Background

The HER2DX assay is prognostic in early-stage HER2-positive breast cancer by integrating tumor and nodal staging, and the expression of 3 gene signatures tracking immunoglobulin (IGG)-mediated immunity, proliferation, and luminal differentiation. Here, we assessed the prognostic value of each of the 3 HER2DX signatures in eTNBC.

Methods

Clinical and genomic data from 704 patients with eTNBC were retrieved from METABRIC (n=267), TCGA (n=118), GSE58812 (n=107), SCANB (n=126), GSE21653 (n=86). Association of IGG signature with event-free survival (EFS) was also obtained from CALGB40603 (n=443). Univariate cox regression models were used to evaluate each of the 3 signatures with relapse-free survival (RFS), EFS and overall survival (OS). Results were pooled using a random effects model to select signatures most consistently associated with survival. A new research-based HER2DX risk score with the IGG signature, tumor size (pT1 vs other) and nodal status (pN0 vs pN1 vs pN2-3) was also evaluated. Univariate cox regression models and C-statistics were used to evaluate the prognostic value of each variable.

Results

Among the 3 signatures, the 14-gene IGG signature was associated with better RFS/OS in METABRIC, better EFS in GSE21653 and CALGB40603 and better OS in SCANB (Table). The pooled analysis confirmed the association of IGG signature with RFS/EFS (HR=0.81 [95% CI 0.70-0.93], I²=18%) and OS (HR=0.80 [0.69-0.92], I²=0%). The new research-based risk score integrating tumor size, nodal status, and IGG signature (called TNBC-DX) was significantly associated with RFS/EFS and OS in all datasets (Table). TNBC-DX risk score showed higher predictive performance compared with clinical variables alone, with a C-index ranging from 0.61 to 0.80 across datasets. Table: 3MO

Conclusions

A risk score integrating tumor size, nodal staging and the IGG signature might be a valuable prognostic biomarker in eTNBC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Brasó-Maristany, L. Paré: Financial Interests, Personal, Licensing Fees, HER2DX patent: Reveal Genomics. P.F. Conte: Financial Interests, Personal, Advisory Board: Daiichi Sankyo/Lilly, Reveal Genomics, Gilead Sciences; Financial Interests, Personal, Speaker’s Bureau: Roche/Genentech, AstraZeneca, Tesaro, BMS, Eli Lilly; Financial Interests, Institutional, Research Grant: Roche, Merck KGaA, Novartis, BMS; Financial Interests, Personal, Licensing Fees, HER2DX Patent: Reveal Genomics; Financial Interests, Personal, Expert Testimony: Roche, AstraZeneca; Financial Interests, Personal, Other, Travel Accomodations: AstraZeneca, Celgene, Novartis, Pfizer. A. Vivancos: Financial Interests, Personal, Stocks/Shares: Reveal Genomics. P. Villagrasa Gonzalez: Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Advisory Board: Reveal Genomics; Financial Interests, Personal, Licensing Fees, HER2DX patent: Reveal Genomics. J. Parker: Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Advisory Board: Reveal Genomics. C.M. Perou: Financial Interests, Personal, Stocks/Shares: Reveal Genomics, BioClassifier LLC; Financial Interests, Personal, Advisory Board: Reveal Genomics. A. Prat: Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Advisory Board: Reveal Genomics; Financial Interests, Personal, Licensing Fees, HER2DX patent: Reveal Genomics; Financial Interests, Personal and Institutional, Other, Grants and Personal Fee: Daiichi Sankyo Roche AstraZeneca Foundation Medicine Oncolytics Biotech Novartis. All other authors have declared no conflicts of interest.

Background

Pelareorep (pela) is an intravenously delivered non-engineered oncolytic reovirus demonstrating anti-tumor activity through innate and adaptive immune responses. Previous data from the AWARE-1 study demonstrated that addition of atezolizumab (atezo) to pela increased the CelTIL score (study’s primary endpoint) by more than 30% in 60% of HR+/HER2- early breast cancer (BC) patients. CelTIL is a composite measure of tumor cellularity and tumor-infiltrating lymphocytes (TILs) and has been associated with a better prognosis in BC. The increase in CelTIL score observed in AWARE-1 was accompanied by PD-L1 upregulation. Here we report additional translational research results from AWARE-1.

Methods

HR+/HER2- early BC patients were enrolled in two cohorts: Cohort 1 (C1)– pela + letrozole (n=10); and Cohort 2 (C2)– pela + letrozole + atezo (n=10). Pela was administered on days 1, 2 and 8, 9, and atezo was given on day 3. Tumor biopsies collected pre-treatment and on days 3 and 21 were examined by immunohistochemistry (IHC), T cell receptor sequencing (TCR-seq), digital spatial profiling (DSP), and the PAM50 assay. Blood samples collected at these timepoints were evaluated by TCR-seq and flow cytometry.

Results

IHC showed a significant increase (p-value=0.04) in caspase 3 staining in all patients from day3 to day 21 that reached significance in C2. PAM50 analysis indicated a conversion of baseline disease from luminal B to luminal A in both cohorts, with 100% of patients converting to luminal A in C2. TCR-seq showed a decrease in pre- vs. post-treatment blood T cell diversity in both cohorts, which was significant (p-value=0.01) in C2. An association between decreased post-treatment T cell diversity and pre- vs. post-treatment increases in TILs was observed in both cohorts, reaching significance in C2 (p-value=0.01). DSP showed an increase in activated T cells but not exhausted T cells in both cohorts.

Conclusions

These data show that pela induces an inflamed tumor phenotype and demonstrate its synergy with atezo. Moreover, these data support pela’s immune-based mechanism of action and suggest that combining pela with atezo may improve outcomes in BC.

Clinical trial identification

EudraCT number: 2018-003345-42.

Legal entity responsible for the study

Oncolytics Biotech Inc.

Funding

Oncolytics Biotech Inc.

Disclosure

J. Gavila Gregori: Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Roche. H. Loghmani: Financial Interests, Personal, Full or part-time Employment: Oncolytics Bioteh Inc. L.M. Manso Sanchez: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Tesaro; Financial Interests, Personal, Advisory Board: Pfizer. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. M. Juan: Financial Interests, Personal, Advisory Role: Grifols. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: AMgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. T.C. Heineman: Financial Interests, Personal, Officer, Chief Medical Officer: Oncolytics Biotech; Financial Interests, Personal, Stocks/Shares: Oncolytics Biotech. All other authors have declared no conflicts of interest.

Background

A possible association between changes in tumor variant allele fraction (VAF) from baseline to cycle 2/ day 1 (C2D1) using the 74-gene Guardant360 assay and progression free survival (PFS) was observed in 45 patients (pts) with ABC treated with a CDK4/6i + ET. Here, we tested the same methodology in an independent dataset and explored the association between overall survival (OS), intrinsic subtype (IS) and ctDNA dynamics.

Methods

Baseline and C2D1 plasma samples were obtained from 113 pts with HR+/HER2-negative ABC treated with CDK4/6i + ET in an international, multicentric observational study. The first 45 pts were used to derive the mean VAF ratio (mVAFR: mean of the log VAFR for all mutations) methodology associated with PFS (NPJ Breast Cancer 2021). mVAFR was calculated for each alteration with a VAF ≥0.4% at any time point. Pts with VAFs <0.4% at all timepoints were considered to have ctDNA-low disease. Molecular response was defined by the mVAFR. The main objective was to assess the association of mVAFR with PFS in the 68-pt independent validation cohort. We also explored the association of mVAFR with OS (n=113) and with IS (n=54). PFS and OS uni- and multivariable cox models were performed adjusting for clinical variables.

Results

With a median follow up (mFUP) of 16.6 months (m), pts with medium or high mVAFR had shorter median PFS than pts with low mVAFR and ctDNA-low disease (11.2 vs 25.0m; adjusted hazard ratio [aHR]=2.85, 95% confidence interval [CI] 1.2-6.7, p=0.017). mVAFR as a continuous variable was also found associated with PFS (HR=2.0, 95% CI 1.0–4.1, p=0.047). In the 113-pt combined cohort, with a mFUP of 19.4m, pts with medium or high mVAFR had shorter OS than pts with either low mVAFR or ctDNA-low disease (31.3m vs not reached; aHR=10.9, 95% CI 3.7-31.6, p<0.001). mVAFR as a continuous variable was also found associated with OS (aHR=4.1, 95% CI 1.7-9.5, p<0.001). Finally, mVAFR was associated with IS (p=0.022).

