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Pharmacokinetics: Z-endoxifen levels per taselisib dose level

Purpose:The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)–positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform–sparing PI3 kinase inhibitor.Patients and Methods:30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a “rolling six” design.Results:Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients.Conclusions:Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.

Supplementary Methods Text

Funding Information: This project was initiated at the Endeavour Breast Project coordinated by Daiichi Sankyo (special thanks to Christian Opitz and Britta Mazur from Daiichi Sankyo). We thank all participants and the steering committee members of the Endeavour Breast Meeting who are not listed as co-authors ( Supplementary Table S4 , available at https://doi.org/10.1016/j.esmoop.2022.100747 ). The authors gratefully acknowledge the support from the AGMT office (particularly Mag. Katrin Dorfinger, Mag. Alexandra Keuschnig, Sebastian Schütz, and Dr. Daniela Wolkersdorfer) and all trial coordinators at the contributing centers. Publisher Copyright: © 2022 The Authors Background: Triple-negative breast cancer (TNBC) is associated with poor prognosis, and new treatment options are urgently needed. About 34%-39% of primary TNBCs show a low expression of human epidermal growth factor receptor 2 (HER2-low), which is a target for new anti-HER2 drugs. However, little is known about the frequency and the prognostic value of HER2-low in metastatic TNBC. Patients and methods: We retrospectively included patients with TNBC from five European countries for this international, multicenter analysis. Triple-negativity had to be shown in a metastatic site or in the primary breast tumor diagnosed simultaneously or within 3 years before metastatic disease. HER2-low was defined as immunohistochemically (IHC) 1+ or 2+ without ERBB2 gene amplification. Survival probabilities were calculated by the Kaplan–Meier method, and multivariable hazard ratios (HRs) were estimated by Cox regression models. Results: In total, 691 patients, diagnosed between January 2006 and February 2021, were assessable. The incidence of HER2-low was 32.0% [95% confidence interval (CI) 28.5% to 35.5%], with similar proportions in metastases (n = 265; 29.8%) and primary tumors (n = 425; 33.4%; P = 0.324). The median overall survival (OS) in HER2-low and HER2-0 TNBC was 18.6 and 16.1 months, respectively (HR 1.00; 95% CI 0.83-1.19; P = 0.969). Similarly, in multivariable analysis, HER2-low had no significant impact on OS (HR 0.95; 95% CI 0.79-1.13; P = 0.545). No difference in prognosis was observed between HER2 IHC 0/1+ and IHC 2+ tumors (HR 0.89; 95% CI 0.69-1.17; P = 0.414). Conclusions: In this large international dataset of metastatic TNBC, the frequency of HER2-low was 32.0%. Neither in univariable nor in multivariable analysis HER2-low showed any influence on OS. publishersversion published

Purpose Everolimus plus exemestane (EVE/EXE) is a registered treatment option for ER-positive, HER2-negative (ER +/HER2-) metastatic breast cancer (MBC), but resistance mechanisms limit efficacy. We aimed to find markers that might help select patients with a higher chance on benefit from EVE/EXE. Methods Immunohistochemistry (IHC) of PTEN, p-AKT(Thr308), p-AKT(Ser473), p-4EBP1, p-p70S6K, p-S6RP(Ser240/244), p-ERK1/2 and p-S6RP (Ser235/236) was performed on primary tumour tissue and on biopsies immediately taken from ER +/HER2- MBC patients before the start of standard EVE/EXE (Eudract 2013-004120-11). Unsupervised hierarchical clustering was executed to create heatmaps to distinguish subgroups of preferentially activated and less-activated PI3K/MAPK proteins. Uni- and multivariate Cox models were used for associations with PFS. Results Primary tumour tissue from 145 patients was retrieved. Median PFS was 5.4 months. Patients without (neo)adjuvant therapy (p = 0.03) or bone only disease (p = 0.04) had longer PFS on EVE/EXE. In primary tumours, neither single proteins nor PI3K/MAPK-associated heatmap subgroups were significantly associated with PFS. In 21 patients a non-osseous biopsy obtained before dosing was useful for continuous scoring, which demonstrated upregulation of several proteins as compared to readings in corresponding primary tumour tissues. These comparisons revealed that increased expression of p-4EBP1 was significantly associated with worse PFS (multivariate HR 3.69, p = 0.05). Conclusions IHC of single proteins or heatmap subgroups of the differentially activated PI3K/MAPK pathways was not able to discriminate patients on EVE/EXE with poor or better PFS. Upregulation of p-4EBP1 in pre-treatment biopsies as compared to levels in primary tumours pointed towards shorter PFS.

