Current Opinion in Obstetrics & Gynecology:
BREAST CANCER: Edited by Gottfried E. Konecny
Updates on the treatment of human epidermal growth factor receptor type 2-positive breast cancer
Kim, Miriama,b; Agarwal, Surbhia; Tripathy, Debua,b,c
aUniversity of Southern California
bKeck School of Medicine
cUSC/Norris Comprehensive Cancer and Department of Medicine, Los Angeles, California, USA
Correspondence to Debu Tripathy, MD, University of Southern California, 1441 Eastlake Avenue, NTT-3429, Los Angeles, California 90033, USA. Tel: +1 323 865 3962; fax: +1 323 865 0061; e-mail: firstname.lastname@example.org
Purpose of review
To review the most recent developments in the treatment of human epidermal growth factor receptor type 2 (HER2)-positive breast cancer with novel HER2-targeting agents and combinations that have significantly improved clinical outcomes.
Since the approval of trastuzumab 15 years ago, the natural history of HER2-positive breast cancer has been altered with improvements in survival for both early and advanced disease with the addition of this agent to standard chemotherapy. The HER2 receptor pathway drives breast cancer growth and aggressiveness, and HER2-targeted agents can improve survival in early and advanced disease. In the advanced setting, two new drugs have been approved since 2012, pertuzumab and ado-trastuzumab emtansine (T-DM1), both of which improve survival without any reciprocal increase in toxicity. However, resistance almost always ensues, pointing to the need to understand the driving mechanisms and to biomarkers that will help individualize therapy and point to newer signal transduction and other modulators.
HER2-positive breast cancer represents a distinct subtype with more aggressive clinical characteristics. HER2-targeted therapies, usually in combination with chemotherapy, are the standard of care, improving the cure rate in early-stage breast cancer and lengthening survival in the advanced setting.
Breast cancer mortality has decreased because of both earlier detection and improvements in therapy. Systemic adjuvant therapy can significantly lower mortality, and the different treatment components such as chemotherapy, hormonal therapy and targeted therapy each contribute to variable degrees depending on individual tumor characteristics. The hormone receptors (estrogen and progesterone) and human epidermal growth factor receptor type 2 (HER2) receptors drive pathways that are important in breast carcinogenesis and are expressed at high levels in about two-thirds and one-fifth of breast cancers, respectively. Both can be targeted with specific drugs that block their pathways and are useful in early stage and advanced breast cancer. In the advanced metastatic setting, the same hormonal and HER2-targeting therapies can be active and lead to responses and improvements in quality and length of life. However, cure is still not possible in metastatic disease because of the evolution of resistance through diverse and poorly understood mechanisms.
HER2 is a transmembrane tyrosine kinase receptor and a member of the epidermal growth factor receptor (EGFR) family that is involved in the regulation of cell proliferation. HER2 pathways also mediate cell survival, angiogenesis, cell motility, alterations in immune function, autophagy, DNA repair and even exhibit distinct epigenetic patterns of gene silencing . Amplification or overexpression of HER2 is observed in 15–25% of breast cancers and has traditionally been associated with more aggressive tumor features, worse clinical outcomes and resistance to hormonal therapy. More recently, the discovery of infrequent mutations in HER2 that result in functional activation without the need for amplification and lead to more aggressive behavior, supports the notion that HER2 can be co-opted as a critical mediator of breast malignancy [2▪]. Therefore, as a driver of the malignant phenotype, blockade of the HER2 function at one or multiple levels would be expected to have a clear impact therapeutically. Moreover, co-targeting of HER2 and mediators of other interacting or downstream pathways such as estrogen receptor or mammalian target of rapamycin (mTOR) would also be expected to demonstrate enhanced activity as has been demonstrated in more recent trials. In the last year, longer follow-up from earlier trastuzumab trials and the introduction of newer generation HER2 antagonists and pathway modulators have further defined and extended the benefit of HER2 blockade in the clinic and reshaped the standards of care [3▪]. One drawback of HER2 blockade, particularly with trastuzumab, is the infrequent risk of cardiac toxicity, primarily cardiomyopathy, which is likely due to the physiologic role of the HER2 signaling pathway in cardiac development and remodeling.
