Abstract 2406
Background
The introduction of anti-HER2 therapies such as trastuzumab for HER2+ metastatic breast cancer (MBC) has led to significant improvements to disease progression. We, and others have reported cases of long-term durable complete response to trastuzumab in HER2+ MBC. However, to-date only clinical and molecular analysis of this “exceptional” cohort exists. We hypothesise that genomic copy number alteration (CNA) burden can act as a prognostic measure of predicting response to trastuzumab in long-term never relapse exceptional responders (ExRs) from rapid non-responders (NR).
Methods
We performed whole exome sequencing (WES) on n = 6 never relapse ExRs (med RFS < 149 mo) and n = 5 corresponding NRs (median RFS < 14 mo). Both tumour and adjacent normal tissue (where available) was sequenced by BGI using the NGS illumina HiSeq PR100 (2 x 100 bp) at a mean depth of 56 x. Reads were aligned to the hg19 reference genome using BWA software. Two-sample t-test with unequal variances was used to evaluate total genome CNA burden. Median CNA burden was used to stratify patients into high and low CNA burden groups, binary CNA stratification groups were further assessed using Kaplan-Meier survival estimation.
Results
We analysed the DNA chromosome disruption (fraction of the genome amplified/deleted) and present CNA burden. We observed the overall fraction of genome CNA burden was more destructed (P = 0.07); while more significantly pronounced in the amplification of the whole genome (P = 0.03) in NR compared to ExRs. We further delineated the distribution of CNA burden in all genomes and identified chromosome 8 as significantly disrupted in NRs (P = 0.02). Kaplan Meier survival analysis revealed that low total CNA burden at Chr8 and Chr17 conferred a statistically significant benefit in overall survival (P = 0.009 and P = 0.016, log rank).
Conclusions
CNA burden in HER2+ MBC exceptional responders may represent a novel prognostic predictor to trastuzumab response. Our investigation of genome-wide CNA burden offers the potential to gain insight into the underlying genetic landscape of long-term, never relapse exceptional response to trastuzumab.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Cancer Clinical Research Trust.
Disclosure
G. Gullo: Honoraria (self): Genomic Health; Travel / Accommodation / Expenses: Roche. J. Crown: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Shareholder / Stockholder / Stock options: OncoMark; Honoraria (self): Amgen; Honoraria (self), Research grant / Funding (institution): Puma Technology; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self): Vertex; Honoraria (self): Genomic Health; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): MSD Oncology. All other authors have declared no conflicts of interest.
Resources from the same session
3180 - Genomic analysis of hepatobiliary lithiasis associated cholangiocarcinoma revealed a distinct subtype feature.
Presenter: Lunda Gu
Session: Poster Display session 2
Resources:
Abstract
4891 - Comparison of the impact of stereotactic body radiation therapy vs. radiofrequency ablation on liver function in patients with single hepatocellular carcinoma: A propensity score matching analysis
Presenter: Masayuki Ueno
Session: Poster Display session 2
Resources:
Abstract
3203 - Exploratory analysis based on tumor location and early metabolic tumor response of REACHIN, a randomized double-blinded placebo-controlled phase II trial of regorafenib after failure of gemcitabine/platinum-based chemotherapy for advanced and metastatic biliary tract tumors.
Presenter: Anne Demols
Session: Poster Display session 2
Resources:
Abstract
1602 - Predictive Value of Neutrophil-Lymphocyte Ratio (NLR) And Platelet-Lymphocyte Ratio (PLR) In Hepatocellular Carcinoma (HCC) Patients Treated with Nivolumab (N)
Presenter: Sirish Dharmapuri
Session: Poster Display session 2
Resources:
Abstract
2848 - Preliminary Safety and Pharmacokinetics of a New Lysosomotropic Oral Agent, GNS561, in a First-in-Human Study in Advanced Primary Liver Cancer Patients
Presenter: Ahmad Awada
Session: Poster Display session 2
Resources:
Abstract
1396 - A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results
Presenter: Josep Llovet
Session: Poster Display session 2
Resources:
Abstract
1139 - Multicentric prospective study of validation of angiogenesis-related gene polymorphisms in HCC patients treated with sorafenib: Final results of INNOVATE study
Presenter: Andrea Casadei-gardini
Session: Poster Display session 2
Resources:
Abstract
4688 - Prognostic and predictive factors from the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in previously treated advanced hepatocellular carcinoma (aHCC)
Presenter: Tim Meyer
Session: Poster Display session 2
Resources:
Abstract
1492 - A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL.
Presenter: David Pinato
Session: Poster Display session 2
Resources:
Abstract
3159 - Anlotinib for advanced hepatocellular carcinoma: interim results from the phase II ALTER0802 study
Presenter: AiPing Zhou
Session: Poster Display session 2
Resources:
Abstract