Background

The late occurrence of isolated local recurrence (LR) of luminal BC calls into question whether these are true LR or new primaries. We evaluated the concordance of the mutation profiles between matched primary tumors (PT) and LR.

Methods

We collected data from women with LR of luminal BC treated at Gustave Roussy and Trieste University Hospital between 1992 and 2018. Following a quality control, targeted NGS was performed on the IonTorrent S5 NGS platform with the Oncomine Tumor Mutation Load Assay covering 409 critical oncogenes or tumor suppressor genes to analyze PT and LR samples. For the bioinformatic analysis, we retained the matched samples that passed quality check and had a total mean depth coverage ≥ 300X. Variants were filtered on their allele frequency ≥ 5% and a read count ≥ 5X, and on the basis of their genomic effect and annotation.

Results

Among the 131 eligible patients, 82 matched PT and LR were sequenced and analyzed. The table summarizes patient, PT and LR characteristics. Median time until LR was 6.0 years. After a median follow-up of 4.6 years following LR, median DDFS and OS were 8.1 and 8.7 years, respectively. In the PT, the main genes with more than 20% of variants were KMT2D, ATRX, MTOR, ATM and KMT2A. In the LR, the main genes with more than 10% of variants were KMT2D, NOTCH2, PIK3CA, and KMT2A. The main gene with recurrent mutation present in both PT and LR was PIK3CA (4.8%). This analysis showed that 17 cases (20%) shared the same variants between PT and LR. Table: 18P

Patient and tumor characteristics

Conclusions

Although we found a wide range of molecular alterations in LR, a minority of patients had concordant mutational profiles between PT and LR. These findings, if confirmed in larger studies, may better guide the choice of therapy after LR excision.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Lacroix-Triki: Financial Interests, Advisory Board: Myriad genetics; Financial Interests, Advisory Board: Exact sciences; Financial Interests, Advisory Board: Rroche diagnostics; Financial Interests, Advisory Board: AstraZeneca; Financial Interests, Advisory Board: Daiichi Sankyo; Financial Interests, Advisory Board: MSD; Financial Interests, Advisory Board: Roche. E. Rouleau: Financial Interests, Invited Speaker: BMS; Financial Interests, Invited Speaker: AstraZeneca; Financial Interests, Invited Speaker: Roche; Financial Interests, Invited Speaker: Clovis; Financial Interests, Invited Speaker: GSK. L. Lacroix: Financial Interests, Advisory Role: Adept Field Solutions; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Bayer; Financial Interests, Advisory Role: Boehringer; Financial Interests, Advisory Role: BMS; Financial Interests, Advisory Role: Lilly; Financial Interests, Advisory Role: Icomed; Financial Interests, Advisory Role: Genomic Health; Financial Interests, Advisory Role: Medimmune; Financial Interests, Advisory Role: Novartis; Financial Interests, Advisory Role: Pfizer; Financial Interests, Advisory Role: QualWorld; Financial Interests, Advisory Role: Taiho Oncology; Financial Interests, Advisory Role: Roche; Financial Interests, Advisory Role: Thermofisher; Financial Interests, Advisory Role: VelaDx; Financial Interests, Sponsor/Funding: Abbott; Financial Interests, Sponsor/Funding: Amgen; Financial Interests, Sponsor/Funding: AstraZeneca; Financial Interests, Sponsor/Funding: Beckman Coulter; Financial Interests, Sponsor/Funding: Bayer; Financial Interests, Sponsor/Funding: Boeringer; Financial Interests, Sponsor/Funding: BMS; Financial Interests, Sponsor/Funding: Illumina; Financial Interests, Sponsor/Funding: Genomic Health; Financial Interests, Sponsor/Funding: Guardant health; Financial Interests, Sponsor/Funding: Lilly; Financial Interests, Sponsor/Funding: Medimmune; Financial Interests, Sponsor/Funding: Myriad; Financial Interests, Sponsor/Funding: Novartis; Financial Interests, Sponsor/Funding: Pfizer; Financial Interests, Sponsor/Funding: Roche; Financial Interests, Sponsor/Funding: Siemens Healthineer; Financial Interests, Sponsor/Funding: Taiho Oncology; Financial Interests, Sponsor/Funding: Thermofisher; Financial Interests, Sponsor/Funding: VelaDx. F. André: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Daiichi; Other, Founder: Pegacsy. B. Pistilli: Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Myriad; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Puma; Financial Interests, Personal, Sponsor/Funding: AstraZeneca; Financial Interests, Personal, Sponsor/Funding: Pierre Fabre; Financial Interests, Personal, Sponsor/Funding: MSD; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Daiichi Sankyo. All other authors have declared no conflicts of interest.

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.