The sequential use of endocrine agents has been the mainstay therapeutic approach for patients with hormone-receptor (HR) metastatic breast cancer for decades, resulting in median survivals in the range of four years. However, eventually resistance to endocrine therapies occurs in all patients with HR-positive metastatic breast cancer. The approval of everolimus for metastatic breast cancer, resistant to non-steroidal aromatase inhibitors, represents a new era in the treatment of this disease, and demonstrates that targeting growth factor pathways appears to reverse resistance to endocrine therapies. An improved understanding of the mechanisms underlying endocrine-resistance should yield new therapeutic approaches and improve outcomes for patients with HR-positive metastatic breast cancer. However, some approaches appear to be more fruitful than others.
The following are what I considered to be the most important findings in this area from the 2012 San Antonio Breast Cancer Symposium.
Signaling through the vascular endothelial growth factor pathway has been demonstrated to play a role in resistance to endocrine agents in preclinical models. A previously reported phase 2 trial in which patients with HR-positive metastatic breast cancer were treated with letrozole and bevacizumab resulted in an encouraging progression-free survival (PFS) of 17 months.
The LEA (Letrozole/Fulvestrant and Avastin) trial is a randomized study that evaluated the addition of bevacizumab to endocrine therapy, either letrozole or fulvestrant, in the first-line, HR-positive metastatic setting. Almost 400 postmenopausal patients were randomized, half of whom had received prior endocrine therapy with an antiestrogen and/or an aromatase inhibitor.
Although the addition of bevacizumab to endocrine therapy improved PFS from 14 to 18 months, this result was not statistically significant. Overall survival was greater than 40 months in each arm of the study, but there was no difference between the two arms. Patients in the bevacizumab arm, as expected, had more treatment-related side effects, but no unexpected toxicities were reported.
In summary, the LEA trial failed to demonstrate a benefit to adding bevacizumab to endocrine therapy in the first-line metastatic setting. Results of the CALGB 40503 trial, which evaluates the addition of bevacizumab to letrozole also in the first-line setting, are awaited. It is possible that bevacizumab may be more effective outside of the first-line setting, where more cancers are likely to be resistant to endocrine therapy and therefore more dependent on growth factor signaling. Further evaluation in this setting may be warranted.
Inhibition of CDKs
A different approach involving inhibition of cyclin-dependent kinases (CDK) in metastatic HR-positive breast cancer produced exciting results. CDKs are a group of serine/threonine kinases that are intimately involved in regulating progression through the cell cycle. PD0332991 is a highly selective inhibitor of CDK 4/6 that prevents DNA synthesis by prohibiting progression from G1 to S phase, resulting in G1 arrest.
Preclinical data with this agent utilizing a large range of breast cancer cells lines indicated that PD0332991 is particularly effective in luminal (HR-positive) cell lines. Additionally, sensitivity to PD0332991 is associated with cell lines with increased expression of cyclin D1 and Rb and decreased expression of p16. Based on these pre-clinical data and phase 1 evaluation, a randomized phase 2 trial was designed to evaluate the addition of PD0332991 to letrozole in the first-line HR-positive metastatic disease setting.
This phase 2 trial was designed in two phases: the first phase enrolled patients with HR-positive metastatic breast cancer unselected for molecular markers; the second exploratory phase was enriched for patients with HR-positive metastatic breast cancer with amplification of CCND1 and/or decreased expression of p16.
Results of the phase 1 part of the trial, which included 66 patients, were presented at the ESMO 2012 meeting in Vienna. Results from all 165 patients enrolled in both phases were then presented at SABCS. The addition of PD0332991 to letrozole resulted in an impressive improvement in PFS from 7.5 to 26.1 months, which was statistically significant with a hazard ratio of 0.37.
The response rate in patients with measurable disease was improved from 31 to 45 percent with the addition of PD0332991 to letrozole. Toxicities were manageable, with uncomplicated neutropenia being one of the more common side effects. Amplification of CCND1 and decreased expression of p16 were not predictive of benefit from PD0332991, and did not add to estrogen receptor expression.
These encouraging results will be confirmed in a planned phase 3 trial.
The Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial was updated with final survival analysis. The trial randomized patients with HR-positive metastatic breast cancer, who had received prior endocrine therapy, to standard-dose fulvestrant at 250 mg every four weeks without a loading dose, or to high-dose fulvestrant at 500 mg every four weeks, with a loading dose of 500 mg on days 1 and 15.
PFS was improved from 5.5 to 6.5 months with the higher dose schedule of fulvestrant, which led to the approval of this dose and schedule in 2010. Final survival times were improved by four months with the high dose compared with the standard dose, resulting in a 19 percent decrease in risk of death.
An analysis of two randomized trials that compared exemestane with fulvestrant at the standard dose with a loading dose of 500 mg on day 1 and 250 mg on day 15 was presented. Similar to the individual results from EFECT (Evaluation of Faslodex vs Exemestane Clinical Trial) and SoFEA (Study of Faslodex vs Exemestane with/without Arimidex), combination results of the two trials demonstrated no difference in PFS or overall survival between exemestane and fulvestrant at this dosing schedule. A comparison of the higher dosing schedule of fulvestrant with exemestane is not available, though this dosing schedule of fulvestrant has been demonstrated to be superior to anastrozole in the first-line setting.
This is an exciting time for the development of agents for HR-positive metastatic breast cancer. The results of the BOLERO-2 and TAMRAD trials are proof of principle that targeting growth factor pathways through mTOR inhibition appears able to reverse resistance to endocrine agents. Future trials should make clear distinctions between HR-positive cancers that remain endocrine-sensitive and those that are truly endocrine-resistant both by clinical and molecular criteria.
Agents that target growth factor pathways may be more effective in endocrine-resistant cancers, which are likely more dependent on these pathways than endocrine-sensitive cancers. Key questions that need to be addressed include optimal sequencing of endocrine agents and when agents, such as everolimus, should be added in HR-positive metastatic breast cancer. Several trials utilizing everolimus and PI3-kinase inhibitors are addressing the latter question.