|Year : 2018 | Volume
| Issue : 8 | Page : 218-223
The clinical benefit of epidermal growth factor receptor and human epidermal growth factor receptor 2 targeted agents adding to endocrine therapy in hormone receptor-positive breast cancer
Huan Li, Qing Zhai, Bo Yu
Department of Pharmacy, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
|Date of Web Publication||26-Mar-2018|
Department of Pharmacy, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032
Source of Support: None, Conflict of Interest: None
Objectives: Studies have suggested that the crosstalk between estrogen receptor and ErbB receptor is involved in endocrine therapy (ET) resistance, which might be overcome by drugs-targeting ErbB receptor. However, the results of clinical studies remain controversial. The aim of this meta-analysis was to evaluate the efficacy and safety of ErbB (mainly epidermal growth factor receptor and human epidermal growth factor receptor 2 [HER2]) inhibitors added to ET for hormone receptor-positive breast cancer patients.
Materials and Methods: Eligible randomized clinical trials on ET with or without ErbB receptor-targeting inhibitors (ERTI) for hormone receptor-positive breast cancer were identified by searching the main electronic databases (up to July 2015). Revman 5.3 was used to analyze the outcomes extracted from the included trials.
Results: In the overall population, ERTI failed to show any significant differences on overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). However, improvement on progression-free survival (PFS) (hazard ratio [HR] 0.84, 95% confidence interval [CI] = 0.76–0.93, P = 0.0005) was observed. For the HER2+ subgroup, ERTI could significantly improve ORR, CBR, PFS, OS, and time to progression compared to endocrine monotherapy. This improvement cannot be found in the HER2− subgroup. The risk of serious adverse events (SAEs) increased significantly when ERTI was present (RR = 2.09, 95% CI = 1.44–3.02, P < 0.0001).
Conclusions: For HR+/HER2+ breast cancer, ERTI added to ET can significantly improve the clinical efficacy with the cost of increasing SAE.
Keywords: Breast cancer, efficacy, ErbB-targeted agents, hormone therapy, meta-analysis
|How to cite this article:|
Li H, Zhai Q, Yu B. The clinical benefit of epidermal growth factor receptor and human epidermal growth factor receptor 2 targeted agents adding to endocrine therapy in hormone receptor-positive breast cancer. J Can Res Ther 2018;14, Suppl S1:218-23
|How to cite this URL:|
Li H, Zhai Q, Yu B. The clinical benefit of epidermal growth factor receptor and human epidermal growth factor receptor 2 targeted agents adding to endocrine therapy in hormone receptor-positive breast cancer. J Can Res Ther [serial online] 2018 [cited 2019 Sep 16];14:218-23. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/218/183190
| > Introduction|| |
Breast cancer is the most common malignant tumor that threatens women worldwide. In Asia, the incidence rate is presenting a rising trend. Breast cancer is now the most frequently diagnosed cancer and is ranked sixth in the mortality rate among Chinese women.
As part of the standard therapy for hormone receptor-positive breast cancer, the emerging resistance to endocrine therapy (ET) is limiting its clinical benefit. The underlying mechanism of the crosstalk with the ErbB receptor pathways might lead to the abnormal activation of the estrogen receptor (ER) pathway, and finally, result in the failure of ET.,,,
Drugs-targeting ErbB receptor, for example, epidermal growth factor receptor (EGFR) inhibitor (gefitinib) and human epidermal growth factor receptor 2 (HER2) inhibitor (lapatinib, trastuzumab) were recommended to improve the efficacy of ET and hopefully to overcome resistance. Several studies tend to support the combination of ErbB-targeted inhibitors and ET.,,, However, the results of other clinical studies remain opposite.,, The aim of this meta-analysis was to evaluate the outcomes of the relevant studies so as to compare the efficacy and safety of ErbB-targeted agents added to ET for hormone receptor-positive breast cancer patients.
| > Materials and Methods|| |
Eligible randomized clinical trials (RCTs) on ET with or without ErbB receptor-targeting inhibitors (ERTI) for hormone receptor-positive breast cancer were identified by searching the electronic database PubMed, Cochrane Library, the clinical trials registry (www.clinicaltrials.gov), and Ovid (up to July 2015). The combination of ET drug (tamoxifen, goserelin, leuprorelin, toremifene, exemestane, letrozole, anastrozole, and fulvestrant) and ErbB–receptor-targeting agents (trastuzumab, pertuzumab, afatinib, T-DM1, lapatinib, gefitinib, and erlotinib) was used as key words. Nonhuman studies were excluded.