Intro MBC is generally considered incurable, but patients with HER2+ disease treated with trastuzumab do relatively well and some have an exceptional durable response and survive over 10 years. We analyzed the clinical-pathological characteristics associated with long-term survival in patients with HER2+ MBC treated with trastuzumab. In addition, we studied the effect of stopping trastuzumab in case of rCR. Methods We included all patients with HER2+ MBC treated with first- or second-line trastuzumab-based palliative therapy between January 2000 and December 2014 in 8 Dutch hospitals (Netherlands Cancer Institute, Erasmus Medical Center, Albert Schweitzer Hospital, Reinier de Graaf Hospital, Amphia Hospital, St. Antonius Hospital, Ikazia Hospital, Haga Hospital). Patients were identified through the Netherlands Cancer Registry and linkage with the institutes' tumor registries. Data was collected from medical records using case record forms. Primary endpoint was overall survival (OS), defined as first-date of MBC until death due to any cause. Kaplan-Meier survival estimates were calculated and multivariable Cox-regression models used to identify prognostic factors for improved survival. Time to progression (TTP) after achieving rCR for patients who continued and stopped trastuzumab and breast cancer specific survival were secondary outcomes. Results We included 744 patients (median age 53, range 24-87). Median follow-up (FU) was 109 months (range 0-178). Clinical factors associated with improved survival in multivariable analyses were single-organ metastases, ER-positivity, no skin or liver metastases, no prior trastuzumab, local therapy of metastatic disease and achievement of rCR. In line with our first single center analyses1, achievement of rCR was the strongest predictor of improved survival (multivariable HR 0.30, 95%CI 0.20-0.46). RCR was observed in 71 patients (10%), of whom 60 had been treated with trastuzumab and chemotherapy, 9 with trastuzumab and hormonal therapy, and 2 with hormonal therapy. In patients with rCR the estimated 10-year OS was 53% versus 7% in patients who did not achieve rCR (p Thirty patients stopped trastuzumab after achieving rCR. Median time between onset of rCR and last gift of trastuzumab in these patients was 6 months (0-132). Twenty-one patients (70%) remain in complete remission after a median FU of 75 months (range 54-90) since onset of rCR. Nine patients experienced disease progression after a median time of 14 months (range 9-62) since last gift of trastuzumab. Of these, 8 patients died due to MBC and one again achieved an ongoing rCR. Out of 39 patients who continued trastuzumab after achieving rCR, 12 are in ongoing remission after a median FU of 71 months (range 51-91). In this group median TTP was 14 months (range 5-23). Conclusion Achieving rCR is strongly associated with long-term survival in patients with HER2+ MBC. Seventy percent of patients who stopped trastuzumab after achieving rCR remained in remission, suggesting this can be an attractive approach in selected patients. External validation of these findings is required, however, as well as additional analyses to characterize the patients -and their tumors- who achieved rCR. 1 Steenbruggen, CancerRes 2017 Citation Format: Steenbruggen TG, Bouwer NI, Smorenburg CH, Rier HN, Jager A, Beelen KJ, ten Tije AJ, de Jong PC, Drooger JC, Holterhues C, Horlings HM, Sanders J, Levin M-D, Sonke GS. What to do with trastuzumab therapy after achieving radiological complete remission (rCR) in HER2+ metastatic breast cancer (MBC)? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-19.

Purpose: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)–positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform–sparing PI3 kinase inhibitor. Patients and Methods: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a “rolling six” design. Results: Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients. Conclusions: Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.

Het verstrekken van steeds duurdere medicijn stelt ziekenhuizen voor dilemma’s. Fizier ging daarover in gesprek met de apotheker, een oncoloog en een financial van het Reinier de Graaf Gasthuis in Delft. ‘Sommigen vinden de discussie niet ethisch, maar het onderwerp is wel bespreekbaar geworden.’

Background Several (activated) proteins of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway have been analyzed for an association with adjuvant tamoxifen benefit in estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer. Currently, no single protein has yielded convincing results allowing clinical implementation. Combining activated proteins could provide more robust predictive potential. We used unsupervised hierarchical clustering of 7 activated proteins downstream in these pathways, discriminated by expression profile, to analyze adjuvant tamoxifen benefit in ER+/HER2- postmenopausal breast cancer patients. Further, we developed a classification tool based on the generated heatmap groups by pathway activation status to categorize future patients into sensitive for or resistant to adjuvant tamoxifen. Methods Primary tumor blocks from 489 ER+/HER2- (stage I-III) postmenopausal patients previously randomized between tamoxifen (1 to 3 years) vs no adjuvant therapy (IKA trial 1982-1993; Beelen et al, Breast Cancer Res, 2014) were used for immunohistochemistry on tissue microarrays. Median follow-up of the patients without a recurrence event was 8.5 years. Scoring of PTEN, p-AKT(Thr308), p-AKT(Ser473) and p-p70S6K(Thr389) was by cytoplasmic intensity (0-3), p-4EBP1(Ser65) and pERK1/2(Thr202/204) by percentage of tumor cells with positive nuclear staining and p-S6RP(Ser235/236) by the percentage of tumor cells with positive membranous staining. Unsupervised hierarchical clustering was performed on tissue from 293 patients with informative data on all 7 proteins. Cox models were used to assess tamoxifen benefit (defined as the Hazard ratio (HR) of tamoxifen treatment vs no adjuvant therapy for recurrence-free interval) and to compare this benefit between subgroups generated by clustering as well as generated by the classification tool. Cox models included covariates (age, histological grade and subtype, tumor size, PR status) and were stratified for lymph node status. Results Two distinct groups were identified based on hierarchical clustering: one with preferentially activated pathway markers (A) and one with relatively no activation (N). Patients in group N derived significant benefit from tamoxifen (multivariable HR 0.28, 95% CI 0.14 − 0.56, p = 0.000324), while patients from group A had no benefit (multivariable HR 1.57, 95% CI 0.44 – 5.56, p = 0.482), p for interaction 0.018. Contradictory, patients in group A had a better prognosis compared to those in group N (multivariable HR 0.17, 95% CI 0.04 − 0.7, p = 0.014). The classification tool was also successful in differentiating ER+/HER2- patients with or without tamoxifen benefit (p for interaction = 0.016). Conclusions Hierarchical clustering of PI3K/MAPK pathway proteins is able to differentiate patients with adjuvant tamoxifen benefit and patients who would potentially need alternative treatment, for instance with inhibitors of the PI3K or MAPK pathway. The classification tool distinguishing patients with and without tamoxifen benefit should be validated in an independent cohort of postmenopausal patients with primary ER+/HER2- breast cancer. Citation Format: Kruger DT, Beelen K, Opdam M, Sanders J, van der Noort V, Boven E, Linn SC. Clustering of activated proteins of the PI3K and MAPK pathways distinguishes ER+/HER2- primary breast cancer patients with preferential tamoxifen benefit [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-12.