Conclusions

Early ctDNA dynamics after CDK4/6i + ET can identify different pt populations. The absence of molecular response identifies pts with poor outcome, and future studies should focus on improving treatment options for this population.

Legal entity responsible for the study

The authors.

Funding

AstraZeneca.

Disclosure

O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Personal, Expert Testimony: Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche; Financial Interests, Personal, Other, International conference travel grants: Pfizer; Financial Interests, Personal, Other, International conference travel grants: Lilly; Financial Interests, Personal, Expert Testimony: Eisai; Financial Interests, Personal, Advisory Board: Pierre Fabre. I. Faull: Financial Interests, Member of the Board of Directors: Guardant Health. J. Odegaard: Financial Interests, Personal, Member of the Board of Directors: Guardant Health. G. Patel: Financial Interests, Personal, Member of the Board of Directors: AstraZeneca. R. McEwen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. D. Carroll: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche; Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Lilly; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Lilly; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Novartis; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor: AstraZeneca; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Non-permanent advisor: MSD; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for NEREA trial (sponsor: SOLTI Group): Puma; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: Amgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

Background

Changes occurring in host-associated microbial communities (i.e. microbiota) may modulate responses to checkpoint blockade immunotherapy. We previously showed that anti-programmed cell death 1 protein P added to microtubule-targeting chemotherapy E has an encouraging antitumor activity in HR+ MBC pts regardless of programmed death-ligand 1 status. The CALADRIO study assessed the impact of gut and oral microbiota on clinical outcome of pts from the KELLY trial.

Methods

The phase 2 KELLY trial investigated the efficacy and safety of P plus E in 44 pts with pre-treated, HR+, HER2-negative, locally recurrent inoperable or MBC (NCT03222856). Fecal and saliva samples were prospectively collected at baseline (BL), after 3 cycles, and end of treatment from a subset of pts. Tumor response was grouped into clinical benefit (CB; complete or partial responses, or stable disease [SD] ≥24 weeks) and no CB (SD <24 weeks or progressive disease) as per RECIST 1.1. Shotgun metagenomic and 16S rRNA gene sequencing were used to characterize fecal and saliva microbiota profiles, respectively. Microbiota data were analyzed using MEGAHIT, LEfSe, Wilcoxon ranked sum, and PERMANOVA methods.

Results

A total of 58 fecal and 68 saliva samples were collected. Overall P+E did not cause significant gut or oral microbiota perturbations, indicating any drug-related microbial toxicity. Across all pts, dominant gut microbiota genera included Bacteroides and Faecalibacterium, with a common oral microbe, Prevotella, also present. LeFSe analysis suggested CB was driven in part by gut-associated Bacteroides fragilis and oral-associated Streptococcus with an abundance ≥50%. Pts experiencing CB had gut and oral microbiota richness at BL and a decrease over treatment potentially related to the antibiotic usage. Several typical oral microbes in both saliva and fecal samples were also observed, suggesting a potential translocation along the oral-gut axis.

Conclusions

These preliminary findings suggest potential avenues for downstream microbiota pts stratification before commencement of treatment. Further investigation is required in larger cohorts.

Clinical trial identification

NCT03222856.

Legal entity responsible for the study

MEDSIR.

Funding

MEDSIR.

Disclosure

M. Gion Cortes: Financial Interests, Personal, Sponsor/Funding: Roche; Financial Interests, Personal, Sponsor/Funding: Pfizer. J.M. Perez Garcia: Non-Financial Interests, Personal, Advisory Role: Roche; Non-Financial Interests, Personal, Advisory Role: Lilly; Non-Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Sponsor/Funding: Roche. A. Prat: Non-Financial Interests, Personal, Full or part-time Employment: Novoartis; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Sponsor/Funding: Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, Amgen, Guardant Health; Non-Financial Interests, Personal, Advisory Role: Amgen, Roche, Novartis, Pfizer, Bristol Myers Squibb, Boehringer, Puma, Oncolytics Biotech, Daiichi Sankyo, AbbVie, AstraZeneca, NanoString Technologies (to the Institution); Financial Interests, Institutional, Funding: Roche, Novartis, Incyte, Puma Biotechnology; Financial Interests, Personal, Ownership Interest: Patents:- PCT/EP2016/080056, - WO/2018/096191, US 63/023785, HER2DX (filing); Financial Interests, Personal, Sponsor/Funding: Daiichi Sankyo; Other, Personal, Other: Oncolytics, Peptomyc S.L. A. Llombart Cussac: Non-Financial Interests, Personal, Leadership Role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD;; Financial Interests, Personal, Stocks/Shares: MEDSIR, Initia-Research; Non-Financial Interests, Institutional, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre Fabre, GenomicHealth, GSK; Non-Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, MSD; Financial Interests, Personal, Funding: Roche, Foundation Medicine, Pierre Fabre, Agendia; Financial Interests, Personal, Sponsor/Funding: Roche, Lilly, Novartis, Pfizer, AstraZeneca. M. Mancino: Financial Interests, Personal and Institutional, Full or part-time Employment: MEDSIR. J. Cortés: Non-Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology.; Financial Interests, Personal, Sponsor/Funding: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo.; Financial Interests, Personal and Institutional, Funding: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London.; Financial Interests, Personal, Stocks/Shares: MEDSIR. A. Malfettone: Financial Interests, Personal and Institutional, Full or part-time Employment: MEDSIR. All other authors have declared no conflicts of interest.

Background

The 27-gene HER2DX prognostic assay has been evaluated in >1300 patients (pts) with early-stage HER2+ breast cancer (BC) (EBioMedicine 2022). Here, we explored the association of the research-based HER2DX with a list of 485 genes linked to relapse-free survival (RFS) in the N9831 pivotal trial (JCO 2015).

Methods

N9831 randomized 1282 pts with early-stage HER2+ BC to adjuvant multi-agent chemotherapy (CT) (arm A), 1-year of trastuzumab starting concomitantly with CT (arm B) and 1-year of trastuzumab after CT (arm C). In JCO 2015, 485 genes were significantly (p<0.01) associated with RFS in 849 pts in arms B/C using DASL technology. Here, the primary objective was to identify available genes from the HER2DX gene list associated with RFS in arms B/C. A representation factor and the probability of finding a gene overlap were calculated. The secondary objective was to compare the expression of the N9831 485 prognostic genes in research-based HER2DX low- vs high-risk groups in 376 HER2+ BCs from METABRIC and TCGA datasets. Differentially expressed genes between both risk groups were identified (false discovery rate<5%).

Results

Five genes (CD27, CD79A, IL2RG, LAX1 and PIM2) were found in both prognostic gene lists (N9831 and HER2DX) and all belong to the HER2DX IGG signature (5 of 11 genes available; 45.5%). In N9831, the RFS hazard ratio estimate for each gene was 0.84 (CD27; p=0.002), 0.78 (CD79A; p=0.005), 0.81 (IL2RG; p=0.002), 0.85 (LAX1; p=0.008) and 0.80 (PIM2; p=0.007). The overlap between the 2 gene lists was not due to chance (enrichment factor=10.7; p<0.001). Of the genes associated with better prognosis in N9831 (n=330), 96.8% in METABRIC and 96.9% in TCGA were significantly more expressed in the research-based HER2DX low-risk group compared to the high-risk group. Of the genes associated with worse prognosis in N9831 (n=155), 66.6% in METABRIC and 35.6% in TCGA were significantly more expressed in the research-based HER2DX high-risk group compared to low-risk group.

