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LBA2 - Assessment of Ki67 and FOXC1-based response predictor tracking proliferation and plasticity as a complementary diagnostic for neoadjuvant Olaparib+Paclitaxel+Darvalumab in primary triple negative breast cancer: retrospective analysis of the I-SPY2 Trial (ID 295)
Abstract
Background
Immune checkpoint inhibitors (ICIs) have shown clinical efficacy when administered in combination with neoadjuvant chemotherapy (NACT) for the treatment of triple negative breast cancer (TNBC). However, suitable complementary diagnostics to help guide and tailor treatment recommendations are still lacking. Ki67 is a well accepted and routinely used marker that tracks proliferation and has been shown to predict efficacy of neoadjuvant chemotherapy. Forkhead Box C1 (FOXC1), a transcriptional driver of cell plasticity/partial EMT/metastasis/immune evasion has proven prognostic value, but remains of uncertain predictive value. We sought to evaluate the potential of a Ki67 and FOXC1-based response predictor as a possible complementary diagnostic for a neoadjuvant regimen comprising of a PARP inhibitor (Olaparib), a Taxane chemotherapeutic (Paclitaxel) and an ICI of the PDL1 class (Durvalumab) in patients diagnosed with primary TNBC.
Methods
41 Pre-NACT tumor biopsy MKI67 and FOXC1 mRNA expression values were retrospectively obtained from TNBC patients who had been enrolled and treated in the I-SPY2 clinical trial (Durvalumab arm: 21, Control arm: 20) and correlated with the rate of observed pathologic complete response (pCR). The area under the curve (AUC) of each model was calculated and used to determine suitable cutoff values to maximize Negative Predictive Value (NPV) and Sensitivity for pCR prediction.
Results
Predicted responders in the Durvalumab Arm had a pCR rate of 75% vs 0% in predicted non-responders, p=0.00013) with NPV and sensitivity of 100%, accuracy of 85.7%, Odds Ratio 51.57 (2.33-1141.00,95% CI). The strategy was not predictive in the Control Arm. Multiple logistic regression pCR-predictive models may further improve predictive accuracy.
Conclusions
Complementary diagnostic role of pre-NACT MKI67 + FOXC1 expression merits prospective clinical trial evaluation in TNBC treated with neoadjuvant combination regimens that include ICIs. This may help to optimize achieved pCR rates and extend disease-free survival in patients diagnosed with TNBC.
Legal entity responsible for the study
The authors
Funding
Has not received any funding
Disclosure
P.S. Ray: Financial Interests, Institutional, Advisory Board: Onconostic Technologies. T. Ray: Financial Interests, Institutional, Full or part-time Employment: Onconostic Technologies. R. Hussa: Financial Interests, Institutional, Member of the Board of Directors: Onconostic Technologies.
1MO - Prognostic and biologic significance of HER2-low expression in early breast cancer (ID 296)
- Paolo Tarantino (Boston, United States of America)
- Qingchun Jin (Boston, United States of America)
- Nabihah Tayob (Boston, United States of America)
- Rinath Jeselsohn (Boston, United States of America)
- Stuart J. Schnitt (Boston, United States of America)
- Julie Vincuilla (Boston, United States of America)
- Tonia Parker (Boston, United States of America)
- Svitlana Tyekucheva (Boston, United States of America)
- Nancy U. Lin (Boston, United States of America)
- Melissa Hughes (Boston, United States of America)
- Anna C. Weiss (Boston, United States of America)
- Tari A. King (Boston, United States of America)
- Elizabeth A. Mittendorf (Boston, United States of America)
- Giuseppe Curigliano (Milan, Italy)
- Sara M. Tolaney (Boston, United States of America)
Abstract
Background
Approximately 50% of HER2-negative breast cancers (BC) show HER2-low expression. It is unclear however whether HER2-low BC should be considered an individual biologic entity, prognostically distinct from HER2-zero BC.
Methods
Data were collected from an institutional database including all consecutive patients with BC who underwent surgery at Dana-Farber Brigham Cancer Center from 1/2016 to 3/2021. Tumors were defined as HER2-low if they had a HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-zero if they had a HER2 IHC score of 0. Clinicopathologic characteristics and disease outcomes were compared between the two cohorts.
