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
3082 - Prognostic and predictive role of body mass index (BMI) in metastatic colorectal cancer (mCRC): a pooled analisys of TRIBE and TRIBE-2 studies by GONO
Presenter: Emanuela Dell'Aquila
Session: Poster Display session 2
Resources:
Abstract
3618 - Drug holidays and overall survival in patients treated for metastatic colorectal cancer
Presenter: Silvio Ken Garattini
Session: Poster Display session 2
Resources:
Abstract
6111 - Quality of life during 1st-line FOLFOXIRI+/- panitumumab in RAS wild-type metastatic colorectal cancer: Results from the randomized VOLFI trial (AIO KRK-0109)
Presenter: Michael Geissler
Session: Poster Display session 2
Resources:
Abstract
1042 - A biomarker combination indicating resistance to FOLFOX plus bevacizumab in metastastic colorectal cancer : results of phase I of the PERMAD trial
Presenter: Thomas Seufferlein
Session: Poster Display session 2
Resources:
Abstract
3291 - Microsatellite Instability (MSI) status and prognosis in colorectal cancer: meta-analysis
Presenter: James Toh
Session: Poster Display session 2
Resources:
Abstract
2046 - Choosing the right strategy based on individualized treatment effect predictions: Combination versus sequential chemotherapy in patients with metastatic colorectal cancer.
Presenter: Miriam Koopman
Session: Poster Display session 2
Resources:
Abstract
2589 - Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer
Presenter: Stefan Kasper
Session: Poster Display session 2
Resources:
Abstract
4944 - POLAF study: Efficacy and safety of FOLFIRI/aflibercept in a phase II trial in patients with metastatic colorectal cancer: Results of plasmatic prognostic and predictive markers
Presenter: Maria Elena Elez Fernandez
Session: Poster Display session 2
Resources:
Abstract
2042 - The accuracy of the clinical PCI score in patients with peritoneal carcinomatosis of colorectal cancer
Presenter: Nadine De Boer
Session: Poster Display session 2
Resources:
Abstract
2667 - The impact of late-line treatment on overall survival (OS) from the initiation of first-line chemotherapy (CT) for patients (pts) with metastatic colorectal cancer (mCRC).
Presenter: Takeshi Kawakami
Session: Poster Display session 2
Resources:
Abstract