Cristina Saura Manich (Barcelona, Spain)
Vall d'Hebron University HospitalAuthor Of 5 Presentations
Panel discussion (ID 477)
HER2-targeted ADCs in breast cancer (ID 391)
2MO - Development of a prognostic gene-expression signature for early stage HER2-positive breast cancer patients (ID 297)
- Serena Di Cosimo (Milan, Italy)
- Chiara Maura Ciniselli (Milan, Italy)
- Christos Sotiriou (Brussels, Belgium)
- Katherine Pogue-Geile (Pittsburgh, United States of America)
- Debora Fumagalli (Brussels, Belgium)
- Evandro De Azambuja (Brussels, Belgium)
- David Venet (Brussels, Belgium)
- Loris De Cecco (Milan, Italy)
- Nan Pong (Pittsburgh, United States of America)
- Vera Cappelletti (Milan, Italy)
- Elda Tagliabue (Milan, Italy)
- Yongyu Wang (Florham Park, United States of America)
- Cristina Saura Manich (Barcelona, Spain)
- Paolo G. Nuciforo (Barcelona, Spain)
- Sherko Kuemmel (Essen, Germany)
- Lajos Pusztai (New Heaven, United States of America)
- Maria Grazia Daidone (Milan, Italy)
- Sara Pizzamiglio (Milan, Italy)
- Giancarlo Pruneri (Milan, Italy)
- Paolo Verderio (Milan, Italy)
Abstract
Background
With increasing evidence showing the complexity of HER2-positive breast cancer, this study aimed to identify a gene-expression signature with potential prognostic value to assist therapeutic decision in the early disease setting.
Methods
Gene-expression profiles of NeoALTTO tumor biopsies before and after 2 weeks of neoadjuvant treatment were generated by microarrays (Clariom S, ThermoFisher). Genes associated with event free survival (EFS) were selected at the two time points with Cox univariate analysis and combined by multivariate approaches. Independent technical and clinical validation were sought.
Results
Overall, 180 patients were analyzed (NeoALTTO cohort, median follow-up 6.7 yrs [IQR 6.1-6.8]; 53 events). The expression of 18 genes combined by principal component analysis (S18) was significantly associated with EFS in the trastuzumab (T)-arm (Hazard Ratio for each unit increment [HR] 2.4, 95%Confidence Interval [CI] 1.6-3.5) and in the entire NeoALTTO cohort (HR 1.7, CI 1.4-2.2). Notably, S18 showed no overlap with HER2 and/or ESR1 genes and/or their signaling. A more parsimonious signature of five genes (S5) was next developed. Both S18 and S5 retained their prognostic value independently of pathological complete response, age, tumor size, estrogen receptor and node status both in the T-arm and in the entire NeoALTTO cohort. The prognostic value of S18 was technically confirmed by RNAseq in the T-arm (HR 2.1, CI 1.4-3.1) and entire cohort (HR1.3, CI 1.03-1.7) whereas the S5 was confirmed within the T-arm alone (HR 1.5, CI 1.1-1.9). An additional technical validation is currently ongoing by customized open arrays. The prognostic capability of S18 was clinically confirmed by in silico analysis of the Italian GHEA expanded access study of adjuvant trastuzumab (HR 1.9,CI 1.2-2.9). Currently, we are seeking to validate the prognostic value of S5 in the NSABP B-31 study and results are expected to be presented at the congress.
Conclusions
These findings hold the potential to accurately identify patients with early HER2-positive breast cancer at low risk of relapse when treated with trastuzumab-based therapy and may be useful to select patients for single or dual anti-HER2 therapies.
Legal entity responsible for the study
Serena Di Cosimo.
Funding
Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC) IG 20774 to Serena Di Cosimo.
