M. Bellet Ezquerra (Barcelona, Spain)

Vall d’Hebron Institute of Oncology (VHIO)

Author Of 2 Presentations

 On-Demand ePoster Display

16P - Understanding the biologic determinants of ribociclib efficacy in breast cancer

Abstract

Background

Ribociclib improves survival in hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (BC). Deeper understanding of the biology associated with ribociclib efficacy is needed, especially within the HER2-enriched (HER2-E) subtype given recent analysis of MONALEESA program. Here, we performed gene expression (GE) analysis with/without ribociclib monotherapy in BC patient-derived xenografts (PDX).

Methods

Eighteen PDXs representative of HR+/HER2- (n=11, 61%), HER2+ (n=6, 33%) and triple-negative (n=1, 6%) BC were treated with ribociclib monotherapy (75 mg/kg/day). The % change in tumor volume from baseline was calculated at day 35. RNA was obtained from flash-frozen tumors at baseline and day 12. PAM50 GE was analyzed by nCounter and associated with tumor response (as a continuous variable) using quantitative Statistical Analysis Microarrays (SAM). Differential GE during ribociclib treatment was identified using two-class paired SAM. All SAM used a false-discovery rate<5%.

Results

Baseline PAM50 subtype distribution was Luminal B (44%), HER2-E (33%) and Basal-like (B-L) (22%). HER2-E and Luminal B PDXs showed a statistically significant higher response to ribociclib (mean change in volume >40% and >140%), than B-L (>660%). Baseline GE analysis identified 6 genes highly expressed in responders (FOXA1, ERBB2, GRB7, MLPH, GPR160 and CXXC5), and 7 lower expressed genes (SFRP1, KRT17, MYC, CDH3, KRT5, MIA and KRT14). Paired GE analyses across PDXs identified 12 upregulated genes during treatment, including estrogen activation-related genes (ESR1, PGR, FOXA1, MAPT or BLVRA); and 12 downregulated genes, including proliferation-related genes (MKI67 or KIF2C) and HER2-E-related genes (ERBB2 or TMEM45B). Similar results were obtained with HR+/HER2- PDXs when analyzed separately.

Conclusions

In BC PDXs, B-L biology associates with lower response to ribociclib monotherapy than Luminal or HER2-E. Ribociclib induces a luminal phenotype with high GE of estrogen-regulated genes and low GE of proliferation genes, a biological switch that could explain the better efficacy of ribociclib in the endocrine therapy (ET)-resistant HER2-E subtype observed in clinical trials when combined with ET.

Legal entity responsible for the study

Institut d'Investigacions Biomèdiques August Pi i Sunyer.

Funding

Has not received any funding.

Disclosure

M. Oliveira: Honoraria (self): Roche, Novartis, Seattle Genetics; Advisory/Consultancy: Roche/Genentech, GlaxoSmithKline, Puma Biotechnology, AstraZeneca, Seattle Genetics; Research grant/Funding (institution): Philips Healthcare (Inst), Roche/Genentech (Inst), Novartis (Inst), AstraZeneca (Inst), Immunomedics (Inst), Seattle Genetics (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Cascadian Therapeutics (Inst), Sanofi (Inst), Celldex Therapeutics; Travel/Accommodation/Expenses: Roche, Novartis, Grünenthal Group, Pierre Fabre, GP Pharm, Eisai. N. Chic: Travel/Accommodation/Expenses: Novartis, Eisai, Pierre Fabre. R. Dienstmann: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Research grant/Funding (self): Merck; Research grant/Funding (self): Pierre Fabre. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca, Daiichi Sankyo, Merck, Sharp and Dohme España SA, Novartis, Pfizer, Puma, Synthon; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene, Clovis Oncology, Eisai, F. Hoffmann-La Roche Ltd., Genomic Health, Odonate Therapeutics, Philips Healthwork, Pierre Fabre, prIME Oncology, Sanofi Aventis, Zymeworks; Research grant/Funding (institution): Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Piqur Therapeutics, Roche, Synthon. A. Prat: Advisory/Consultancy, Research grant/Funding (self): Novartis Farma, SA; Advisory/Consultancy: Lilly Spain; Advisory/Consultancy: Pfizer, SLU; Advisory/Consultancy, Research grant/Funding (self): Roche Farma, SA; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Amgen, SA; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Oncolytics Bioteck; Research grant/Funding (self): Sysmex Europe GmbH; Research grant/Funding (self): Medica Scientia Inno, Research, SL; Research grant/Funding (self): Celgene, SLU; Research grant/Funding (self): Astellas Pharma, SA; Research grant/Funding (self): NanoString Technologies; Officer/Board of Directors, Member executive Board: Breast International Group (BIG).; Officer/Board of Directors, Member executive Board and Foundation: SOLTI; Research grant/Funding (self): Puma; Research grant/Funding (self): Incyte. V. Serra: Research grant/Funding (self): Novartis, Genentech. All other authors have declared no conflicts of interest.

