scholarly journals Relationship of PIK3CA Mutation and PI3K Pathway Activity with Antiproliferative Response to Anastrozole in Er+ Breast Cancer

2013 ◽  
Vol 24 ◽  
pp. iii29 ◽  
Author(s):  
C. Segal ◽  
E. Lopez-Knowles ◽  
V. Patel ◽  
I. Garcia-Murillas ◽  
N. Turner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pik3ca Mutation ◽  
Pi3k Pathway ◽  
Pathway Activity ◽  
Relationship Of

PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 509-509 ◽  
Author(s):  
Mafalda Oliveira ◽  
Alejandro Navarro ◽  
Leticia De Mattos-Arruda ◽  
Gessamí Sánchez-Ollé ◽  
Meritxell Bellet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Mtor Inhibitors ◽  
Pi3k Pathway ◽  
Time To Progression ◽  
Prospective Trials

509 Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]

Use of alpelisib in the treatment of hormone receptor positive metastatic breast cancer: An institutional experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15216-e15216
Author(s):  
Tsering G. Lama Tamang ◽  
Daniel Kyung ◽  
Lauren Eisenbud ◽  
Tianyi Tang ◽  
Ritesh Parajuli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Real World Data ◽  
Tumor Registry ◽  
Hormone Receptor Positive ◽  
Heavily Pretreated ◽  
Institutional Experience

e15216 Background: Mutations in PI3K pathway is a known mechanism of resistance to endocrine therapy in breast cancer. Alpelisib is an alpha-specific PI3K inhibitor. Alpelisib with Fulvestrant is approved for treatment (Tx) of PIK3CA mutated HR+ metastatic breast cancer (MBC) that progress on hormonal therapy. Despite its approval by the FDA, real world data on the use of Alpelisib for the management of MBC is lacking. This abstract reviews the safety and efficacy of Alpelisib in the management of patients with MBC. Methods: A retrospective review of the tumor registry database at a single institution was conducted to identify patients with HR+ MBC. Detailed clinical and pathologic data of PIK3CA mutated patients treated with Alpelisib were obtained. Genomic profiling was done with Foundation One. Results: Table highlights the characteristics of the four patients. All were treated with Alpelisib and Fulvestrant after PIK3CA mutation was demonstrated. 3 patients were heavily pretreated with systemic Tx including CDK 4/6 inhibitors. All patients responded to Alpelisib and Fulvestrant despite treatment history. Mucositis, rash, hyperglycemia and pancytopenia were the observed adverse events (A/E). All A/E were adequately managed except in one patient that required discontinuation of Tx. None has clinically progressed. Conclusions: Our data suggests that Alpelisib and Fulvestrant is tolerated and improves outcomes in patients with HR+ MBC. Alpelisib and Fulvestrant could be an effective therapy in patients who have also progressed on systemic chemotherapy including CDK 4/6 inhibitors. Although our sample size is small, we hope that our experience could guide clinicians in the management of patients with HR+ MBC who harbor the PIK3CA mutation and are being treated with Alpelisib. [Table: see text]

scholarly journals Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition

2014 ◽  
Vol 16 (3) ◽  
Author(s):  
Elena López-Knowles ◽  
Corrinne V Segal ◽  
Qiong Gao ◽  
Isaac Garcia-Murillas ◽  
Nicholas C Turner ◽  
...  
Keyword(s):  
Pik3ca Mutation ◽  
Aromatase Inhibition ◽  
Pathway Activity ◽  
Relationship Of

scholarly journals Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

2020 ◽  
Author(s):  
Márcia A. Inda ◽  
Paul van Swinderen ◽  
Anne van Brussel ◽  
Cathy B. Moelans ◽  
Wim Verhaegh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Signaling Pathway ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Pathway Activity ◽  
Micro Scale ◽  
Scale Heterogeneity ◽  
Macro Scale ◽  
Heterogeneity Analysis

