Abstract 2196
Background
Despite decades of research, performance of DPYD genotyping to predict FP toxicity (tox) is poorly documented. GPCO-UNICANCER and RNPGx groups initiated the FUSAFE MA on individual patient data (IPD) to assess the prognostic value of consensual deleterious DPYD variants on grade (G) 4-5 FP tox.
Methods
Eligibility criteria included unbiased recruitment of Caucasian patients (pts) without FP dose adjustment based on DPD status. Main endpoint was 12 weeks hematological or digestive G4-5 tox. Age, sex, body mass index (BMI), advanced stage (M- vs M+), FP drug (5FU vs capecitabine), FP administration (bolus±continuous vs continuous alone or p.o.) and associated anticancer drugs (AAD) were collected. Multivariable logistic models were applied. Performance was assessed by AUC and diagnostic indices maximizing Youden index.
Results
From the 18 identified eligible studies (10230 pts), 14 were included (9030 pts), with complete IPD collected for 6403 pts (84% colorectal, 16% M+, 66% 5FU, 80% AAD). G4-5 tox prevalence was 8% (518 events). DPYD variants *2A, D949V, *13 and HapB3 were carried by 0.9%, 1.2%, 0.2% and 3.9% of pts, respectively. The clinical model (M1) retained age, sex, BMI, FP-administration, AAD. Adding variants *2A/D949V/*13 (at least one mutated allele) significantly (p<.0001) improved the model (M2). Further adding HapB3 did not improve the model (p=.24, M3). M3-adjusted OR (95%CI) was 10.0 (6.9-14.7) for the 3 variants *2A/D949V/*13 and 2.1 (1.4-3.0) for HapB3. Similar results were observed on colorectal pts only, or when excluding bolus administration alone.Table:
569P
Model | AUC (area under the curve) | Sensitivity | Specificity | Positive predictive value | Negative predictive value |
---|---|---|---|---|---|
M1 | 0.725 | 69.7% | 65.4% | 15.1% | 96.1% |
M2 | 0.750 | 75.5% | 62.8% | 15.2% | 96.7% |
M3 | 0.752 | 76.4% | 61.9% | 15.0% | 96.8% |
Conclusions
This is the largest MA on DPYD genotyping and toxicity. It shows the relevance of clinical variables and of the 3 consensual DPYD variants. Despite its association with tox, HapB3 does not improve the discriminant ability to identify pts at risk of G4-5 toxicity.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Centre Antoine Lacassagne, Nice, France (Dr Marie-Christine Etienne-Grimaldi, coordinator).
Funding
French Cancer Institute (INCa) funding (PHRC-K 14-193 FUSAFE) and French Ligue Nationale Contre le Cancer.
Disclosure
V. Boige: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Ipsen; Advisory / Consultancy: Prestizia; Advisory / Consultancy: Eisai; Travel / Accommodation / Expenses: Sanofi. J. Taieb: Advisory / Consultancy: Amgen; Advisory / Consultancy: Lily; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: Celgene; Advisory / Consultancy: Servier; Advisory / Consultancy: Sirtex; Advisory / Consultancy: Pierre Fabre. D. Meulendijks: Full / Part-time employment: AstraZeneca UK. C. Palles: Advisory / Consultancy: Oxford Cancer Biomarkers. U. Zanger: Licensing / Royalties: Robert Bosch GmbH. M. Boisdron-Celle: Speaker Bureau / Expert testimony, Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: ODPM. A. Marinaki: Full / Part-time employment: Viapath. E. Gross: Licensing / Royalties: Klinikum Rechts der Isar der Technischen Universitat Munchen. All other authors have declared no conflicts of interest.
Resources from the same session
5203 - Novel fusion genes identified from matched primary and recurred breast cancers by RNA-sequencing
Presenter: Soojeong Choi
Session: Poster Display session 2
Resources:
Abstract
5873 - Association between PIK3CA mutation status and development of brain metastases in HR+/HER2- metastatic breast cancer
Presenter: Donna Fitzgerald
Session: Poster Display session 2
Resources:
Abstract
3588 - The role of AXL as mechanism of resistance to trastuzumab and a prognostic factor in breast cancer HER2 positive: a translational approach.
Presenter: Anna Adam-Artigues
Session: Poster Display session 2
Resources:
Abstract
5640 - Untargeted assessment of tumor fractions in plasma for monitoring and prognostication from metastatic breast cancer patients undergoing systemic treatment
Presenter: Marija Balic
Session: Poster Display session 2
Resources:
Abstract
2616 - Clinical application of mutational analysis in breast cancer patients: the relevance of PIK3CA analysis for precision medicine.
Presenter: Juan Miguel Cejalvo
Session: Poster Display session 2
Resources:
Abstract
3870 - A retrospective gene expression analysis of surgically-removed Breast Cancer Brain Metastasis (BCBM)
Presenter: Meritxell Mallafré-Larrosa
Session: Poster Display session 2
Resources:
Abstract
1240 - Endocrine therapy alone versus targeted combination strategy as first line treatment in elderly patients with hormone receptor-positive advanced breast cancer: meta-analysis of Phase II and III randomized clinical trials
Presenter: Claudia Omarini
Session: Poster Display session 2
Resources:
Abstract
5535 - Alpelisib (ALP) + fulvestrant (FUL) for patients with hormone receptor–positive (HR+), HER2− advanced breast cancer (ABC): management and time course of key adverse events of special interest (AESIs) in SOLAR-1
Presenter: Hope Rugo
Session: Poster Display session 2
Resources:
Abstract
3093 - Changes in Hormone-Receptor status in Luminal breast cancers between primary tumor and metastases: results of the observational cohort GIM-13 AMBRA Study
Presenter: Marina Cazzaniga
Session: Poster Display session 2
Resources:
Abstract
1378 - MONARCH 3: Updated time to chemotherapy and disease progression following abemaciclib plus aromatase inhibitor (AI) in HR+, HER2- advanced breast cancer (ABC)
Presenter: Miguel Martín
Session: Poster Display session 2
Resources:
Abstract