Adjuvant therapy with antiestrogens targeting estrogen receptor α (ER) signaling prevents disease recurrence in many patients with early-stage ER+ breast cancer. However, a significant number of cases exhibit de novo or acquired endocrine resistance. While other clinical subtypes of breast cancer (HER2+, triple-negative) have disproportionately higher rates of mortality, ER+ breast cancer is responsible for at least as many deaths because it is the most common subtype. Therefore, identifying mechanisms that drive endocrine resistance is a high clinical priority. A large body of experimental evidence indicates that oncogenic signaling pathways underlie endocrine resistance, including growth factor receptor tyrosine kinases (HER2, epidermal growth factor receptor [EGFR], fibroblast growth factor receptor 1/2 [FGFR], insulin-like growth factor-1 receptor [IGF-1R]/ insulin receptor [InsR]), PI3K/AKT/ mTOR, MAPK/ERK, Src, CDK4/CDK6, and ER itself. Combined targeting of ER and such pathways may be the most effective means to combat antiestrogen resistance, and clinical trials testing such strategies show promising results. Herein, we discuss pathways associated with endocrine resistance, biomarkers that may be useful to predict response to targeted agents, and avenues for further exploration to identify strategies for the treatment of patients with endocrine-resistant disease.
More than 75% of breast cancers express estrogen receptor α (ER) and/or progesterone receptor (PR, an ER-regulated gene product). These cancers comprise the so-called “ER+” subtype, and the number of ER+ breast cancers is projected to increase.1 Such patients are typically treated with antiestrogen therapies that inhibit ER function. There are 3 main types of anti-estrogens: (1) selective ER modulators (SERMs) such as tamoxifen (which has mixed agonist/antagonist activity); (2) selective ER downregulators (SERDs) such as fulvestrant; (3) agents that reduce circulating estrogen levels such as aromatase inhibitors (AIs; letrozole, anastrozole, exemestane). Such endocrine therapies are some of the most effective targeted anticancer agents in history. Most patients who succumb to ER+ breast cancer were treated at some point with an antiestrogen,2-4 so their disease is likely endocrine resistant. It therefore remains a clinical priority to understand mechanisms driving endocrine-resistance in ER+ breast cancer. Herein, the discussion of endocrine resistance refers to cancers that grow in the presence of an antiestrogen; cancers that recur or progress after cessation of antiestrogen therapy may not be endocrine-resistant, and such patients may benefit from continued endocrine therapy.4
ER+ breast cancers can exhibit de novo or acquired endocrine resistance. Common clinical scenarios of endocrine resistance include: (1) de novo resistance where a patient presents with metastatic disease resistant to all hormonal therapies, or recurs soon after starting adjuvant hormonal therapy and does not respond to further endocrine manipulation; (2) de novo resistance to some but not other hormonal therapies; (3) acquired resistance after initial response to endocrine therapy, followed by temporary response to additional hormonal therapies until the cancer becomes refractory to all endocrine agents; (4) progression after initial response to a hormonal agent, and then transient response to the same agent introduced years later. Preclinical evidence suggests that the cellular and molecular mechanisms governing de novo versus acquired resistance may be the same, and that mechanisms of resistance to different classes of antiestrogens are similar. However, such findings may be biased by our ER+ models. Instances of cancers that respond to the AI exemestane following progression on a nonsteroidal AI (letrozole or anastrozole), or that respond to fulvestrant following progression on an AI, support the existence of agent-specific and class-specific types of endocrine resistance.
GROWTH FACTOR RECEPTOR SIGNALING PATHWAYS PROMOTE ENDOCRINE RESISTANCE
The only clinically available marker of antiestrogen resistance is HER2 overexpression.5 The findings that HER2 overexpression promotes the agonistic effects of tamoxifen, and that AI therapy is more effective than tamoxifen in patients with ER+/HER2+ disease prompted a switch to non-SERM therapies for these patients.6,7 However, less than 10% of ER+ breast cancers overexpress HER2, and HER2 is viewed as clinically more important than ER because HER2+ breast cancer is generally more aggressive. Thus, such patients are often treated with HER2-directed (trastuzumab) and endocrine therapies, either sequentially or in combination. Retrospective clinical data suggest that endocrine therapy is beneficial in combination with anti-HER2 therapy8, but these observations await confirmation in a prospective study.
