Christelle Levy (Caen, France)
Centre Francois BaclesseAuthor Of 2 Presentations
104P - HELENA : Study of HER2-Low as a prEdictive factor of response to Neoadjuvant chemotherapy in eArly breast cancer (ID 116)
- Marion Bertho (Caen, France)
- Francois Cherifi (Caen, France)
- Angelique Da Silva (Caen, France)
- Alison C. Johnson (Caen, France)
- Cecile Blanc Fournier (Caen, France)
- Antonin Broyelle (Lille, France)
- Olivia Abramovici (Lille, France)
- Adeline Morel (Caen, France)
- Ioana Hrab (Caen, France)
- Djelila Allouache (Caen, France)
- Carine Segura Djezzer (Caen, France)
- Christelle Levy (Caen, France)
- Clemence Boscher (Caen, France)
- Maud Villemin (Caen, France)
- Pauline Rottier (Caen, France)
- Justine Lequesne (Caen, France)
- George Emile (Caen, France)
Abstract
Background
HER2 expression has a prognostic and predictive impact in early breast cancer (BC). HER2-positive BC (score 3+ or 2+ with in situ hybridization (ISH) amplification) are treated with anti-HER2 therapies. HER2-low BC (score 1+ or 2+ without ISH amplification) are less defined and until now, no specific treatment has been provided for this subgroup. We tried to explore the response of HER2-low early BC to neoadjuvant chemotherapy (NAC) according to the HER2 score (1+ or 2+).
Methods
We designed a retrospective study in two French comprehensive cancer centers. All patient with HER2-low BC treated by NAC from January 2014 to December 2020 were included. First we analyzed the pathological complete response (pCR) to NAC with Sataloff or RCB score, according to the HER2 tumors score. Others objectives were to assess disease free survival (DFS) and overall survival (OS) according to HER2 score. Univariate and multivariate analysis were performed.
Results
We included 237 tumors of 229 patients. Of these, 160 (67.5%) tumors were HER2 1+ and 77 were HER2 2+. Hormone receptor (HR) were positive for 152 tumors (64.1%). The median age was 53.9 years. pCR was achieved in 38 tumors (17%) without difference between HER2 1+ and HER2 2+ subgroups (p=0.77). DFS and OS were statistically worse for HER2 1+ patients compared to HER2 2+ patients (Log-rank p=0.037 and p=0.042, respectively). After adjustment on age, HR and menopausal status, HER2 score was still associated with DFS and OS, with better survival for HER2 2+ patients (HR=0.35 [0.15-0.84], HR=0.24 [0.07-0.81] respectively).
Conclusions
In the HER2-low BC, no difference in pCR were observed between HER2 1+ and HER2 2+ but patients with HER2 2+ BC had a better DFS and OS than others. Further investigations are needed to confirm these results.
Legal entity responsible for the study
Centre François Baclesse.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
LBA1 - Unraveling the mechanism of action and resistance to Trastuzumab deruxtecan (T-DXd): biomarker analyses from patients from DAISY trial (ID 281)
- Maria Fernanda Mosele (Villejuif, France)
- Amélie Lusque (Toulouse, France)
- Veronique Dieras (Rennes, France)
- Elise Deluche (Limoges, France)
- Agnès Ducoulombier (Nice, France)
- Barbara Pistilli (Villejuif, France)
- Thomas Bachelot (Lyon, France)
- Frédéric Viret (Marseille, France)
- Christelle Levy (Caen, France)
- Nicolas Signolle (Villejuif, France)
- Diep TRAN (Villejuif, France)
- Ingrid J. Garberis (Villejuif, France)
- Loic Le-Bescond (Gif sur Yvette, France)
- ALICIA TRAN DIEN (Villejuif, Cedex, France)
- Nathalie Droin (Villejuif, Cedex, France)
- Maki Kobayashi (Tokyo, Japan)
- Tomoya Kakegawa (Tokyo, Japan)
- Marta Jimenez (Paris, France)
- Magali Lacroix-Triki (Villejuif, France)
- Fabrice André (Villejuif, France)
Abstract
Background
T-DXd is an anti-HER2 antibody-drug conjugate that has demonstrated high antitumor activity in HER2-positive and HER2-low metastatic breast cancer (mBC). We aimed to unravel the mechanism of action and resistance to T-DXd in patients from DAISY trial.
