F. Brasó-Maristany (Barcelona, Spain)

IDIBAPS - Institut D'Investigacions Biomèdiques August Pi i Sunyer

Author Of 3 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.

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23P - CDK4/6 inhibition and endocrine therapy (ET) in the HER2-enriched subtype (HER2-E) in hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer (ABC): a retrospective analysis of real-world data

Abstract

Background

The HER2-E subtype within HR+/HER2- ABC represents 10-25% and is characterized by poor prognosis. In the MONALEESA program, ribociclib + ET was found highly active in this subtype compared to ET. Here, we explored the prognostic and predictive value of HER2-E in patients (pts) treated with a CDK4/6 inhibitor (CDK4/6i) + ET in the real-world setting.

Methods

This is a retrospective study of 144 consecutive pts with HR+/HER2- ABC treated with a CDK4/6i + ET in the first line setting from 2014-2020 in Hospital 12 de Octubre (Madrid) and Clinic of Barcelona. Research-based PAM50 was performed in FFPE tumors collected before CDK4/6i (primary tumors or metastatic biopsies). Univariate and multivariable cox model progression-free survival (PFS) analyses were performed adjusting for the presence of visceral or “de novo” disease, menopausal status and performance status.

Results

114 pts (79%) had PAM50 data (50% primary/50% metastatic), and 47%/46%/7% received palbociclib/ribociclib/abemaciclib. Subtype distribution: Luminal A (33%), Luminal B (37%), HER2-E (19%), normal-like (8%) and Basal-like (5%). Median PFS for HER2-E disease was 7.4 months (mo) (95% confidence interval [CI] 5.0-22.0) and 21.1 mo (95% CI 16.6-31.3) for non-HER2-E disease (adjusted hazard ratio [aHRatio]=2.38, p=0.010). Median OS for HER2-E disease was 30.9 months (mo) (95% confidence interval [CI] 13.2-not reached [NR]) and NR (95% CI 47.2-NR) for non-HER2-E disease (aHRatio=4.39, p=0.021). Although exploratory and statistically non-significant, the PFS HRatio estimates of ribociclib vs palbociclib/abemaciclib in Luminal A, Luminal B and HER2-E subtype were 0.88, 0.90 and 0.44, respectively. Finally, the overall response rate of ribociclib in Luminal A/B and HER2-E disease was 40.5% and 42.9% vs 36.8% and 25.0% with palbociclib/abemaciclib.

Conclusions

In a real-world setting, we confirmed the poor prognosis of the HER2-E subtype in HR+/HER2- ABC. Despite the limitations, our results support the observation from the ML program where ribociclib in combination with ET was particularly active in the HER2-E subtype.

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III (PI19/01846) (to A.P.) Instituto 299 de Salud Carlos III (PI18/01408) (to E.C.) Breast Cancer Research Foundation (to 300 A.P.) PhD4MD (to N.C.) Fundació La Marató TV3 (to A.P) RESCUER Horizon 2020 301 (to A.P.) Save the Mama (to A.P.) Pas a Pas (to A.P.) Asociación Cáncer de Mama 302 Metastásico (to A.P.) Fundación Científica Asociación Española Contra el Cáncer (to 303 F.B.M.) Fundación SEOM (SEOM 2018 Grant: Fellowship for Training in 304 Research in Reference Centers) (to T.P.).

Disclosure

O. Martínez-Sáez: Advisory/Consultancy: Roche; Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: Eisai. P. Tolosa: Honoraria (institution), Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Eisai. T. Pascual: Advisory/Consultancy: Roche; Advisory/Consultancy: Genentech. N. Chic: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Pierre Fabre. J.C. Laguna: Speaker Bureau/Expert testimony: Kyowa Kirin. M. Vidal: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Daiichi Sankyo; Travel/Accommodation/Expenses: Pfizer. M. Muñoz: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Lilly; Speaker Bureau/Expert testimony: Pierre Fabre; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Eisai. A. Prat: Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Amgen; Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self): MSD Oncology; Advisory/Consultancy: NanoString Technologies; Honoraria (self): Lilly; Advisory/Consultancy: Pfizer. E.M. Ciruelos: Advisory/Consultancy: MSD; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest.