Conclusions

The biology captured by HER2DX is significantly associated with prognostic genes found in pts treated with adjuvant trastuzumab-based CT in the N9831 trial. This result reinforces the prognostic ability of HER2DX in early-stage HER2+ BC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

F. Brasó-Maristany: Financial Interests, Personal, Invited Speaker: Reveal Genomics. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche. L. Pare Brunet: Financial Interests, Personal, Full or part-time Employment: Reveal Genomics. M. Marín-Aguilera: Financial Interests, Personal, Full or part-time Employment: Reveal Genomics. P.F. Conte: Financial Interests, Personal, Expert Testimony, expert testimony for drug approval with AIFA: Roche; Financial Interests, Personal, Advisory Board, advisory board for alpelisb trial: Novartis; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Merch Kga; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis. V. Guarneri: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Invited Speaker: Synton Biopharmaceuticals; Financial Interests, Institutional, Invited Speaker: Merck. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. A. Vivancos: Financial Interests, Personal, Other, Consultant: Sysmex; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Bristol Meyers Squibb; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Other, Technology Transfer DX Field: Ferrer; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Bristol Meyers Squibb; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Novartis; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Debio; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: SYSMEX; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Cellestia Biotech; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Roche; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Chittern. J. Parker: Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Advisory Board: Reveal Genomics. P. Villagrasa Gonzalez: Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Officer: Reveal Genomics. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: Eli Lilly; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Novartis; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Gilead; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Genentech/Roche; Financial Interests, Personal, Other, Consultant: Nektar; Financial Interests, Personal, Other, Consultant: NanoString; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Eisai; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Sanofi; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Seagen; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Ad board participant/consultant/DSMC: Odonate; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Other, Consultant: Athenex; Financial Interests, Personal, Advisory Board, Ad board participant: OncoPep; Financial Interests, Personal, Advisory Board, Ad board participant: OncoSec; Financial Interests, Personal, Advisory Board, Ad board participant: Certara; Financial Interests, Personal, Advisory Board, Ad board participant: Mersana Therapeutics; Financial Interests, Personal, Advisory Board, Ad board participant: Ellipses Pharma; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: 4D Pharma; Financial Interests, Personal, Advisory Board, Ad board participant/consultant: Puma; Financial Interests, Personal, Invited Speaker, Invited speaker for pharma supported educational activity: Chugai Pharmaceuticals; Financial Interests, Personal, Advisory Board, Advisory board participant: G1 Therapeutics; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory Board participation: Zentalis; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board participation: OncXerna; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Eli Lilly; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Sanofi; Financial Interests, Institutional, Funding: Seagen; Financial Interests, Institutional, Funding: Odonate; Financial Interests, Personal and Institutional, Invited Speaker: CytomX; Financial Interests, Institutional, Funding: Cyclacel; Financial Interests, Institutional, Funding: Exelixis; Financial Interests, Institutional, Funding: Gilead; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Nektar; Financial Interests, Institutional, Funding: Genentech/Roche. L.A. Carey: Financial Interests, Institutional, Funding, research funding: Syndax; Financial Interests, Institutional, Funding, research funding: Immunomedics; Financial Interests, Institutional, Funding, research funding: Novartis; Financial Interests, Institutional, Funding, research funding: NanoString Technologies; Financial Interests, Institutional, Funding, research funding: AbbVie; Financial Interests, Institutional, Funding, research funding: Seattle Genetics; Financial Interests, Institutional, Funding, research funding: Veracyte; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: sanofi; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: Novartis; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: G1 Therapeutics; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: Genentech/Roche; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: GlaxoSmithKline; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: AstraZeneca/ Daiichi Sankyo; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: Apitude Health; Non-Financial Interests, Advisory Role, uncompensated relationship - all monies go to UNC. Dr. Carey does not have any signatory authority over any UNC account: Exact Sciences. C.M. Perou: Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Advisory Role: Reveal Genomics; Financial Interests, Personal, Stocks/Shares: BioClassifier LLC; Financial Interests, Personal, Advisory Role: BioClassifier LLC. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: AMgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

Background

Several Breast Cancer Multigene Signatures (BCMS) are available to profile early breast cancer (eBC) but knowledge regarding their use in clinical practice is scarce. PROCURE Project preliminary results were presented at ESMO Breast Virtual Congress 2021 (Abstract 549). Final results regarding the panelist opinion on the utility of BCMS in treatment decision making for different eBC patient profiles are now available.

Methods

The Delphi questionnaire developed by the Scientific Committee was administered twice to 133 experts across 11 European countries. The questionnaire included 5 sections: 1) Panelists’ profile and experience with BCMS, 2) Current clinical practice in eBC and use of BCMS, 3) Panelists’ opinion on the utility of the BCMS in eBC according to patient profiles, 4) Agreement with a set of recommendations on the use of BCMS in clinical practice and 5) Identification of unmet needs and future applications of BCMS. 70% agreement was used to determine consensus on a topic.

Results

Panelists agreed on the clinical utility of BC molecular intrinsic subtypes for prognosis or residual risk of recurrence with standard of care in eBC HR+ (76%) and to identify a group of patients that can safely avoid chemotherapy (75%). Additionally, panelist agreed on the importance of BCMS prognostic results when deciding chemotherapy in the adjuvant setting in eBC patients with node negative (88%) or with 1 to 3 positive lymph nodes (75%). Regarding BCMS use in different patient profiles, panelists agreed on their utility in post-menopausal eBC patients (90%) and on the absence of utility in the metastatic setting (74%), in eBC patients with an HER2 overexpressed profile (82%) and in eBC triple negative (TN) (74%). Also, just 27% of the panelist considered that BCMS can be useful in the neoadjuvant setting.

Conclusions

The low percentage of panelists performing BCMS in the neoadjuvant setting, the misconception regarding their predictive value on chemotherapy benefits and the fact that some experts consider BCMS useful in TN, HER2+ eBC or in the metastatic setting show that there is a need of education on how to interpret BCMS results.

Legal entity responsible for the study

Veracyte Inc.

Funding

Veracyte Inc.

Disclosure

G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Ellipsis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Veracyte; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS; Financial Interests, Institutional, Funding, Phase I studies: Novartis; Financial Interests, Institutional, Funding, Phase I studies: AstraZeneca; Financial Interests, Institutional, Funding, Phase I studies: Daiichi Sankyo; Financial Interests, Institutional, Funding, Phase I studies: Roche; Financial Interests, Institutional, Funding, Phase I studies: Blueprint Medicine; Financial Interests, Institutional, Funding, Phase I studies: Kymab; Financial Interests, Institutional, Funding, Phase I studies: Astellas; Financial Interests, Institutional, Funding, Phase I studies: Sanofi; Financial Interests, Institutional, Funding, Phase I studies: Philogen; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori. F. Cardoso: Financial Interests, Personal, Other, Consultancy: Amgen; Financial Interests, Personal, Other, Consultancy: Astellas/Medivation; Financial Interests, Personal, Other, Consultancy: AstraZeneca; Financial Interests, Personal, Other, Consultancy: Celgene; Financial Interests, Personal, Other, Consultancy: Daiichi Sankyo; Financial Interests, Personal, Other, Consultancy: Eisai; Financial Interests, Personal, Other, Consultancy: GE Oncology; Financial Interests, Personal, Other, Consultancy: Genentech; Financial Interests, Personal, Other, Consultancy: GlaxoSmithKline; Financial Interests, Personal, Other, Consultancy: Macrogenics; Financial Interests, Personal, Other, Consultancy: Medscape; Financial Interests, Personal, Other, Consultancy: Merck-Sharp; Financial Interests, Personal, Other, Consultancy: Merus BV; Financial Interests, Personal, Other, Consultancy: Mylan; Financial Interests, Personal, Other, Consultancy: Mundipharma; Financial Interests, Personal, Other, Consultancy: Novartis; Financial Interests, Personal, Other, Consultancy: Pfizer; Financial Interests, Personal, Other, Consultancy: Pierre Fabre; Financial Interests, Personal, Other, Consultancy: prIME Oncology; Financial Interests, Personal, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Sanofi; Financial Interests, Personal, Other, Consultancy: Samsung Bioepis; Financial Interests, Personal, Other, Consultancy: Seagen; Financial Interests, Personal, Other, Consultancy: Teva; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Daiichi; Financial Interests, Institutional, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: Fresenius GmbH; Financial Interests, Institutional, Invited Speaker: Genentech; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker: Ipsen; Financial Interests, Institutional, Invited Speaker: Incyte; Financial Interests, Institutional, Invited Speaker: Nektar Therapeutics; Financial Interests, Institutional, Invited Speaker: Nerviano; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker: Medigene; Financial Interests, Institutional, Invited Speaker: MedImmune; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Millenium; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Pierre Fabre; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Sanofi-Aventis; Financial Interests, Institutional, Invited Speaker: Sonus; Financial Interests, Institutional, Invited Speaker: Taiho Oncology; Financial Interests, Institutional, Invited Speaker: Tesaro; Financial Interests, Institutional, Invited Speaker: Tigris; Financial Interests, Institutional, Invited Speaker: Wilex; Financial Interests, Institutional, Invited Speaker: Wyeth; Non-Financial Interests, Leadership Role, President: ABC Global Alliance and ABC Consensus Conference and Guidelines; Non-Financial Interests, Member: ESMO; Non-Financial Interests, Member: ESO; Non-Financial Interests, Member: EORTC; Non-Financial Interests, Member: BCG; Non-Financial Interests, Member: IBCSG; Non-Financial Interests, Member: SOLTI; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Member: AACR; Non-Financial Interests, Member: EACR; Non-Financial Interests, Member: SIS; Non-Financial Interests, Member: ASPIC. M.I. Gnant: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Other, Consulting on scientific matters: LifeBrain; Financial Interests, Personal, Expert Testimony: Veracyte; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Full or part-time Employment: ABCSG GmbH; Financial Interests, Invited Speaker: Pfizer; Other, Spouse is employed by: Sandoz. N. Harbeck: Financial Interests, Invited Speaker: Amgen; Financial Interests, Invited Speaker: AstraZeneca; Financial Interests, Invited Speaker: Daiichi Sankyo; Financial Interests, Invited Speaker: Exact Sciences; Financial Interests, Invited Speaker: Gilead; Financial Interests, Invited Speaker: Lilly; Financial Interests, Invited Speaker: MSD; Financial Interests, Invited Speaker: Novartis; Financial Interests, Invited Speaker Pierre Fabre; Financial Interests, Invited Speaker: Pfizer; Financial Interests, Invited Speaker: Roches; Financial Interests, Invited Speaker: Seagen; Financial Interests, Advisory Board: AstraZeneca; Financial Interests, Advisory Board: Daiichi Sankyo; Financial Interests, Advisory Board: Gilead; Financial Interests, Advisory Board: Lilly; Financial Interests, Advisory Board: MSD; Financial Interests, Advisory Board: Novartis; Financial Interests, Advisory Board: Pfizer; Financial Interests, Advisory Board: Roche; Financial Interests, Advisory Board: Sandoz; Financial Interests, Advisory Board: Seagen. J. King: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Seagen; Financial Interests, Personal, Speaker’s Bureau: Novartis. A. Laenkholm: Financial Interests, Advisory Board: Merck; Financial Interests, Advisory Board: Agilent; Financial Interests, Funding: Novartis; Financial Interests, Funding: Roche. F. Penault-Llorca: Financial Interests, Funding: Veracyte; Financial Interests, Funding: Myriad; Financial Interests, Funding: Illumina; Financial Interests, Advisory Board: Veracyte; Financial Interests, Advisory Board: Exact Science; Financial Interests, Advisory Board: Myriad; Financial Interests, Advisory Board: Agendia; Financial Interests, Advisory Board: Illumina; Financial Interests, Other: Myriad; Financial Interests, Other: Veracyte. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: Amgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation.