Introduction The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that genetic aberrations in malignant cells influence the immune landscape of tumors. Phosphatidylinositol 3-kinase (PI3K) is the most common altered pathway in ER-positive breast cancer. It is unknown whether changes in the PI3K pathway result in a different composition of the breast tumor microenvironment. Here we present the retrospective analysis of a prospective randomized trial in ER-positive breast cancer on the prognostic and predictive value of specific tumor-associated lymphocytes in the context of PI3K alterations. Methods We included 563 ER-positive tumors from a multicenter trial for stage I to III postmenopausal breast cancer patients, who were randomized to tamoxifen or no adjuvant therapy. The amount of CD8-, CD4-, and FOXP3-positive cells was evaluated by immunohistochemistry and quantified by imaging-analysis software. We analyzed the associations between PIK3CA hotspot mutations, PTEN expression, phosphorylated proteins of the PI3K and MAPK pathway (p-AKT, p-ERK1/2, p-4EBP1, p-p70S6K), and recurrence-free interval after adjuvant tamoxifen or no adjuvant treatment. Results CD8-positive lymphocytes were significantly more abundant in PIK3CA-mutated tumors (OR = 1.65; 95% CI 1.03–2.68). While CD4 and FOXP3 were not significantly associated with prognosis, patients with tumors classified as CD8-high had increased risk of recurrence (HR = 1.98; 95% CI 1.14–3.41; multivariable model including PIK3CA status, treatment arm, and other standard clinicopathological variables). Lymphocytes were more often present in tumors with increased PI3K downstream phosphorylation. This was most pronounced for FOXP3-positive cells. Conclusion These exploratory analyses of a prospective trial in luminal breast cancer suggest high CD8 infiltration is associated with unfavorable outcome and that PI3K pathway alterations might be associated with the composition of the tumor microenvironment. Electronic supplementary material The online version of this article (10.1186/s13058-019-1176-2) contains supplementary material, which is available to authorized users.

Item does not contain fulltext BACKGROUND: In 2007 the St. Gallen consensus panel defined three endocrine response classes: highly endocrine responsive (ER-H), incomplete endocrine responsive (ER-I) and non-endocrine responsive tumours (ER-N). However, it is uncertain whether ER-I tumours are less responsive than ER-H tumours. We investigated whether recurrence rates vary over time between response classes. Additionally, we investigated the most predictive response class definition for tamoxifen benefit. PATIENTS AND METHODS: We recollected tumours from 646 patients who participated in a randomized trial of adjuvant tamoxifen vs. OBSERVATION: Estrogen receptor (ER), progesterone receptor (PgR), HER2 status and tumour grade were revised centrally. St. Gallen classes were evaluated for recurrence free interval (RFI). Change in hazards over time was assessed. Subsequently, 6 alternative response class definitions were compared to optimize the cut-off for PgR and ER. RESULTS: Schoenfeld residuals indicate a failure of proportional hazards between the endocrine response groups (p = 0.0001). The HR for recurrence risk shifted over time with the ER-H group initially being at lower risk (HR ER-H vs. ER-I 0.5), but after six years the recurrence risk increased (HR 1.9). The cut-off values for ER and PgR that statistically best discriminated RFI in the first 4 years for lymph node positive patients were ER >/= 50% and PgR >/= 75%. CONCLUSION: We demonstrated a marked variability in endocrine therapy benefit. Patients with ER-H tumours have a larger benefit during adjuvant tamoxifen and in the first years after accomplishing of the therapy, but suffer from late recurrences. This might have implications for optimal treatment duration.

