22-40%
PIK3R1 Pi3K-AKT-mTOR inhibitors 19-38% 31-41% 5-8% 7-18% 6-20%
KRAS MEK inhibitors 17-23% 7-33% 2-6% 2-14% 10-17%
FGFR2 FGFR inhibitors 11-13% 14-16% 8 % 0 % 0-2%
ARID1A Synthetic lethal interactions
39-47% 39-60% 7-11% 14-21% 10-24%
TP53 G2/M checkpoint inhibition Synthetic lethal interact?
6-10% 21-35% 59-93% 28-46% 44-91%
ERBB2 amplification
ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %
Mutation Potential actionability
Adaptado de Urick, Nat Rewiew 2019.
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Somatic aberration frequencies for major diver genes in EC
EEC SEC CCEC UCS
grade 3 grade 1-2
PTEN PI3K-AKT inhibitors PARP inhibitors CDK4/6 inhibitors
52-82% 62-90% 2-3% 0-21% 11-33%
PI3KCA Pi3K-AKT-mTOR inhibitors 38-54% 45-59% 15-35% 24-36% 22-40%
PIK3R1 Pi3K-AKT-mTOR inhibitors 19-38% 31-41% 5-8% 7-18% 6-20%
KRAS MEK inhibitors 17-23% 7-33% 2-6% 2-14% 10-17%
FGFR2 FGFR inhibitors 11-13% 14-16% 8 % 0 % 0-2%
ARID1A Synthetic lethal interactions
39-47% 39-60% 7-11% 14-21% 10-24%
TP53 G2/M checkpoint inhibition Synthetic lethal interact?
6-10% 21-35% 59-93% 28-46% 44-91%
ERBB2 amplification
ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %
Mutation Potential actionability
Adaptado de Urick, Nat Rewiew 2019.
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TP53mut EC Are they HRD?
De Longe et al, Clin Cancer Res 2018.
Functional HRD test: RAD51 foci postRT
• 50% TP53mut EC were HRD • HRD could be explained by mutations
or delections in BRCA or HR genes • Benefit or PARP inhibitors?
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TP53mut EC Wee-1 inhibitors
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TP53mut EC Wee-1 inhibitors: ADAVOSERTIB Single arm, two-stage phase 2 trial
Liu et al, ASCO 2020.
34 patients Recurrent or persistent USC • Prior lines:
- At least 1 prior plt-based cht for adv USC
- Pts MSI-H/MMRd must have had prior antiPD1/PDL1 therapy
- No overall line limit
mFUp: 5.9 months Median prior lines: 3 (1-8)
Clinical activity is durable in many patients
mDOR: 9.03 months (95% CI 5.29-NA)
No clear correlation between molecular alterations and outcomes.
N=34
CR 1 (2.9%)
PR 9 (26.4%)
SD ≥ 6 months < 6 months
7 (20.6%) 9 (26.5%)
ORR 10 (29.4%)
CBR (CR+PR+SD≥6m)
17 (50%)
Median PFS 6,14 m (95% CI 4.21-9.92)
PFS rate at 6m 59.6% (95% CI 40.6-74.3)
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Somatic aberration frequencies for major diver genes in EC
EEC SEC CCEC UCS
grade 3 grade 1-2
PTEN PI3K-AKT inhibitors PARP inhibitors CDK4/6 inhibitors
52-82% 62-90% 2-3% 0-21% 11-33%
PI3KCA Pi3K-AKT-mTOR inhibitors 38-54% 45-59% 15-35% 24-36% 22-40%
PIK3R1 Pi3K-AKT-mTOR inhibitors 19-38% 31-41% 5-8% 7-18% 6-20%
KRAS MEK inhibitors 17-23% 7-33% 2-6% 2-14% 10-17%
FGFR2 FGFR inhibitors 11-13% 14-16% 8 % 0 % 0-2%
ARID1A Synthetic lethal interactions
39-47% 39-60% 7-11% 14-21% 10-24%
TP53 G2/M checkpoint inhibition Synthetic lethal interact?