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109P - Subsequent therapies after progressing to CDK4/6 inhibition (CDK4/6i) in hormone receptor positive/HER2 negative (HR+/HER2-) advanced breast cancer (ABC)

Abstract

Background

There is limited data in the real world setting regarding the effectiveness of subsequent lines of treatment after progressing to CDK4/6i. The optimal therapeutic sequence is still unknown and predictors are needed.

Methods

This is a retrospective single-center study of 99 consecutive patients (pts) with HR+/HER2- ABC who progressed to CDK4/6i + endocrine therapy (ET) in the 1st or 2nd line setting between 05/2015-01/2021. Research-based PAM50 subtyping using the nCounter platform was performed in tumor samples collected before CDK4/6i. Median progression free survival (mPFS) and overall survival (mOS) were calculated using the Kaplan Meier method.

Results

mPFS with CDK4/6i in 1st line (59%) was 10.4 months (m) and 11.7m in 2nd line (41%). At the time of the analysis, 71% of patients had progressed to the subsequent line. mPFS and mOS after CDK4/6i were 5.3 and 19.6m, respectively. No correlation was observed between previous PFS on CDK4/6i and mPFS (p=0.74). mPFS with chemotherapy (CT) (45%) was 6.4m; with ET alone (18%), 2.9m; with ET + everolimus (eve) (10%), 5.1m; with PIK3CA inhibitors + ET (9%), 5.4m; and with other CDK4/6i + ET (3%), 9.1m. Fourteen percent of pts did not receive any subsequent treatment. Responses were only observed with CT (12/44), eve + ET (1/10) and CDK4/6i re-treatment (2/3). PAM50 data was available for 75 pts (75%). Luminal A (30%) showed a mPFS of 6.4m and mOS was not reached; Luminal B (33%), 7.6 and 42.1m; HER2-enriched (19%), 1.8 and 11.6m; Basal-like (10%), 7.9 and 11.5m. Luminal vs. non-luminal disease with ET had a mPFS of 2.9 and 3.7m (p=0.99); with target therapies + ET, 13.8 and 1.7m (p=0.026) and with ET 7.0 and 6.1m (p=0.094). Pts who showed progression to CDK4/6i as the best response (n=19) had a mPFS of 1.7m when treated with ET combinations (n=4) and 8.1m with CT (n=15).

Conclusions

Our exploratory results show limited benefit with post-CDK4/6i therapies, independently from previous PFS. PAM50 subtype remains prognostic in this context. Primary CDK4/6i refractory tumors might benefit more from CT than ET.

Legal entity responsible for the study

Hospital Clinic y Provincial of Barcelona.

Funding

Instituto de Salud Carlos III (PI19/01846) (to A.P.) Breast Cancer Research Foundation (to 300 A.P.) PhD4MD (to N.C.) Fundació La Marató TV3 (to A.P) RESCUER Horizon 2020 301 (to A.P.) Save the Mama (to A.P.) Pas a Pas (to A.P.) Asociación Cáncer de Mama 302 Metastásico (to A.P.) Fundación Científica Asociación Española Contra el Cáncer (to 303 F.B.M.) Fundación SEOM (SEOM 2018 Grant: Fellowship for Training in 304 Research in Reference Centers) (to T.P.).

Disclosure

J.C. Laguna: Speaker Bureau/Expert testimony: Kyowa Kirin. T. Pascual: Advisory/Consultancy: Roche; Advisory/Consultancy: Genentech. N. Chic: Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Novartis; Speaker Bureau/Expert testimony: Eisai; Travel/Accommodation/Expenses: Pier Fabre. M. Vidal: Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): Daiichi Sankyo; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Novartis. R. Moreno: Speaker Bureau/Expert testimony: Eisai. A. Prat: Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Lilly; Honoraria (self): Daiichi Sankyo; Travel/Accommodation/Expenses: Daiichi Sankyo; Research grant/Funding (self): Roche; Research grant/Funding (self): Novartis; Advisory/Consultancy: NanoString Technologies; Advisory/Consultancy: Amgen; Advisory/Consultancy: Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Bristol-Myers Squibb. M. Muñoz: Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pierre Fabre; Honoraria (self): Eisai; Advisory/Consultancy: Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Eisai; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Lilly. O. Martínez-Sáez: Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Roche; Speaker Bureau/Expert testimony: Eisai. All other authors have declared no conflicts of interest.

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Presenter Of 1 Presentation

 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.

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