Background Controversy exists for the use of Ki67 protein expression as a predictive marker to select patients who do or do not derive benefit from adjuvant endocrine therapy. Whether other proliferation markers, like Cyclin D1, and mitotic count can also be used to identify those estrogen receptor α (ERα) positive breast cancer patients that derive benefit from tamoxifen is not well established. We tested the predictive value of these markers for tamoxifen benefit in ERα positive postmenopausal breast cancer patients. Methods We collected primary tumor blocks from 563 ERα positive patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial) with a median follow-up of 7.8 years. Mitotic count, Ki67 and Cyclin D1 protein expression were centrally assessed by immunohistochemistry on tissue microarrays. In addition, we tested the predictive value of CCND1 gene copy number variation using MLPA technology. Multivariate Cox proportional hazard models including interaction between marker and treatment were used to test the predictive value of these markers. Results Patients with high Ki67 (≥5%) as well as low (

Background: The phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer which can result in antioestrogen resistance. Single protein markers failed to be introduced into clinical practice. We, therefore, aimed to find a better read-out of activation of the PI3K and MAPK pathways in ER+/HER2− breast cancer. Assessment of seven PI3K/MAPK proteins might better reflect pathway activation and distinguish patients without adjuvant tamoxifen benefit. Methods: Tumour blocks were recollected from 293 primary postmenopausal ER+/HER2− breast cancer patients randomised between tamoxifen and no adjuvant therapy. PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-ERK1/2 and p-S6RP expression was assessed by immunohistochemistry followed by unsupervised hierarchical clustering. The primary endpoint was recurrence-free interval. Multivariate Cox models were used to assess tamoxifen benefit. A classification tool was developed based on protein expression profile. Results: Subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. Patients in group N derived significant benefit from tamoxifen (multivariate hazard ratio (HR) = 0.23, p = 0.000101), while patients from group A did not (multivariate HR = 1.37, p = 0.64), p for interaction 0.020. Our generated classification tool confirmed these results (p for interaction 0.024). Conclusions: Hierarchical clustering of seven PI3K/MAPK proteins reflects pathway activation and can guide treatment decisions in primary ER+/HER2− postmenopausal breast cancer patients.

Both preclinical and clinical data suggest that activation of the PI3K/AKT/mTOR pathway in response to hormonal therapy results in acquired endocrine therapy resistance. We evaluated differences in activation of the PI3K/AKT/mTOR pathway in estrogen receptor α (ERα) positive primary and corresponding metastatic breast cancer tissues using immunohistochemistry for downstream activated proteins, like phosphorylated mTOR (p-mTOR), phosphorylated 4E Binding Protein 1 (p-4EBP1) and phosphorylated p70S6K (p-p70S6K). For p-mTOR and p-4EBP1, the proportion of immunostained tumor cells (0–100%) was scored. Cytoplasmic intensity (0–3) was assessed for p-p70S6K. The difference between expression of these activated PI3K/AKT/mTOR proteins- in primary and metastatic tumor was calculated and tested for an association with adjuvant endocrine therapy. In patients who had received endocrine therapy (N = 34), p-mTOR expression increased in metastatic tumor lesions compared to the primary tumor (median difference 45%), while in patients who had not received adjuvant endocrine therapy (N = 37), no difference was found. Similar results were observed for p-4EBP1 and p-p70S6K expression. In multivariate analyses, adjuvant endocrine therapy was significantly associated with an increase in p-mTOR (p = 0.01), p-4EBP1 (p = 0.03) and p-p70S6K (p = 0.001), indicating that compensatory activation of the PI3K/AKT/mTOR pathway might indeed be a clinically relevant resistance mechanism resulting in acquired endocrine therapy resistance. What's new? Inhibitors of the PI3K/AKT/mTOR pathway can overcome the resistance to estrogen-depletion therapy that often develops in metastatic breast cancer. In this study, the authors compared primary and metastatic tumors; their results suggest that activation of the PI3K/AKT/mTOR pathway in patients who receive adjuvant endocrine therapy is a clinically relevant mechanism of acquired hormone resistance. For identification of companion diagnostics for PI3K/AKT/mTOR inhibitors, the authors conclude that analyzing primary tumor tissue may often fail to predict treatment response in metastatic breast cancer.

Although tamoxifen is a classical example of a targeted drug, a substantial proportion of estrogen receptor alpha positive breast cancer patients does not benefit from the drug. Over the last few decades, many potential biomarkers have been discovered in cell biological studies that may aid in the prediction of tamoxifen sensitivity and guide in treatment selection. Nonetheless, the transition of such a biomarker from the scientific community towards a diagnostic test that can be used in daily clinical practice has been far from ideal, and such markers seldom face clinical introduction. From a large number of potential predictive biomarkers as described in cell biological literature, the clinical (translational) scientist has to make a decision which of these biomarkers should be tested in clinical material to determine their clinical validity. This problem is not trivial, since patient samples with clinical follow-up are a valuable asset that should therefore be cherished. In this review, we will describe a number of ‘cell biological biomarkers’ for tamoxifen resistance and their possible clinical implications. This may guide the clinical scientist in choosing what potential biomarkers to test on tumour samples, which may catalyse the translation of scientific discoveries into daily clinical practice of breast cancer medicine.

