PI3K Pathway Activation in Breast Cancer Is Associated with the Basal-Like Phenotype and Cancer-Specific Mortality.

Abstract

Background: Current biological therapies for breast cancer are tailored to steroid hormone (ER, PR) and HER2 receptor status. Understanding the biological basis of resistance to current targeted therapies and the identification of new potential therapeutic targets is an ongoing challenge. The PI3K pathway is altered in a high proportion of breast cancers and may be associated with specific phenotypes and therapeutic resistance. We undertook an integrative study of mutational, copy number and expression analysis of key regulators of the PI3K pathway in a cohort of 292 invasive breast cancer patients with known treatment outcomes.Material and Methods: Mutations in 3 "hotspots" in exons 9 and 20 of the PIK3CA gene were determined by sequencing and PIK3CA gene copy number by qPCR. PTEN loss and Akt activation i.e. pAkt (Ser473) were assessed by immunohistochemistry using tissue microarrays. Cores were scored by 2 independent observers blinded to clinicopathological data and patient outcome and a histoscore calculated by multiplying the percent positive cells and staining intensity in a range 0-3. Standard statistical tests were applied to assess relationship between the measured parameters and patient outcome.Results: Alterations identified included PIK3CA mutations (12/168 i.e. 7%), PIK3CA copy number gain (28/209 i.e. 14%), PTEN loss (73/258 i.e. 28%) and AKT activation (62/258 i.e. 24%). Overall at least one parameter was altered in 72% i.e. 139 of 193 assessable primary breast cancers. PI3K pathway activation was significantly associated with ER negative (P=0.0008) and PR negative (P=0.006) status, high tumor grade (P=0.032) and a "basal-like" phenotype (P=0.01), where 92% (25/27) of tumors had an altered pathway. In univariate analysis PI3K pathway aberrations were associated with death from breast cancer however this relationship was not maintained in multivariate analysis. No association was identified between an activated pathway and outcome in tamoxifen- or chemotherapy-treated patients.Discussion: We conclude that >70% of breast cancers have an alteration in at least one component of the PI3K pathway and this might be exploited to therapeutic advantage especially in "basal-like" cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2123.

Comprehensive analysis of PTEN status in breast carcinomas

“…In contrast, complete loss of PTEN was more frequent in ER2 than ER1 tumors (7/19 vs. 12/116, p50.006), consistent with a recent report. 6 HER2 overexpression and complete loss of functional PTEN were not identified in the same tumor in this study, which is consistent with a previous report 22 which found no PTEN point mutations in HER2 overexpressing tumors, but in contrast to other studies which identified both HER2 overexpression and reduced or absent PTEN expression in 4% of their cohorts. 6,8 Therefore complete loss of PTEN and HER2 overexpression appear to be rarely present in the same tumor suggesting that each of these events activate the PI3K pathway sufficiently to not require additional alterations affecting this pathway.…”

“…6 HER2 overexpression and complete loss of functional PTEN were not identified in the same tumor in this study, which is consistent with a previous report 22 which found no PTEN point mutations in HER2 overexpressing tumors, but in contrast to other studies which identified both HER2 overexpression and reduced or absent PTEN expression in 4% of their cohorts. 6,8 Therefore complete loss of PTEN and HER2 overexpression appear to be rarely present in the same tumor suggesting that each of these events activate the PI3K pathway sufficiently to not require additional alterations affecting this pathway. Similarly, PIK3CA mutations were identified in combination with either HER2 overexpression or PTEN complete loss in only four tumors in this study thus multiple alterations in this pathway are predominantly mutually exclusive as has been previously described.…”

“…This is lower than the proportion of tumors with PI3K pathway activation recently reported in a study of primary breast cancers (72%; 139/193 tumors) but any variation is likely to be the result of differences in the assessment of PI3K pathway activation. 6 Lopez-Knowles et al included PIK3CA copy number gain and AKT activation as criteria for PI3K pathway activation but did not take into account HER2 overexpression and no molecular characterization of PTEN was undertaken. 6 A third of tumors (44/134) in this series harbored a PIK3CA mutation, consistent with the reported mutation rate of 25%.…”

“…6 Lopez-Knowles et al included PIK3CA copy number gain and AKT activation as criteria for PI3K pathway activation but did not take into account HER2 overexpression and no molecular characterization of PTEN was undertaken. 6 A third of tumors (44/134) in this series harbored a PIK3CA mutation, consistent with the reported mutation rate of 25%. 3 Differences in mutation frequencies can often be attributed to the extent to which the gene is screened, ranging from two exons to all coding exons.…”

“…1,2 Activating mutations in PIK3CA, which encodes the PI3K catalytic subunit, have been reported in approximately a quarter of breast tumors 3 and copy number gain of this gene has been identified in 1-14% of breast cancers. [4][5][6] Approximately one fifth of breast cancers are described as having loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression (range 4-48%) [6][7][8][9][10][11][12][13][14][15] and epigenetic silencing of the PTEN gene through promoter hypermethylation has been reported in 34% 16 and 48% 17 of breast cancers. Loss of heterozygosity at the PTEN locus is observed in 40% of invasive breast carcinomas 18,19 but mutations in this gene have only been identified in 2-9% of breast cancers 3,7,[20][21][22] suggesting that PTEN haploinsufficiency may have tumorigenic consequences.…”