Konecny, Gottfried E.
Amplification of the HER2 gene, which results in HER2 protein overexpression , is present in 20–25% of human breast cancers and is associated with an aggressive form of the disease with significantly shortened disease-free survival (DFS) and overall survival (OS) . Trastuzumab is a humanized monoclonal antibody targeted against the extracellular portion of HER2. This is the first HER2-targeted agent to be approved by the United States Food and Drug Administration (FDA) for the treatment of both early stage and metastatic HER2-positive breast cancer [3,4]. Subsequently, lapatinib, an orally bioavailable small molecule dual HER2-specific and HER1-specific tyrosine kinase inhibitor (TKI), received FDA approval in combination with capecitabine for patients with advanced HER2-positive breast cancer . However, despite these treatment advances, resistance to these agents is common, and HER2-positive breast cancer will eventually progress in most patients, highlighting the need to develop new agents and combination strategies to overcome resistance and improve efficacy.
This review will summarize the most recent developments in treatments targeting HER2. Here, we will update the reader on the recent findings with established HER2 inhibitors, discuss new HER2 inhibitors and treatment paradigms, review clinically relevant mechanisms of resistance, and discuss how combination strategies may yield synergistic effects and help improve outcomes for patients with HER2-positive breast cancer.
UPDATE ON ADJUVANT TRASTUZUMAB STUDIES
In the adjuvant setting, trastuzumab is recommended by both U.S. [National Comprehensive Cancer Network (NCCN)] and European (St. Gallen) guidelines for use as monotherapy after completion of chemotherapy, and in combination with paclitaxel or docetaxel after completion of doxorubicin plus cyclophosphamide, or given concurrently with carboplatin and docetaxel [6,7]. These recommendations are based on the results from four large clinical trials that have recently been updated [8▪▪,9,10]. Results of these individual studies are condensed in a new meta-analysis that summarized that the combination of trastuzumab with adjuvant chemotherapy led to a significant improvement in DFS, OS, locoregional recurrence, and distant recurrence, compared with chemotherapy alone .
However, when trastuzumab was given after four cycles of doxorubicin, cyclophosphamide chemotherapy in combination with single-agent paclitaxel or docetaxel, grade 3 or 4 congestive heart failure has been reported to occur in up to 4% of patients (NSABP B-31, 4%; NCCTG N9831, 2.3%; HERA, 1.9% versus 1.3, 0.9, and 0% in control arms, respectively) which is attributable to the use of an anthracycline-based chemotherapy with trastuzumab [10,12,13▪▪]. It is important to point out that these rates of congestive heart failure were seen in the setting of randomized clinical trials for which patients were only eligible if they had a normal baseline cardiac function and an unremarkable cardiac history. After its approval, however, trastuzumab is being used more widely, for example, in patients with hypertension, with diabetes, or with borderline cardiac ejection fraction. A recent retrospective analysis of the NSABP B-31 study of risk factors for trastuzumab-induced or chemotherapy-induced cardiac events found that the risk of congestive heart failure was significantly increased in patients more than 60 years old (6.1%, P = 0.025), taking hypertensive medications (6.7%, P = 0.03), with borderline ejection fraction of 50–54% (12.9%, P < 0.001) [13▪▪]. Moreover, an additional 147 patients (6.9%, randomly assigned to both arms of NSABP B-31) did not meet the criteria for the initiation of trastuzumab because of a decrease in the left ventricular ejection fraction (LVEF) more than 15% from baseline or below the lower limit of normal. A low baseline LVEF, taking antihypertensive, diabetic, or lipid-lowering medications, correlated with myocardial changes during the doxorubicin, cyclophosphamide portion of treatment that resulted in patients not meeting the protocol criteria for the initiation of trastuzumab [13▪▪].