AbstractBackgroundTargeted drug treatment aims to block tumor driving signaling pathways, and is generally based on analysis of one primary tumor (PT) biopsy. Phenotypic heterogeneity within primary and between primary and metastatic lesions was investigated.MethodsActivity of androgen and estrogen receptor, PI3K-FOXO, Hedgehog, TGFβ, and Wnt signaling pathways was measured in breast cancer samples using a novel mRNA-based assay platform. Macro-scale heterogeneity analysis was performed on multiple spatially distributed PT tissue blocks from 17 luminal A-like, 9 luminal B-like, and 9 ER-negative primary breast cancers; micro-scale heterogeneity analysis was performed on four “quadrant” samples of a single tissue block of respectively 9, 4, and 4 matched PT. Samples from 6 PT with matched lymph node (LN, n=23) and 9 PT with distant metastatic sites (DS, n=12) were analyzed. Statistical variance analysis was performed with linear mixed models. A “checkerboard” model was introduced to explain the observed heterogeneity in PT.ResultsWithin PT, macro-scale heterogeneity in signaling pathway activity was similar to micro-scale heterogeneity, with a possible exception of the PI3K pathway. Variation was significantly higher on microscale for Hedgehog and TGFβ pathways. While pathway activity scores correlated significantly between different locations in the PT, positive correlations decreased between PT and LN, and even more between PT and DS metastases, including the emergence of a negative correlation for the ER pathway.ConclusionWith a possible exception of the PI3K pathway, variation in signaling pathway activity within a single PT tissue block was generally representative for the whole PT, but not for DS or LN metastases. The higher variation in TGFβ and HH pathway activity on microscale suggested the presence of multiple small cancer cell clones. While analysis of multiple sub-samples of a single biopsy block may be sufficient to predict PT response to some targeted therapies, such as hormonal therapy, metastatic breast cancer treatment requires analysis of metastatic biopsies. The findings on phenotypic intra-tumor heterogeneity are compatible with currently emerging ideas on a Big Bang type of cancer evolution.

scholarly journals Heterogeneity in Signaling Pathway Activity within Primary and between Primary and Metastatic Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1345
Author(s):  
Márcia A. Inda ◽  
Paul van Swinderen ◽  
Anne van Brussel ◽  
Cathy B. Moelans ◽  
Wim Verhaegh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Tumor Heterogeneity ◽  
Metastatic Breast ◽  
Big Bang ◽  
Pi3k Pathway ◽  
Pathway Activity ◽  
Micro Scale ◽  
Macro Scale ◽  
Scale Variation

Targeted therapy aims to block tumor-driving signaling pathways and is generally based on analysis of one primary tumor (PT) biopsy. Tumor heterogeneity within PT and between PT and metastatic breast lesions may, however, impact the effect of a chosen therapy. Whereas studies are available that investigate genetic heterogeneity, we present results on phenotypic heterogeneity by analyzing the variation in the functional activity of signal transduction pathways, using an earlier developed platform to measure such activity from mRNA measurements of pathways’ direct target genes. Statistical analysis comparing macro-scale variation in pathway activity on up to five spatially distributed PT tissue blocks (n = 35), to micro-scale variation in activity on four adjacent samples of a single PT tissue block (n = 17), showed that macro-scale variation was not larger than micro-scale variation, except possibly for the PI3K pathway. Simulations using a “checkerboard clone-size” model showed that multiple small clones could explain the higher micro-scale variation in activity found for the TGFβ and Hedgehog pathways, and that intermediate/large clones could explain the possibly higher macro-scale variation of the PI3K pathway. While within PT, pathway activities presented a highly positive correlation, correlations weakened between PT and lymph node metastases (n = 9), becoming even worse for PT and distant metastases (n = 9), including a negative correlation for the ER pathway. While analysis of multiple sub-samples of a single biopsy may be sufficient to predict PT response to targeted therapies, metastatic breast cancer treatment prediction requires analysis of metastatic biopsies. Our findings on phenotypic intra-tumor heterogeneity are compatible with emerging ideas on a Big Bang type of cancer evolution in which macro-scale heterogeneity appears not dominant.

scholarly journals Relationship between stemness and transcriptionally-inferred PI3K activity in human breast cancer