ADJUVANT THERAPY FOR HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR TYPE 2-POSITIVE BREAST CANCER
The initial therapeutic agent studied in HER2 + metastatic breast cancer was trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of HER2 and improves survival when added to chemotherapy. Large phase III adjuvant trials of similar design all testing trastuzumab given either concurrently or sequentially following chemotherapy quickly ensued (summarized in Table 1) [4–6]. The National Surgical Adjuvant and Bowel Project (NSABP) B-31 trial compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel every 3 weeks with the same regimen plus trastuzumab. The North Central Cancer Trial Group (NCCTG) N9831 trial compared AC followed by weekly paclitaxel with the same regimen plus trastuzumab, either sequentially following completion of chemotherapy or concomitantly combined with paclitaxel. An updated combined analysis of these two trials showed that patients receiving trastuzumab had a 37% reduction in the risk of death (P < 0.001) . The Breast Cancer International Research Group (BCIRG)-006 trial compared AC followed by docetaxel every 3 weeks, with or without trastuzumab, and docetaxel, carboplatin plus trastuzumab, and found that both trastuzumab-containing regimens were superior to chemotherapy alone in terms of overall survival, whereas the nonanthracycline arm resulted in less cardiac toxicity . The Herceptin Adjuvant (HERA) trial also confirmed that trastuzumab for 1 year following primary chemotherapy improved disease-free survival, with slightly lower magnitude, possibly because of sequential design or because 65% of patients crossed over from the control arm after early demonstration of benefit . The HERA study also compared 1–2 years of adjuvant trastuzumab and found no difference in outcome . Conversely, a trial of shorter duration of 6 months compared with 1 year failed to show noninferiority because of fewer than anticipated events; therefore, more follow-up is needed to determine whether early discontinuation, for example, resulting from cardiac dysfunction, might yield equivalent benefit [8▪].
Several dilemmas and ongoing controversy exist in the treatment of early-stage HER2 + breast cancer. Clinically significant and symptomatic cardiomyopathy can occur in 3–4% of cases when trastuzumab is given after anthracycline therapy concurrently with taxanes, although when given sequentially or with nonanthracycline, tends to be seen at a rate of 1–2% or less [9▪]. Risk factors for cardiac problems include older age, history of hypertension and prior receipt of anthracycline therapy. Subclinical declines in cardiac ejection fraction occur more frequently – up to 10–15% – and lead to treatment suspension or discontinuation. Although both clinical and subclinical cardiomyopathy resolve in most cases, some patients require long-term medications and the long-term effects remain unknown. Monitoring cardiac function with nuclear or echocardiographic imaging periodically is recommended, whereas blood-based monitoring and prophylactic preventions with cardiac medications remain under study . The management of low-risk HER2-positive breast cancer remains unsettled, as the very small reductions in the already favorable relapse and death rates must be balanced against side-effects of therapy. Node-negative cancers under 1 cm were not well represented in the adjuvant trials, and uncontrolled cohort studies suggest that the recurrence rates are low, but still in the 5–10% range, and have suggested small benefits from trastuzumab-based therapy [11▪]. Still, these benefits appear to be negligible for very low-risk (<5 mm, estrogen receptor+, or low grade) tumors. Uncontrolled trials of less toxic regimens such as weekly paclitaxel plus trastuzumab have been conducted for low-risk tumors and hormonal/trastuzumab therapy has been suggested by some, but randomized trials are not practical given the very low expected event rates.
NEOADJUVANT THERAPY FOR HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR TYPE 2-POSITIVE BREAST CANCER AS STANDARD CARE AND AN INVESTIGATIONAL TOOL
Neoadjuvant, or preoperative, therapy is used for locally advanced breast cancer to increase the chances of successful surgical resection or breast-conserving surgery. Longer-term follow-up of randomized trials in the neoadjuvant setting has also shown improvements in disease-free survival as it has in the adjuvant setting, and the benefits of systemic chemotherapy in general have been shown to be equal whether given pre or postoperatively. Therefore, given the much larger size of adjuvant trials, the definitive regimens shown in Table 1 represent the best standards of care when preoperative therapy is chosen. The addition of trastuzumab to chemotherapy has also been shown to increase the likelihood of a complete pathological response (pCR), usually defined as the eradication of all invasive disease based on pathological examination of the breast and removed axillary nodes. The achievement of a pCR has been associated with better long-term outcomes of recurrence-free and overall survival, particularly in the HER2-positive subtype, thus allowing this approach to be used as a research tool to test novel agents in a short timeframe and to conduct correlative tissue studies to identify predictive biomarkers [12,13▪].