These circumstances make it especially important to have a nonanthracycline-based regimen available for the adjuvant treatment of HER2-positive primary breast cancer. As such, the BCIRG 006 study enrolled 3222 women with HER2-amplified early breast cancer and randomly assigned them to receive either one of the three following treatment arms: a nonanthracycline-based chemotherapy plus trastuzumab (TCH; docetaxel, carboplatin, and trastuzumab), an anthracycline-based chemotherapy plus trastuzumab (doxorubicin and cyclophosphamide, followed by docetaxel and trastuzumab), or the anthracycline-based chemotherapy alone. Efficacy analysis at 65 months demonstrated that women receiving either trastuzumab-containing regimen had significantly improved DFS and OS compared with women receiving the nontrastuzumab-containing regimen and that those patients receiving the nonanthracycline-containing regimen TCH had the added benefit of experiencing significantly less cardiotoxicity when compared with the anthracycline–trastuzumab-based regimen (0.4 versus 2.0%, P < 0.001) [8▪▪]. According to the current guidelines, clinical evaluation before treatment with trastuzumab should include careful screening for cardiac risk factors and consequent close cardiac monitoring according to specific circumstances.
ROLE OF TOP2A COAMPLIFICATION
HER2 amplification/overexpression has been associated with responsiveness to anthracycline-based combination chemotherapy [14–16]. However, recent clinical studies suggested that the value of HER2 for predicting response to anthracycline-containing combination chemotherapy may be more likely related to the concomitant amplification of the TOP2A gene [17–21,22▪]. The TOP2A gene is frequently either coamplified or deleted in breast cancers with HER2 amplification and encodes topoisomerase II-a, a key enzyme in DNA replication, cell-cycle progression, and chromosome segregation . TOP2A rather than HER2 may be more important for predicting response to anthracyclines as its gene product is the molecular target of topoisomerase II inhibitors such as doxorubicin or epirubicin [24,25]. A recent analysis of the BCIRG 006 study indicates that coamplification of TOP2A occurs in 35% of HER2-positive cancers . Among patients with HER2-positive breast cancers without TOP2A coamplification, the DFS benefit with trastuzumab-containing regimens was even greater than that seen in the overall analysis of all patients [8▪▪]. However, in the 35% of HER2-positive cancers in which TOP2A was coamplified, the rates of DFS for the trastuzumab-containing regimens were virtually indistinguishable from the rate with standard therapy. This subpopulation of patients appeared to derive no additional benefit from trastuzumab [8▪▪] (Fig. 1).
SEQUENCING OF ADJUVANT TRASTUZUMAB THERAPY
A recent update of the NCCTG N9831 study provided important insights whether trastuzumab should be given concurrent with chemotherapy or can equally be administered subsequent to chemotherapy. There was an increase in DFS with concurrent trastuzumab and paclitaxel relative to sequential administration (hazard ratio 0.77, P = 0.02; however, this P value did not meet the prespecified O’Brien–Fleming boundary of 0.00116) . Nonetheless, on the basis of this positive risk–benefit ratio, it has been recommended that trastuzumab be incorporated into a concurrent regimen with taxane chemotherapy as an important standard-of-care treatment alternative to a sequential regimen .
BENEFIT OF TRASTUZUMAB IN SMALL TUMORS
Although small tumors (<1 cm) were not included in the majority of randomized trials that assessed trastuzumab, women with node-negative, HER2-positive tumors that are 0.6–1.0 cm in size are thought to benefit from adjuvant trastuzumab therapy, because of HER2's prognostic relevance in these small tumors . In addition, a subgroup analysis from the BCIRG 006 study has shown a consistent benefit of trastuzumab irrespective of the tumor size [8▪▪]. Among patients with HER2-positive tumors measuring 1 cm or less in the greatest diameter, the estimated 5-year rates of DFS were 86% in the group receiving doxorubicin and cyclophosphamide followed by docetaxel (AC-T) plus trastuzumab and 86% in the group receiving TCH, compared to 72% in the group receiving AC-T (hazard ratio for AC-T plus trastuzumab 0.36, P = 0.03; hazard ratio for TCH 0.45, P = 0.09) [8▪▪]. Furthermore, a retrospective analysis of 276 patients with small, node-negative, HER2-positive primary tumors between 0.1 and 1.0 cm in size (pT1a/b) found that adjuvant trastuzumab-based chemotherapy was associated with improved DFS at 40 months (99 versus 93%, P = 0.018), and the greatest benefit was seen in patients with hormone receptor negative tumors and tumors with lymph vascular invasion .
