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

[Lani]

gene expression profiles

from ASCO abstracts--

Gene expression analysis for prediction of early brain metastasis (BM) in HER2-positive (HER2+) breast cancer patients (pts).
Sub-category:
Metastatic Breast Cancer
Category:
Breast Cancer--Metastatic Breast Cancer
Meeting:
2008 ASCO Annual Meeting



Abstract No:
1019
Citation:
J Clin Oncol 26: 2008 (May 20 suppl; abstr 1019)
Author(s):
R. Duchnowska, J. Jassem, M. A. Thorat, A. Morimiya, G. W. Sledge, L. Li, W. Biernat, C. Szczylik, P. S. Steeg, S. S. Badve
Abstract:
Background: BM is a common occurrence in HER2+ breast cancer pts. If the pts most likely to develop BM could be identified, prophylactic strategies might prevent or delay occurrence of this failure. We explored gene expression differences between HER2+ breast cancers with early vs late occurrence of BM. Methods: Study group included 90 HER2+ breast cancer pts, 43 of whom developed BM (BM+): 22 and 21 pts with <3 and >3 yrs in time from diagnosis to BM, respectively; 47 patients had not developed BM (BM-) at the last follow-up. We performed cDNA-mediated annealing, selection, extension, and ligation (DASL) assay (Illumina Corp) for expression of 502 known cancer genes using 200 ng RNA from archived FFPET. T-test with unequal variances was applied after sample median normalization. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis. Results: A binary comparison of BM+ vs BM- revealed 25 differentially expressed genes (p <0.05). For BM+ in <3 yrs vs >3 yrs comparison, 95 genes were differentially expressed with a p value <0.05. Up-regulated gene pathways included Glucocorticoid Receptor, PI3K/AKT & PTEN, IGF-1, P53 and NF-κB. Down-regulated gene pathways were cell cycle G1/S checkpoint regulation, cell-cycle G2/M DNA damage checkpoint, Vitamin D and retinoic acid receptor signaling. Conclusions: Early BM occurrence in HER-2+ breast cancer pts can be predicted by gene expression in primary tumors. Altered cell cycle regulation seems to be particularly important. Analyses are ongoing to generate a gene-expression signature to predict development of BM.

[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

[harrie]

I wonder of any of these gene expressions were analyzed on the Oncotype dx.

[Lani]

Actually oncodx is a very simple test--it includes 21 genes including about 6 "housekeeping genes" not related to the likelihood breast cancer spread, if I remember correctly

The most important genes within it are easily tested separately (although most are measured in a different way with oncodx, ie by mRNA levels):
ER, PR, her2, GRB7 (next door neighbor to her2 on chromosome 17 which
some researchers feel may be the real culprit rather than her2 itself), Ki67.

SO far I think we've got 11, that leaves about 10. Will check them out when I can.

[BonnieR]

Can someone interpret any of this for me?Thanks.