Background

The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is »60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond.

Trial design

RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

AstraZeneca.

Disclosure

J. Balmana: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MedSir. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. I. Blancas López-Barajas: Non-Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Institutional, Research Grant: Lilly; Non-Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Kiowa-Kirin; Financial Interests, Personal, Advisory Board: Veracyte; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Pierre Fabre; Financial Interests, Personal, Speaker’s Bureau: Celgene; Financial Interests, Personal, Sponsor/Funding: Roche; Financial Interests, Personal, Sponsor/Funding: Pierre Fabre; Financial Interests, Personal, Sponsor/Funding: Novartis; Financial Interests, Personal, Sponsor/Funding: Pfizer; Financial Interests, Personal, Sponsor/Funding: Lilly; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: Amgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. V. Serra Elizalde: Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Other, WO2019122411A1: Methods based on the detection of rad51 foci in tumor cells: TBD; Financial Interests, Institutional, Research Grant, Testing various novel targeted agents in patient-derived tumour models: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Cyclin-dependent kinase (CDK) 4/6 inhibition + ER signaling blockade is a highly effective treatment option for metastatic ER+/HER2− BC. Preclinical studies show evidence of CDK 4/6 and programmed death-1 (PD-1) blockade synergy. CheckMate 7A8, a non-comparative, phase 2 study, evaluated neoadjuvant NIVO + PALBO + ANA in patients (pts) with ER+/HER2− primary BC. Here, we report safety outcomes from the safety run-in phase.

Methods

Eligible pts were men or postmenopausal women with newly diagnosed, histologically confirmed, untreated ER+/HER2− BC with primary tumor ≥ 2 cm, an ECOG performance status of 0/1, and eligible for post-treatment surgery. Pts received NIVO 480 mg IV every 4 wks (1 cycle), PALBO 125 mg (dose level [DL] 1) or 100 mg (DL 2) PO once daily (QD) for 3 wks per cycle, and ANA 1 mg PO QD, for 5 cycles total/until disease progression. Primary endpoint (safety run-in phase) was the number of pts with occurrence of dose-limiting toxicity (treatment-emergent adverse events [AEs] within 4 wks of treatment start).

Results

As of safety data review on 6 May 2021, 21 pts (DL 1: n = 9; DL 2: n = 12) were treated. Most common grade ≥3 treatment-related AEs (TRAEs) were elevated alanine or aspartate aminotransferase, neutropenia, and decreased white blood cell count in DL 1 (n = 2 each; 22.2%), and decreased neutrophil count (n = 5; 41.7%) in DL 2. 5 pts (DL 1) and 4 pts (DL 2) discontinued treatment due to toxicity, mainly grade ≥3 hepatic TRAEs (Table). The study was closed on 27 July 2021 after safety run-in ended. Additional safety and preliminary efficacy data (database lock: 3 February 2022) will be presented. Table: 92MO

Conclusions

Neoadjuvant NIVO + PALBO + ANA showed a higher incidence of grade ≥3 hepatic TRAEs than historical single-agent safety profiles. These findings show a potential safety risk for the use of endocrine therapy with PD-1 + CDK 4/6 blockade.

Clinical trial identification

NCT04075604.

Editorial acknowledgement

Writing and editorial assistance was provided by Vidya Rajagopalan of Evidence Scientific Solutions, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb, Princeton, NJ, USA.

Funding

Bristol Myers Squibb, Princeton, NJ, USA.

Disclosure

G. Jerusalem: Financial Interests, Institutional, Research Grant: Novartis, Pfizer; Financial Interests, Institutional, Royalties: Roche; Financial Interests, Personal, Other, Consulting Fees: Novartis, Amgen, Roche, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, AbbVie; Financial Interests, Personal, Invited Speaker, Honoraria: Novartis, Roche, Amgen, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Seagen; Financial Interests, Personal, Other, Travel/Accommodations/Expenses/Accommodations: Novartis, Roche, Pfizer, Lilly, Amgen; Financial Interests, Personal, Other, Travel/Accommodations/Expense: Bristol Myers Squibb, AstraZeneca; Financial Interests, Personal, Advisory Board: Novartis, Roche, Amgen, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, AbbVie; Financial Interests, Personal, Other, Medical Writing: Novartis, Roche, Lilly, Amgen, Bristol Myers Squibb, AstraZeneca, MedImmune, Merck. A. Prat: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Other, Honoraria: Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Roche, Amgen, Bristol Myers Squibb, Boehringer, Puma, Oncolytics Biotech, Daiichi Sankyo, AbbVie, AstraZeneca, NanoString Technologies; Financial Interests, Institutional, Sponsor/Funding, Research Funding: Novartis, Roche, Incyte, Puma Biotech; Financial Interests, Personal, Invited Speaker, Honoraria: Roche; Financial Interests, Personal, Stocks/Shares: Reveal Genomics; Financial Interests, Personal, Other, Honoraria: MSD Oncology, Lilly, Daiichi Sankyo, Amgen, Guardant Health; Financial Interests, Personal, Other, Travel/Accommodations/Expense: Daiichi Sankyo. R.F. Salgado: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb; Non-Financial Interests, Personal, Other, Travel/Accommodations: Roche, Puma, Merck. M. Reinisch: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Daiichi Sankyo, Roche, Seagen, Somatex, MSD, Lilly, Pfizer; Financial Interests, Personal, Member, Honoraria: Novartis; Financial Interests, Personal, Advisory Board, Consultancy: Somatex; Financial Interests, Personal, Other, Travel: Pfizer, Novartis. C. Saura: Financial Interests, Personal, Advisory Board: AstraZeneca, AX'Consulting, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann, ISSECAM, Medical Statistics Consulting, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, Seagen, Zymeworks; Non-Financial Interests, Institutional, Research Grant: Aragon Pharmaceuticals, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Bristol Myers Squibb, Byondis B.V., Cytomx Therapeutics, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, GlaxoSmithkline, Immunomedics, Innoup Farma, International Breast Cancer Study Group (IBCSG), Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merck, Merus, Millennium Pharmaceuticals, Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Sanofi-Aventis, Seattle Genetics, Synthon, Zenith Pharma; Non-Financial Interests, Personal, Member: American Association for Cancer Research (AACR), American Society for Clinical Oncology (ASCO), Geicam (Spanish Breast Cancer Research Group), SOLTI group (Academic research group in breast cancer), Spanish Society of Medical Oncology (SEOM). J. Filian, F. Ades, A. Mazzei-Abba: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. N. Huang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S.M. Tolaney: Financial Interests, Personal and Institutional, Other, Ad Board Participant/Consultant; Research Funding (to institution): Bristol Myers Squibb, AstraZeneca, Eli Lilly, Merck, Novartis, Seagen, Sanofi, Eisai, Gilead, Pfizer, Genentech/Roche, Odonate; Financial Interests, Institutional, Research Grant: Nektar, NanoString, Exelixis, Cyclacel; Financial Interests, Personal, Advisory Board: Certara, Mersana Therapeutics, G1 Therapeutics, OncoSec, OncoPep, CytomX, Athenex, Ellipses Pharma, 4D Pharma, Puma, Zymeworks, Zentalis, Reveal Genomics, OncXerna, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Chugai Pharma; Financial Interests, Personal, Other, Consultant: Blueprint Medicines. All other authors have declared no conflicts of interest.