Inclusion and exclusion criteria
Phase II and III RCTs comparing the efficacy of ET with or without ERTI for patients with hormone receptor-positive breast cancer were included in the analysis. The main outcomes of the included studies were overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), progression-free survival (PFS), time to progression (TTP) (time to progress), and adverse events (AEs).
Nonhuman studies, studies with no control groups, and studies which did not evaluate the efficacy of ERTI added to ET were excluded from the analysis. Observational cohort studies and studies with no detailed outcomes were also excluded from the analysis.
Data extracting and analysis
For dichotomous outcomes (ORR, CBR, and AE), the number of outcome events and a total number of patients were extracted and recorded. For time-to-event outcomes (OS, PFS, TTP, hazard ratios [HRs], and 95% confidence intervals [CIs]) were extracted or calculated based on the given figures.
Revman 5.3 (Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark) was used to analyze the outcomes. Mantel–Haenszel method was used for ORR, CBR, and AE. Risk ratio (RR) was calculated to evaluate the relative benefit or relative risk. Generic inverse variance method was used to evaluate OS, PFS, and TTP by comparing the HRs. Chi-square test was used to test the heterogeneity of the results. If P > 0.05, fixed-effects model was applied, whereas if P < 0.05 and I2 >50%, there might be significant heterogeneity between the included studies, and random-effects model would be used. Funnel plots were used to assess publication bias.
| > Results|| |
A total of 673 records were identified. According to the inclusion and exclusion criteria, 655 were excluded based on titles and abstracts, and 18 studies were selected for further evaluation. Two pharmacists independently reviewed the full texts. Eight studies were finally included [Table 1]. Detailed inclusion and exclusion criteria are shown in [Figure 1]. Among all the included studies, three studies compared the benefit of adding gefitinib, a selective EGFR inhibitor, to standard ET, three studies compared the benefit of adding lapatinib, a dual inhibitor of both EGFR and HER2, to standard ET, two studies compared the benefit of adding trastuzumab, a HER2 targeted inhibitor, to standard ET. No published studies on other targeted drugs were found.
The results of ERTI added to ET are shown in [Table 2]. In the overall population, ERTI added to ET had no improvements in ORR, CBR, and OS, while improved PFS by 16%. In HER2-positive subgroup, ET combined with ERTI showed marked improvements in PFS, TTP, CBR, and ORR; however, no significant improvement was found in OS. In HER2-negative subgroup, no improvements were found.
|Table 2: Clinical efficacy of ErbB-targeting inhibitor added to endocrine therapy|
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In the overall population, gefitinib improved PFS by 17% (95% CI = 0.64–1.07, P= 0.14), lapatinib significantly improved PFS (HR = 0.88, 95% CI = 0.79–0.99, P= 0.03). For HER2-positive subgroup, lapatinib showed significant improvements in ORR, CBR, and PFS, but no significant improvement was found in OS, trastuzumab significantly improved PFS, TTP, CBR, and ORR by 37%, 34%, 39%, and 159%, respectively, but did not improve OS (P = 0.47). For HER2-negative subgroup, no significant improvement was found. Details are shown in [Table 3].
|Table 3: Clinical efficacy of gefitinib/lapatinib/trastuzumab added to endocrine therapy|
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ERTI significantly increased the risk of AEs (RR = 1.21, 95% CI = 1.14–1.27, P < 0.00001), especially serious AEs (SAEs) (combination vs. endocrine monotherapy RR = 2.09, 95% CI = 1.44-3.02, P < 0.00001) [Table 4].
|Table 4: Safety profile of ErbB-targeting inhibitor added to endocrine therapy|
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| > Discussion|| |
One of the many challenges in treating ER-positive breast cancer is the resistance to ET. The crosstalk between ER and growth factor receptor signaling pathways has prompted the clinical trials on the efficacy of ERTI added to ET. Our meta-analysis collected the existing published studies on this topic and compared the outcomes systematically. The results showed that ERTI added to ET had no improvement in ORR, CBR, or OS in the overall population, but there was significant improvement found in PFS.