DURATION OF TRASTUZUMAB TREATMENT
The Herceptin Adjuvant (HERA) trial is addressing the question of the optimal duration of trastuzumab therapy. Data from the 2-year arm of the ongoing study were recently presented at the 2012 Meeting of the European Society of Medical Oncology and indicate that 2-year treatment is not better than the current standard duration of 1 year . At a median follow-up of 8 years, the HERA trial confirms that 1 year of adjuvant therapy with trastuzumab should remain the standard of care for treatment of women with HER2-positive invasive early breast cancer. DFS was 75.8% for 2 years of trastuzumab versus 76% for 1 year of trastuzumab. To date, it is unclear whether shorter durations of trastuzumab may be comparable to the current standard treatment of 1 year .
Lapatinib, a reversible, small molecule TKI has been shown to cause cell cycle arrest and to promote apoptosis by blocking cell signaling pathways that are activated by HER2 and EGFR, including the PI3K/Akt/mTOR pathway and the Ras/Raf/MAPK pathway . Early clinical trials indicated modest clinical activity (response rates <10%) for single-agent lapatinib in patients whose disease had progressed when receiving trastuzumab , but the combination of lapatinib and capecitabine showed significantly superior efficacy compared with capecitabine alone in such patients . Moreover, a dual targeting approach with a combination of trastuzumab and lapatinib improved progression-free survival (PFS) compared with lapatinib alone in patients with metastatic breast cancer (MBC) who had not had a response to trastuzumab . In fact, in an updated final analysis, lapatinib plus trastuzumab offered a significant OS benefit (hazard ratio 0.74, P = 0.026) with a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination [35▪▪]. Results of the NEO-ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, a study of neoadjuvant lapatinib and/or trastuzumab therapy in patients with newly diagnosed HER2-positive breast cancer, have recently been published [36▪]. The study randomized 455 patients with HER2-positive primary breast cancer to receive lapatinib, trastuzumab, or the combination of both with weekly paclitaxel chemotherapy given for 12 weeks duration prior to surgery. The pathologic complete response (pCR) rate was significantly higher with the combination of lapatinib and trastuzumab compared with trastuzumab or lapatinib alone (51.3 versus 29.5 or 24.7%, respectively, P < 0.001) [36▪]. Importantly, pCR has predicted long-term outcome in neoadjuvant studies and is therefore thought to be a potential surrogate marker for survival [37,38]. These data suggest that the combined use of trastuzumab and lapatinib might provide superior efficacy to either agent used alone. A large adjuvant trial is now ongoing (ALTTO) and the results are eagerly awaited.
A NEW HER2 INHIBITOR: PERTUZUMAB
Among the peptide growth factor receptors frequently implicated in the development and progression of breast cancer are four members of the type I receptor tyrosine kinase family, which include EGFR or HER1, HER2, HER3, and HER4 . Binding of receptor-specific ligands to the ectodomain of HER1, HER3, and HER4 results in the formation of receptor oligomers to which HER2 is recruited as the preferred partner [40–43]. HER2 does not interact directly with a growth factor ligand. Instead, the receptor functions by ligand-independent interaction with both itself or other HER kinase family members such as HER3 [44,45]. Pertuzumab is a humanized monoclonal antibody that targets the HER2 receptor. Unlike trastuzumab which binds to the subdomain IV of HER2, pertuzumab binds to the dimerization subdomain II of HER2, blocking the interaction with other members of the HER family . A phase II study in patients with HER2-positive MBC with progression during prior trastuzumab therapy provided the first evidence that the combination of the two antibodies pertuzumab and trastuzumab was clinically active and well tolerated . FDA approval for pertuzumab was based on a multicenter, double-blind trial in which 808 patients with HER2-positive MBC were randomly assigned to receive docetaxel and trastuzumab plus either pertuzumab or placebo as the first-line treatment for metastatic disease [48▪▪]. Pertuzumab treatment increased median PFS by 6.1 months (18.5 versus 12.4 months). An OS interim analysis performed at the time of the PFS analysis showed a strong trend for improvement with pertuzumab treatment (hazard ratio 0.64, P = 0.0053), but the hazard ratio and P value for this analysis did not meet the predefined stopping boundary; thus, the survival results were deemed exploratory [48▪▪] (Fig. 2).
