Learning Objectives
After completing this course, the reader will be able to:
Describe how PTEN loss, PIK3CA mutations, and AKT dysregulation affect the phosphatidylinositol 3‐kinase ...(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling network in human breast cancer.
Review the current state of AKT and mTOR inhibitor development, and describe its potential for clinical applications.
This article is available for continuing medical education credit at CME.TheOncologist.com
The phosphatidylinositol 3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) network plays a key regulatory function in cell survival, proliferation, migration, metabolism, angiogenesis, and apoptosis. Genetic aberrations found at different levels, either with activation of oncogenes or inactivation of tumor suppressors, make this pathway one of the most commonly disrupted in human breast cancer. The PI3K‐dependent phosphorylation and activation of the serine/threonine kinase AKT is a key activator of cell survival mechanisms. The activation of the oncogene PIK3CA and the loss of regulators of AKT including the tumor suppressor gene PTEN are mutations commonly found in breast tumors. AKT relieves the negative regulation of mTOR to activate protein synthesis and cell proliferation through S6K and 4EBP1. The common activation of the PI3K pathway in breast cancer has led to the development of compounds targeting the effector mechanisms of the pathway including selective and pan‐PI3K/pan‐AKT inhibitors, rapamycin analogs for mTOR inhibition, and TOR‐catalytic subunit inhibitors. The influences of other oncogenic pathways such as Ras‐Raf‐Mek on the PI3K pathway and the known feedback mechanisms of activation have prompted the use of compounds with broader effect at multiple levels and rational combination strategies to obtain a more potent antitumor activity and possibly a meaningful clinical effect. Here, we review the biology of the network, its role in the development and progression of breast cancer, and the evaluation of targeted therapies in clinical trials.
摘要
在细胞的存活、增殖、迁移、代谢、血管生成以及凋亡中，磷脂酰肌醇3激酶（PI3K）/AKT/哺乳类雷帕霉素靶蛋白（mTOR）信号网络起着关键的调节功能。该网络各个基因水平出现的遗传紊乱（无论是原癌基因激活还是抑癌基因失活所致）使其成为人类乳腺癌中最常见的异常之一。PI3K激活丝氨酸/苏氨酸激酶AKT依赖性的磷酸化是细胞存活的关键因素。癌基因PIK3CA激活和包括抑癌基因PTEN在内的AKT调节因子活性缺失是乳腺癌中最为常见的突变形式。AKT通过激活S6K和4EBP1，解除mTOR通路的负调控，促进蛋白合成及细胞增殖。乳腺癌中PI3K通路经常处于激活状态，因此可针对该通路的效应子机制开发化合物，包括pan‐PI3K/pan‐AKT选择性抑制剂、抑制mTOR的雷帕霉素类似物和催化TOR的亚基抑制剂。其他癌症发生通路（例如Ras‐Raf‐Mek对PI3K通路）的影响以及已知的活化反馈机制，在多个层面促使具有广泛效应的化疗物用于临床、合理的联合用药策略，以期获得更强效的抗癌活性以及可能的有意义的临床疗效。本文综述了该信号网络的生物学特征、其在乳腺癌发生发展中的作用，以及其在临床试验中靶向治疗的疗效评估。
The phosphatidylinositol 3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) network plays a key regulatory function in cell survival, proliferation, migration, metabolism, angiogenesis, and apoptosis. Genetic aberrations found at different levels make this pathway one of the most commonly disrupted in human breast cancer. Because the PI3K pathway has divergent downstream effects, the identification of the key effectors of the pathway and their presence in the different subtypes of breast tumors will allow the development of ideal targeted therapies with meaningful clinical efficacy.
Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily ...and trametinib 2 mg every day (D+T).
We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%.
Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% 95% confidence interval (CI), 31.0%-65.5%, median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively.
HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.
This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to ...assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM).
In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017.
Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators.
Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.
Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by ...inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.