6-10% 21-35% 59-93% 28-46% 44-91%
ERBB2 amplification
ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %
Mutation Potential actionability
Adaptado de Urick, Nat Rewiew 2019.
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Serous EC Her2/neu + Phase II trial Carboplatin-Paclitaxel ± Trastuzumab
61 patients Stage III-IV
Fader et al, J Clin Oncol 2018.
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Serous EC Her2/neu + Phase II trial Carboplatin-Paclitaxel ± Trastuzumab. Update analysis
Fader et al, SGO 2020.
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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#SEOM20
Título de la diapositiva
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#SEOM20
Somatic aberration frequencies for major diver genes in EC
EEC SEC CCEC UCS
grade 3 grade 1-2
PTEN PI3K-AKT inhibitors PARP inhibitors CDK4/6 inhibitors
52-82% 62-90% 2-3% 0-21% 11-33%
PI3KCA Pi3K-AKT-mTOR inhibitors 38-54% 45-59% 15-35% 24-36% 22-40%
PIK3R1 Pi3K-AKT-mTOR inhibitors 19-38% 31-41% 5-8% 7-18% 6-20%
KRAS MEK inhibitors 17-23% 7-33% 2-6% 2-14% 10-17%
FGFR2 FGFR inhibitors 11-13% 14-16% 8 % 0 % 0-2%
ARID1A Synthetic lethal interactions
39-47% 39-60% 7-11% 14-21% 10-24%
TP53 G2/M checkpoint inhibition Synthetic lethal interact?
6-10% 21-35% 59-93% 28-46% 44-91%
ERBB2 amplification
ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %
Mutation Potential actionability
Adaptado de Urick, Nat Rewiew 2019.
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Relationship between endocrine signaling, PI3K pathway and cell-cycle in tumour cells
MacKay HJ et al. 2020 ASCO Educational Book.
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Endocrine therapy in EC
NCCN guidelines versión 2.2020. Endometrial carcinoma.
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Endocrine therapy in EC
1. Van Weelden et al, Front Oncol 2019. 2. Fiorica JV et al. Gyncol Oncol 2004. 3. Singh M et al, Gynecol Oncol 2007. 4. Covens A et al, Gynecol Oncol 2011.
5. Linderman et al, BMC Cancer 2014. 6. Ethier J-L et al, Gynecol 2017.
• The “original” targeted treatment • Who benefits? • Lack of randomized trials and validated predictors of reponse
Study Drug ORR (%)
GOG 153 2 TAM + MA G1: 38% G2: 24% G3: 22%
• Grade
• ER/PR status Study Treatment N ER GOG 119 3 TAM + MPA 60 +ve 47%
-ve 26%
GOG 188 4 Fulvestrant 67 +ve 16% -ve 0%
Lindermann 5 Exemestane 51 +ve 10.0% -ve 0%
Meta-analysis 6 ET 1837 +ve 26.5% -ve 9.2%
TAM: Tamoxifen. MPA: medroxyprogesterone acetate. ORR: overall response rate. OR: Odds ratio. ET: endocrine therapy
ET 1 RR
TAM 10-53%
Other SERM and SERD 9-31%
AI 8-9%
Progestin and TAM 9-58%
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LET: letrozole. TAM: Tamoxifen. MA: megestrol acetate.
PI3K-AKT-mTOR targeted agents in EC Phase II trials
Study N Treatment ORR (%) Biomarkers
GOG 248 55 Temsirolimus +/- MA and TAM
20 Mutations in AKT1, TSC1, TSC2 and CTNN1B
Slomovitz 38 Everolimus + LET 32 Endometrioid histology CTNBB1
GOG 3007 37 36
Everolimus + LET vs TAM/MA
24 22
No prior ChT: 53 vs 43%
Soliman 54 Everolimus + LET +/- metformin
28 PgR+ ve (ORR 45%)
Slomovitz et al, J Clin Oncol 2015. Myers A et al, Gynecol Oncol 2016. Slomovitz et al, SGO
2018. Soliman et al, Clin Cancer Res 2020.
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CDK4/6 inhibitors in EC Phase II trials.
