cáncer de endometrio: del conocimiento molecular a la ...€¦ · cáncer de endometrio: del...

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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

❑ 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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Introduction Endometrial cancer: histological clasification

Endometrioid Serous Clear Cels Carcinosarc.

grade 1-2 grade 3

80% 10% 3%

#SEOM20 TCGA, Nature 2013. Talhouk, Br J Cancer 2015.

ProMisE

Introduction Endometrial cancer: molecular clasification

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grade 1-2 grade 3

Urick, Nature Rev 2019.

Introduction Endometrial cancer: histological & molecular clasification

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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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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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grade 1-2 grade 3


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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




• p53 mutated EC



• Conclusions

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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




• p53 mutated EC



• Conclusions

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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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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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Agenda




• p53 mutated EC



• Conclusions

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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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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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EEC SEC CCEC UCS

grade 3 grade 1-2


52-82% 62-90% 2-3% 0-21% 11-33%






39-47% 39-60% 7-11% 14-21% 10-24%


6-10% 21-35% 59-93% 28-46% 44-91%

ERBB2 amplification

ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %



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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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EEC SEC CCEC UCS

grade 3 grade 1-2


52-82% 62-90% 2-3% 0-21% 11-33%






39-47% 39-60% 7-11% 14-21% 10-24%


6-10% 21-35% 59-93% 28-46% 44-91%

ERBB2 amplification

ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %



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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




• p53 mutated EC



• Conclusions

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EEC SEC CCEC UCS

grade 3 grade 1-2


52-82% 62-90% 2-3% 0-21% 11-33%






39-47% 39-60% 7-11% 14-21% 10-24%


6-10% 21-35% 59-93% 28-46% 44-91%

ERBB2 amplification

ERBB2 inhibitors 3 % 4 % 26-44% 11 % 9 %



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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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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




• p53 mutated EC



• 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




• p53 mutated EC



• 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.

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