In the NEOSPHERE (NCT01426880) neoadjuvant trial, patients with operable, locally advanced, or inflammatory HER2-positive breast cancer were randomized to receive one of four combination treatments: docetaxel plus trastuzumab and pertuzumab, docetaxel plus trastuzumab, docetaxel plus pertuzumab, or pertuzumab plus trastuzumab (without chemotherapy) . A statistically significant increase in pCR rate was seen when pertuzumab was combined with docetaxel and trastuzumab compared with the docetaxel and trastuzumab combination (45.8 versus 29%; P = 0.014). A pooled analysis of cardiac safety in 598 patients participating in pertuzumab clinical trials showed no apparent increase in cardiac dysfunction when pertuzumab was given concurrently with trastuzumab . The role of pertuzumab in primary breast cancer is currently being evaluated in the ongoing APHINITY (NCT01358877) trial, in which patients with early stage HER2-positive breast cancer are randomized to standard postoperative adjuvant trastuzumab-based chemotherapy with or without pertuzumab therapy. Moreover, a randomized phase III study, MARIANNE (NCT01120184), is currently studying T-DM1 alone or in combination with pertuzumab compared with trastuzumab plus a taxane as the first-line treatment for HER2-positive MBC.
HER2 ANTIBODY–DRUG CONJUGATE: TRASTUZUMAB EMTANSINE
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). After T-DM1 binds HER2, the HER2/T-DM1 complex undergoes internalization, followed by lysosomal degradation . This process results in the intracellular release of DM1-containing products that bind to tubulin and prevent microtubule polymerization (reviewed in ). In addition, T-DM1 has also retained the mechanisms of action of trastuzumab, including disruption of the PI3K/AKT signaling pathway and Fcγ-receptor-mediated, antibody-dependent cellular cytotoxicity . Importantly, T-DM1 demonstrates preclinical activity in experimental models that are refractory to trastuzumab or lapatinib .
Results from a phase II study were recently published, in which T-DM1 was administered every 3 weeks to patients with HER2-positive MBC who had failed prior treatment with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. In patients with confirmed HER2-positive tumors, the response rate was 41.3% and the median PFS was 7.3 months. This study is remarkable as T-DM1 was very well tolerated and had single-agent activity in patients with HER2-positive MBC who had previously received both approved HER2-directed therapies and multiple chemotherapy agents .
Results from a phase III study were recently published, in which T-DM1 was administered every 3 weeks to patients with HER2-positive MBC who had failed prior treatment with trastuzumab and a taxane. This study (EMILIA; NCT00829166) compared the safety and efficacy of T-DM1 to that of the combination of capecitabine and lapatinib. Importantly, T-DM1 significantly prolonged PFS and OS with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane [55▪▪]. Among 991 randomly assigned patients, the median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio 0.65; P < 0.001), and the median OS was 30.9 versus 25.1 months (hazard ratio 0.68, P < 0.001) (Fig. 3). Moreover, the rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57 versus 41%) [55▪▪]. The most commonly reported grade 3 or 4 events with T-DM1 were thrombocytopenia (12.9%) and elevated serum concentrations of aspartate aminotransferase (4.3%) and alanine aminotransferase (2.9%) [55▪▪].