Disclosure
Y. Wang: Financial Interests, Personal, Funding: Wang. All other authors have declared no conflicts of interest.
87P - EPClin vs OncotypeDx in invasive lobular cancer (ILC) (ID 101)
- Ines Leao (Vila Nova de Gaia, Portugal)
- Esther Zamora (Barcelona, Spain)
- Patricia Gomez Pardo (Barcelona, Spain)
- Miriam A. Arumi de Dios (Barcelona, Spain)
- Isabel Pimentel (Barcelona, Spain)
- Santiago Escriva de Romani (Barcelona, Spain)
- Carolina Ortiz Velez (Barcelona, Spain)
- Mara Cruellas Lapena (Barcelona, Spain)
- Lucia Sanz (Barcelona, Spain)
- Maria Borrell (Barcelona, Spain)
- KREINA S. VEGA CANO (Barcelona, Spain)
- Diego Gómez-Puerto (Barcelona, Spain)
- Javier De La Torre (Barcelona, Spain)
- Martin Espinosa-Bravo (Barcelona, Spain)
- Ana Mafalda Antunes De Melo e Oliveira (Barcelona, Spain)
- ROBERTA Fasani (Barcelona, Spain)
- Paolo G. Nuciforo (Barcelona, Spain)
- Cristina Saura Manich (Barcelona, Spain)
- Vicente Peg (Barcelona, Spain)
- Meritxell Bellet (Barcelona, Spain)
Abstract
Background
ILC represents ≈10% of all breast cancers (BC). Genomic signatures (GS) used to define prognosis and chemo (CT) benefit in early BC may capture mainly the biology of the most frequent invasive carcinoma non otherwise specified. Utility of OncotypeDx (ODx) for adjuvant CT decisions has been questioned in ILC. By contrast, EPclin performance seems to be similar for both histologies. We studied the role of ODx and EPclin to guide CT in our series of ILC patients (pts).
Methods
Pts with pT1-2N0-1 ER+/PgR±/HER2- ILC diagnosis from 2017 to 2021 and with EPclin or ODx data were reviewed (cohort 1 and 2, respectively). In each cohort, pts were classified in high vs low risk groups and clinicopathological features, percent of high risk pts and prescribed CT were analyzed. High risk defined as: EPClin score ≥3.3; ODx recurrence score ≥26 if >50y and ≥21 if ≤50y. In cohort 1, the likelihood of ODx high risk was calculated (https://utgsm.shinyapps.io/OncotypeDXCalculator/). Risk groups by ODx and by Endopredict (molecular part of EPclin assay, High risk ≥5) were correlated with Ki67, as both are based only in genomic results, while EPclin score also takes pT and pN into account.
Results
46 pts eligible. Median age: 61y; pre-menopausal: 33; EPClin 25, ODx 21; with no differences in pathological features between cohorts. Proportion of high risk pts and CT indication were both 48% with EPClin and 9.5% and 19% with ODx, respectively. In cohort 1, the calculated probability of an ODx high risk result was 4% for EPclin low risk and 5% for EPclin high risk pts. Risk groups defined by Endopredict correlated with median Ki67 (low risk 3% vs high risk 11%. P=.05), while no association with ODx was seen (low risk 8% vs high risk 13%).
Conclusions
In our ILC pts the EPclin use correlated with a greater proportion of high risk pts compared to ODx, consistently with prior non-comparative studies. Albeit findings are limited for the type of analysis (2 separate small size cohorts), the similarity in clinic-pathologic features among cohorts and the disparity between the EPClin risk groups and those predicted by the ODx calculator support a distinct performance of both GS in ILC. Interestingly, Ki67 values were associated with Endopredict score but not with ODx categories, suggesting that EPclin captures better the ILC underlying biology.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
92MO - Neoadjuvant nivolumab (NIVO) + palbociclib (PALBO) + anastrozole (ANA) for estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2_) primary breast cancer (BC): CheckMate 7A8 (ID 4)
- Sara M. Tolaney (Boston, United States of America)
- Guy Jerusalem (Liège, Belgium)
- Aleix Prat (Barcelona, Spain)
- Roberto F. Salgado (Wilrijk, Belgium)
- Mattea Reinisch (Essen, Germany)
- Cristina Saura Manich (Barcelona, Spain)
- Manuel Ruiz Borrego (Seville, Spain)
- Petros Nikolinakos (Athens, United States of America)
- Jeiry Filian (Princeton, United States of America)
- Felipe Ades (Lawrenceville, United States of America)
- Ning Huang (Princeton, United States of America)
- Antonella Mazzei-Abba (Boudry, Switzerland)
Abstract
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.
TRAEs leading to discontinuation, n (%) Dose level 1 (n = 9) Dose level 2 (n = 12) Any grade Grade 3/4 Any grade Grade 3/4 Increased ALT 2 (22.2) 2 (22.2) 1 (8.3) 1 (8.3) Hypertransaminasaemia 0 0 1 (8.3) 1 (8.3) Increased AST 2 (22.2) 2 (22.2) 0 0 Increased transaminases 1 (11.1) 1 (11.1) 0 1 (8.3) Febrile neutropenia 1 (11.1) 1 (11.1) 0 0 Rash 1 (11.1) 1 (11.1) 0 0 Pneumonitis 1 (11.1) 0 1 (8.3) 0
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.