These findings have therefore led to more recent randomized trials investigating newer HER2-targeted agents in combination with chemotherapy as well as dual HER2-directed drugs used together alone or with chemotherapy. The newer agents include lapatinib, a small molecule oral tyrosine kinase inhibitor against HER2 and EGFR type 1. Lapatinib has been shown to improve progression-free survival when added to the oral fluoropyrimidine chemotherapeutic prodrug, capecitabine, in patients with metastatic HER2-positive breast cancer who have progressed on trastuzumab and this combination was therefore approved in 2007 as second-line therapy . Another agent, pertuzumab, is a humanized monoclonal antibody that, like trastuzumab, binds the extracellular domain of HER2, but at a different site such that it inhibits dimerization of HER2 with its partners, EGFR, HER3 and HER4, a process that is necessary for optimal growth signaling. Pertuzumab was approved in the metastatic setting in 2012 in combination with trastuzumab and docetaxel, as it has been shown to improve disease-free and overall survival compared with a prior standard of trastuzumab and docetaxel [15▪▪,16▪].
Five randomized trials have assessed the efficacy of lapatinib in the neoadjuvant setting (Table 2) [17–22,23▪]. The GeparQuinto trial compared trastuzumab with lapatinib, each combined with epirubicin plus cyclophosphamide followed by docetaxel . The pCR rate was significantly higher in the trastuzumab arm compared with the lapatinib arm (30.3 vs. 22.7%, P = 0.04), mirroring effects on progression-free survival that have been found in the metastatic setting. Four trials (NeoALTTO, CHER-LOB, US Oncology and CALGB 40601) compared three regimens: dual HER2-targeting lapatinib + trastuzumab vs. either drug alone given with chemotherapy prior to surgery [18–21]. The rate of pCR was higher in all studies with dual lapatinib/trastuzumab compared with either trastuzumab or lapatinib alone, whereas the lapatinib arms had slightly lower pCR rates than trastuzumab. These differences tended to be magnified in estrogen receptor-negative subsets of patients. The NeoSphere trial compared dual HER2 targeting therapy with trastuzumab plus pertuzumab to either trastuzumab or pertuzumab alone in the presence of chemotherapy, and also included a fourth arm of dual HER2 therapy without chemotherapy prior to surgery (Table 2). This trial also showed a higher pCR rate with dual compared with the single agent arms (45.8 vs. 29 and 24%) in the presence of docetaxel therapy, whereas a provocative pCR rate of nearly 17% was seen in the absence of chemotherapy . The TRYPHAENA trial evaluated the combination of pertuzumab and trastuzumab in all three arms, given either concurrently with the anthracycline epirubicin followed by docetaxel, sequentially after epirubicin in combination with docetaxel, or concurrently with a nonanthracycline regimen (docetaxel and carboplatin) [23▪]. The rates of pCR were higher when dual therapy was used for all six cycles and highest in the docetaxel and carboplatin arm, but all confidence intervals overlapped. None of the dual-targeted arms exhibited significant increases in toxicity including cardiac events. In summary, these neoadjuvant studies suggest superior clinical efficacy with dual targeting, but improvements in recurrence still represent the endpoint of meaningful clinical benefit. The US Food and Drug Administration (FDA) has begun to consider accelerated adjuvant therapy approval using neoadjuvant pCR data as long as the recurrence endpoint is ultimately met, and on this basis, the addition of pertuzumab to trastuzumab and docetaxel in the neoadjuvant setting has recently been approved by the US FDA.
ADVANCES IN THE TREATMENT OF ADVANCED METASTATIC HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR TYPE 2-POSITIVE BREAST CANCER
Metastatic breast cancer remains a significant challenge and remains incurable except in rare cases in which all evident disease can be treated with surgery or radiation. Although improvement in responses, time to progression and overall survival were initially reported with the addition of trastuzumab to chemotherapy in 1998, clinical resistance to therapy eventually develops in virtually all cases. Since the initial pivotal trial reported by Slamon et al. in 2001 using either paclitaxel or doxorubicin plus cyclophosphamide, additional chemotherapy partners such as platinum agents, vinorelbine, gemcitabine and capecitabine have been tested and found to be active. However, very few comparative trials have been done to define the optimal initial chemotherapy partner with trastuzumab. One recent interesting trial showed that vinorelbine was equally as effective as the more commonly used taxane docetaxel for first-line therapy with significantly less toxicity . Trastuzumab and lapatinib also improve disease-free survival when added to hormonal therapy in the absence of chemotherapy, partially reversing the known resistance to hormonal therapy driven by the HER2 signaling pathway; however, none of these trials have shown a survival advantage. Still, the use of hormonal and HER2-directed therapy without chemotherapy is typically reserved for patients with lower burden and minimally symptomatic disease with HER2 and estrogen receptor co-expression. One recently published large prospective cohort study suggested that either concurrent or sequential hormonal therapy, given either with or without chemotherapy, was associated with a better disease-free and overall survival in patients with HER2 and estrogen receptor-positive advanced breast cancer [25▪].
