predicting which her2+ breast cancer patients will get brain mets by primary tumor

[Lani]

in her2+ bc patients


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HER2, EGFR, PIK3CA mutations in HER2+ metastatic breast cancer (MBC) patients (pts) treated with trastuzumab (T): Incidence and correlation with response.
Sub-category:
Metastatic Breast Cancer
Category:
Breast Cancer--Metastatic Breast Cancer
Meeting:
2008 ASCO Annual Meeting



Abstract No:
1031
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 1031)
Author(s):
S. Gori, V. Ludovini, M. Colozza, L. Pistola, F. R. Tofanetti, A. Flacco, J. Foglietta, E. Minenza, L. Stocchi, V. De Angelis, L. Crinò
Abstract:
Background: Resistence mechanisms to T are still undefined. EGFR, pMAPK, pAKT and PTEN status by IHC were not correlated with response to T in our previously series of 45 HER2+ MBC pts. No data are reported about incidence of HER2, EGFR and PIK3CA genes mutations and their correlations with response to T. in HER2+ MBC pts. Methods: From 4/1999 to 3/2006, 133 consecutive pts were treated with T. Tumor tissues for this analysis were available from 41 pts. Genomic DNA was isolated from paraffin-embedded tumor specimens, amplified for HER2 (exons 19, 20, 21 and 22, encoding the kinase domain), EGFR (exons 18, 19, 20 and 21) and PIK3CA (exons 9 and 20, encoding a part of elical and kinase domains, respectively) genes by nested polymerase chain reaction and sequenced in both sense and antisense directions. Results: We found mutations of HER2 in 3 pts (7.3%), of EGFR in 6 pts (14.6 %) and PIK3CA in 5 pts (12.2%) with HER2+ tumors (Table); correlations with response to T are reported (Table). The same HER2 mutation in exon 20 was identified in 2 pts with pAKT+ tumor (IHC) and no response to T. PIK3CA mutations were associated with pAKT+ status only in 2 pts. In all 5 tumors with PIK3CA mutations, a PTEN+ status (IHC) was observed, consistent with the speculation that PIK3CA mutations and loss of PTEN expression are mutually exclusive. A pt presented 2 mutations: 1 in ex 20 of HER2 (P780_H781insC) and 1 in ex 20 of PIK3CA (L1026P). CNS metastases developed in 9/13 (69.2%) pts with mutations of these genes, but only in 12/28 (42.8%) pts without mutations. Conclusions: In our series of HER2+ MBC pts the incidence of HER2, EGFR and PIK3CA mutations is relatively low and therefore any correlation with response to T is difficult. An intriguing observation is the higher incidence of CNS metastases reported in the 13 pts with these mutations. If confirmed in larger studies, these data could help to identify HER2+ pts with a higher risk of brain metastases.
Gene Exon Mutation
analysis Mutation
code Response
to T. CNS
metastases
HER2 20
20
21 insertion
insertion
missense P780_H781insC
P780_H781insC
S856P PD
SD
CR YES
YES
YES
EGFR 18
20
20
20
21
21 missense
missense
missense
missense
missense
missense T710I
L815P
S784F
V765M
E872K;
E866K
H835P CR
PD
CR
PR
CR
PR NO
NO
YES
YES
YES
YES
PIK3CA 9
20
20
20
20 missense
missense
missense
missense
missense D549N
H1048Y
A987V
M1004I;
H1048Y
L1026P PR
PD
PR
PR
SD YES
YES
NO
NO
YES