Comparative efficacy and safety of CDK4/6 and PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive,HER2-negative metastatic breast cancer: a systematic review and network meta-analysis

BackgroundCDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors are both emerging agents for hormonal receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. Evidence for the comparisons from head-to-head comparative trials is currently insufficient. This meta-analysis assessed the comparative efficacy and safety of these two groups of agents for HR+/HER2- metastatic breast cancer.MethodsSystematic searches of PubMed, Embase, CENTRAL, SciSearch between January 2010 to December 2019 were conducted. Randomized controlled trials (RCTs) which evaluated clinical benefits and toxicities of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy were adopted. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoint was treatment-related adverse event (TRAE). Pooled hazard ratio (HR) and risk rate (RR) were used to assess the differences between CDK4/6 and PI3K/AKT/mTOR inhibitors.ResultsA total of twenty RCTs including 9771 participants were identified in this study. Pooled results showed that PFS was considerably prolonged by targeted therapy plus endocrine therapy. PFS was relatively better in CDK4/6 inhibitors than that of PI3K inhibitor group (HR, 1.43; 95%CrI, 1.12-1.61). Similar results were demonstrated in results after balancing lines of therapy or metastatic sites, both in viscera and bone-only. Coalesced outcomes revealed that CDK4/6 inhibitors plus endocrine therapy could significantly improve OS (HR, 0.78; 95%CrI, 0.65-0.94) than PI3K/mTOR inhibitors. Safety profiles of diarrhea and rash were consistent between CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors with no difference of estimated RR. Several TRAEs signified specificity, for instance, myelosuppression in CDK4/6 inhibitors or hyperglycemia in PI3K/mTOR inhibitors.ConclusionsClinical efficacy is in favor of CDK4/6 inhibitors, and safety profiles are comparable between CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors plus endocrine therapy.     

PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy

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.     

Antihormonal therapy in breast cancer and mTOR inhibitors

Hormonal dependence of breast cancer has been known for a long time, yet about half of breast cancers with estrogen receptor will not respond to antihormonal therapy. Now, we know that this resistance may be related to a dysfunction of the estrogen pathway, or that of growth factors and particularly the pathway of cell activation PI3K/Akt/mTOR. Prevention of these different mechanisms of resistance could involve combination therapies such as anti-estrogens (SERMs, aromatase inhibitors) with inhibitors of the activity of growth factors that are particularly temsirolimus and everolimus for the activation pathway cell PI3K/Akt/mTOR.     

Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive,HER2-negative breast cancer

Endocrine therapy is a crucial treatment for estrogen receptor-positive (ER+) breast cancer, with proven clinical benefits. However, adaptive mechanisms emerge in the tumor, causing resistance to endocrine therapy. A better understanding of resistance mechanisms is needed to overcome this problem and to develop new, precise treatment strategies. Accumulating genetic and cancer biological studies demonstrate the importance of understanding the PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2? breast cancer. PIK3CA (which encodes phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α) is frequently mutated in breast cancer, and 30% of advanced ER+ HER2? breast cancers have an activating PIK3CA mutation. AKT1 mutations (E17K) have been found in 1.4–8% of breast cancer patients. ER+ breast cancer patients preferentially demonstrate gain of CCND1 (cyclin D1; 58% in luminal B vs. 29% in luminal A) and CDK4 (25% in luminal B vs. 14% in luminal A) and loss of CDKN2A (p16) and CDKN2C (p18), which are negatively regulated with the cell cycle and are correlated with the CDK4/6/RB pathway. Abnormalities in PI3K/Akt/mTOR and CDK4/6/RB pathways due to genetic alterations result in deregulated kinase activity and malignant transformation. This review focuses on the recent reports of the essential role of PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2? breast cancer.     