In another recent randomized phase II study, 137 patients who had never had chemotherapy or targeted therapy to treat their locally advanced or metastatic HER2-positive breast cancer were randomized to either T-DM1 or standard treatment with trastuzumab plus docetaxel. Patients on T-DM1 had significantly longer PFS compared with those on standard therapy (14.2 versus 9.2 months, hazard ratio 0.59, P = 0.035). Overall toxicity was far lower among those on the investigational agent (46.4 versus 89.4%) and more women on standard care discontinued therapy because of the side-effects (28.8 versus 7.2%) [56▪▪]. An ongoing phase III randomized study (MARIANNE; NCT 01120184) is comparing T-DM1 alone or in combination with pertuzumab to trastuzumab plus a taxane in the first-line HER2-positive MBC setting.
TREATMENT BEYOND PROGRESSION: STOP TRASTUZUMAB OR CONTINUE?
At the time of disease progression, clinicians frequently continue trastuzumab but change to an alternative chemotherapy. The role of continued trastuzumab after progression in women with HER2-positive MBC receiving concurrent chemotherapy is controversial mostly because prospective clinical trials that establish a benefit from continued trastuzumab have been difficult to complete  or because studies have been observational and not randomized, and thus treatment groups have not been comparable [58,59]. However, preclinical data on the chemotherapy-sensitizing effect of trastuzumab [60,61] and limited clinical data from Refs. [57–59] suggest that continuation of trastuzumab beyond progression may be important.
If continuing trastuzumab and changing to an alternative chemotherapy is effective, the obvious question is whether adding another HER2 inhibitor to trastuzumab would have a similar effect. Preclinical studies suggested that lapatinib has synergistic activity if combined with trastuzumab and that it may have clinical activity in patients with disease resistant to trastuzumab . In addition, there is preclinical evidence for synergy between trastuzumab and pertuzumab in HER2-overexpressing breast cancer cells . Moreover, the combination of pertuzumab and trastuzumab was effective following progression on trastuzumab in preclinical breast cancer models . Synergies are likely seen because trastuzumab's and pertuzumab's or lapatinib's modes of action are complementary. For example, trastuzumab disrupts the ligand-independent association of HER2 and HER3, thus inhibiting downstream PI3K pathway signaling in vitro. This mechanism is distinct from that of pertuzumab, which inhibits ligand-dependent HER2 and HER3 hetero-oligomer formation . The mechanisms of action of trastuzumab and lapatinib are similarly complementary. For example, lapatinib which is a small molecule inhibitor of the kinase domain can inhibit the cleaved and constitutively activated truncated form of HER2 (p95HER2), but trastuzumab cannot . On the other hand, lapatinib has no impact on the cleavage of HER2 to p95HER2, whereas trastuzumab can inhibit this process . Two recent studies in patients with HER2-positive MBC that failed prior trastuzumab-based therapy have assessed the efficacy and toxicity of adding another HER2 inhibitor to trastuzumab. One study randomized patients progressing on trastuzumab-based therapy to either single-agent lapatinib or continued trastuzumab with lapatinib and reported a longer PFS and OS time with the dual blockade using two anti-HER2 agents [35▪▪]. Another study evaluated the combination of pertuzumab and trastuzumab and provided the first evidence that the combination was clinically active and well tolerated in patients who failed prior trastuzumab-based therapy . Importantly, the data from both of these studies support the notion that dual HER2 blockade is a clinically meaningful approach in patients with HER2-positive MBC progressing on trastuzumab-based therapy.
COMBINING HER2 INHIBITORS IN THE NEOADJUVANT SETTING
Neoadjuvant chemotherapy represents an option for patients with early breast cancer when an indication for chemotherapy is given . Assessing the pCR rate has provided a possibility of measuring early in-vivo response to systemic treatment and has predicted long-term outcome in several neoadjuvant studies , and is therefore a potential surrogate marker for survival specifically in patients with HER2-positive (nonluminal) and triple-negative tumors [69▪▪,70]. Results of the NEO-ALTTO trial, a study of neoadjuvant lapatinib and/or trastuzumab therapy, in patients with newly diagnosed HER2-positive breast cancer, demonstrated that the pCR rate was significantly higher with the combination of lapatinib and trastuzumab compared with trastuzumab or lapatinib alone (51.3 versus 29.5 or 24.7%, respectively) when given in conjunction with preoperative chemotherapy [36▪]. These findings corroborate the preclinical synergy and the improved efficacy of this combination seen in patients with MBC thought to be refractory to trastuzumab therapy alone [35▪▪] (Fig. 4).