For HER2+ subgroup, ET combined with ERTI displayed significant benefits in ORR, CBR, PFS, and TTP; however, the benefit in OS did not reach statistical significance. The difference between PFS and OS indicated that ERTI added to ET delayed the progression of the disease, but the OS was not improved because of acquired resistance to ERTI and tumor recurrence., No benefit was found in the outcomes of the HER2-negative subgroup. Apart from the studies included in this meta-analysis, there was one terminated RCT evaluating the efficacy of AZD8931 in combination with anastrozole in HER2-negative advanced breast cancer patients, which also showed no benefit on the combination group.
The results of subgroup analysis based on the mechanisms of ERTI showed that drugs-targeting HER2 (lapatinib and trastuzumab) had more specific clinical benefit compared with EGFR inhibitor (gefitinib). Preclinical studies showed that gefitinib reversed ET resistance.,, However, in our study, no significant benefit was found for gefitinib added to ET, suggesting that the crosstalk theory between ER and EGFR may not be applied to in vivo tumors. Despite this negative result, two studies conducted retrospective analysis displayed more pronounced PFS benefit in endocrine naïve group, suggesting that gefitinib may have better efficacy in this subgroup population., No subgroup analysis based on the EGFR status or considering EGFR mutation was conducted in our study due to lack of data. Further large-scale clinical trials on different populations need to be done to verify the efficacy of gefitinib added to ET for breast cancer.
The results regarding to safety showed that adding ERTI increased the risk of AEs, especially SAE. However, the percentages of SAE were relatively small, and most of the AEs were predictable and manageable. A study assessed the quality of life (QOL) in HR+/HER2+ metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib. Results of this study showed that lapatinib added to letrozole significantly prolonged PFS of the patients while maintaining QOL during treatment, which confirmed that the benefit of lapatinib added to ET in HR+/HER2+ patients far outweighed the increased risk of AEs due to the addition of targeted drugs. A Phase III trial reported that rash (grade ≥2) strongly correlated with improvements in OS and PFS of EGFR inhibitors (erlotinib) in nonsmall-cell lung cancer and pancreatic cancer. It might be that the probability of AEs would also be different between HER2+ subgroup and HER2-negative subgroup, but there were no available data to further investigate this correlation.
There are a number of limitations in this meta-analysis. First of all, the included studies differ from each other in terms of endpoints. Second, the outcomes were extracted from published studies instead of first-hand data, which indicates that there is a possibility of publication bias. Third, there were inevitable differences between studies, such as treatment regimens, severity of the disease, and the methods used to evaluate the endpoints. Finally, there were no large-scale RCTs in Asians; the results from these studies may not be translatable to Asian population.
There were other meta-analyses displayed the clinical benefit of targeted agents added to standard chemotherapy or ET for metastatic breast cancer., Our study specifically focused on ERTI combined with ET. We included eight high-quality RCTs to evaluate the efficacy of EGFR and HER2 targeted inhibitors added to ET in both neoadjuvant setting and the adjuvant setting. The extraction of the data was double-checked to ensure the accuracy. We conducted subgroup analysis and discussed the efficacy of different groups based on the mechanisms of the targeted drugs.
| > Conclusions|| |
For HR+/HER2+ breast cancer, ERTI (lapatinib and trastuzumab) added to ET significantly improved the clinical efficacy; no significant differences were identified for HR+/HER2− breast cancer. Targeted drugs added to ET increased the risk of AEs, but most of them were manageable. The efficacy of gefitinib added to ET and efficacy of other targeted drugs need further research.
Financial support and sponsorship
This study is supported by the National Natural Science Foundation (81201807 to BY) and by the Science and Technology Commission of Shanghai Municipality (14411970300 to QZ).
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Fan L, Strasser-Weippl K, Li JJ, St Louis J, Finkelstein DM, Yu KD, et al.