Collapse

40TiP - SOLTI-1802 ONAWA Trial: A Window of Opportunity Trial of Onapristone (ONA) in Postmenopausal Women with Estrogen and Progesterone Receptor-Positive/HER2-negative (ER+/PgR+/HER2-) Early Breast Cancer (EBC)

Abstract

Background

PgR expression is a biomarker of ER functionality, cellular progression to malignancy, and response to endocrine therapy (ET) in HR+ BC. ONA, a type I antiprogestin showed activity in patients with metastatic BC, but early trials with its immediate release formulation showed liver toxicity and further studies were halted. The development of a new extended-release formulation (Context Therapeutics, PA, USA), which is associated with a lower liver toxicity (Cottu PH, PLOS ONE, 2018) has strongly supported the relaunching of ONA clinical development. ONA blocks Ser294 phosphorylation of PgR, a posttranslational event associated with elevated PgR transcriptional activity coupled to rapid PgR turnover and also, downregulates PgR gene targets both in tumor cells expressing a sumo-deficient/phospho-mimic activated (KR) and non-activated (WT) PgR phenotype, independent to the presence of progesterone. Considering BC heterogeneity and that PgR analysis by standard immunohistochemistry (IHC) does not perfectly correlate with PgR target gene expression, the identification of biomarkers allowing the selection of patients with PgR-driven tumors that may benefit from antiprogestins treatment is currently an unmet need.

Trial design

ONAWA is an open-label, single arm, multicenter window of opportunity clinical trial of ONA (50 mg extended-release tablets BID for 21 days) for postmenopausal women with EBC amenable to receive a short course of ET before surgery. Ten patients with ER+/PgR+/HER2- and ki67 ≥ 15% BC will be enrolled at 4 sites of the SOLTI network. The primary objective is to evaluate the biological activity of ONA by the rate of Complete Cell Cycle Arrest determined by Ki67 (≤2.7%). Secondary endpoints include safety and correlating biological activity with IHC of tumor expression (ER, PgR, Ser294-PgR, CD24, CD44, ALDH1, Ki67), estradiol, and progesterone blood levels, and gene expression profile (NanoString nCounter® Breast 360TM panel). The study was approved in July 2020 and recruitment started in November 2020. Seven patients have been enrolled at the time of this submission.

Clinical trial identification

NCT04142892; EudraCT Number: 2019-001433-13.

Legal entity responsible for the study

SOLTI Breast Cancer Research Group.

Funding

Context Therapeutics.

Disclosure

X. González-Farré: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): Eisai; Honoraria (self): SOLTI. P. Villagrasa: Speaker Bureau/Expert testimony: NanoString. A. Prat: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (self): NanoString; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: Amgen; Advisory/Consultancy: Puma. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Hoffman-La Roche; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Genomic Health; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sharp and Dhome España SA; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Philips Healthwork; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: prIME Oncology; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Puma; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Synthon; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi Aventis. All other authors have declared no conflicts of interest.

Collapse

Presenter Of 1 Presentation

 On-Demand ePoster Display

40TiP - SOLTI-1802 ONAWA Trial: A Window of Opportunity Trial of Onapristone (ONA) in Postmenopausal Women with Estrogen and Progesterone Receptor-Positive/HER2-negative (ER+/PgR+/HER2-) Early Breast Cancer (EBC)

Abstract

Background

PgR expression is a biomarker of ER functionality, cellular progression to malignancy, and response to endocrine therapy (ET) in HR+ BC. ONA, a type I antiprogestin showed activity in patients with metastatic BC, but early trials with its immediate release formulation showed liver toxicity and further studies were halted. The development of a new extended-release formulation (Context Therapeutics, PA, USA), which is associated with a lower liver toxicity (Cottu PH, PLOS ONE, 2018) has strongly supported the relaunching of ONA clinical development. ONA blocks Ser294 phosphorylation of PgR, a posttranslational event associated with elevated PgR transcriptional activity coupled to rapid PgR turnover and also, downregulates PgR gene targets both in tumor cells expressing a sumo-deficient/phospho-mimic activated (KR) and non-activated (WT) PgR phenotype, independent to the presence of progesterone. Considering BC heterogeneity and that PgR analysis by standard immunohistochemistry (IHC) does not perfectly correlate with PgR target gene expression, the identification of biomarkers allowing the selection of patients with PgR-driven tumors that may benefit from antiprogestins treatment is currently an unmet need.

Trial design

ONAWA is an open-label, single arm, multicenter window of opportunity clinical trial of ONA (50 mg extended-release tablets BID for 21 days) for postmenopausal women with EBC amenable to receive a short course of ET before surgery. Ten patients with ER+/PgR+/HER2- and ki67 ≥ 15% BC will be enrolled at 4 sites of the SOLTI network. The primary objective is to evaluate the biological activity of ONA by the rate of Complete Cell Cycle Arrest determined by Ki67 (≤2.7%). Secondary endpoints include safety and correlating biological activity with IHC of tumor expression (ER, PgR, Ser294-PgR, CD24, CD44, ALDH1, Ki67), estradiol, and progesterone blood levels, and gene expression profile (NanoString nCounter® Breast 360TM panel). The study was approved in July 2020 and recruitment started in November 2020. Seven patients have been enrolled at the time of this submission.

Clinical trial identification

NCT04142892; EudraCT Number: 2019-001433-13.

Legal entity responsible for the study

SOLTI Breast Cancer Research Group.

Funding

Context Therapeutics.

Disclosure

X. González-Farré: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): Eisai; Honoraria (self): SOLTI. P. Villagrasa: Speaker Bureau/Expert testimony: NanoString. A. Prat: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (self): NanoString; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: Amgen; Advisory/Consultancy: Puma. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Hoffman-La Roche; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Genomic Health; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sharp and Dhome España SA; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Philips Healthwork; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: prIME Oncology; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Puma; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Synthon; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi Aventis. All other authors have declared no conflicts of interest.

Collapse