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More recently, researchers seek to understand the mechanisms related to tumor dissemination in hopes of therapeutically targeting this process.
Metastatic breast cancer (MBC) is a fatal disease involving the expansion of cancerous cells from the breast to other areas of the body. Treatments for MBC are often limited to palliative care; as a result of MBC is usually fatal. As research continues, factors such as age at diagnosis, hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) overexpression/amplification, and site of metastases are currently used to stratify patients into groups with different prognoses and to predict response to systemic treatments. More recently, researchers seek to understand the mechanisms related to tumor dissemination in hopes of therapeutically targeting this process. HRs are expressed in about two-thirds of breast tumors and endocrine therapy is probably the most important systemic therapy for HR-positive breast cancer. Selective estrogen modulators (SERMs) and aromatase inhibitors (AIs) represent the standard options in patients with HR-positive MBC, with selection based on previous exposure and sensitivity in the adjuvant setting. Preclinical models have identified several molecular abnormalities (eg, EGFR and HER-2 overexpression, ESR1 mutations) associated with endocrine resistance, providing rationale for conducting prospective studies. Novel therapeutic agents targeting the PI3KCA/mTOR cyclin-dependent kinases (CDKs) demonstrated the most promising results, with significant impact on the management of patients with endocrine resistance. Future challenges are represented by the testing of sensitive diagnostic tools with the ability to identify predictive markers allowing more personalized therapeutic choice and possibly monitoring.
Massimo Cristofanilli, MD, FACP
Breast cancer is the most prevalent female malignancy and the second most common cause of death in developed countries. In 2013 in the United States, an estimated 234,580 women were diagnosed with invasive breast cancer and 40,030 died from it.1 During the last decades, breast cancer survival has increased considerably2 in Western countries due to earlier diagnosis and increasing use of adjuvant and neoadjuvant therapies, but recent statistics suggest that approximately 30% to 70% of patients with primary breast cancer worldwide eventually develop recurrence and die of metastasis every year with an estimated increased mortality of 14%.3 Recent years have produced remarkable changes both in the treatment philosophy of metastatic breast cancer (MBC) and in the available therapies, contributing to improvements in survival rates and quality of life in Western Europe and the United States, with the potential to extend some of these benefits to low and medium income countries worldwide.4
Estrogen receptors (ERs) are expressed in about two-thirds of breast tumors, and endocrine therapy is probably the most important systemic therapy for hormone receptor (HR-) positive breast cancer.5,6 Several prospective studies established the superiority of aromatase inhibitors (AIs) in the management of ER-positive MBC.7-10 Fulvestrant (Faslodex), a pure estrogen receptor antagonist, demonstrated efficacy comparable to anastrozole and subsequently defined a role and a treatment schedule/ dosage, providing another available therapeutic option.10
More recently, a prospective, open label, randomized phase III study evaluated the combination of fulvestrant and anastrozole (Arimidex) compared with single agent anastrozole in postmenopausal women with ER-positive locally advanced or MBC.11 A total of 695 patients were randomly assigned to the two treatment arms. Forty percent of patients were de novo stage IV disease. Moreover, approximately 40% of patients had previously been exposed to tamoxifen and only 30% had received adjuvant chemotherapy. The results demonstrated superiority of the combination arm with a median progression- free survival (PFS) of 15 months (95% confidence interval [CI], 13.2-18.4) compared with 13.5 months for the single agent (95% CI, 12.1-15.1; P = .007 stratified log-rank test), suggesting a role for such combination in the management of a selected subset of patients.
Two other studies have evaluated the combination of fulvestrant with an AI in advanced setting.12,13 The Fulvestrant and Anastrozole Combination Therapy (FACT) trial was a multicenter, international, randomized study that enrolled 514 patients treated with either the combination regimen or single agent anastrozole.12 Approximately a third of patients were endocrine therapy naïve (34.4% vs 30.2% anastrozole vs combination respectively). Prior adjuvant chemotherapy exposure was also more frequent in the anastrozole group (49.6% vs 41.9%). There was no statistically significant difference in overall response rate (ORR) (33.6% vs 31.8% for anastrozole vs combination respectively) and median time to progression (TTP) of 10.2 months for anastrozole compared with 10.8 months for anastrozole plus fulvestrant (hazard ratio [HR] = 0.99, 95% CI, 0.81-1.20; P = .91). The Study of Faslodex with or without Arimidex vs Exemestane following progression on non-steroidal Aromatase inhibitors (SoFEA) was a multicenter, phase III randomized controlled trial.13
Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250-mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). A total of 723 patients underwent randomization: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4.4 months (95% CI 3.4- 5.4) in patients assigned to fulvestrant plus anastrozole, 4.8 months (3.6-5.5) in those assigned to fulvestrant plus placebo, and 3.4 months (3.0-4.6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (HR = 1.00, 95% CI 0.83-1.21; log-rank P = .98), or between those assigned to fulvestrant plus placebo and exemestane (HR = 0.95, 95% CI, 0.79-1.14; log-rank P = .56).
