In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e13025-e13025
Abstract:
e13025 Background: Frequent coactivation of both PI3K/AKT and MAPK pathways has been seen in a number of different tumor types. Preclinical studies also provide a clear rationale for the co-inhibition of these, "semi-parallel" pathways. Methods: We reviewed the records of 1,672 consecutive advanced cancer patients (pts) in our Phase I Clinical Trials Program and investigated the clinical impact of simultaneous blockade of both PI3K/AKT and MAPK pathways in patients with oncogenic alterations in both signaling pathways from 317 pts who received PI3K pathway inhibitor and/or MAPK pathway inhibitor. Results: 163 of 317 pts (51.4%) were tested for comprehensive tumor genomic analysis using DNA array-based CGH/PCR-based DNA sequencing. PI3K pathway genetic alterations (PIK3CA mutation, n=3; PTEN deletion, n=18; AKT amplification, n=10) were detected in 29 of the 163 (17.8%) pts. RAS/RAF pathway genetic alterations (KRAS mutation, n=33; HRAS mutation, n=4; BRAF mutation, n=6) were detected in 43 of the 163 (26.4%) pts. Simultaneous oncogenic alterations in both PI3K/AKT and MAPK pathways were detected in 12 pts (colorectal cancer, n=7; pancreatic cancer, n=2; melanoma, n=2; non-seminomatous germ cell tumor, n=1). Six of 8 (75%) pts treated with personalized treatment based on dual pathways inhibition had tumor regression with prolonged duration of time to treatment failure compared to that of pts treated with single pathway inhibition. A pt with pancreatic cancer harboring simultaneous KRAS mutation and AKT2 amplification treated with combination MEK1/2 inhibitor and AKT inhibitor showed central cavitations of numerous lung metastatic lesions along with a decrease in CA19-9, which may reflect treatment effect. Conclusions: These data could serve as a platform for therapeutic decision making. The strategy of targeting parallel pathways may be especially important in pts with coexisting PI3K/AKT and MAPK pathway genetic alterations. The data also suggest the need to further investigate the role of molecular profiling and matching pts with targeted drugs for personalized treatment.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.e13025
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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