Background

The PAMELA trial tested the hypothesis that patients (pts) with the HER2-enriched (HER2-E) subtype benefit the most from dual HER2 blockade. Here, we evaluated the survival outcomes of this trial.

Methods

PAMELA is a non-randomized, open-label, multicentric, prospective translational research study in stage I-IIIA HER2+ breast cancer designed to evaluate the ability of the PAM50 intrinsic subtypes to predict pCR in the breast (pCRB; in situ allowed) following 18 weeks of neoadjuvant lapatinib and trastuzumab. Patients with HR+ disease received letrozole (if postmenopausal) or tamoxifen (if pre-menopausal). The primary objective was to compare the pCRB rates of the HER2-E versus the non-HER2-E subtypes in the intent-to-treat population. Exploratory endpoints included disease-free survival (DFS) and distant disease-free survival (DDFS) measured from the date of surgery.

Results

139 (92%) of 151 included pts from PAMELA had follow-up information after surgery. 127 (91.4%) pts received adjuvant chemotherapy (CT), 69 (49.6%) pts with anthracycline-based CT. Median follow-up was 76.7 months [1.2-91.6]. 13 (9.4%) relapse events have occurred (9 distant metastatic events, 1 contralateral recurrence, 2 invasive locoregional relapses [ILR] and 1 in situ recurrence). 6 year DFS and DDFS were 91.7% and 93.7%, respectively. Of the 127 pts that received CT, 38 pts (29.9%) achieved pCRB. Among these, 4 relapses (1 metastatic, 1 contralateral recurrence, 1 ILR and 1 in situ recurrence) were observed. Among the 89 pts with no pCRB, 9 relapses (8 metastatic events and 1ILR) were observed. Of the 12 patients who did not receive CT, 6 (50%) pts achieved a pCRB, and no relapse events were observed. Tumor stage was associated with DDFS (p=0.032) but not with DFS. Of the 44, 88 and 7 pts with stage I, II and III tumors; 1, 6, and 2 distant relapses were observed, respectively. pCRB, intrinsic subtype or TILs were not associated with DFS or DDFS.

Conclusions

Despite the small sample size, PAMELA opens the door to study dual HER2 blockade without chemotherapy in selected pts. Achieving pCRB was not associated with survival in this exploratory analysis.

Clinical trial identification

NCT01973660.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

Novartis.

Disclosure

T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. M. Oliveira: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Seattle Genetics; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Genentech; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Immunomedics; Financial Interests, Institutional, Invited Speaker: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: GSK; Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim; Financial Interests, Institutional, Invited Speaker: Zenith Epigenetics; Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research. J. Cortés: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Cellestia; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Erytech; Financial Interests, Personal, Advisory Board: Athenex; Financial Interests, Personal, Advisory Board: Polyphor; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: LEUKO; Financial Interests, Personal, Advisory Board: Bioasis; Financial Interests, Personal, Advisory Board: Clovis oncology; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Celgene; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Samsung Bioepis; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Hibercell; Financial Interests, Personal, Advisory Board: BioInvent; Financial Interests, Personal, Advisory Board: Gemoab; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Ariad Pharmaceuticals; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Baxalta GMBH/Servier Affaires; Financial Interests, Institutional, Research Grant: Bayer healthcare; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Guardanth Health; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Piqur Therapeutics; Financial Interests, Institutional, Research Grant: Puma B; Financial Interests, Institutional, Research Grant: Queen Mary University of London; Other, Travel cost and expenses: Roche; Other, Travel cost and expenses: Novartis; Other, Travel cost and expenses: Eisai; Other, Travel cost and expenses: Daiichi Sankyo. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: Amgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

Background

Neoadjuvant endocrine therapy (NET) is an attractive scenario to find novel biomarkers in oestrogen receptor-positive/HER2-negative breast cancer (ER+/HER2- BC). In this context, PAM50 multigene panel has been validated as a relapse predictor. This study aims to determine if PAM50-derived risk of recurrence (ROR) indexes at diagnosis correlate with biomarkers of response to NET.

Methods

We collected samples from postmenopausal ER+/HER2- BC patients treated with NET (n=58) over 3 months. We analyzed gene expression by Prosigna®-PAM50 to determine at diagnosis the ROR indexes: the original, the one related to intrinsic subtypes genset (ROR-S) and ROR plus a proliferation index (ROR-P). We pathologically characterized surgical tumour specimens and evaluated Ki67 expression by IHC. We studied the statistical association between ROR and (1) Ki67 expression at surgery, (2) ΔKi67 ( = [(Ki67 (%)surgery) – (Ki67 (%)baseline)] / (Ki67 (%) in baseline)) and (3) mPEPI score (Table).

Results

First, we observed that tumours with a low ROR-S/P at diagnosis present low Ki67 expression after NET, conversely to those with a high ROR-S/P; both, p <0.0001. Regarding to ΔKi67 and ROR, tumours with strong decrease in Ki67 expression after NET presented a low ROR-S/P at diagnosis, compared to those with increase or not change in Ki67; p = 0.0041 and p = 0.0071, respectively. Similarly, we found a significant association between mPEPI and ROR-S/P. Tumours with low mPEPI also presented low ROR-S/P at diagnosis while high mPEPI correlates with high ROR-S/P; p = 0.0195 and p = 0.005, respectively. Table: 96P

Distribution of ROR-S/P, mPEPI score and Ki67 expression

Conclusions

This study supports use of PAM50 derived ROR indexes as a tool to individualize the use of NET, conjointly with other clinical parameters. However, more data is needed to validate these findings.

Legal entity responsible for the study

Biodonostia Health Research Institute, San Sebastián, Spain and Gipuzkoa Cancer Unit/OSI Donostialdea – Onkologikoa, San Sebastián, Spain.

Funding

Biodonostia Health Research Institute, San Sebastián, Spain and Gipuzkoa Cancer Unit/OSI Donostialdea – Onkologikoa, San Sebastián, Spain.

Disclosure

All authors have declared no conflicts of interest.

Background

HER2 positivity is a driver of endocrine resistance in hormone receptor-positive (HR+) breast cancer (BC). However, clinical data suggests the existence of a subset of HR+/HER2+ BC that might be endocrine sensitive with a natural history similar to HR+/HER2-, especially when HER2 signaling is blocked. Given the scarcity of data on genomic bases of endocrine sensitivity in HR+/HER2+ BC, we planned this gene expression analysis in the context of the PerELISA trial. Our aim is to characterize genomic features associated with endocrine sensitivity in HR+/HER2+ BC.

Methods

PerELISA is a multicentric neoadjuvant phase II trial that evaluated the efficacy of a chemotherapy-free regimen based on dual HER2 blockade (trastuzumab-pertuzumab) in combination with letrozole in HR+/HER2+ BC selected on the basis of Ki67 response after 14 days of letrozole alone (Guarneri, Ann Oncol 2019). Endocrine sensitivity was defined by protocol as relative Ki67 reduction ≥20% from baseline at day 14 (antiproliferative response). Expression of 555 genes on baseline tumor samples from 56 patients was quantified by nCounter platform.