Laboratory models and clinical data suggest that blockade of the HER2 receptor continues to be important even after resistance develops, counter to the usual dogma of discontinuing a particular class of drug following progression. Studies have shown that both lapatinib and trastuzumab improve disease-free survival when added to capecitabine after progression on trastuzumab-containing therapy [11▪,26]. This is supported by additional nonrandomized trials showing significant activity in multiple lines of therapy with the continued use of trastuzumab with changing chemotherapy agents . Thus, the concept of ‘oncogene addiction’ appears to hold in the clinic, although drugs that possess different mechanisms of action to squelch the HER2 signaling pathway, and other interacting networks, are necessary to provide more than small increments that might be seen by sequential chemotherapy treatment. One example of this is the use of dual therapy with two established drugs, trastuzumab and lapatinib, which is known to improve response rates as described in the neoadjuvant section of this review, and has recently been shown to improve survival when added to lapatinib alone in patients who have previously received trastuzumab .
Newer-generation agents have been tested in definitive trials in recent years leading to two new approved drugs summarized in Table 3[15▪▪,16▪,29,30▪▪,31]. Pertuzumab, described earlier, inhibits dimerization of HER2 with other HER family members and although not very active as a single agent, it has activity in refractory disease in combination with trastuzumab. A pivotal phase III trial comparing docetaxel and trastuzumab with or without pertuzumab has shown significant improvements in time to progression, overall survival and quality of life [15▪▪,16▪,32]. The addition of pertuzumab was associated with more diarrhea and infection rate, but no difference in cardiac toxicity. Ado-trastuzumab emtansine (T-DM1) is in immunoconjugate of trastuzumab linked to a potent antimicrotubule agent, emtansine, which is internalized upon binding HER2-positive cells, releasing emtansine and leading to cell kill. In a randomized phase II trial in the first-line setting comparing with docetaxel and trastuzumab, T-DM1 improved disease-free survival and was associated with fewer adverse events . In the second-line setting, a pivotal phase III trial compared T-DM1 with the approved second-line regimen of capecitabine plus lapatinib and showed a significantly improved disease-free survival and overall survival (on the second interim analysis), with a very favorable toxicity profile compared with the standard arm, with mostly subclinical thrombocytopenia (13% Grade 3/4) and rare transaminitis (3–4% Grade 3/4) [30▪▪]. Other strategies to augment the efficacy of HER2 targeting (or reverse resistance) include blockade of downstream mediators of receptor kinase signaling, including PI3 kinase, Akt and mTOR [33▪]. The mTOR inhibitor everolimus was recently tested by addition to vinorelbine and trastuzumab in the second-line setting and yielded a modest but statistically significant improvement in PFS . A first-line trial of everolimus will be reported in the near future.
The management of HER2-positive breast cancer has evolved significantly in the last few years and the trend promises to continue as additional targets that can be used to suppress bypass pathways will continue to emerge and be tested. At the current time, blockade of HER2 with agents proven to improve survival with acceptable side effects represents the standard of care for both early stage and advanced disease
This work was supported in part by the Department of Defense Breast Cancer Research Program of the Office of the Congressionally Directed Medical Research Programs (CDMRP), Grant W81XWH-11–1-0472.
Conflicts of interest
D.T. has received funding to conduct research from Genentech/ Roche for clinical research contracted under the University of Southern California.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Bravatà V, Cammarata FP, Forte GI, Minafra L. Omics’ of HER2-positive breast cancer. OMICS. 2013; 17:119–129.
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This article shows that HER2 somatic mutation, rather than amplification, can activate HER2 in breast cancer, and these tumors are sensitive to HER2-targeted therapy.
3▪. Hurvitz SA, Hu Y, O’Brien N, Finn RS. Current approaches and future directions in the treatment of HER2-positive breast cancer. Cancer Treat Rev. 2013; 39:219–229.
This article reviews the mechanism of resistance to HER2-targeted agents and the current approaches under study to overcome these mechanisms.
4. Romond E, Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. Cancer Res. 2012; 72:(Suppl 3):
5. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365:1273–1283.