The NEOSPHERE neoadjuvant trial compared docetaxel plus trastuzumab and pertuzumab (arm B), docetaxel plus trastuzumab (arm A), docetaxel plus pertuzumab (arm D), and pertuzumab plus trastuzumab (without chemotherapy, arm C) in patients with operable, locally advanced, or inflammatory HER2-positive breast cancer . A statistically significant increase in pCR rate was seen when pertuzumab was combined with docetaxel and trastuzumab compared with the docetaxel and trastuzumab combination (pCR rate 45.8 versus 29%). Both pertuzumab and trastuzumab demonstrated a comparable efficacy when added to docetaxel (pCR rate 24 versus 29%). Of note, patients treated with the chemotherapy-free combination of pertuzumab and trastuzumab had a pCR of 17% (Fig. 5).
The challenge for clinicians going forward will be how best to incorporate the many HER2 therapies that are in clinical development. Adjuvant clinical trials in breast cancer are already very large and expensive, and will by necessity require even more subjects to detect smaller differences achieved with newer agents or new combinations. In contrast, neoadjuvant studies allow the rapid assessment of novel anti-HER2 agents [71,72] and new combination regimens [36▪,49] using smaller clinical trials. As such, neoadjuvant studies in HER2-positive breast cancer can facilitate the rapid incorporation of therapeutic approaches currently in development that likely will yield additional clinically meaningful improvements for patients with HER2-positive cancer. In addition, neoadjuvant studies in HER2-positive breast cancer will facilitate the identification of tissue biomarkers that in the near future may allow the selection of patients with HER2-positive breast cancer who can be successfully treated by HER2 inhibition alone and may not require the addition of traditional chemotherapy or surgery.
COMBINATIONS WITH DOWNSTREAM PATHWAY INHIBITORS
Preclinical and clinical data suggest that HER2 induction of vascular endothelial growth factor (VEGF) expression plays a role in the pathogenesis of HER2-positive breast cancer [73–75]. Thus, the combination of a VEGF inhibitor with a HER2 inhibitor merited clinical investigation. Results of a phase II, open-label, nonrandomized trial in 50 women who received trastuzumab and bevacizumab as the first-line therapy for HER2-overexpressing MBC showed that this combination achieved an objective response rate of 48% . A phase III, randomized, open-label, adjuvant trial (BETH; NCT00625898) is determining the value of adding bevacizumab to chemotherapy plus trastuzumab in primary HER2-positive breast cancer. The study has completed enrollment and the results are eagerly awaited. Resistance to HER2-targeted therapies may also be related to deregulation of phosphatase and tensin homolog (PTEN). PTEN is a negative regulator of PI3K; therefore, loss of PTEN enables continued Akt activation . Resistance to anti-HER2 therapy also has been associated with activating mutations in genes coding for proteins of the PI3K/Akt/mTOR pathway [78,79]. Introduction of mutant PIK3CA into HER2-overexpressing breast cancer cells conferred resistance to growth inhibition by trastuzumab and lapatinib . Given the role of PTEN and PI3K pathway mutations in anti-HER2 therapy resistance, combination therapy with an mTOR inhibitor and an anti-HER2 agent represents a rational choice for investigation. Currently, a phase III randomized, double-blind, placebo-controlled trial (BOLERO 1, NCT00876395) is ongoing to assess the value of adding everolimus to weekly paclitaxel and trastuzumab in the first-line HER2-positive MBC setting. Dual inhibition of HER2, along with other parallel activated receptor tyrosine kinases, is also being explored in clinical studies. As such, both MET and IGF1R have been implicated as potential trastuzumab resistance factors in breast cancer cell lines [81,82]. Importantly, however, whether combinations with inhibitors to these receptor tyrosine kinases will exhibit clinical activity in HER2-positive breast cancer overall or in selected patients has yet to be proven.