Results

Using unpaired two-groups SAM analysis (FDR<1%), we identified 13 genes overexpressed in endocrine sensitive as compared to non-endocrine sensitive BC (NAT1, RERG, SCUBE2, RGS22, ERBB4, PGR, ADRA2A, H19, ESR1, IKBKB, CA12, CELSR1, IL6ST). No underexpressed gene was identified with FDR <1%. A published signature of RB loss (RBsig), previously reported to potentially predict resistance to CdK4/6 inhibitors in HR+/HER2- BC and to be associated with pCR rates in HR+/HER2+ BC treated with neoadjuvant chemotherapy (Malorni, Oncotarget 2016) was computed. RBsig levels were significantly lower in endocrine sensitive as compared to non-endocrine sensitive BC (t-test p=0.007).

Conclusions

A subgroup of HR+/HER2+ BC is sensitive to endocrine treatment, showing biological processes similar to those identified in HR+/HER2- BC. These patients might potentially represent ideal candidates for trials testing CdK 4/6 inhibitors in HR+/HER2+ BC.

Clinical trial identification

NCT02411344; EudraCT number: 2013-002662-40.

Legal entity responsible for the study

The authors.

Funding

Roche Italy (study drugs and financial support, but had no role in study design, data collection, data analysis, data interpretation); Italian Ministry of Health (GR-2013-02356771 to VG); Instituto de Salud Carlos III (ISCIII) through the Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013–2016 (PI16/00904 to AP), Banco Bilbao Vizcaya Argentaria Foundation to AP, Pas a Pas to AP, Save the Mama to AP; and the Breast Cancer Research Foundation to AP.

Disclosure

G. Griguolo: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eli Lilly; Other, Travel Support: Novartis; Other, Travel Support: Amgen; Other, Trave Support: Pfizer; Other, Travel Support: Daiichi Sankyo. M.V. Dieci: Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Eli lilly; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Exact Science; Financial Interests, Personal, Other, Consultancy: Pfizer; Financial Interests, Institutional, Research Grant: Veneto Institute of Oncology IOV-IRCCS; Financial Interests, Institutional, Research Grant: Italian Ministry of health; Financial Interests, Institutional, Research Grant: University of Padova. A. Frassoldati: Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal, Other, Personal fees: Novartis; Financial Interests, Personal, Other, Personal fees: Pfizer; Financial Interests, Personal, Other, Personal fees: Eli Lilly; Financial Interests, Personal, Other, Personal fees: Daiichi; Financial Interests, Personal, Other, Personal fees: Seagen. G.V. Bianchi: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Eli Lilly. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. F. Miglietta: Financial Interests, Personal, Other, Personal fees: Roche. P.F. Conte: Financial Interests, Personal, Expert Testimony, expert testimony for drug approval with AIFA: Roche; Financial Interests, Personal, Advisory Board, advisory board for alpelisb trial: Novartis; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: Merch Kga; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Novartis. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: AMgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. V. Guarneri: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Institutional, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Invited Speaker: Synton Biopharmaceuticals; Financial Interests, Institutional, Invited Speaker: Merck. All other authors have declared no conflicts of interest.

Background

Although the optimal sequential treatment (neoadjuvant therapy [NA] vs upfront surgery) for patients (pts) with cT1-2 cN0 HER2+ is unknown, previous studies suggest that NA is associated with lower rates of pN+ compared to those undergoing upfront surgery. Here, we evaluated the incidence of pathologic nodal disease in cT1-2 cN0 HER2+ pts treated with upfront surgery vs NA at 2 major academic hospitals in Spain.

Methods

We include consecutive pts with cT1-2 cN0 M0 HER2+ breast cancer treated with primary surgery or anti-HER2 NA followed by adjuvant anti-HER2 therapy between 01/2012 and 09/2021. Axillary ultrasound was performed in 86.7%. Nodes with isolated tumor cells were considered negative in the upfront surgery setting but positive when found after NA. Descriptive statistics were used, and the proportions between the 2 groups were compared with chi-square or Fisher exact testing.

Results

Among 293 pts analyzed; 122 (41.6%) were treated with initial surgery and 171 (58.4% with NA (72.9% multi-agent chemo + trastuzumab, 14.7% taxane + trastuzumab and 12.4% only anti-HER2 agents). No differences in mean age, grade or hormone receptor status were observed between pts who underwent NA vs pts with upfront surgery. Tumor size was significantly smaller in upfront surgery than in NA group (cT1a/b 68.0% vs 19.3%; p<0.001). Interestingly, the incidence of pN+ disease was higher among pts with upfront surgery than among pts with NA (26/122 (21.3%) vs 18/171 (10.5%); p=0.011). However, there were no significant differences in pN+ across cT categories among pts treated with upfront surgery (16.9% in cT1a/b vs 30.8% in cT1c-2; p=0.080). There was no difference in use of lymphadenectomy between both groups (surgery: 24/122 [19.7%] vs NA: 24/171 [14.0%], p=0.199).

Conclusions

Axillary positivity was lower in pts with cT1-2 cN0 HER2+ breast cancer undergoing NA compared to those pts treated with upfront surgery. The high rate of pN+ in upfront surgery in small tumors suggests the need of tools to properly select pts candidates to NA versus upfront surgery now that adjuvant opportunities such as T-DM1 are available. The most appropriate NA regimen in this setting is currently unknown.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Medical advisory: Reveal Genomics. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Personal, Expert Testimony: Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche; Financial Interests, Personal, Other, International conference travel grants: Pfizer; Financial Interests, Personal, Other, International conference travel grants: Lilly; Financial Interests, Personal, Expert Testimony: Eisai; Financial Interests, Personal, Advisory Board: Pierre Fabre. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research:: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardant Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: Amgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

Background

In patients with operable early HER2+ breast cancer (BC), neoadjuvant systemic treatment (NST) is a standard approach. Recent studies for dual HER2 blockage regimes revealed pathologic complete response (pCR) rates up to 75%. These data cast doubt on the role of locoregional therapy in this population. In ELPIS trial, our multidisciplinary team proposes to omit surgery and sentinel node dissection (but not radiotherapy) in 25 highly selected patients who achieve, following anti-HER2 NST, a complete response by imaging (MRI) and a negative vacuum-assisted breast biopsy (VAC) in the tumor residual bed.

Trial design

ELPIS is single arm, unicenter, exploratory study in women with primary operable HER2+, HER2-enriched (HER2-E)/ERBB2-high BC according to PAM50 and a ERBB2 pre-defined cutoff (Prat, JNCI2020), to evaluate the omission of surgery and lymph node dissection in patients who achieving a complete response following standard anti-HER2 NST. Eligibility criteria include tumor largest diameter ≤4 cm by MRI, unifocal, cN0 operable BC. Eligible patients will receive anthracycline based chemotherapy (only tumor size >2cm and ≤ 4 cm) and weekly paclitaxel for 12 weeks with trastuzumab and pertuzumab subcutaneous FDC (TP) for 5 doses. After NST, a breast MRI will be performed. If a complete response is observed on breast MRI, patients will undergo a VAC. If in the VAC are found histological changes in the tumor bed without neither invasive nor in situ carcinoma disease, patients will be eligible to omit loco-regional surgery. Whole breast radiotherapy without nodal radiotherapy will then be performed. TP will be continued to complete 1 year. If invasive and/or in situ disease are identified, patients will undergo surgery and radiotherapy if it is indicated and they will continue with T-DM1. The primary objective is to estimate the loco-regional invasive disease-free survival at 3-year of patients who achieve a complete response based on MRI and VAC and omit loco-regional surgery. Tumor tissue and blood samples will be collected for biomarker research. The first patient was enrolled on March 30th 2020.

Clinical trial identification

NCT04578106, First Posted: October 8, 2020.

Legal entity responsible for the study

Fundacio Clinic Barcelona.

Funding

Roche Pharma AG.