The next era of treatment for hormone receptor-positive,HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies

Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients. Addition of phosphatidylinositol-3 kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors to combined CDK4/6 and endocrine inhibitor regimens may help prolong CDK4/6 inhibitor sensitivity. Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, and endocrine therapy have shown encouraging signs of clinical activity. However, further research is needed to help understand the extent of treatment benefit from triplet therapy and where this strategy will fit in the treatment sequence for patients with HR+ breast cancer.     

mTOR抑制剂在乳腺癌内分泌治疗耐药中的研究进展

PI3K/Akt/mTOR信号转导通路可抑制肿瘤细胞凋亡、促进细胞生存、调节细胞周期,促进肿瘤新生血管的形成以及侵袭与转移,在肿瘤的发生、发展、治疗及转归中发挥着重要作用。该信号通路与乳腺癌关系非常密切,是乳腺癌新的治疗靶点及研究热点。mTOR抑制剂通过不同的靶点作用于PI3K/Akt/mTOR信号转导通路上,从而达到其抗癌作用。内分泌治疗是乳腺癌的重要治疗方式之一,与化疗等其他治疗方式一样,内分泌治疗同样也面临治疗耐受这一难题。随着越来越多的信号通路被揭示,单一阻断某一位点已经不能满足治疗的需要,寻找多条通路的共同抑制位点成为研究人员关注的焦点。本文就mTOR抑制剂在乳腺癌内分泌治疗耐药中的作用及其临床试验结果进行综述,以期进一步了解mTOR抑制剂的临床作用。      

Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer.

PURPOSE: The phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown. EXPERIMENTAL DESIGN: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide. RESULTS: Basal expression of the pathway was not significantly correlated with response or patient outcome. Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P < 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P < 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02). CONCLUSIONS: Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.     

Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia

Women with type 2 diabetes mellitus (T2DM) are at a greater risk of developing and dying from breast cancer than women without T2DM. Insulin resistance and hyperinsulinemia underlie the pathogenesis of T2DM. In the MKR mouse model of insulin resistance, we have previously shown increased activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway in association with accelerated mammary tumor growth. In this study, we demonstrate that inhibiting PI3K with the oral pan-class I PI3K inhibitor, NVP-BKM120 reduced the growth of Met-1 and MCNeuA mammary tumor orthografts in the MKR mouse. NVP-BKM120 treatment decreased phosphorylation of Akt and S6 ribosomal protein (S6rp); no change in Erk1/2 phosphorylation was seen. Hyperglycemia, hypertriglyceridemia and greater hyperinsulinemia developed in the MKR mice treated with NVP-BKM120. We previously reported reduced tumor growth using intraperitoneal rapamycin in the MKR mouse, with the development of hyperglycemia and hypertriglyceridemia. Therefore, we examined whether the oral PI3K/mTOR inhibitor NVP-BEZ235 augmented the tumor suppressing effects of PI3K inhibition. We also investigated the effect of targeted PI3K/mTOR inhibition on PI3K/Akt/mTOR and Erk1/2 signaling, and the potential effects on glycemia. NVP-BEZ235 suppressed the growth of Met-1 and MCNeuA tumor orthografts, and decreased Akt and S6rp phosphorylation, despite increased Erk1/2 phosphorylation in Met-1 orthografts of MKR mice. Less marked hyperglycemia and hyperinsulinemia developed with NVP-BEZ235 than NVP-BKM120. Overall, the results of this study demonstrated that inhibiting PI3K/Akt/mTOR signaling with the oral agents NVP-BKM120 and NVP-BEZ235 decreased mammary tumor growth in the hyperinsulinemic MKR mouse. Inhibiting PI3K alone led to more severe metabolic derangement than inhibiting both PI3K and mTOR. Therefore, PI3K may be an important target for the treatment of breast cancer in women with insulin resistance. Monitoring for hyperglycemia and dyslipidemia should be considered when using these agents in humans, given the metabolic changes detected in this study.     

Targeting endocrine resistance: is there a role for mTOR inhibition?

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a critical intracellular signaling cascade that mediates both growth factor-induced proliferation and cell survival with deregulated signaling through this pathway, a feature of most cancers. Here, we review the role of the PI3K/Akt/mTOR pathway in endocrine-resistant breast cancer and discuss preclinical and clinical studies combining endocrine therapy with mTOR inhibition. Key to the success of such an approach will be a clinical trial design incorporating appropriate tumor selection and validation of biomarkers predicting benefit. Ultimately, a greater understanding of the biology and compensatory mechanisms will allow the partnering of key signal transduction inhibitors together to provide maximal "vertical" or "horizontal" blockade with further preclinical and clinical studies planned to examine possible synergistic combinations with endocrine therapy.     

