The interactions between the estrogen receptor (ER) and HER2 pathways in breast cancers are clearly complex and remain incompletely understood. Historically, cancers that express both ER and HER2 were thought to be intrinsically resistant to endocrine therapy, likely due to HER2 being the dominant pathway. However, recent genomic analyses of ER-positive, HER2-positive breast cancers suggest the existence of a subtype that may be driven by ER and consequently sensitive to endocrine agents.1
In fact, inhibition of HER2 alone in ER-positive, HER2-positive breast cancers may allow ER to act as an escape pathway resulting in resistance to HER2-directed agents.2,3 Likewise, there is evidence to suggest a role for HER2 signaling in resistance to endocrine therapy.4,5 Given the known crosstalk between the ER and HER2 pathways, both in the HER2-positive and HER2-normal settings, a dual approach in which both pathways are inhibited concomitantly may represent an optimal therapeutic approach to overcome the potential resistance associated with targeting either pathway alone.
ER-Positive, HER2-Positive Breast Cancer
Johnston et al6 evaluated the addition of lapatinib (Tykerb), a tyrosine kinase inhibitor that targets both EGFR and HER2, to letrozole in patients with ER-positive advanced breast cancer. In the 200 patients accrued to the trial with ER-positive, HER2-positive disease, there was a significant improvement in progression-free survival of 5 months among patients who were randomly assigned to receive lapatinib, which led to U.S. Food and Drug Administration approval of this regimen.
Similarly, the addition of trastuzumab (Herceptin) to anastrozole significantly improved progression-free survival by 2 months in patients with advanced ER-positive, HER2-positive breast cancer.7 In the Cancer and Leukemia Group B (CALGB) trial recently reported by Burstein et al8 —reviewed in this issue of The ASCO Post—progression-free survival was improved by 2.5 months for patients with ER-positive, HER2-positive breast cancer treated with lapatinib and fulvestrant (Faslodex) compared to fulvestrant alone, but this difference was not significant, likely due to the small numbers of patients in this analysis.
Given emerging data demonstrating considerable heterogeneity in cancers that express both hormone receptors (HR) and HER2,1 including the surprising finding that almost one-third of these cancers have a luminal A phenotype using intrinsic subtyping, future studies should stratify based on genomic subtypes to identify which HR-positive, HER2-positive cancers can be successfully treated with combined ER and HER2 blockade, potentially avoiding unnecessary chemotherapy.
In the meantime, the results of the CALGB trial,8 though not statistically significant, are in keeping with other trials, 6,7 and combined HER2 blockade with lapatinib and ER blockade with letrozole remains a viable treatment option for selected patients with ER-positive, HER2-positive advanced breast cancer.
ER-Positive, HER2-Normal Breast Cancer
The mechanisms underlying resistance to endocrine agents in ER-positive, HER2-normal breast cancers remain poorly understood, but enhanced signaling through growth factor pathways, including members of the epidermal growth factor receptor (EGFR) family, has been demonstrated in preclinical2 and clinical studies.3 The improved outcome noted in recent trials9,10 with inhibition of mTOR in patients with ER-positive, HER2-normal breast cancer supports the importance of these pathways in resistance to endocrine agents.
The CALGB trial reported by Burstein et al8 demonstrated no benefit for the addition of lapatinib to fulvestrant in patients with ER-positive, HER2-normal cancers. Likewise, Johnston et al6 noted no difference in progression-free survival with the addition of lapatinib to letrozole in patients with ER-positive, HER2-normal breast cancer. However, a preplanned analysis of this trial6 noted a nonsignificant improvement in progression-free survival of 5 months for the approximately 200 patients with endocrine-resistant cancers who received lapatinib plus letrozole compared to letrozole alone, supporting a potential role for the EGFR/HER2 pathways in these resistant cancers.
This hypothesis is not, however, supported by the CALGB trial.8 Progression-free survival in the control arm was only 3 months, suggesting that the majority of patients enrolled had endocrine-resistant cancers, but no benefit for the addition of lapatinib to fulvestrant was noted. Furthermore, a phase II trial11 failed to note a benefit for the addition of trastuzumab to endocrine therapy specifically in patients with endocrine-resistant metastatic breast cancer.
As Burstein et al concluded, there are currently no conclusive data to support the addition of agents targeting the EGFR/HER2 pathway in ER-positive, HER2-normal cancer, particularly with the significant increase in toxicity. The fact that inhibition of a single growth factor receptor has now been demonstrated to be ineffective in several trials,6,8,12 while inhibition of mTOR,9,10 a final common protein downstream of these growth factor receptors, appears effective, suggests the possibility of compensatory signaling through other growth factors, which may be worth evaluating in metastatic specimens from prior and ongoing trials. ■
Disclosure: Dr. O’Regan reported no potential conflicts of interest.
References
1. Carey LA, Barry WT, Pitcher B, et al: Gene expression signatures in pre- and post-therapy specimens from CALGB 40601, a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. 2014 ASCO Annual Meeting. Abstract 506. Presented May 31, 2014.
2. Xia W, Bacus S, Hegde P, et al: A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci USA 103:7795-7800, 2006.
3. Paplomata E, Nahta R, O’Regan RM: Systemic therapy for early stage breast cancer: Time for a less-is-more approach. Cancer. October 24, 2014 (early release online).
4. Schafer JM, Bentrem DJ, Takei H, et al: A mechanism of drug resistance to tamoxifen in breast cancer. J Steroid Biochem Mol Biol 83:75-83, 2002.
5. Kaklamani VG, Cianfrocca M, Ciccone J, et al: Increased HER2/neu expression in recurrent hormone receptor-positive breast cancer. Biomarkers 15:191-193, 2010.
6. Johnston S, Pippen J Jr, Pivot X, et al: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27:5538-5546, 2009.
7. Kaufman B, Mackey JR, Clemens MR, et al: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. J Clin Oncol 27:5529-5537, 2009.
8. Burstein HJ, Cirrincione CT, Barry WT, et al: Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: A randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance). J Clin Oncol 32:3959-3966, 2014.
9. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.
10. Bachelot T, Bourgier C, Cropet C, et al: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol 30:2718-2724, 2012.
11. Zelnak AB, Paplomata E, Murali S, et al: Phase 2 trial of trastuzumab and/or everolimus in hormone-resistant HER2-negative metastatic breast cancer. 2014 ASCO Annual Meeting. Abstract 576. Presented June 2, 2014.
12. Martin M, Loibl S, von Minckwitz G, et al: Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: First efficacy results from the LEA study. 2012 San Antonio Breast Cancer Symposium. Abstract S1-7. Presented December 5, 2012.
Dr. O’Regan is Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology and Chief of Hematology and Medical Oncology, Georgia Cancer Center for Excellence at Grady Memorial Hospital.