Summary Introduction Macrolides are of unique interest in preventing COPD exacerbations because they possess a variety of antibacterial, antiviral and anti-inflammatory properties. Recent research ...has generated renewed interest in prophylactic macrolides to reduce the risk of COPD exacerbations. Little is known about how well these recent findings fit within the context of previous research on this subject. The purpose of this article is to evaluate, via exploratory meta-analysis, whether the overall consensus favors prophylactic macrolides for prevention of COPD exacerbations. Methods EMBASE, Cochrane and Medline databases were searched for all relevant randomized controlled trials (RCTs). Six RCTs were identified. The primary endpoint was incidence of COPD exacerbations. Secondary endpoints including mortality, hospitalization rates, adverse events and likelihood of having at least one COPD exacerbation were also examined. Results There was a 37% relative risk reduction (RR = 0.63, 95% CI: 0.45–0.87, p value = 0.005) in COPD exacerbations among patients taking macrolides compared to placebo. Furthermore, there was a 21% reduced risk of hospitalization (RR = 0.79, 95% CI: 0.69–0.90, p -value = 0.01) and 68% reduced risk of having at least one COPD exacerbation (RR = 0.34, 95% CI 0.21–0.54, p -value = 0.001) among patients taking macrolides versus placebo. There was also a trend toward decreased mortality and increased adverse events among patients taking macrolides but these were not statistically significant. Conclusions Prophylactic macrolides are an effective approach for reducing incident COPD exacerbations. There were several limitations to this study including a lack of consistent adverse event reporting and some degree of clinical and statistical heterogeneity between studies.
To evaluate the clinical outcomes and relationship between tumor size, lymph node status, and prognosis in a large cohort of patients with confirmed triple receptor-negative breast cancer (TNBC).
We ...reviewed 1,711 patients with TNBC diagnosed between 1980 and 2009. Patients were categorized by tumor size and nodal status. Kaplan-Meier product limit method was used to calculate overall survival (OS) and relapse-free survival (RFS). A Sidak adjustment was used for multiple group comparisons. Cox proportional hazards models were fit to determine the association of tumor size and nodal status with survival outcomes after adjustment for other patient and disease characteristics.
Median age was 48 years (range, 21 to 87 years). At a median follow-up of 53 months (range, 0.7 to 317 months), there were 614 deaths and 747 recurrences. The 5-year OS was 80% for node-negative patients (N0), 65% for one to three positive lymph nodes (N1), 48% for four to nine positive lymph nodes (N2), and 44% for ≥ 10 positive lymph nodes (N3; P < .0001). The 5-year RFS rates were 67% for N0, 52% for N1, 36% for N2, and 33% for N3 (P < .0001). Pairwise comparison by nodal status showed that when comparing N0 with node-positive disease, there was a significant difference in OS and RFS (P < .001 all comparisons). However, when comparing N1 with N2 and N3 disease regardless of tumor size, there were no significant differences in OS or RFS.
In patients with TNBC, once there is evidence of lymph node metastasis, the prognosis may not be affected by the number of positive lymph nodes.
Adjuvant systemic therapies in breast cancer Hernandez-Aya, Leonel F; Gonzalez-Angulo, Ana M
The Surgical clinics of North America,
04/2013, Letnik:
93, Številka:
2
Journal Article
Recenzirano
Although some women with early breast cancer (BC) may be cured with loco-regional treatment alone, up to 20% of patients with early-stage BC will ultimately experience treatment failure and ...recurrence. A substantial portion of the success in improving clinical outcomes of patients with BC is related to the standardized use of adjuvant therapies. The identification of tumor subtypes with prognostic value has contributed to the idea of tailoring treatments using biologic predictive factors to identify the patients who will most likely respond to therapy and minimize the exposure of "nonresponders" to the side effects of the treatment.
Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor ...DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance.
ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB).
High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P < 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients.
Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.
Background
Triple negative breast cancer (TNBC) has worse prognosis than other subtypes of breast cancer, and many patients develop brain metastasis (BM). We developed a simple predictive model to ...stratify the risk of BM in TNBC patients receiving neo‐adjuvant chemotherapy (NAC), surgery, and radiation therapy (RT).
Methods
Patients with TNBC who received NAC, surgery, and RT were included. Cox proportional hazards method was used to evaluate factors associated with BM. Significant factors predictive for BM on multivariate analysis (MVA) were used to develop a risk score. Patients were divided into three risk groups: low, intermediate, and high. A receiver operating characteristic (ROC) curve was drawn to evaluate the value of the risk group in predicting BM. This predictive model was externally validated.
Results
A total of 160 patients were included. The median follow‐up was 47.4 months. The median age at diagnosis was 49.9 years. The 2‐year freedom from BM was 90.5%. Persistent lymph node positivity, HR 8.75 (1.76‐43.52, P = 0.01), and lack of downstaging, HR 3.46 (1.03‐11.62, P = 0.04), were significant predictors for BM. The 2‐year rate of BM was 0%, 10.7%, and 30.3% (P < 0.001) in patients belonging to low‐, intermediate‐, and high‐risk groups, respectively. Area under the ROC curve was 0.81 (P < 0.001). This model was externally validated (C‐index = 0.79).
Conclusions
Lack of downstaging and persistent lymph node positivity after NAC are associated with development of BM in TNBC. This model can be used by the clinicians to stratify patients into the three risk groups to identify those at increased risk of developing BM and potentially impact surveillance strategies.
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