Administration of anti-HER2 therapies in clinical practice has dramatically improved the natural course of HER2-positive breast cancer . However, despite these treatment advances, resistance to trastuzumab is common, highlighting the need to develop new agents and combination strategies to overcome resistance and improve efficacy. A dual targeting approach which uses a trastuzumab backbone with the addition of a second-generation anti-HER2 drug has proven to be successful by improving the clinical outcomes in patients with MBC thought to be refractory to trastuzumab therapy alone. Moreover, in the neoadjuvant setting, dual anti-HER2 blockade combinations and chemotherapy have almost doubled the rates of pCR compared to single anti-HER2 therapy. In summary, given the high response rates following dual HER2 inhibition and given the high prevalence of intrinsic and acquired resistance to single-agent regimens targeting HER2, it is fair to say that the treatment paradigm is shifting toward a dual therapeutic approach that will yield clinically meaningful improvements for patients with HER2-positive breast cancer. The high efficacy obtained by newer HER2 inhibitors and by combination approaches gives us a reason to believe that in the near future it may be possible to select patients who can be successfully treated by HER2 inhibition alone without a need for traditional chemotherapy or surgery.
Conflicts of interest
G.E.K. has received honoraria from Genentech, Sanofi-Aventis, Novartis, and Amgen.
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
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 87–88).
1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER 2/neu oncogene. Science 1987; 235:177–182.
2. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244:707–712.
3. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783–792.
4. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673–1684.
5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355:2733–2743.
6. NCCN Practice Guidelines in Oncology. National Comprehensive Cancer Network 2012. http://www.nccn.org/
7. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes – dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22:1736–1747.
8▪▪. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:1273–1283.
A large phase III study demonstrating the superiority of trastuzumab in combination with nonanthracycline-based regimen (docetaxel/carboplatin/trastuzumab versus anthracycline-based chemotherapy) in primary operable breast cancer.
9. Gianni L, Dafni U, Gelber RD, 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.
10. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:3366–3373.
11. Yin W, Jiang Y, Shen Z, et al. Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PLoS One 2011; 6:e21030.
12. Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol 2010; 28:3422–3428.
13▪▪. Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSAB 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.
The most comprehensive report on the potential risk of cardiotoxicity when combining trastuzumab with an anthracycline-based chemotherapy regimen.
14. Paik S, Bryant J, Park C, et al. ErbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998; 90:1361–1370.
15. Pritchard KI, Shepherd LE, O’Malley FP, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006; 354:2103–2111.
16. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008; 100:14–20.
17. Jarvinen TA, Tanner M, Rantanen V, et al. Amplification and deletion of topoisomerase II alpha associate with ErbB-2 amplification and affect sensitivity to the topoisomerase II inhibitor doxorubicin in breast cancer. Am J Pathol 2000; 156:839–847.
18. Di Leo A, Gancberg D, Larsimont D, et al. HER-2 amplification and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res 2002; 8:1107–1116.
19. Durbecq V, Paesmans M, Cardoso F, et al. Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Mol Cancer Ther 2004; 3:1207–1214.
20. Knoop AS, Knudsen H, Balslev E, et al. Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 2005; 23:7483–7490.
21. Tanner M, Isola J, Wiklund T, et al. Topoisomerase II alpha gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu-amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 2006; 24:2428–2436.
22▪. Press MF, Sauter G, Buyse M, et al. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol 2011; 29:859–867.
In a study involving nearly 5000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an improved response to anthracycline-based chemotherapy.
23. Jarvinen TA, Tanner M, Barlund M, et al. Characterization of topoisomerase II alpha gene amplification and deletion in breast cancer. Genes Chromosomes Cancer 1999; 26:142–150.