In summary, these studies suggest that a combination of fulvestrant and AI should be considered an appropriate choice only for a selected population of de novo stage IV or endocrine-naïve HR-positive postmenopausal patients. Unfortunately, after an initial response to hormonal therapy, most ER-positive tumors develop resistance leading to disease progression.14 Preclinical models have shown that an adaptive upregulation of growth factor signaling is associated with acquired resistance to endocrine therapies, whereas overexpression of human epidermal growth factor receptor 2 (HER2) in ER-positive breast cancer is responsible for de novo resistance to tamoxifen and AIs.15,16
Furthermore, studies on ER biology have highlighted the fundamental role of other signaling pathways in the development of resistance to hormone therapies.17 It has been suggested that overactive growth factor receptor signaling through multiple intracellular pathways may contribute to the evolution of an endocrine resistance phenotype. Manipulation of growth factor signaling networks has emerged as an attractive strategy to delay the onset, or potentially even overcome the resistance to endocrine therapy in breast cancer.18 In this context, a number of clinical trials have tested the use of HER2/neu antagonists, insulin-like growth factor 1 receptor (IGF1R) inhibitors, tyrosine kinase inhibitors (TKIs), multikinase inhibitors, cyclin- dependent inhibitors, mTOR antagonists, and src-inhibitors19,20 together with hormone therapy. More recently, new ER alpha mutations were described in tumor samples from patients with endocrine-resistant disease, particularly in cases of long-term exposure to antiestrogen therapy.21-23
These studies suggest that the increased routine use of molecular diagnostics platforms in the evaluation of patients with MBC will contribute to improving our understanding of the complex biology of this disease, particularly in ER-positive breast cancer considering the availability of multiple molecularly targeted therapies.
Preclinical data have provided evidence that crosstalk between growth factor receptor and ER pathways may mediate the development of resistance to endocrine therapy in HR-positive disease.17,18 For example, increased expression of epidermal growth factor receptor (EGFR), human ErbB2 (HER2), and insulin- like growth factor 1 receptors can elicit tamoxifen resistance, as can activation of their downstream signaling pathway components, particularly extracellular signal-regulated kinase and phosphoinositol-3-kinase.16,24 EGFR overexpression is also predictive of a decreased benefit from tamoxifen,18,19 and patients with higher EGFR expression are less likely to respond to tamoxifen and have a significantly shorter time to treatment failure.25
The combination of endocrine therapy and trastuzumab (Herceptin) or lapatinib (Tykerb) is a first-line therapeutic option in patients with HER2-positive/HR-positive metastatic tumors based of the results of two prospective randomized studies.26,27
The TAnDEM trial was the first randomized phase III study to combine a hormonal agent and trastuzumab, an anti- HER2 antibody, without chemotherapy as treatment for HER2- positive and HR-positive MBC.26 Postmenopausal women were randomly assigned to 1 mg per day of oral anastrozole with or without trastuzumab until progression. Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in all measured endpoints compared with patients receiving anastrozole alone. PFS was 4.8 month versus 2.4 months, and there was a nonsignificant difference in overall survival (OS) of 28.5 months for the combination versus 23.9 months for single agent letrozole. The ORR, consisting of only partial response, was 20% versus 7%, respectively, and the clinical benefit rate (CBR), 43% versus 28%, respectively.
The second study was a multicenter, open-label, randomized phase III trial (EGFR30008) designed to determine the efficacy of lapatinib, a HER2-targeting TKI, in combination with letrozole (Femara) for the treatment of HR-positive, HER2- positive, and HER2-negative advanced breast cancer in postmenopausal women.27 At baseline, the majority of patients included in this study had stage IV disease and received ≥6 months of prior hormone therapy. Patients were randomized in a 1:1 fashion between December 2003 and December 2006 to receive either lapatinib (1500 mg daily) plus letrozole (2.5 mg daily) or letrozole alone (2.5 mg daily). Results showed that the addition of lapatinib to letrozole increased PFS and ORR compared with letrozole alone in HER2-positive disease. PFS was 8.2 months in the letrozole combined with lapatinib arm versus 3 months in the letrozole and placebo arm. OS was 33.3 months versus 32.3 months (unpublished data), respectively, and ORR was 28% versus 15%, respectively. As expected, there was no survival or response benefit in the HER2-negative cohorts.