Preclinical studies have implicated additional growth factor receptor signaling pathways in endocrine resistance. EGFR, IGF-1R, InsR, Ron, and FGFR1 activation promote anti-estrogen resistance in model systems.9-13 Such receptors converge on the PI3K/AKT/mTOR and MEK/ERK pathways, which have also been implicated in antiestrogen resistance.7,10,13,14 Components of these pathways are often genomically altered in human cancers.15,16 Whether mechanisms of resistance to tamoxifen, fulvestrant, and AIs are common remains to be determined, but activation of the PI3K or MEK pathways confers resistance to all forms of endocrine therapy. Many of these findings are supported by correlative, retrospective clinical evidence. For example, patients with FGFR1-overexpressing ER+ tumors had shorter distant recurrence-free survival following adjuvant treatment with tamoxifen compared with patients with FGFR1-normal tumors.11 Patients with ER+ tumors exhibiting a (phospho)protein signature of PI3K hyperactivation exhibited shorter recurrence-free survival following adjuvant endocrine therapy compared with patients with PI3K-low tumors.13 Similarly, patients with ER+ tumors exhibiting a gene expression signature of IGF-1R activation had a worse prognosis compared with patients with IGF-1R-inactive tumors.17 Such findings have led to ongoing trials testing novel agents targeting these signaling pathways in combination with antiestrogens.
ER PROMOTES ENDOCRINE RESISTANCE: CROSSTALK BETWEEN ER AND GROWTH FACTOR RECEPTOR PATHWAYS
The best-characterized mechanism of ER signaling involves estrogen-induced dimerization and phosphorylation of ER to promote transcriptional activity. However, growth factor receptor signaling pathways can modulate ER activation. The PI3K effector AKT, the TORC1 effector p70S6K, and ERK can phosphorylate ER to promote estrogen-induced, tamoxifen-induced, and ligand-independent ER transcriptional activity.18-20 PI3K, Ras, and ERK can also promote activation of ER cofactors (Fig. 1).21-26 In turn, ER drives expression of genes encoding growth factor receptor pathway components. Neoadjuvant estrogen deprivation therapy with an AI reduced AKT and mTOR activation in ER+ tumors in patients, and such reductions correlated with improved clinical response and outcome, suggesting that estrogen-induced signaling activates these pathways.27,28
Reciprocal crosstalk between ERα and growth factor receptor signaling pathways. RTKs and GPCRs activate the PI3K (blue) and MEK signaling pathways. These signal transducers can then phosphorylate ER (green) and/or coactivators and corepressors to modulate ER transcriptional activity not necessarily dependent on ER ligands. In turn, ER transcribes genes encoding components of growth factor signaling pathways, thus completing a signaling cycle of RTKs to ER to RTKs. ER also complexes with RTKs and Src to rapidly induce nongenomic signaling. ER-interacting proteins are shown in color. Figure was modified from Miller and colleagues14 and reprinted with permission (Copyright 2011, American Society of Clinical Oncology).
While clinical findings imply that antiestrogens should suppress growth factor receptor signaling, preclinical evidence shows that such crosstalk is more complex. Forced PI3K pathway activation (by knockdown of PTEN, or overexpression HER2, IGF-1R, or activated AKT1) confers resistance to tamoxifen, fulvestrant, and estrogen deprivation in ER+ breast cancer cell lines. Such resistance is typically reversible by inhibition of PI3K.7,18,29 ER+ MCF-7 breast cancer xenografts with acquired resistance to tamoxifen exhibit increased expression of IGF-1R, HER2, and EGFR.30 AI-resistant MCF-7/aromatase cells and xenografts exhibit increased levels of HER2 and the EGFR ligand amphiregulin, and lower levels of ER.31,32 Long-term estrogen-deprived, ER+ breast cancer cell lines (which model AI resistance) exhibit hyperactivation of IGF-1R/InsR/PI3K/AKT/mTOR signaling.13 MCF-7 cells and xenografts with acquired fulvestrant resistance shown similar changes.10,33 At first glance, such findings seem to conflict with clinical observations.27,28 However, cells may escape estrogen/ER dependence via upregulation of growth factor receptor pathways by an alternative mechanism(s) (i.e., independent of ER). The majority of well-characterized breast cancer cell lines are ER-, so generation of more ER+ models may help capture the heterogeneity of ER+ breast cancers. Patient-derived ER+ breast cancer xenografts may also present clinically-relevant models to study endocrine resistance. While patient-derived ER+ tumors do not graft well in immunodeficient mice, a recently derived immunodeficient knock-in mouse expressing human prolactin (hPRL) has an ER+ tumor graft success rate of 43.1% and is expected to increase the capacity to generate such models.34
Preclinical and clinical evidence implicate ER itself in endocrine resistance. Most breast cancers that progress on antiestrogen therapy retain ER. Following progression on an AI, patients are often switched to fulvestrant, which effectively inhibits and partially downregulates ER.35,36 Approximately 30% of patients who progress on an AI respond to second-line fulvestrant.37,38 High-dose fulvestrant may provide a longer time-to-progression than estrogen deprivation with the AI anastrozole as first-line treatment for advanced breast cancer.39 In ER+ cell lines with acquired resistance to estrogen deprivation, ER remains transcriptionally active, and treatment with fulvestrant or knock-down of ER expression inhibits cell growth.40 These data suggest that ER may remain active under estrogen-depleted (AI-treated) conditions, and that further inhibition/downregulation of ER (with fulvestrant) may be superior to AI therapy.