Methods
DAISY is a phase II clinical trial (NCT04132960) that assessed T-DXd efficacy in mBC according to HER2-expression (HER2-positive, HER2-low, and HER2-negative). Bystander effect and T-DXd uptake were analyzed by immunohistochemistry (IHC) (HER2, gH2AX, and T-DXd) on tumor biopsies at baseline and on-treatment (n=10 patients). T-DXd immune effects were explored by multiplex immunofluorescence (CD3, CD4, CD8, CD68, FoxP3, PD-1, PD-L1, CK/SOX10 antibodies) on tumor biopsies at baseline and on-treatment (Day 22 or 43, n=31 patients). Mechanisms of resistance were analyzed on tumor samples at baseline (n=118) and at progression by whole exome sequencing (n=24) and IHC (n=25). The predictive value of HER2 spatial distribution was investigated by artificial intelligence (AI) using weakly supervised and clustering algorithms on HER2-positive slides images at baseline (n=61).
Results
Molecular analyses showed that cancer cells expressing low levels of HER2, but not HER2-null cells, uptake T-DXd (p=0.053). In the whole population (n=31), a decrease of PDL1-positive cells was associated with a best objective response (BOR) (p=0.008). No modulation of T cells and macrophages was observed (p=0.6 and p=0.9 respectively). A decrease of PDL1 expression was detected in HER2-positive mBC (n=18; p=0.02). Clustering algorithms identified a cluster associated with a lower BOR (p=0.007), whose features identified by AI included a high percentage of HER2-negative cells currently under investigation. At progression, a decrease of HER2 expression was observed in 13/25 (52%) patients (p=0.07). DNA sequencing and final AI results will be available at the meeting.
Conclusions
A correlation between HER2 expression and T-DXd uptake in cancer cells was observed in on-treatment biopsies. T-DXd did not modulate intratumoral lymphocytes but decreased PDL1 expression. WES analyses at baseline and progression samples will be presented on-site.
Legal entity responsible for the study
The authors
Funding
Unicancer and Daiichi Sankyo
Disclosure
V. Dieras: Financial Interests, Personal, Advisory Board, Travel Expenses: Roche, Novartis, Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Invited Speaker, Travel Expenses: Lilly, Pfizer, AstraZeneca, MSD, Daiichi Sankyo, Seagen, Gilead; Financial Interests, Personal, Principal Investigator, Travel Expenses: Pfizer, Daiichi Sankyo, Seagen; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Principal Investigator: AbbVie; Non-Financial Interests, Personal, Advisory Board: Eisai, Pierre Fabre Oncologie. E. Deluche: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Fresenius Kabi, Lilly; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Other, scientific events: Lilly, GSK; Financial Interests, Personal, Other, funding for conference travel: AstraZeneca-Daiichi, Roche, Amgen. B. Pistilli: Financial Interests, Institutional, Other, Consulting Fees: AstraZeneca, Pfizer; Financial Interests, Personal, Other, Consulting Fees: Myriad, Pierre Fabre; Financial Interests, Institutional, Speaker’s Bureau: Daiichi Sankyo, Novartis, Puma; Financial Interests, Institutional, Writing Engagements: Daiichi Sankyo, Novartis, Puma; Financial Interests, Personal, Other, Attending Meetings and/or Travel: AstraZeneca, Pierre Fabre, MSD; Financial Interests, Institutional, Advisory Board: Novartis, AstraZeneca, Daiichi Sankyo. T. Bachelot: Financial Interests, Personal, Advisory Board: Roche, Novartis, AstraZeneca, Pfizer, Seagen; Financial Interests, Institutional, Research Grant: Novartis, Roche, AstraZeneca, Seagen, Pfizer; Financial Interests, Personal, Invited Speaker: Roche. D. Tran: Non-Financial Interests, Institutional, Full or part-time Employment, Full-time: DIEP T. N. TRAN. N. Droin: Non-Financial Interests, Institutional, Full or part-time Employment, Part-time: Nathalie Droin. M. Kobayashi, T. Kakegawa: Other, Personal, Full or part-time Employment, Employee of Daiichi Sankyo RD Novare, which belongs to Daiichi Sankyo Group. Daiichi Sankyo Group is developing T-DXd: Daiichi Sankyo RD Novare. M. Lacroix-Triki: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca, Daiichi Sankyo. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi; Other, Founder: Pegacsy. All other authors have declared no conflicts of interest.