In HER-2 negative disease several studies have tested the clinical value of EGFR-modulation combined with endocrine therapy. Cristofanilli et al28 evaluated the efficacy and tolerability of anastrozole combined with gefitinib (Iressa) compared with anastrozole plus placebo in postmenopausal women with HR-positive MBC who had not received prior endocrine therapy or chemotherapy or who developed metastatic disease during/after adjuvant tamoxifen. Despite the fact that the study was discontinued after 54% of patient recruitment (94 out of required 174) because of slow enrollment, patients receiving the combination of anastrozole and gefitinib showed a longer PFS, which was the primary endpoint of the study, compared with those receiving anastrozole plus placebo (HR gefitinib/placebo, 0.55; 95% CI, 0.32—0.94; median PFS, 14.7 vs 8.4 months). The post hoc subset analysis of PFS for patients who had received prior endocrine treatment compared with those who were endocrine therapy naïve showed a more pronounced benefit for patients who had not previously received endocrine therapy. Similarly Osborne et al29 reported an improved PFS in patients with newly diagnosed metastatic disease or patients who had relapsed after adjuvant tamoxifen (treatment stopped ≥1 year before study entry) (stratum 1) treated with tamoxifen plus gefitinib. Patients who received tamoxifen plus gefitinib and had recurred during/after adjuvant AI or after failed first-line AI (stratum 2) reported no advantage in clinical benefit.
AZD8931 is an orally bioavailable, reversible, tyrosine kinase, equipotent inhibitor of EGFR, HER2, and HER3 signaling.30 The agent demonstrated anticancer activity in a range of in vitro and in vivo preclinical tumor models, with particular activity in inhibiting signaling driven through ligand stimulation.
The MINT study prospectively tested the hypothesis that adding AZD8931 to anastrozole would delay the development of clinical endocrine resistance in postmenopausal patients with endocrine therapy-naïve advanced breast cancer.31
Patients were randomized 1:1:1 to AZD8931 20 mg twice daily in combination with anastrozole 1 mg daily; AZD8931 40 mg twice daily in combination with anastrozole 1 mg daily; or matched AZD8931 placebo twice daily in combination with anastrozole 1 mg daily. Between June 2010 and June 2012, 359 patients were randomized to receive AZD8931 20-mg (n = 118), 40-mg (n = 120), or placebo (n = 121) in combination with anastrozole. At the interim analysis, median PFS in the AZD8931 20 mg, 40 mg, and placebo arms were 10.9, 13.8, and 14.0 months, respectively, suggesting lack of benefit from the combination. Moreover, AZD8931 was associated a significant EGFR-mechanism based toxicity, causing treatment delays and discontinuation. As a consequence, the trial was discontinued for toxicity and lack of efficacy, with impact on the further clinical development of AZD8931. Moreover, the study clearly demonstrated the need to consider endocrine therapy resistance of previous exposure as a more appropriate clinical testing scenario in view of the lack of a defined molecular signature for patient selection.
The phosphoinositide-3-kinase (PI3-kinase)-Akt-mTOR pathway is a major signaling pathway in normal and cancer physiology with high rate of mutational activation of the pathway in breast cancer.20,32 The pathway can be activated by genomic amplification or overexpression of receptor tyrosine kinases, such as HER2, EGFR, and IGF1R. Activating mutations in the catalytic PI3-kinase subunit PIK3CA occur in 36% of breast cancers overall and are especially prevalent in luminal and HER2-amplified breast cancers (29%-45%). Drugs targeting mTOR include rapamycin and its analogues everolimus and temsirolimus, which allosterically inhibit mTORC1 only, and mTOR kinase inhibitors, which inhibit both mTORC1 and mTORC2.33-35 The randomized phase III BOLERO-2 trial tested everolimus (Afinitor) plus the steroidal AI exemestane (Aromasin) versus placebo plus exemestane in women with metastatic ER-positive/HER2-negative breast cancer that had progressed on prior therapy with nonsteroidal AIs.35 The trial was stopped early after a planned interim data analysis showed that the study had met its prespecified endpoint of PFS. The everolimus arm showed an increase in response rate (7% vs 0.4%) and a significant increase in PFS (10.6 vs 4.1 months by central review). A nonsignificant increase was seen in OS in the everolimus arm, but OS data are immature.
