Mutational Analysis of PI3K/AKT Signaling Pathway in Tamoxifen Exemestane Adjuvant Multinational Pathology Study

Sabine, Victoria; Crozier, Cheryl; Brookes, Cassandra; Drake, Camilla; Piper, Tammy; Velde, Cornelis J.H. van de; Hasenburg, Annette; Kieback, Dirk G.; Markopoulos, Christos; Dirix, Luc; Seynaeve, Caroline; Rea, Daniel; Bartlett, John M.S.

doi:10.1200/jco.2013.53.8272

Cited by 101 publications

(94 citation statements)

References 35 publications

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“…16 We also investigated the interaction between antiproliferative response and PIK3CA mutations. In keeping with other series, 2,6 approximately 40% of tumors carried a mutation in the PIK3CA gene, 84% of these in one of the hotspots in the helical and kinase domains. Baseline Ki-67 expression was comparable between wildtype and mutant samples (23.3%, 20.7%, and 25.5% for wild-type, helical, or kinase mutations), confirming previously reported results.…”

Section: Discussionsupporting

confidence: 87%

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Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor–Positive Breast Cancer

Schmid

Pinder

Wheatley

et al. 2016

JCO

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. (2016). Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer. Journal of Clinical Oncology, 34(17), 1987-1994. DOI: 10.1200/JCO.2015 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. PurposePreclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Patients and MethodsIn this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. ResultsThere was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, $ 79.0%) for the combination and 66.0% (95% CI, # 75.4%) for anastrozole (geometric mean ratio [combination: anastrozole], 0.48; 95% CI, # 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, # 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. ConclusionAdd...

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Section: Discussionsupporting

confidence: 87%

“…5,6 Conversely, PIK3CA mutations have not been shown to be predictive of response to endocrine treatment or mTOR-targeted therapies. 7,8 However, preclinical studies suggest that PIK3CA mutations are predictive of sensitivity to PI3K inhibitors but do not explain all of the sensitivity observed.…”

Section: Introductionmentioning

confidence: 99%

Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor–Positive Breast Cancer

Schmid

Pinder

Wheatley

et al. 2016

JCO

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show abstract

“…Our PIK3CA mutation rate (23.3%) was consistent with the literature, as well as our rate of different hotspot mutations [3,14,19,[22][23][24][25][26][27][28][29][30][31][32][33][34]. Also, we confirmed significant associations of different types of PIK3CA mutations with clinicopathological and molecular characteristics.…”

Section: Discussionsupporting

confidence: 91%

“…Notably, many studies examining the prognostic significance of PIK3CA mutations in breast cancer [35] have been published, however very few included a large enough number of patients [3,14,19,[22][23][24][25][26][27][28][29][30][31][32][33][34]. Also, less than half of them [22,24,26,28,30,31,33] used data from clinical trials, thus excluding the effect of treatment heterogeneity when evaluating prognostic factors. Up to now, results are largely inconclusive with some studies showing favorable and other adverse impact of PIK3CA mutations on patient outcome, while a significant number of reports did not show any prognostic significance.…”

Section: Discussionmentioning

confidence: 99%

1976 Significance of PIK3CA mutations in patients with early breast cancer treated with adjuvant chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) study

Papaxoinis¹,

Kotoula²,

Alexopoulou³

et al. 2015

European Journal of Cancer

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“…Among these, the Ras/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway has been established (23). Novel treatments targeting the RSK, PI3K/Akt and MEK/ERK signaling pathways are currently under evaluation in numerous types of tumors in clinical trials (24)(25)(26). AML is an aggressive hematological disorder characterized by an abnormal increase of immature hematopoietic progenitor cells known as 'blasts', which lose their ability to differentiate normally and continue to proliferate.…”

Section: A B Discussionmentioning

confidence: 99%

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Deng

Jiang

et al. 2017

Oncology Letters

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Abstract. Ribosomal S6 kinases (RSKs) are directly regulated by extracellular signal-regulated kinase (ERK) signaling and are implicated in cell growth, survival, motility and senescence. The present study observed that RSK1 was overexpressed in primary untreated leukemia patient bone marrow samples compared with the expression at the complete remission stage, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a high RSK1 expression (relative expression ≥10) was associated with a significantly shorter overall survival (P=0.038) compared with that in patients with low RSK1 expression (relative expression <10). The current study also investigated the effect of luteolin, a novel p90 ribosomal S6 kinase (RSK) inhibitor extracted from Reseda odorata L., which shows strong biochemical functions including anti-allergy, anti-inflammation and anti-cancer functions, in MOLM-13 and Kasumi-1 leukemic cells. The cell viability, apoptosis and migration ability analysis were assessed by performing a cell counting kit-8 assay, Annexin V-FITC/PI double staining and migration filter assay, respectively. The results indicated that luteolin inhibited the growth of the leukemic cell lines through induction of apoptosis, while the migration ability was also suppressed. Overexpression of RSK1 by plasmid transfection was found to decrease the luteolin-induced apoptosis and migration capabilities. By contrast, knockdown of the RSK1 expression by small interfering RNA appeared to induce the same effect as luteolin on MOLM-13 and Kasumi-1 leukemic cells. In conclusion, these results suggest that luteolin inhibits leukemic cell proliferation and induces apoptosis by inhibition of the RSK1 pathways. IntroductionRibosomal S6 kinases (RSKs) are a family of serine/threonine protein kinases that are directly regulated by extracellular signal-regulated kinase (ERK) signaling. RSK1, a member of the RSK family, was initially identified as an X-linked gene in patients with mental retardation (1-3). Typically, RSK is expressed in the cerebellum during embryogenesis and silenced postnatally. Aberrant RSK signaling is integral for various types of cancer, including breast, colon and renal cancer, as well as melanoma. Li et al (4) observed that the p90 RSK2-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells. Degen et al (5) also demonstrated this phenomenon, and further observed that overexpression of RSK3 and RSK1 supports cellular proliferation under the PI3K signaling pathway blockade. This occurs through the inhibition of apoptosis and regulation of cellular translation in squamous carcinoma cell through phosphorylation of RSK and eukaryotic translation initiation factor 4B. It is thus reported that RSK1 serves a role in squamous carcinoma cell growth and proliferation. In addition, Cohen et al (6) observed that RSK1 overexpression is associated with sunitinib resistance in renal cell carcinoma cell lines. Elf et al (7) also reported that, altho...

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Mutational Analysis of PI3K/AKT Signaling Pathway in Tamoxifen Exemestane Adjuvant Multinational Pathology Study

Cited by 101 publications

References 35 publications

Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor–Positive Breast Cancer

Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor–Positive Breast Cancer

1976 Significance of PIK3CA mutations in patients with early breast cancer treated with adjuvant chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) study

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

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