Breast cancer in China. Lancet Oncol 2014;15:e279-89.
Chen WQ, Zheng RS, Zhang SW, Li N, Zhao P, Li GL, et al.
Report of incidence and mortality in China cancer registries, 2008. Chin J Cancer Res 2012;24:171-80.
Chongqing T, Liubao P, Xiaohui Z, Jianhe L, Xiaomin W, Gannong C, et al.
Cost-utility analysis of the newly recommended adjuvant chemotherapy for resectable gastric cancer patients in the 2011 Chinese National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology: Gastric cancer. Pharmacoeconomics 2014;32:235-43.
Ziauddin MF, Hua D, Tang SC. Emerging strategies to overcome resistance to endocrine therapy for breast cancer. Cancer Metastasis Rev 2014;33:791-807.
Fan W, Chang J, Fu P. Endocrine therapy resistance in breast cancer: Current status, possible mechanisms and overcoming strategies. Future Med Chem 2015;7:1511-9.
Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, et al.
Molecular changes in tamoxifen-resistant breast cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 2005;23:2469-76.
Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 2005;11(2 Pt 2):865s-70s.
Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: Molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev 2008;29:217-33.
Huober J, Fasching PA, Barsoum M, Petruzelka L, Wallwiener D, Thomssen C, et al.
Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer-results of the eLEcTRA trial. Breast 2012;21:27-33.
Cristofanilli M, Valero V, Mangalik A, Royce M, Rabinowitz I, Arena FP, et al.
Phase II, randomized trial to compare anastrozole combined with gefitinib or placebo in postmenopausal women with hormone receptor-positive metastatic breast cancer. Clin Cancer Res 2010;16:1904-14.
Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, 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 2009;27:5529-37.
Johnston S, Pippen J Jr., Pivot X, Lichinitser M, Sadeghi S, Dieras V, 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 2009;27:5538-46.
Burstein HJ, Cirrincione CT, Barry WT, Chew HK, Tolaney SM, Lake DE, 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 2014;32:3959-66.
Guarneri V, Generali DG, Frassoldati A, Artioli F, Boni C, Cavanna L, et al.
Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol 2014;32:1050-7.
Smith IE, Walsh G, Skene A, Llombart A, Mayordomo JI, Detre S, et al.
A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer. J Clin Oncol 2007;25:3816-22.
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16.
Creedon H, Byron A, Main J, Hayward L, Klinowska T, Brunton VG. Exploring mechanisms of acquired resistance to HER2 (human epidermal growth factor receptor 2)-targeted therapies in breast cancer. Biochem Soc Trans 2014;42:822-30.
Thery JC, Spano JP, Azria D, Raymond E, Penault Llorca F. Resistance to human epidermal growth factor receptor type 2-targeted therapies. Eur J Cancer 2014;50:892-901.
Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro
and in vivo
. Cancer Res 2001;61:8887-95.
Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al.
Mechanisms of tamoxifen resistance: Increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004;96:926-35.
Martin LA, Farmer I, Johnston SR, Ali S, Marshall C, Dowsett M. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 2003;278:30458-68.
Osborne CK, Neven P, Dirix LY, Mackey JR, Robert J, Underhill C, et al.
Gefitinib or placebo in combination with tamoxifen in patients with hormone receptor-positive metastatic breast cancer: A randomized phase II study. Clin Cancer Res 2011;17:1147-59.
Sherrill B, Amonkar MM, Sherif B, Maltzman J, O'Rourke L, Johnston S. Quality of life in hormone receptor-positive HER-2+metastatic breast cancer patients during treatment with letrozole alone or in combination with lapatinib. Oncologist 2010;15:944-53.
Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007;13:3913-21.
Kawalec P, Lopuch S, Mikrut A. Effectiveness of targeted therapy in patients with previously untreated metastatic breast cancer: A systematic review and meta-analysis. Clin Breast Cancer 2015;15:90-100.e1.
Harris CA, Ward RL, Dobbins TA, Drew AK, Pearson S. The efficacy of HER2-targeted agents in metastatic breast cancer: A meta-analysis. Ann Oncol 2011;22:1308-17.
[Table 1], [Table 2], [Table 3], [Table 4]