Study Treatment N mPFS mOS Outcomes
Colon-Otero et al. Ribociclib + LET 20 5.4 m (3.1-11.8)
15,7 m (6.8-NA)
PFS at 23 w - G1-2: 64% - G3: 22%
PALEO Palbociclib + LET 73 8.3 vs 3.0 (HR 0.56)
NR No prior MA/MPA: HR 0.55 (0.29-1.04) Relapse disease: HR 0.61 (0.34-1.09)
Colon-Otero et al, ASCO 2019. Mirza M et al, ESMO 2020.
• ER+ve (≥10%) • Endometroid EC • ≥ 1 systemic therapy
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Título de la diapositiva
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Título de la diapositiva
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CDK4/6 inhibitors in EC Phase II trials.
Study Treatment N mPFS mOS Outcomes
Colon-Otero et al. Ribociclib + LET 20 5.4 m (3.1-11.8)
15,7 m (6.8-NA)
PFS at 23 w - G1-2: 64% - G3: 22%
PALEO Palbociclib + LET 73 8.3 vs 3.0 (HR 0.56)
NR No prior MA/MPA: HR 0.55 (0.29-1.04) Relapse disease: HR 0.61 (0.34-1.09)
Colon-Otero et al, ASCO 2019. Mirza M et al, ESMO 2020.
• ER+ve (≥10%) • Endometroid EC • ≥ 1 systemic therapy
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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Precision Medicine Clinical Utility of Prospective Molecular Characterization in Adv EC
189 pts with advanced-stage EC, 75% high-grade Profiled by MSK-IMPACT (341-410 genes), matched normal from blood * Allele-specific copy-number analysis by FACETS * MSIsensor * Germline analysis
Genomic alterations of MSS samples split by histology and grade
* 3 pts BRCA2 mutations (1 SEC, 2 UCS) * 1 pts germine MLH1 mutation (grade 2 EEC)
Soumerai, Clin Cancer Res 2018.
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Clinical Utility of Prospective Molecular Characterization in Adv EC
Soumerai, Clin Cancer Res 2018.
67% (127/189) pts at least one actionable alteration
35% 29% 16% 7%
27% (34/127) enrolled in matched clinical trials 47% (16/34) achieved clinical benefit
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Precision Medicine
Mangast PK et al, JCO Precis Oncol 2018. Barroilhet, Gynecol Oncol 2018.
• TAPUR Study – Targeted Agent and Profiling Utilization Registry Study
Phase II, prospective, non-randomized, open-label, multi-basket trials Identify signals of drug activity for targeted treatment matched to pre-specificied genomic alterations.
• NCI-MATCH trial -NCI Molecular Analysis for Therapy Choice Trial
For FDA approved drugs outside of approved indications
6000 pts screened 30 treatment arms Interim analysis: * 23% gene abnormality
Cancer N Assigend to treat.
Ovarian 530 14.1%
Uterine 300 26.3%
Cervical 70 27.2%
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Agenda
• Introduction: histological & molecular clasification
• POLE mut and MMRd EC
• MMRp EC & immunotherapy: potential predictive factors
• p53 mutated EC
• p53 wild-type EC
• Precision medicine
• Conclusions
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Conclusions
• Moving into a new era with treatment defined by molecular characteristics of the patient´s tumor.
• MSI-H/MMRd is a valuable biomarker for immunotherapy.
• Relevant targets in USC (TP53mut) are Her2, Wee-1 and HRD.
• Endometrioid histology (p53wt) and patients without prior chemotherapy
benefit more from mTOR inhibitors.
• Revisting endocrine therapy: role, predictive biomarkers and new
combinations (CDK4/6 inhibitors).
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Muchas gracias por su atención.