COMBINED TARGETING OF ER AND GROWTH FACTOR RECEPTOR PATHWAYS ABROGATES ENDOCRINE RESISTANCE
PI3K/AKT/mTOR signaling is required for growth of endocrine-resistant breast cancer cell lines. The estrogen-independent growth of long-term estrogen-deprived cells is inhibited by the PI3K/mTOR inhibitor BEZ235, or the TORC1 inhibitor everolimus (Afinitor, now approved for treatment of advanced ER+ breast cancer in combination with the AI exemestane).13 Similarly, the pan-PI3K inhibitor buparlisib (BKM120) inhibits estrogen-independent growth of MCF-7 xenografts in mice, and the PI3K/mTOR inhibitor wortmannin inhibits growth of letrozole-resistant MCF-7/aromatase xenografts.40-42 Estrogen stimulation blocks the apoptotic effects of BEZ235 in ER+ cells, suggesting that combined blockade of ER and PI3K may be most effective.43 Indeed, combined treatment with fulvestrant and buparlisib induced regression of MCF-7 xenografts, and fulvestrant plus the IGF-1R/InsR inhibitor OSI-906 completely inhibited tumor growth, while single-agent treatments only slowed growth.12,40
CELL CYCLE DEFECTS PROMOTE ANTIESTROGEN RESISTANCE
Dysregulation of cell cycle checkpoints is common in cancer. Since ER regulates the expression of many genes involved in cell cycle progression, and antiestrogens block such ER functions, antiestrogen resistance can arise by genetic alterations that circumvent the requirement for ER. A commonly deregulated checkpoint involves the Cyclin-D/CDK4/CDK6/Rb pathway. Cyclin-D1/CDK4 and Cyclin-D3/CDK6 complexes phosphorylate Rb family proteins, thereby promoting activation of E2F transcription factors to drive expression of genes encoding proteins required for cell cycle progression. Genes encoding Cyclin-D1, Cyclin-D3, CDK4, and CDK6 are amplified, and the Rb tumor suppressor is lost or mutationally inactivated in many cancers. Rb loss confers tamoxifen resistance in ER+ models.44 Patients with ER+ breast cancer exhibiting a gene expression signature of Rb loss had shorter recurrence-free survival following adjuvant tamoxifen.44 A tumor gene expression signature of E2F activation was associated with higher residual tumor cell proliferation following presurgical AI therapy.40 Therefore, activation of the CDK4/CDK6/E2F axis promotes endocrine resistance, and treatment with a CDK4/6 inhibitor or knockdown of CDK4 expression abrogates endocrine-resistant cell proliferation.40,45 For reasons that remain unclear, ER+ breast cancer cell lines are much more sensitive to CDK4/6 inhibition than ER- cell lines.46 In a recent phase II trial, the CDK4/6 inhibitor PD-0332991 in combination with the AI letrozole extended progression-free survival compared with letrozole alone as first-line treatment for metastatic ER+/HER2- breast cancer.47 This drug combination is being tested in a phase III study.
BIOMARKERS OF RESPONSE TO TARGETED AGENTS (?)