Disclosure

T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lilly. M. Munoz: Financial Interests, Personal, Expert Testimony: Roche; Financial Interests, Personal, Expert Testimony: Novartis; Financial Interests, Personal, Other, International conference travel grants: Roche; Financial Interests, Personal, Other, International conference travel grants: Pfizer; Financial Interests, Personal, Other, International conference travel grants: Lilly; Financial Interests, Personal, Expert Testimony: Eisai; Financial Interests, Personal, Advisory Board: Pierre Fabre. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Amgen; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Amgen; Financial Interests, Personal, Invited Speaker, Lecture fees: BMS; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: BMS; Financial Interests, Personal, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: NanoString; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Other, Contracted research: Novartis; Financial Interests, Institutional, Other, Contracted research: Roche; Financial Interests, Institutional, Other, Contracted research: Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Contracted research; Financial Interests, Personal, Invited Speaker, Lecture fees: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Oncolytics; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: MSD; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Guardan Health; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Lilly; Financial Interests, Institutional, Other, Clinical trials: Lilly; Financial Interests, Institutional, Other, Contracted research: Boehringer; Financial Interests, Institutional, Other, Contracted research: Sysmex Europa GmbH; Financial Interests, Institutional, Other, Contracted research: Medica Scientia inno. Research; Financial Interests, Institutional, Other, Contracted research: Celgene; Financial Interests, Institutional, Other, Contracted research: Astellas; Financial Interests, Institutional, Other, Clinical trials: Roche; Financial Interests, Institutional, Other, Clinical trials: AMgen; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Institutional, Other, Clinical trials: Boehringer; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

Background

A better understanding of the clinicopathological characteristics and clinical outcomes of all genes associated with hereditary breast cancer (HBC) is needed. Here, we describe the clinicopathological characteristics and the outcomes of patients (pts) with HBC identified at Hospital Clinic of Barcelona (HCB).

Methods

This is a retrospective study of 903 consecutive women diagnosed of BC and tested at the Hereditary Cancer Unit at HCB between 2016-2021. TruSight Cancer panel was used to analyze 16 genes in pts fulfilling clinical criteria for HBC. The primary objective was to determine the prevalence of pathogenic mutations (PM) and variants of uncertain significance (VUS). The secondary objective was to determine the pathological characteristics of tumors with a PM: pathologic Complete Response (pCR) following neoadjuvant (NA) chemotherapy (CT) and relapse-free survival (RFS). Student’s t-test or Mann–Whitney U test and Chi-squared or Fisher’s exact tests were used to compare the continuous and categorical variables respectively.

Results

PM and VUS were found in 108 (11.9%) and 164 (18%) pts, respectively. The PM identified were BRCA2 (31.5%), BRCA1 (23%), PALB2 (13%), CHEK2 (12%), ATM (7.4%), TP53 (4.6%), BRIP1 (3.7%), PTEN (2%), RAD51C (0.9%), MSH2 (0.9%). In pts with BRCA1-PM, higher rates of premenopausal status (84% vs. 76%, p=0.003), triple-negative BC (TNBC) (68% vs 25%, p=0.01), high Ki67 (70% vs 25%; p=0.009) and more tumor-infiltrating lymphocytes (37% vs 7%; p=0.04) were found compared to nonBRCA1-PM. In cases with BRCA2-PM, the 2 most common subtypes were Luminal B (33%) and Luminal A (20%). In cases with PALB2-PM, the 2 most common subtypes were Luminal B (56%) followed by TNBC (33%). No cases with CHEK2-PM were TNBC. The pCR rates following multi-agent NACT in 45 pts with a PM were 50% for BRCA1-PM, 21% for BRCA2-PM and 50% for PALB2. In 100 pts with early-stage BC and a PM, the 5-year RFS was 69% (95% CI 56%-85%).

Conclusions

Current clinical criteria for germline testing in BC pts identify 12% of pts with a PM. Overall, pts with early-stage BC and a PM were found to have a poor prognosis with a high rate of RFS. A better description of this group of pts would help us provide more suitable treatments.

Legal entity responsible for the study

Hospital Clinic of Barcelona.

Funding

Has not received any funding.

Disclosure

M.J. Vidal Losada: Other, Personal, Speaker’s Bureau: SOLTI. A. Prat: Financial Interests, Personal, Member of the Board of Directors: REVEAL; Financial Interests, Personal, Member of the Board of Directors: SOLTI; Financial Interests, Personal, Full or part-time Employment: QuironSalud. All other authors have declared no conflicts of interest.

Background

Efficacy and safety analysis from PATRICIA’s cohorts A & B showed that palbociclib plus trastuzumab is safe, exhibiting promising survival outcomes in trastuzumab pretreated HER2+/HR+ PAM50 Luminal A/B advanced BC (Ciruelos E. et al, CCR 2020), that were maintained after a median of >3 years of follow-up. Based on these encouraging results, PATRICIA trial is currently randomizing patients with HER2+/HR+, PAM50 Luminal tumors to palbociclib, trastuzumab and ET or TPC.

Trial design

PATRICIA is a randomized open-label, adaptive design, phase II study. Patients must have histologically confirmed HER2+/HR+ and PAM50-centrally confirmed Luminal A or B intrinsic subtype and have received at least 1 one prior line of anti-HER2 based regimes for locally advanced or metastatic BC. Patients are randomized 1:1 ratio to receive trastuzumab plus palbociclib at a standard dose of 125 mg/day orally 3 weeks/1 week off and ET (Cohort C1) or TPC (cohort C2). TPC options in cohort C2 are T-DM1, any ET or chemotherapy (gemcitabine, vinorelbine, capecitabine, eribulin, paclitaxel or a taxane) plus trastuzumab. Stratification factors include the number of previous regimens for advanced BC (1-2 vs ≥ 3) and the presence of visceral disease (yes vs no). Primary endpoint is progression-free survival. Secondary endpoints include disease control rate, overall objective response rate and median duration of response, safety, quality of life and biomarker analysis in tumor tissue and blood samples collected during the study. The study has an 80% power with one-sided alpha=0.1 to detect a HR of 0.62 in favor of the palbociclib cohort. A total of 102 patients with HER2+/HR+ PAM50 Luminal A or B tumors will be recruited in 35 sites in Spain. As of February 15^th, 2022, 156 patients were screened and 48 were included.

Clinical trial identification

NCT02448420.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

Pfizer.

Disclosure

E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche, Lilly; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for NEREA trial (sponsor: SOLTI Group): Puma; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. J. Ponce: Financial Interests, Other: Seagen, Novartis, Pfizer, AstraZeneca/Daiichi Sankyo, Lilly, Roche; Financial Interests, Advisory Role: Seagen, Novartis, AstraZeneca/Daiichi Sankyo, Roche. S. Pernas Simon: Financial Interests, Advisory Board: AstraZeneca, Daiichi Sankyo, Polyphor, Novartis, Seattle Genetics, Eisai, Pierre Fabre, Roche. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, LEUKO, Bioasis, Clovis Oncology, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Ellipses, Hibercell, BioInvent, Gemoab, Gilead; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo. I. Fernández: Financial Interests, Advisory Board: Roche, AstraZeneca; Financial Interests, Speaker’s Bureau: Pfizer, AstraZeneca, Roche, MSD, Clovis, Glaxo. M. Oliveira: Financial Interests, Personal, Advisory Board: Roche, GSK, Puma Biotechnology, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche, Seattle Genetics, Novartis, MSD, Guardant Health, Pfizer, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Genentech, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer Ingelheim, Zenith Epigenetics; Financial Interests, Invited Speaker: Roche; Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research: Roche, NanoString, Novartis, Roche, Pfizer, Boehringer, Sysmex Europa GmbH, Medica Scientia inno. Research, Celgene, Astellas; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer, Novartis, Amgen, BMS, NanoString, Contracted research, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Amgen, BMS; Financial Interests, Institutional, Invited Speaker, Lecture fees: NanoString; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Puma, Oncolytics, MSD, Guardan Health, Lilly; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Institutional, Other, Clinical trials: Lilly, Roche, Amgen, Boehringer; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. All other authors have declared no conflicts of interest.

Background

SOLTI TOT-HER3 study (NCT04610528) previously reported the biologic and clinical activity of HER3-DXd, a HER3 directed antibody drug conjugate, across the first 30 patients (Prat A, SABCS 2021). Here, we present the efficacy and safety results across all patients in the initial study cohort.

Methods

This window of opportunity, multicenter, pre-operative trial enrolled patients with untreated HR+/HER2- operable (≥1 cm) breast cancer (BC). Patients were categorized based on pre-treatment (pre-) ERBB3 mRNA levels and received a single dose of HER3-DXd (6.4 mg/kg). Primary objective was to evaluate the CelTIL score (Nuciforo P, Ann Oncol 2018) variation between pre- and post-treatment (C1D21) samples. Clinical, proteomic and genomic variables were associated with CelTIL changes. Adverse events (AEs) were graded according to CTCAE v5.0.