Personalized medicine for oestrogen receptor-α (ERα)-positive breast cancer requires predictive biomarkers for broad endocrine resistance as well as biomarkers capable of predicting resistance to a specific agent. In addition, biomarkers could be used to select patients that might benefit from the addition of treatments that do not target ERα. However, biomarker identification studies seem to be far from consistent and identified biomarkers seldom face an introduction into clinical practice. Importantly, most of the studies that seek to identify biomarkers have been performed using material from consecutive series of patients treated with tamoxifen (the most commonly prescribed ERα antagonist). Consequently, the predictive value of any biomarker identified is confounded by its prognostic value. Another important issue is the lack of differentiation between premenopausal and postmenopausal patients with breast cancer. The hormonal environment of a tumour in patients who are premenopausal is intrinsically distinct from those arising in postmenopausal women. Biomarkers of different biological mechanisms might enable the prediction of either broad endocrine resistance or resistance to a specific agent in each of these patient subtypes. Ultimately, improvements to study design are needed to establish the clinical validity of the most promising biomarkers to predict benefit from endocrine therapy.

SummaryA large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy.

Background Estrogen Receptor alpha (ERα)-positive breast cancer patients receive endocrine therapy, often in the form of tamoxifen. However, resistance to tamoxifen is frequently observed. A signalling cascade that leads to tamoxifen resistance is dictated by activation of the Protein Kinase A (PKA) pathway, which leads to phosphorylation of ERα on Serine 305 and receptor activation, following tamoxifen binding. Thus far, it remains elusive what protein complexes enable the PKA-ERα interaction resulting in ERα Serine 305 phosphorylation. Methods We performed immunohistochemistry to detect ERαSerine 305 phosphorylation in a cohort of breast cancer patients who received tamoxifen treatment in the metastatic setting. From the same tumor specimens, Agilent 44 K gene expression analyses were performed and integrated with clinicopathological data and survival information. In vitro analyses were performed using MCF7 breast cancer cells, which included immunoprecipitations and Fluorescence Resonance Energy Transfer (FRET) analyses to illustrate ERα complex formation. siRNA mediated knockdown experiments were performed to assess effects on ERαSerine 305 phosphorylation status, ERα/PKA interactions and downstream responsive gene activity. Results Stratifying breast tumors on ERα Serine 305 phosphorylation status resulted in the identification of a gene network centered upon AKAP13. AKAP13 mRNA expression levels correlate with poor outcome in patients who received tamoxifen treatment in the metastatic setting. In addition, AKAP13 mRNA levels correlate with ERαSerine 305 phosphorylation in breast tumor samples, suggesting a functional connection between these two events. In a luminal breast cancer cell line, AKAP13 was found to interact with ERα as well as with a regulatory subunit of PKA. Knocking down of AKAP13 prevented PKA-mediated Serine 305 phosphorylation of ERα and abrogated PKA-driven tamoxifen resistance, illustrating that AKAP13 is an essential protein in this process. Conclusions We show that the PKA-anchoring protein AKAP13 is essential for the phosphorylation of ERαS305, which leads to tamoxifen resistance both in cell lines and tamoxifen-treated breast cancer patients. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1591-4) contains supplementary material, which is available to authorized users.

BACKGROUND: Activation of the PI3K/MAPK pathways results in anti-estrogen resistance in vitro, however a biomarker that can predict clinical resistance has not yet been identified. Common drivers of these pathways are PIK3CA mutations, loss of PTEN and over-expression of HER2 and IGF-1R. We aimed to test the prognostic and predictive value of PI3K/MAPK pathway drivers as well as downstream activated proteins in postmenopausal breast cancer patients. METHODS: We collected primary tumor tissue from 563 ERα positive breast cancer patients who were randomized between tamoxifen (1–3 years) versus no adjuvant systemic therapy. PIK3CA hotspot mutations were assessed by Sequenom Mass Spectrometry. Immunohistochemistry was performed for expression of PTEN, IGF-1R and the downstream markers p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interaction between these markers and treatment. RESULTS: No significant interaction between any of the tested PI3K/MAPK pathways drivers and tamoxifen was found. [/bold]However, interactions were identified between tamoxifen and the downstream activated proteins (p-AKT(Thr308), p- mTOR, p-p70S6K and p-ERK1/2). After correcting for multiple testing, p-p70S6K remained significantly associated with tamoxifen resistance. Patients whose tumor did not express p-p70S6K did derive significant benefit from tamoxifen (HR 0.24, 95 % CI= 0.12–0.47, p < 0.0001), while patients whose tumor did express p-p70S6K did not (multivariate HR=1.02, 95% CI=0.48–2.21, p = 0.95), p for interaction 0.003. CONCLUSION: We conclude that the downstream marker of PI3K/MAPK activation p-p70S6K predicts tamoxifen resistance in ERα positive postmenopausal breast cancer patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-03.