6. Gianni L, Dafni U, Gelber R, et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011; 12:236–244.
7. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al. HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up. Cancer Res. 2012; 72:(Suppl 3):
8▪. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013; 14:741–748.
Six months of trastuzumab failed to show noninferiority over 1 year of treatment.
9▪. Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012; 30:3792–3799.
Analysis of the NSABP B-31 trial, a large phase III adjuvant trial using trastuzumab, showed that the development of cardiac events was uncommon and usually reversible.
10. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis. Eur J Cancer. 2013; 49:2900–2909.
11▪. Rodrigues MJ, Peron J, Frénel JS, et al. Benefit of adjuvant trastuzumab-based chemotherapy in T1ab node-negative HER2-overexpressing breast carcinomas: a multicenter retrospective series. Ann Oncol. 2013; 24:916–924.
This retrospective study evaluating the efficacy of adjuvant therapy in node-negative HER2-positive breast cancer showed a small but significant reduced risk of recurrence.
12. von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012; 30:1796–1804.
13▪. Kim MM, Allen P, Gonzalez-Angulo AM, et al. Pathologic complete response to neoadjuvant chemotherapy with trastuzumab predicts for improved survival in women with HER2-overexpressing breast cancer. Ann Oncol. 2013; 24:1999–2004.
This retrospective study showed that pCR was the strongest predictor of recurrence and survival in HER2-positive breast cancer.
14. Cameron D, Casey M, Oliva C, et al. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010; 15:924–934.
15▪▪. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012; 366:109–119.
First publication of the CLEOPATRA study, the pivotal study showing a marked improvement in time to progression from the addition of the dimerization-inhibiting antibody, pertuzumab, to trastuzumab plus docetaxel and led to FDA approval of this regimen as first-line therapy for HER2-positive metastatic breast cancer.
16▪. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013; 14:461–471.
Updated analysis of the CLEOPATRA study showed that the addition of pertuzumab to trastuzumab and docetaxel improved overall survival in HER2-positive metastatic breast cancer.
17. Untch M, Loibl S, Bischoff J, et al. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012; 13:135–144.
18. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012; 379:633–640.
19. Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol. 2012; 30:1989–1995.
20. Holmes FA, Nagarwala YM, Espina VS, et al. Correlation of molecular effects and pathologic complete response to preoperative lapatinib and trastuzumab, separately and combined prior to neoadjuvant breast cancer chemotherapy. J Clin Oncol. 2011; 29:
No 15_suppl (May 20 Supplement), Abstract 506
21. Carey LA, Berry DA, Ollila D, et al. Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol. 2013; 31:(Suppl):
22. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012; 13:25–32.
23▪. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013; 24:2278–2284.
The addition of pertuzumab to trastuzumab in combination with standard neoadjuvant chemotherapy showed a trend toward improved pCR without increased toxicity.
24. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011; 29:264–271.
25▪. Tripathy D, Kaufman PA, Brufsky AM, et al. First-line treatment patterns and clinical outcomes in patients with HER2-positive and hormone receptor-positive metastatic breast cancer from registHER. Oncologist. 2013; 18:501–510.
Analysis of a large prospective cohort of patients showed that using both hormone and HER2-targeted therapy prolonged survival in patients with HR+ and HER2-positive metastatic breast cancer.
26. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009; 27:1999–2006.
27. Petrelli F, Barni S. A pooled analysis of 2618 patients treated with trastuzumab beyond progression for advanced breast cancer. Clin Breast Cancer. 2013; 13:81–97.
28. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012; 30:2585–2592.
29. Hurvitz SA, Dirix L, Kocsis J, et al. Phase ii randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer. J Clin Oncol. 2013; 31:1157–1163.
30▪▪. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012; 367:1783–1791.
T-DM1 prolonged overall survival with less toxicity than lapatinib plus capecitabine as a second-line agent in HER2-positive metastatic breast cancer – this pivotal trial was the basis of the FDA approval of this agent.
31. O’Regan R, Ozguroglu M, Andre F, et al. Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab- resistant, advanced breast cancer (BOLERO-3). J Clin Oncol. 2013; 31:(Suppl):
32. Cortés J, Baselga J, Im YH, et al. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013; 24:2630–2635.
33▪. Gradishar WJ. Emerging approaches for treating HER2-positive metastatic breast cancer beyond trastuzumab. Ann Oncol. 2013; 24:2492–2500.
Review of ongoing and recently completed phase II and III clinical trials of investigational HER-targeted agents.
breast cancer; HER2; lapatinib; pertuzumab; trastuzumab
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