The benefit of everolimus was consistent across subgroups divided by age, prior therapy, and sensitivity to previous hormonal therapy. A recent update analysis of the study confirms the statistically significant advantage in PFS of the combination regimen, clearly supporting this regimen as standard of care in ER-positive patients demonstrating progression after AIs, while the role of mTOR inhibitors in newly recurred disease is under investigation. Additional analysis of this study also demonstrated the efficacy of the combination in patients with more aggressive features of disease such as visceral metastases.36 Moreover, similar benefit has been shown in elderly patients (>70 years of age) but requiring reduced dosage intensity because of toxicity profile.37
In contrast, in the recently reported randomized phase III HORIZON trial, the combination of oral temsirolimus and letrozole did not improve response rates or PFS when compared with letrozole plus placebo as first-line treatment for women with locally advanced or metastatic ER-positive breast cancer.38 A key difference between the trial populations is that none of the patients in HORIZON had any prior AI exposure, although approximately 40% had received adjuvant tamoxifen, whereas BOLERO-2 participants essentially all experienced disease progression on prior nonsteroidal AI therapy. This difference is reflected in the response rates seen in the AI plus placebo arms: 27% in HORIZON and 0.4% in BOLERO-2.
Dysregulation of cell cycle checkpoints is common in cancer. 39 There are four proliferative cyclin-dependent kinases (CDKs): CDK 1, which predominantly regulates the transition from G2 to M phase, and CDK 2/4/6, which regulate the transition from G1 to S phase. Inactivation of the G1 to S phase checkpoint through several events such as deletion of the retinoblastoma (Rb) protein or cyclin-dependent kinase inhibitor 2A (CDKN2A), CDK 4 point mutation, or cyclin D1 (CCND1) amplification is a characteristic feature of human malignancy.39,40 Activation of the CDK 4/CDK 6/E2F axis promotes endocrine resistance, and treatment with a CDK 4/6 inhibitor or knockdown of CDK 4 expression abrogates endocrine-resistant cell proliferation.41
Moreover, preclinical models suggest a peculiar sensitivity of ER-positive breast cancer cell lines to CDK 4/6 inhibition, indicating a definitive path for clinical investigation.41 Palbociclib (PD-0332991) is an orally bioavailable selective inhibitor of CDK 4/6 that prevents DNA synthesis by blocking progression of the cell cycle from G1 to S phase.42,43 A randomized phase II study examined postmenopausal women with hormone- sensitive, ER-positive, HER2-negative advanced breast cancer who had not received any prior systemic anticancer therapy for their advanced disease.44 Patients who received palbociclib plus the oral nonsteroidal AI letrozole had significantly longer PFS compared with patients who received letrozole alone (26.1 vs 7.5 months; HR = 0.37; P <.001). This promising agent is currently being tested in two phase III trials in combination with letrozole or faslodex (+/- LHRH agonist) respectively.
The increased use of novel molecular diagnostics is changing our understanding of the complexity and heterogeneity of HR-positive disease, allowing a more accurate prediction of sensitivity to therapeutic endocrine manipulations. The identification of genomic abnormalities (eg, ESR1 and CH1 mutations) and activation of molecular pathways regulating cell cycle, proliferation, migration, angiogenesis, and metastasis promoted the evaluation of multiple novel targeted agents in advanced HR-positive breast cancer. In patients with HRpositive (HER2-negative) disease, targeting of the PI3KCA/ mTOR pathway and cell cycle regulators currently appears to be the most promising approach for patients progressing after standard endocrine therapy. Those agents are effective but also associated with significant toxicity and costs, requiring additional efforts to identify specific molecular signatures with the ability to predict the benefit of targeted agents. In fact, significant research questions to be addressed relate to the role of other PI3KCA-modulators in patients with disease recurring after standard AI or after combination regimens (including everolimus). Moreover, the availability of selective inhibitors of CDK 4/6 should suggest the design of strategies focused on a molecular-driven selection allowing more rational choices for these patients.
ABOUT THE AUTHOR
Affiliation: Massimo Cristofanilli, MD, FACP, is professor of Medical Oncology, deputy director of Translational Research, and director of the Jefferson Breast Cancer Clinical Program and Center at Thomas Jefferson University in Philadelphia, PA.
Disclosure: Dr. Cristofanilli reports no relevant conflicts of interest to disclose.
Address correspondence to:
Massimo Cristofanilli, MD, FACP, 1025 Walnut St, Suite 700, Philadelphia, PA 19107
phone: 215-503-5098; fax: 215-503-3448