Introduction: Therapy resistance to adjuvant tamoxifen in estrogen receptor positive (ER+) breast cancer (BC) is related to activation of downstream proteins in the PI3K/AKT/mTOR pathway. However, clinical efficacy of mTOR inhibitors has so far been modest. Growing evidence shows that genomic make-up of cancer cells plays a crucial role in an anti-cancer immune response and this is reflected in the presence of tumor infiltrating immune cells. This begs the need for understanding the relationship between tumor-related immune activity, PIK3CA hot-spot mutations (PIK3CAm) and PI3K/AKT/mTOR pathway activation in ER+BC. Material and methods: The IKA trial recruited stage I to III postmenopausal BC patients (1982 till 1994), who were randomized to tamoxifen or no adjuvant therapy. Sequenom mass spectrometry-based genotyping was used for PIK3CAm assessment. Immune markers and phosphorylation status of proteins in the PI3K/AKT/mTOR pathway [p-AKT (Thr308 and 473), p-mTOR, p-ERK1/2, p-p-70S6K and p-4EBP1] were assessed by immunohistochemistry and scored by two pathologists. Expression of CD4, CD8 and FOXP3 was evaluated using automatic scoring by image-analysis software (SlidePath® or AxioVision®) and compared with manual scoring by two pathologists. Associations were assessed using multivariable logistic regression models, including as co-variables: age, tumor grade, lymph node status, tumor size, and progesterone receptor and HER2 status. Results: We included 563 ER+BC cases. PIK3CAm were found in 159 (32%) of the 486 tumors genotyped. On average, PI3K/AKT/mTOR downstream proteins and immune markers were scored in 409 tumors (range: 366 to 438). Stromal CD8 expression, but not CD4 or FOXP3, was significantly higher in PIK3CA mutated tumors (OR=1.11; 95%CI: 1.02-1.22). Stromal FOXP3 expression, but not CD4 or CD8, was significantly increased in tumors with activated proteins from the PI3K/AKT/mTOR pathway (except p-mTOR). The largest association was with p-4EBP1 (OR=1.34; 95%CI: 1.21-1.48) and smallest with p-70S6K (OR=1.15; 95%CI: 1.08-1.22). Conclusion: In our dataset of ER+BC, PIK3CAm are associated with higher level of CD8+ T cells. Tumors with activation of the PI3K/Akt/mTOR pathway tend to have more FOXP3+ T cells. Together, our results suggest that PIK3CA mutation/activation harbor an immune-related tumor microenvironment. Citation Format: Marcelo Sobral-Leite, Izhar Salomon, Mark Opdam, Karin Beelen, Ronald L. van Vlierberghe, Erik J. Blok, Hugo M. Horlings, Joyce Sanders, Koen Van de Vijver, Peter J. Kuppen, Sabine Linn, Marjanka K. Schmidt, Marleen Kok. Cancer-immune interactions in luminal breast cancers: PI3KCA mutations, PI3K/AKT/mTOR activation and tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5612. doi:10.1158/1538-7445.AM2017-5612

Background: The combination of PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes of hormone receptor positive (HR+) metastatic breast cancer (MBC) patients. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant (MUT) PI3Kα isoforms than wild-type (WT) via a unique mechanism. Phase Ib data of POSEIDON with Taselisib + tamoxifen (TAM) demonstrated encouraging activity in patients with heavily pre-treated MBC, with an acceptable toxicity profile (Baird et al, ASCO 2016). The recommended phase II dose (RP2D) was Taselisib 4mg plus TAM 20mg, both administered on a daily continuous schedule. ctDNA monitoring may have value in drug development by (1) assessing predictive biomarkers to therapy, (2) providing an early indication of treatment response, and (3) shedding light on potential mechanisms of acquired drug resistance. In some patients included in phase Ib of POSEIDON, tumor response was preceded by a corresponding early change in plasma PIK3CA ctDNA levels. Methods: The phase II portion of the POSEIDON trial is a two-arm, randomized, double blind study of Taselisib plus TAM versus placebo (PLA) plus TAM in pre- and postmenopausal women with HR+/HER2- MBC. In the first part of the Phase II, 180 patients will be randomized (1:1) to receive continuous TAM with either Taselisib at the RP2D or PLA until disease progression, unacceptable toxicity or patient / physician decision. Crossover is allowed upon progressive disease in those patients receiving PLA plus TAM, after collection of tumor and blood samples for exploratory biomarker analysis. Stratification is based on menopausal status, histology [lobular breast cancer (LBC) vs. ductal/others], PIK3CA mutation (WT vs. exon 9 vs. exon 20), prior everolimus, timing of recurrence/progression after prior endocrine therapy, number of prior chemotherapy (CT) lines, and treatment center. After recruiting the initial 180 patients, trial will focus in LBC, until a total number of 110 patients with LBC are enrolled. Other key eligibility criteria include presence of measurable or evaluable disease (RECIST 1.1), prior progression to endocrine treatment, maximum of 5 prior CT lines in the metastatic setting, absence of diabetes under medical treatment, and absence of chronic inflammatory bowel disease. Primary endpoint is investigator-assessed PFS. Key secondary endpoints are PFS in LBC, objective response rate, clinical benefit rate, safety, and exploratory biomarker analysis (including ctDNA). The study has a 90% power at a two-sided log-rank test significance level of 0.2 to detect an HR of 0.64, which corresponds to an increase in median PFS from 4.5 months in the PLA plus TAM arm to 7 months in the Taselisib plus TAM arm. Enrollment to POSEIDON Phase II started in June 2016 (Clinicaltrials.gov NCT02285179). Citation Format: Oliveira M, Baird RD, van Rossum AGJ, Beelen K, Garcia-Corbacho J, Mandjes IAM, Vallier AL, van Werkhoven E, Garrigós L, Kumar S, van Tinteren H, Muñoz S, Linossi C, Rosing H, Miquel JM, Schrier M, de Vries Schultink A, Saura C, Gallagher WM, Bernards R, Tabernero J, Cortés J, Caldas C, Linn SC. Phase II of POSEIDON: A phase Ib / randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-11.