Following the identification of growth factor receptor pathways as causes of endocrine resistance, much effort was expended to identify biomarkers predictive of sensitivity to drugs targeting the various nodes of these pathways in order to identify patient subpopulations that may reap greater benefit from treatment. Such biomarkers were typically identified by screening large panels of cell lines, and searching for genetic or proteomic markers enriched in sensitive or resistant lines. The most mature targeted agent to combat endocrine resistance mediated by growth factor receptor signaling is everolimus, but biomarkers associated with everolimus sensitivity in breast cancer remain unclear.
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, occur in 28-47% of ER+ breast cancers, and are associated with sensitivity to PI3K and AKT inhibitors in cancer cell lines.13,16,48-50 Thus, PIK3CA was a logical biomarker to select patients for inclusion in early-phase clinical trials with PI3K/AKT inhibitors. However, this genetic biomarker has not been evaluated in the context of PI3K inhibition with endocrine therapy. Early clinical data showed that among 8 patients with advanced ER+ breast cancer who exhibited a response (by [18F]FDG-PET) to buparlisib plus an AI, only two patients had PIK3CA-mutant tumors.51 In another study considering patients enrolled in phase I trials testing PI3K/AKT/mTOR inhibitors, there was a higher response rate in tumors containing a PIK3CA mutation compared with those with wild-type PIK3CA (30% vs. 10%).52 These data imply that (1) a significant fraction of PIK3CA-wild-type tumors can respond to PI3K inhibition, and (2) a better biomarker of response is needed.
Genetic biomarkers are easier to measure and more reliable in archived tissue than (phospho)protein biomarkers. While it has been considered that the degree of PI3K pathway activation may predict sensitivity to pathway inhibition, the levels of phospho-AKT were not associated with sensitivity to AKT inhibition in cancer cell lines.50 Furthermore, PIK3CA mutations are not associated with PI3K pathway activation in cell lines as assessed by AKT phosphorylation.53
The most appropriate biomarker of sensitivity to PI3K pathway inhibitors may be pharmacodynamic. If a tumor is sensitive to a drug, the tumor should exhibit a rapid metabolic response. This concept is being pursued in ongoing clinical trials testing novel agents. Early clinical data suggest that a metabolic response to buparlisib plus an AI as assessed by [18F]FDG-PET after two weeks of therapy is associated with longer time-on-study, and thus improved response, in patients with metastatic disease.54 With such a pharmacodynamic biomarker, each patient serves as their own control, and drug response can be assessed within weeks of initiation of therapy. A similar strategy is being tested in the presurgical/neoadjuvant setting, where changes in molecular markers (e.g., phospho-S6 as a marker of TORC1 activation) are detected by comparing pre- and post-treatment tumor tissues.
In contrast to PI3K pathway biomarkers, cancer cell sensitivity to CDK4/6 inhibitors may be more predictable using genetic biomarkers. Genomic loss of Rb renders a cell insensitive to CDK4/6 inhibition,55,56 so patients with Rb-deficient tumors should not be treated with a CDK4/6 inhibitor. Amplification of the gene encoding Cyclin-D1, or loss of the gene encoding p16INK4A, may be indicative of cells that have hyperactivated CDK4/6 signaling. Whether these genetic lesions are associated with greater sensitivity to CDK4/6 inhibition is being tested in the trials with letrozole ± PD-0332991.
Over two decades of research has led to the implication of two major signaling axes in endocrine resistance: (1) growth factor receptor/PI3K/AKT/mTOR, and (2) CDK4/CDK6/Rb/E2F. Drugs targeting these pathways are being tested clinically in combination with antiestrogens, and have shown promising results thus far. A looming concern is that inherent biases in the model systems used to identify mechanisms of endocrine resistance guided pathway identification. For example, there is an over-representation of PIK3CA mutations among ER+ breast cancer cell lines compared with ER+ tumors. If PIK3CA mutations confer sensitivity to PI3K inhibitors, most ER+ breast cancer cell lines will likely respond. However, many ER+ breast tumors are PIK3CA-wild-type, and available ER+ models to study this genotype are few. With the establishment of more ER+ breast cancer cell lines and patient-derived tumor xenografts, it is hoped that we will establish a broader genotypic repertoire of ER+ breast cancer models, and begin to identify novel drug targets for endocrine-resistant cancers.
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