PI3K Pathway Mutations and PTEN Levels in Primary and Metastatic Breast Cancer

TPS664 Background: PI3K pathway activation plays a crucial role in mediating endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. We have shown previously that BKM120 in combination with fulvestrant induced synergistic apoptotic cell death in long-term estrogen deprived ER+ breast cancer (LTED) cell line models, supporting the clinical investigation of this combination in ER+ breast cancer. Methods: The study is composed of the dose escalation cohort (phase IA) and the expansion cohort (phase IB). In phase IA, a standard 3+3 phase I design is employed to determine the maximum tolerated dose (MTD) of the combination of BKM120 and fulvestrant in patients (pts) with ER+ metastatic breast cancer (MBC). In phase IB, an additional 10 pts will be enrolled at the MTD to further examine the toxicity profile and preliminary efficacy of this combination. Steady state concentrations of BKM120 will be analyzed. Postmenopausal women with ER+ MBC and measurable disease per RECIST are eligible. Pts who are currently taking fulvestrant without disease progression are eligible. There is no restriction on the number of prior lines of systemic therapy for metastatic disease in phase IA but < 3 lines is required in phase IB. Treatment consists of fulvestrant 500 mg IM administered monthly on day (d) 1 of each 28-d cycle, following the loading dose of 500 mg on d1 and d15, and BKM120 orally daily on d1-28 of each cycle. The starting dose level (DL) is DL1 (Table). Correlative studies include assessing PI3K pathway abnormalities (loss of PTEN and PIK3CA mutation) on archival tumor specimen, and treatment induced inhibition of PI3K pathway activity (pAKT, pS6, Cyclin D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation (Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining) on tumor biopsies collected at baseline and cycle 2 day 1 in consented patients. Enrollment to DL1 is complete and the study is currently enrolling pts to DL2. [Table: see text]

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

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15216 ◽

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]

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PI3K pathway protein analyses in metastatic breast cancer patients receiving standard everolimus and exemestane

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-020-03291-x ◽

2020 ◽

Vol 146 (11) ◽

pp. 3013-3023

Author(s):

Dinja T. Kruger ◽

Mark Opdam ◽

Vincent van der Noort ◽

Joyce Sanders ◽

Michiel Nieuwenhuis ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Primary Tumour ◽

Metastatic Breast ◽

Resistance Mechanisms ◽

Pi3k Pathway ◽

Tumour Tissue ◽

Breast Cancer Patients ◽

Cox Models ◽

Pre Treatment

Abstract 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.

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

10.1101/2020.07.27.223834 ◽

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.

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Evaluation of overall survival (OS) in patients (pts) with metastatic breast cancer (MBC) according to phosphathidylinositol-3-kinase (PI3K) pathway status.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.e21130 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. e21130-e21130

Author(s):

L. De Mattos-Arruda ◽

M. Oliveira ◽

G. Sánchez-Ollé ◽

D. Moreno-Fernandez ◽

B. Graña ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Pi3k Pathway

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A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.508 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 508-508 ◽

Cited By ~ 12

Author(s):

Ian E. Krop ◽

Cristina Saura ◽

Jordi Rodon Ahnert ◽

Carlos Becerra ◽

Carolyn D. Britten ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase I ◽

Dose Escalation ◽

Single Agent ◽

Metastatic Breast ◽

Pi3k Pathway ◽

Dose Escalation Study ◽

Her2 Breast Cancer ◽

Disease Stabilization

508 Background: Alterations in the PI3K/AKT/mTOR pathway have been implicated in resistance to trastuzumab (T) in HER2+ breast cancer. BEZ235, a potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth inhibition and apoptosis in HER2+ breast cancer models, including those harboring PI3K pathway alterations, and with T resistance. In a Phase I study, BEZ235 was well tolerated as a single agent in pts with advanced solid tumors. The aim of this study was to determine the MTD of BEZ235 in combination with T in pts with T-resistant HER2+ metastatic breast cancer (mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant HER2+ mBC (i.e. disease progression during adjuvant therapy or metastatic disease on therapy with T) received oral BEZ235 daily, with weekly T (2 mg/kg). Pts were eligible for enrollment if a tumor sample was demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 mg/day (10 pts), administered either in capsule form (400 mg) or in sachet form (600 mg and 800 mg). The MTD of BEZ235 in combination with T was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) suspected to be related to study treatment were diarrhea (4 pts) and nausea (2 pts). No deaths related to study treatment occurred. 1 pt with lung and brain metastases had a partial response. 4 pts had disease stabilization for ≥4 cycles (16 weeks), including 1 pt with liver metastases, in whom BEZ235/T treatment resulted in disease stabilization for more than 21 cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated an acceptable safety profile in pts with HER2+ mBC and PI3K pathway alterations. Following the Bayesian model recommendation, the MTD for BEZ235 in combination with T was estimated to be 600 mg/day. The safety expansion arm is ongoing at the MTD.

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PI3K Pathway Mutations and PTEN Levels in Primary and Metastatic Breast Cancer

Breast Diseases A Year Book Quarterly ◽

10.1016/j.breastdis.2011.10.024 ◽

2011 ◽

Vol 22 (4) ◽

pp. 367-370

Author(s):

T.W. Miller ◽

C.L. Arteaga

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Pi3k Pathway

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

Cancers ◽

10.3390/cancers13061345 ◽

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.

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