Contains fulltext : 136517.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycine (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients. METHODS: We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1-3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor alpha positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy. RESULTS: Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P < 0.0001), while patients whose tumor did express p-p70S6K did not (HR = 1.02, P =0.95), P for interaction 0.004. In systemically untreated breast cancer patients, p-p70S6K was associated with a decreased risk for recurrence. CONCLUSIONS: Patients whose tumor expresses p-p70S6K, as a marker of downstream PI3K and/or MAPK pathway activation, have a favorable prognosis, but do not benefit from adjuvant tamoxifen. A potential benefit from inhibitors of the PI3K/Akt/mTOR pathway in these patients needs to be further explored.

Contains fulltext : 136461.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) alpha-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERalpha-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERalpha-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins. METHODS: Primary tumors from 563 ERalpha-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction. RESULTS: PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found. CONCLUSION: PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERalpha- positive, postmenopausal, early breast cancer patients.

Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I–III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1–3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19*2 and CYP2C19*17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19*17. Patients with at least one CYP2C19*2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19*2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19*2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19*2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment. Electronic supplementary material The online version of this article (doi:10.1007/s10549-013-2568-0) contains supplementary material, which is available to authorized users.

2520Background: Endocrine therapy resistance remains a major challenge in the treatment of HR-positive breast cancer. The strategy of combining PI3K-AKT-mTOR pathway inhibitors with endocrine therapy can improve clinical outcomes (eg. BOLERO-2, BELLE-2) but at the cost of increased toxicity. Taselisib is a potent, selective, beta-isoform sparing inhibitor of PI3K designed to have a better therapeutic index than first-generation pan-PI3K inhibitors. Methods: Pts with prior exposure to endocrine therapy were enrolled using a 3+3 design, testing taselisib in combination with tamoxifen 20mg qd. A (21 day on / 7 day off) intermittent schedule was also compared with daily continuous dosing (28/28). The primary objective was to determine the recommended phase II dose and schedule. Other objectives included: pharmacokinetics (PK), pharmacodynamics (PD) and serial monitoring of plasma ctDNA using digital PCR / tagged amplicon deep-sequencing. Results: 30 pts were enrolled in 3 cohorts: taselisib 2mg (21/7), 4mg (2...

Background In patients with hormone receptor-positive breast cancer, activation of the PI3K-Akt-mTOR pathway is associated with resistance against endocrine therapy. Previous research has shown that genetic aberrations in this pathway occur frequently, including mutation and/or amplification in PI3K subunits or PI3K effectors as well as loss of lipid phosphatases (Fu X, et al. The Breast; 2013). Central review of the BOLERO-2 randomized phase III trial in which patients refractory to a non-steroidal aromatase inhibitor were randomized between exemestane combined with the mTOR inhibitor everolimus versus exemestane and placebo has shown a progression-free survival (PFS) of, respectively, 11.0 and 4.1 months [hazard ratio = 0.38 (95% confidence interval 0.31-0.48; log-rank P Trial design/Aims This is a Dutch prospective, open-label, single-arm, investigator-initiated, multicenter trial in which approximately 30 hospitals will participate. A total of 175 patients will be included for baseline blood sampling and archival tumor tissue collection. From 50 patients, a fresh tumor biopsy is required at baseline and from 30 out of 50, another tumor biopsy will be collected upon progressive disease. Exploratory biomarker assessment includes immunohistochemistry (total and phosphorylated PI3K, AKT, mTOR, p70S6K and 4EBP1), tissue phosphoproteomics and circulating tumor DNA (mutations). The results of the biomarker analysis will be compared with clinicopathological characteristics and PFS. Eligibility Postmenopausal patients with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, refractory to anastrozole or letrozole will be included. No previous treatment with exemestane or mTOR inhibitor for advanced disease is allowed and Informed consent must be signed before enrollment. Statistical methods Since the majority of the tests involve the use of new techniques, the study will be mainly explorative in design. The association between potential biomarkers and clinicopathological characteristics will be tested using Fisher exact test or the Mann-Whitney test. PFS curves will be drawn using the Kaplan-Meier method. PFS in association with potential biomarkers will be tested using Cox proportional hazard regression analysis. Present and target accrual Recently, the study has been opened for inclusion. A period of 2 years is planned for patient enrollment. Up to May 2014, two patients were included. ClinicalTrials.gov identifier NCT02109913 Financial support is received from Novartis, the Netherlands. Citation Format: Dinja T Kruger, Karin Beelen, Connie R Jimenez, Maurice PHM Jansen, Stefan Sleijfer, Sabine C Linn, Epie Boven. PI3K-Akt-mTOR pathway analysis to obtain further insight in the efficacy of everolimus in combination with exemestane in metastatic, ER-positive breast cancer: A Dutch breast cancer research group (BOOG) study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-02.