Results
5235 HER2-negative BC patients were eligible for analysis; 4429 estrogen receptor (ER)+, 67 ER-low (1-9%), 739 ER-negative. Hormone receptor(HR)-expression was significantly more common among HER2-low compared with HER2-zero BC (89.9% vs 80.9%, p<0.001). Most other clinicopathological differences were explained by the different rate of HR+ tumors. When evaluated as a continuous variable, ER expression was significantly associated with HER2 expression (p<0.001), and the rate of HER2-low tumors increased progressively with increasing ER expression (Table). Among patients receiving neoadjuvant chemotherapy (n=657), those with HER2-zero tumors had higher pCR rates compared with HER2-low (27% vs 17%, p=0.002). However, statistical difference was lost when separately analyzing HR+ (8% vs 14%, p=0.078), ER-low (25% vs 38.9%, p=0.46), HR+ without ER-low (6.9% vs 10.4%, p=0.277), TNBC (30.8% vs 35.4%, p=0.40) and when adjusting for confounders. No difference in disease-free survival or overall survival was observed among patients with HR+ tumors or TNBC depending on HER2-low expression. Proportion of tumors with HER2-low versus HER2-zero expression according to tumor subtype and ER expression
TNBC ER-low (1-9%) ER-moderate (10-49%) ER-high (50-95%) ER-very-high (>95%) HER2-low 40% 46% 55% 58% 62% HER2-zero 60% 54% 45% 42% 38%
Conclusions
Our results do not support the interpretation of HER2-low BC as a distinct biologic subtype. HER2-low expression is continuously associated with the level of ER expression. ER-low tumors are enriched among HER2-zero cases and may confound prognostic analyses.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
P. Tarantino: Financial Interests, Personal, Advisory Role: AstraZeneca. N.U. Lin: Financial Interests, Institutional, Other: Genentech, Merck, Pfizer; Financial Interests, Personal, Other: Seattle Genetics; Financial Interests, Personal, Advisory Role: Puma, Daiichi Sankyo, AstraZeneca, Denali Therapeutics, California Institute for Regenerative Medicine, Prelude Therapeutics. T.A. King: Financial Interests, Personal, Invited Speaker: Exact Sciences; Financial Interests, Personal, Advisory Role: PrecisCA Cancer Information Service. E.A. Mittendorf: Financial Interests, Personal, Advisory Role: Exact Science, Bristol Myers Squib, Genentech/Roche, Lilly, Merck. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Ellipsis, Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, 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. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly, Pfizer, Novartis, Merck, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, Puma; Financial Interests, Personal, Other, Consultant: Nektar, NanoString, Athenex, Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, OncoPep, OncoSec, Certara, Mersana Therapeutics, Ellipses Pharma, G1 Therapeutics; Financial Interests, Personal, Advisory Board, Ad board participant/consultant/DSMC: Odonate; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Invited Speaker, Invited Speaker for Pharma Supported Educational Activity: Chugai Pharmaceuticals; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks, Zentalis, Reveal Genomics, OncXerna; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. All other authors have declared no conflicts of interest.
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.
3MO - Association of the research-based HER2DX signatures with survival in early-stage triple-negative breast cancer (eTNBC) (ID 298)
- Benedetta Conte (Genova, Italy)
- Fara Brasó-Maristany (Barcelona, Spain)
- Tomas Pascual (Barcelona, Spain)
- Francesco Schettini (Barcelona, Spain)
- Johan Staaf (Lund, Sweden)
- Laia Paré (Barcelona, Spain)
- Mercedes Marín-Aguilera (Barcelona, Spain)
- Olga Martínez-Sáez (Barcelona, Spain)
- Adela Rodriguez Hernandez (Barcelona, Spain)
- Maria Jesus Vidal Losada (Barcelona, Spain)
- Pier Franco Conte (Padova, Italy)
- Ana Vivancos (Barcelona, Spain)
- Patricia Villagrasa Gonzalez (Barcelona / Barcelona, Spain)
- Joel Parker (Chapel Hill, United States of America)
- Charles M. Perou (Chapel Hill, United States of America)
- Aleix Prat (Barcelona, Spain)
Abstract
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.
IGG signature TNBC-DX risk score Dataset RFS or EFS HR (95% CIs) OS HR (95% CIs) RFS or EFS HR (95% CIs) OS HR (95% CIs) GSE21653 0.53 (0.35-0.82) NA 3.34 (1.82-6.13) NA GSE58812 1.00 (0.69-1.45) 0.99 (0.67-1.46) NA NA METABRIC 0.81 (0.66-0.99) 0.81 (0.67-0.96) 2.00 (1.52-2.62) 1.47 (1.17-1.84) TCGA 0.86 (0.52-1.45) 0.63 (0.32-1.26) 2.58 (1.37-4.84) 3.26 (1.57-6.80) SCANB NA 0.68 (0.47-0.98) NA 2.37 (1.38-4.10) CALGB40603 0.82 (0.66-0.99) NA NA NA Pooled Results 0.81 (0.70-0.93) I2=18% 0.80 (0.69-0.92) I2=0% 2.32 (1.73-3.12) I2=22% 2.05 (1.27-3.32) I2=67%
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.