CDK4/6抑制剂的联合治疗模式

 细胞周期素依赖激酶（CDKs）抑制剂联合内分泌治疗已经用于晚期乳腺癌的治疗。除了内分泌治疗，CDK4/6抑制剂还可以联合表皮生长因子受体（EGFR）抑制剂、磷脂酰肌醇-3激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂、化学治疗、免疫治疗、分子靶向治疗和其他治疗。联合治疗模式克服了CDK4/6抑制剂的耐药并提高了临床疗效，开启了肿瘤精准治疗的一扇新窗口。     

Tumor‐associated macrophages secrete CC‐chemokine ligand 2 and induce tamoxifen resistance by activating PI3K/Akt/mTOR in breast cancer

Breast cancer is the most prevalent malignancy among women. Although endocrine therapy is effective, the development of endocrine resistance is a major clinical challenge. The tumor microenvironment (TME) promotes tumor malignancy, and tumor‐associated macrophages (TAM) within the TME play a crucial role in endocrine resistance. Herein, we aimed to elucidate the relationship between TAM and the endocrine‐resistant phenotype of breast cancer. Macrophages were cultured with conditioned medium (CM) from tamoxifen‐sensitive (MCF7‐S) or ‐resistant (MCF7‐R) MCF7 breast cancer cells. M2 polarization was detected by CD163 immunofluorescence. To determine the effect on endocrine resistance, MCF7 cells were cultured in the supernatant of different TAM, and then treated with tamoxifen. CC‐chemokine ligand 2 (CCL2) immunohistochemistry was carried out on pathological sections from 100 patients with invasive estrogen receptor‐positive breast cancer. We found that macrophages cultured in the CM of MCF7‐S and MCF7‐R cells were induced into TAM, with a more obvious M2 polarization in the latter. Tamoxifen resistance was increased by culture in TAM medium. TAM secreted CCL2, which increased endocrine resistance in breast cancer cells through activation of the PI3K/Akt/mTOR signaling pathway. High expression of CCL2 was correlated with infiltration of CD163+macrophages (r = 0.548, P < .001), and patients with high CCL2 expression presented shorter progression‐free survival than those with low CCL2 expression (P < .05). We conclude that CCL2 secreted by TAM activates PI3K/Akt/mTOR signaling and promotes an endocrine resistance feedback loop in the TME, suggesting that CCL2 and TAM may be novel therapeutic targets for patients with endocrine‐resistant breast cancer.     

Overcoming acquired resistance to letrozole by targeting the PI3K/AKT/mTOR pathway in breast cancer cell clones

Development of resistance to endocrine therapy is a clinical issue in estrogen receptor (ER)-positive breast cancer. Here we show that persistent activation of AKT/mTOR signaling is crucial to the acquisition of letrozole resistance in cell clones generated from MCF-7/AROM-1 aromatase-expressing breast cancer cells after prolonged letrozole exposure. ERα plays a marginal role in this context. As a proof of concept, the association between PI3K/AKT/mTOR signaling and insensitivity to endocrine therapies was confirmed in breast cancer patients who developed early letrozole resistance in neoadjuvant setting. In addition our results suggest that, regardless of the mechanism mediating the activation of AKT/mTOR pathway, either RAD001 or NVP-BEZ235 treatment may represent a promising strategy to overcome acquired resistance to letrozole in breast cancers dependent on AKT/mTOR signaling.     

The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth, and survival under physiological conditions. However, aberrant PI3K/Akt/mTOR signaling has been implicated in many human cancers, including acute myelogenous leukemia (AML). Therefore, the PI3K/Akt/mTOR network is considered as a validated target for innovative cancer therapy. The limit of acceptable toxicity for standard polychemotherapy has been reached in AML. Novel therapeutic strategies are therefore needed. This review highlights how the PI3K/Akt/mTOR signaling axis is constitutively active in AML patients, where it affects survival, proliferation, and drug-resistance of leukemic cells including leukemic stem cells. Effective targeting of this pathway with small molecule kinase inhibitors, employed alone or in combination with other drugs, could result in the suppression of leukemic cell growth. Furthermore, targeting the PI3K/Akt/mTOR signaling network with small pharmacological inhibitors, employed either alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit pharmacological inhibitors of the PI3K/Akt/mTOR cascade which show efficacy and safety in the clinical setting are now underway.     