BACKGROUND: Activation of the PI3K pathway as an adaptive change in response to estrogen depletion results in acquired endocrine therapy resistance in vitro. Metastatic breast cancer patients with previous exposure to endocrine therapy do derive substantial benefit from the addition of an mTOR inhibitor to endocrine therapy compared to endocrine therapy alone. This suggests that compensatory PI3K pathway activation might play a role in the development of clinical resistance to endocrine therapy. We evaluated the activation of the downstream PI3K pathway protein mTOR in primary breast tumors and matched metastatic lesions. METHODS: From a previously described series of breast cancer patients from whom both primary tumor tissue as well as metastatic tumor tissue was collected, we selected estrogen receptor α (ERα) positive patients who had received endocrine therapy (N = 34) and who did not receive endocrine therapy (N = 37). The difference in expression of phosphorylated mTOR (p-mTOR) between primary and metastatic tumor was assessed by immunohistochemistry, which was scored by using the proportion of tumor cells with sub-membranous p-mTOR expression. We assessed whether this p-mTOR difference between primary and metastatic tumor was associated with clinico-pathological factors (location of metastasis, lymph node status, T-stage, grade, progesterone receptor status) or varied between patients who did and did not receive endocrine therapy, using Mann-Whitney tests. In addition we performed a linear regression model including the same clinico-pathological factors. RESULTS: In patients who had received endocrine therapy we observed an increase in p-mTOR expression in metastatic tumor lesions compared to the primary tumor (median difference 45%). This was significantly different from the mTOR changes observed in patients who did not receive endocrine therapy (median difference between metastatic and primary lesion 0 %) (p = 0.003). The difference remained significant in the multivariate regression model (p = 0.001). None of the other factors was significantly associated with a differential p-mTOR change. CONCLUSION: In patients who received previous adjuvant endocrine therapy, the increase in p-mTOR expression in metastatic tumor lesions compared to the primary tumor is significantly higher than in patients who did not receive endocrine therapy. Compensatory activation of the PI3K pathway might therefore be a clinically relevant resistance mechanism resulting in secondary endocrine therapy resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD01-02.

544 Background: Elevated insuline-like growth factor 1 receptor (IGF-1R) signaling activates the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways and result...

562 Background: The sensitivity of the estrogen receptor (ERα) to anti-estrogen therapy can be affected by phosphorylation events. In premenopausal breast cancer patients, phosphorylation of the ERα at serine 118 (ERαS118-p) is predictive for benefit from adjuvant tamoxifen. Since ERαS118-p represents the common hallmark of different signaling cascades that differ in E2 dependency, the resulting effect on estrogen sensitivity may differ between pre- and postmenopausal patients. Phosphorylation of serine 167 (ERαS167-p) has been associated with favorable disease outcome, but whether ERαS167-p can predict tamoxifen sensitivity is currently unknown. We tested the predictive value of both ERαS118-p and ERαS167-p for benefit from adjuvant tamoxifen in postmenopausal breast cancer patients. Methods: We collected primary tumor blocks from 563 ERα positive (stage I-III) postmenopausal patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial). The median follow-up of patients without a recurrence event was 9.4 years. Immunohistochemistry was performed on a TMA using monoclonal antibodies for ERαS118-p and ERαS167-p. The percentage of positive nuclei was scored and a score of ≥ 10 % was considered as positive. Multivariate Cox models were used to assess hazard ratios (HRs) for recurrence free interval and the interaction between these phosphorylations and tamoxifen treatment. Results: We did not find a significant interaction between either ERαS118-p (p=0.99) or ERαS167-p (p=0.44) and tamoxifen, suggesting that the relative benefit from adjuvant tamoxifen in postmenopausal patients is not dependent on the presence of one of these phosphorylations. Both tamoxifen treated patients as well as control patients had a better prognosis when their tumor was positive for ERαS118-p (adjusted HR 0.60 p=0.02) or ERαS167-p (adjusted HR 0.62, p=0.02) compared to patients whose tumor did not express these ERα phosphorylations. Conclusions: In postmenopausal patients ERαS118-p and ERαS167-p are both associated with better prognosis, but do not predict differential benefit from tamoxifen.

576 Background: Three endocrine response classes are defined in the St. Gallen guidelines: highly endocrine responsive (ER-H) (expression of both ER and progesterone receptor (PgR) in >50% of tumor...