Results

Overall, 78 patients were enrolled and 77 were evaluable for the primary endpoint. Baseline characteristics were: mean age 53 years; median tumor size 21 mm; cN0 71%; mean Ki67 27%. Based on pre-ERBB3, tumors were classified as high (n=21), medium (n=21), low (n=21) and ultralow (n=14). All PAM50 subtypes were identified: Luminal (Lum) A 52%, LumB 41%, HER2-Enriched 3% and Basal-like 4%. The overall response rate was 45%. CelTIL increased significantly at C1D21 (mean diff.+6.8, p<0.001). This increase was observed among responders (p<0.001) but not in patients with stable disease (p=0.135). Non-Lum subtypes and high Risk Of Recurrence score were associated with high CelTIL response. Pre-ERBB3 was not associated with CelTIL change or clinical response. Paired Ki67 significantly decreased (p<0.001), while ERBB3 mRNA did not (p=0.13). At C1D21, immune genes were induced and proliferation genes were suppressed (False Discovery Rate=5%). Overall, 74 (95%) patients reported any grade AEs. Most common grade 3-4 AEs were: neutropenia (n=6), ALT increase (n=2) and diarrhea (n=1).

Conclusions

In untreated early HR+/HER2- BC, a single dose of HER3-DXd led to clinically meaningful response, increased immune infiltration and suppression of proliferation across varied levels of baseline ERBB3 mRNA. The safety profile was consistent with that previously reported.

Clinical trial identification

NCT04610528, released on October 30th 2020.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

Daiichi Sankyo.

Disclosure

A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research: Roche, Nanostring, Novartis, Roche, Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer, Novartis, Amgen, BMS, Nanostring, Contracted research, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Amgen, BMS, Puma, Oncolytics, MSD, Guardant Health, Lilly; Financial Interests, Institutional, Invited Speaker, Lecture fees: Nanostring; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Institutional, Other, Clinical trials: Lilly, Roche, Amgen, Boehringer; Financial Interests, Institutional, Other, Contracted research: Boehringer, Sysmex Europa GmbH, Medica Scientia inno. Research, Celgene, Astellas; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche. J.M. Cejalvo Andujar: Financial Interests, Personal, Speaker’s Bureau: Novartis, Pfizer, Roche. M. Margeli Vila: Financial Interests, Personal, Advisory Board: Novartis, Roche, Pfizer; Financial Interests, Personal, Research Grant: Roche, AstraZeneca, Eisai, Novartis, Pfizer. P. Tolosa: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Roche, Eli Lilly, AstraZeneca. J. Cruz Jurado: Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Lilly, Amgen, GlaxoSmithKline, Seagen, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Speaker’s Bureau: GlaxoSmithKline, AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Lilly, Celgene, Astellas, Amgen, Pfizer. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau, Educational activities: Roche, Lilly; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for NEREA trial (sponsor: SOLTI Group): PUMA; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. S. Pernas Simon: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Polyphor, Novartis, Seattle Genetics, Roche, Eisai, Pierre Fabre, Lilly. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly. M. Oliveira: Financial Interests, Personal, Other: Roche, Pierre Fabre, Novartis, Eisai, Immunomedics, AstraZeneca, Genentech, Seagen, Boehringer Ingelheim, PUMA Biotechnology, GSK, Zenith Epigenetics. Financial Interests, Personal, Advisory Role: Roche, GSK, PUMA Biotechnology, AstraZeneca, Pierre Fabre iTEOS. All other authors have declared no conflicts of interest.

Background

SOLTI TOT-HER3 study (NCT04610528) previously reported the biologic and clinical activity of HER3-DXd, a HER3 directed antibody drug conjugate, across the first 30 patients (Prat A, SABCS 2021). Here, we present the efficacy and safety results across all patients in the initial study cohort.

Methods

This window of opportunity, multicenter, pre-operative trial enrolled patients with untreated HR+/HER2- operable (≥1 cm) breast cancer (BC). Patients were categorized based on pre-treatment (pre-) ERBB3 mRNA levels and received a single dose of HER3-DXd (6.4 mg/kg). Primary objective was to evaluate the CelTIL score (Nuciforo P, Ann Oncol 2018) variation between pre- and post-treatment (C1D21) samples. Clinical, proteomic and genomic variables were associated with CelTIL changes. Adverse events (AEs) were graded according to CTCAE v5.0.

Results

Overall, 78 patients were enrolled and 77 were evaluable for the primary endpoint. Baseline characteristics were: mean age 53 years; median tumor size 21 mm; cN0 71%; mean Ki67 27%. Based on pre-ERBB3, tumors were classified as high (n=21), medium (n=21), low (n=21) and ultralow (n=14). All PAM50 subtypes were identified: Luminal (Lum) A 52%, LumB 41%, HER2-Enriched 3% and Basal-like 4%. The overall response rate was 45%. CelTIL increased significantly at C1D21 (mean diff.+6.8, p<0.001). This increase was observed among responders (p<0.001) but not in patients with stable disease (p=0.135). Non-Lum subtypes and high Risk Of Recurrence score were associated with high CelTIL response. Pre-ERBB3 was not associated with CelTIL change or clinical response. Paired Ki67 significantly decreased (p<0.001), while ERBB3 mRNA did not (p=0.13). At C1D21, immune genes were induced and proliferation genes were suppressed (False Discovery Rate=5%). Overall, 74 (95%) patients reported any grade AEs. Most common grade 3-4 AEs were: neutropenia (n=6), ALT increase (n=2) and diarrhea (n=1).

Conclusions

In untreated early HR+/HER2- BC, a single dose of HER3-DXd led to clinically meaningful response, increased immune infiltration and suppression of proliferation across varied levels of baseline ERBB3 mRNA. The safety profile was consistent with that previously reported.

Clinical trial identification

NCT04610528, released on October 30th 2020.

Legal entity responsible for the study

SOLTI Cancer Research Group.

Funding

Daiichi Sankyo.

Disclosure

A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Institutional, Other, Contracted research: Roche, Nanostring, Novartis, Roche, Pfizer; Financial Interests, Personal, Invited Speaker, Lecture fees: Pfizer, Novartis, Amgen, BMS, Nanostring, Contracted research, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Amgen, BMS, Puma, Oncolytics, MSD, Guardant Health, Lilly; Financial Interests, Institutional, Invited Speaker, Lecture fees: Nanostring; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Personal, Expert Testimony, Advisory role/consultancy: Peptomyc; Financial Interests, Institutional, Other, Clinical trials: Lilly, Roche, Amgen, Boehringer; Financial Interests, Institutional, Other, Contracted research: Boehringer, Sysmex Europa GmbH, Medica Scientia inno. Research, Celgene, Astellas; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation. O. Martinez Saez: Financial Interests, Personal, Invited Speaker: Novartis, Eisai; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel expenses: Roche. J.M. Cejalvo Andujar: Financial Interests, Personal, Speaker’s Bureau: Novartis, Pfizer, Roche. M. Margeli Vila: Financial Interests, Personal, Advisory Board: Novartis, Roche, Pfizer; Financial Interests, Personal, Research Grant: Roche, AstraZeneca, Eisai, Novartis, Pfizer. P. Tolosa: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, Roche, Eli Lilly, AstraZeneca. J. Cruz Jurado: Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Lilly, Amgen, GlaxoSmithKline, Seagen, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Speaker’s Bureau: GlaxoSmithKline, AstraZeneca, Roche, Novartis, PharmaMar, Eisai, Lilly, Celgene, Astellas, Amgen, Pfizer. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau, Educational activities: Roche, Lilly; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for NEREA trial (sponsor: SOLTI Group): PUMA; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. S. Pernas Simon: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Polyphor, Novartis, Seattle Genetics, Roche, Eisai, Pierre Fabre, Lilly. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly. M. Oliveira: Financial Interests, Personal, Other: Roche, Pierre Fabre, Novartis, Eisai, Immunomedics, AstraZeneca, Genentech, Seagen, Boehringer Ingelheim, PUMA Biotechnology, GSK, Zenith Epigenetics. Financial Interests, Personal, Advisory Role: Roche, GSK, PUMA Biotechnology, AstraZeneca, Pierre Fabre iTEOS. All other authors have declared no conflicts of interest.