PI3K/Akt/mTOR信号通路在上皮源性恶性肿瘤中的研究进展

磷脂酰肌醇3-激酶/蛋白激酶B/哺乳类动物雷帕霉素靶蛋白(PI3K/Akt/mTOR)信号通路不仅与细胞的增殖、存活及迁移密切相关,其与肿瘤的发生和发展也具有相关性.近年来,以该通路作为抗肿瘤治疗的靶点已成为研究的热点.本文就PI3K/Akt/mTOR信号通路在上皮来源恶性肿瘤活化、发生、发展中的作用,特别是皮肤鳞癌中的最新研究进展作一综述,并为皮肤肿瘤治疗及新药开发做一展望.     

Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway.

The PTEN protein is a lipid phosphatase with putative tumor suppressing abilities, including inhibition of the PI3K/Akt signaling pathway. Inactivating mutations or deletions of the PTEN gene, which result in hyper-activation of the PI3K/Akt signaling pathway, are increasingly being reported in human malignancies, including breast cancer, and have been related to features of poor prognosis and resistance to chemotherapy and hormone therapy. Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the PI3K/Akt signaling pathway becomes a fundamental proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore further this hypothesis in breast cancer cells. To this end, we have determined the growth response to inhibition of the PI3K/Akt signaling pathway in a series of breast cancer cell lines with different PTEN levels. The PTEN-negative cell line displayed greater sensitivity to the growth inhibitory effects of the PI3K inhibitor, LY294002 and rapamycin, an inhibitor of the PI3K/Akt downstream mediator mTOR, compared with the PTEN-positive cell lines. To determine whether or not these differences in response are specifically due to effects of PTEN, we developed a series of cell lines with reduced PTEN protein expression compared with the parental cell line. These reduced PTEN cells demonstrated an increased sensitivity to the anti-proliferative effects induced by LY294002 and rapamycin compared with the parental cells, which corresponded to alterations in cell cycle response. These findings indicate that inhibitors of mTOR, some of which are already in clinical development (CCI-779, an ester of rapamycin), have the potential to be effective in the treatment of breast cancer patients with PTEN-negative tumors and should be evaluated in this setting.     

PI3K/Akt/mTOR inhibitors in breast cancer

Activation of the phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase I to III trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR (PAM) pathway.KEYWORDS : Breast cancer, phosphoinositide 3 kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR), everolimus     

Predictive markers for efficacy of everolimus plus exemestane in patients with luminal HER2-negative metastatic breast cancer

Metastatic breast cancer (MBC) is essentially incurable despite recent improvements in systemic therapies. We often encounter difficulties in choosing the most appropriate treatments, with optimal timing, for individual patients. Everolimus, one of the mTOR inhibitors, is usually used with endocrine therapy for MBC. Identification of predictive markers for everolimus-based treatment remains a major issue, but to date, no predictive markers have been established. We retrospectively investigated predictive markers for treatments with everolimus plus exemestane in patients with ER-positive and HER2-negative breast cancer. Clinicopathological features of 18 patients, with locally advanced disease or MBC given everolimus plus exemestane treatments, were examined in relation to treatment effects. Also, primary breast cancer specimens, all ER positive and HER2 negative, were immunohistochemically investigated for phospho-S6 (pS6) and PTEN, to evaluate the mTOR and PIK3CA/Akt pathways. Those showing a good clinical response had a significantly lower Ki67 labeling index than the poor responders. A similar trend was observed in pS6 level but without statistical significance. Interestingly, there was no correlation between the Ki67 labeling index and pS6, and when both indexes were low, the good clinical response rate was high. The median progression-free survival was longer in the group showing a low Ki67 labeling index (109 weeks) than in that with high Ki67 (19 weeks). There was no trend between PTEN expression and treatment effects. Our results suggest that the primary tumor in luminal HER2-negative breast cancer patients with a low Ki67 labeling index and pS6 level has the potential to respond well to everolimus plus exemestane.     

PI3K/Akt/mTOR信号传导通路与恶性肿瘤浸润和转移的研究进展

PI3K/Akt/mTOR信号通路作为细胞内重要信号传导通路之一,通过影响下游多种效应分子的活化状态,在细胞内发挥着抑制凋亡、促进增殖的关键作用,它与人类多种肿瘤的发生发展密切相关.本文综述了PI3K/Akt/mTOR信号通路的组成与功能、调节以及其抗肿瘤细胞凋亡作用机理等方面的研究进展,并就其抗细胞凋亡作用在肿瘤治疗中的应用作了评述,期待为以PI3K/Akt/mTOR信号通路中关键分子为靶点的肿瘤治疗研究提供参考.