2020 ◽  
Author(s):  
Ralitsa R. Madsen ◽  
Oscar M. Rueda ◽  
Xavier Robin ◽  
Carlos Caldas ◽  
Robert K. Semple ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pi3k Pathway ◽  
Activity Score ◽  
Breast Cancers ◽  
Mutation Status ◽  
Pathway Activity ◽  
Molecular Tests ◽  
Pi3k Activity ◽  
Mutational Status ◽  
Per Se

ABSTRACTThe development of reliable, prognostically informative molecular tests to direct targeted cancer therapy is a major challenge. In 2019, the PI3Kα inhibitor alpelisib was approved for the treatment of advanced breast cancer, in combination with the oestrogen receptor degrader fulvestrant, with some evidence for improved therapeutic response in patients classified as having tumours which were positive for mutation in PIK3CA, the gene encoding PI3Kα. Using human pluripotent stem cells, we recently demonstrated that the PIK3CAH1047R oncogenic hotspot variant shows marked PIK3CA allele dose-dependent activation of PI3K signalling and induction of self-sustained stemness. Together with recent discoveries of multi-copy and double-cis PIK3CA mutations in human cancers, this calls for a re-evaluation of the PIK3CA genotype-phenotype relationship and the current use of binary stratification by PIK3CA mutation status. Using computational analyses, we thus investigated the relationship between PIK3CA mutational status, PI3K activity/signalling strength and stemness. Stemness and PI3K activity scores were calculated using open-source methods and well-established transcriptional signatures. We report that a high PI3K pathway activity score, but not the presence of PIK3CA mutation per se, predicts increased breast cancer dedifferentiation and higher stemness, correlating with reduced overall survival. Our data (1) corroborate reports that the presence of a PIK3CA mutation per se does not predict high PI3K pathway activation or poor prognosis; (2) suggest that stratification of breast cancer for PI3K-based therapy might benefit from the use of a PI3K pathway activity score rather than binary PIK3CA mutation status alone; (3) suggest that combination of PI3K pathway inhibitors with differentiation-promoting treatments warrants evaluation in aggressive breast cancers with high PI3K activity and stemness scores.

Effect of eribulin on cell growth and PI3K pathway activity with and without RAD001 in triple-negative and HER2-expressing breast cancer.

2013 ◽  
Vol 31 (26_suppl) ◽  
pp. 173-173 ◽  
Author(s):  
David Luyimbazi ◽  
Thehang H. Luu ◽  
Quanhua Xing ◽  
Jin Yan ◽  
Dylan Tully ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pi3k Pathway ◽  
Western Blots ◽  
Pathway Activity ◽  
Phosphorylated Akt

173 Background: Patients with triple-negative breast cancer have high levels of Akt expression and activation of the PI3K-mTOR pathway. Eribulin is a microtubule-targeting agent with benefits in treating refractory triple negative disease. Our objective was to evaluate its efficacy in inhibiting PI3K pathway activity and cell growth both alone and in combination with the mTOR inhibitor RAD001. Methods: MDA468, BT549 and SKBR3 breast cancer cell lines were used for this study. MTT assays were used to assess growth inhibition after 72 hour treatment with eribulin alone and in combination with RAD001. Combination indices (CI) generated by Chou-Talalay plots were used to quantify synergy. Western blots were used to evaluate the expression of phosphorylated Akt-Ser473 (pAkt) and S6K1 after 24 hours of treatment with both agents. Results: Both MDA468 and SKBR3 cells treated with eribulin in varying concentrations showed inhibition of pAkt expression. Standard dilutions of eribulin in combination with log dilutions of RAD001 resulted in marked synergistic growth inhibition (CI<<1) in both MDA468 and BT549 cells. Western blot analysis for MDA468 cells treated with the combination erubulin and RAD001 showed a dose related suppression of pAkt along with complete inhibition of pS6K1, while RAD001 alone increased pAkt. Conclusions: Our study shows dose related inhibition of Akt activation as well as inhibition of cell growth in triple negative breast cancer and HER2 cell lines treated with eribulin alone or combined with RAD001. We also show reversal of the pAkt feedback response seen with mTOR inactivation, and a significant synergistic growth inhibition with combination treatment. These findings point to a potential role for eribulin and RAD001 in the treatment of refractory triple-negative breast cancer. [Table: see text]

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