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
4401 - Real-world effectiveness of first-line palbociclib + letrozole for metastatic breast cancer 4 years post approval in the US
Presenter: Jonathan Kish
Session: Poster Display session 2
Resources:
Abstract
5876 - Palbociclib-Fulvestrant (PALBO-FUL) and Everolimus -Exemestane (EVE-EXE) for Second line Hormonal Treatment (HT) of Metastatic Breast Cancer (MBC) with Lobular Histology: a Propensity Score Matched Analysis of a Multicenter ‘Real-World’ Patients (pts) Series.
Presenter: Armando Orlandi
Session: Poster Display session 2
Resources:
Abstract
3587 - Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC)
Presenter: E Dees
Session: Poster Display session 2
Resources:
Abstract
5696 - Final results of the STEM trial: SFX-01 in the Treatment and Evaluation of ER+ Her2- Metastatic breast cancer (mBC)
Presenter: Sacha Howell
Session: Poster Display session 2
Resources:
Abstract
1475 - Alpelisib (ALP) + Fulvestrant (FUL) in Hormone-Receptor Positive (HR+), Human Epidermal Growth Factor Receptor-2–Negative (HER2–) Advanced Breast Cancer (ABC): Subgroup Analysis by Presence of Visceral Metastasis (VM) in the SOLAR-1 Trial
Presenter: Mario Campone
Session: Poster Display session 2
Resources:
Abstract
2549 - Phase 1 Dose Escalation Study of a Selective Androgen Receptor Modulator RAD140 in Estrogen Receptor Positive (ER+), HER2 Negative (HER2-) Breast Cancer (BC)
Presenter: Erika Hamilton
Session: Poster Display session 2
Resources:
Abstract
3787 - A Phase I study of XZP-3287, a novel oral CDK4/6 Inhibitor, administered on a continuous dosing schedule, in patients with advanced solid tumours
Presenter: Binghe Xu
Session: Poster Display session 2
Resources:
Abstract
4835 - Phase-I dose-escalation and expansion study of the PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors
Presenter: Huiping Li
Session: Poster Display session 2
Resources:
Abstract
5083 - Phase 2 study of DHP107 (Liporaxel®, oral paclitaxel) in first-line, HER2 negative recurrent/metastatic breast cancer (OPTIMAL study, NCT03315364)
Presenter: Jin-Hee Ahn
Session: Poster Display session 2
Resources:
Abstract
2674 - Multicenter Phase I Trial of Trastuzumab Emtansine (T-DM1) in Combination with Non-Pegylated Liposomal Doxorubicin (NPLD) in HER2[+] Metastatic Breast Cancer (MBC). THELMA Study
Presenter: Elena López-Miranda
Session: Poster Display session 2
Resources:
Abstract