24. Kauraniemi P, Barlund M, Monni O, et al. New amplified and highly expressed genes discovered in the ERBB2 amplicon in breast cancer by cDNA microarrays. Cancer Res 2001; 61:8235–8240.
25. Di Leo A, Isola J. Topoisomerase II alpha as a marker predicting the efficacy of anthracyclines in breast cancer: are we at the end of the beginning? Clin Breast Cancer 2003; 4:179–186.
26. Perez EA, Suman VJ, Davidson NE, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 2011; 29:4491–4497.
27. Seshadri R, Firgaira FA, Horsfall DJ, et al. Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The South Australian Breast Cancer Study Group. J Clin Oncol 1993; 11:1936–1942.
28. Frenel JS, Rodrigues MJ, Peron J, et al. Impact of adjuvant trastuzumab-based chemotherapy in T1ab node-negative HER2 overexpressing breast carcinomas. J Clin Oncol 2012; 30(suppl.; abstr 601).
29. Goldhirsch A, Piccart M, 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. Presented at European Society of Medical Oncology 2012 Congress; 28 September –2 October 2012; Vienna, Austria. Abstract LBA 6.
30. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHER Trial. J Clin Oncol 2009; 27:5685–5692.
31. Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res 2006; 66:1630–1639.
32. Blackwell KL, Pegram MD, Tan-Chiu E, et al. Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol 2009; 20:1026–1031.
33. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355:2733–2743.
34. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 2010; 28:1124–1130.
35▪▪. 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.
These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination, and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.
36▪. 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.
The first study to show that dual inhibition of HER2 might be a valid approach to the treatment of HER2-positive breast cancer in the neoadjuvant setting.
37. Kaufmann M, Hortobagyi GN, Goldhirsch A, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: an update. J Clin Oncol 2006; 24:1940–1949.
38. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 2008; 26:778–785.
39. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2:127–137.
40. Riese DJ II, van Raaij TM, Plowman GD, et al. The cellular response to neuregulins is governed by complex interactions of the ErbB receptor family. Mol Cell Biol 1995; 15:5770–5776.
41. Pinkas-Kramarski R, Soussan L, Waterman H, et al. Diversification of Neu differentiation factor and epidermal growth factor signalling by combinatorial receptor interactions. EMBO J 1996; 15:2452–2467.
42. Graus-Porta D, Beerli RR, Daly JM, et al. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 1997; 16:1647–1655.
43. Klapper LN, Glathe S, Vaisman N, et al. The ErbB2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci USA 1999; 96:4995–5000.
44. Garrett TP, McKern NM, Lou M, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 2003; 11:495–505.
45. Sliwkowski MX, Schaefer G, Akita RW, et al. Coexpression of ErbB2 and ErbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 1994; 269:14661–14665.
46. Baselga J. A new anti-ErbB2 strategy in the treatment of cancer: prevention of ligand dependent ErbB2 receptor heterodimerization. Cancer Cell 2002; 2:93–95.
47. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that had progressed during prior trastuzumab therapy. J Clin Oncol 2010; 28:1138–1144.
48▪▪. 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.
The first study to show that pertuzumab plus trastuzumab plus docetaxel, compared with trastuzumab plus docetaxel, significantly prolonged progression-free survival in patients with HER2-positive metastatic breast cancer.
49. 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 randomized multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13:25–32.
50. Ewer MS, Baselga J, Clark E, et al. Cardiac tolerability of pertuzumab + trastuzumab + docetaxel in patients with HER2-positive metastatic breast cancer in the CLEOPATRA study. J Clin Oncol 2012; 30(suppl.; abstr. 533).
51. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody–cytotoxic drug conjugate. Cancer Res 2008; 68:9280–9290.
52. LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique antibody–drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res 2011; 17:6437–6447.
53. Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 2011; 128:347–356.
54. Krop I, LoRusso P, Miller KD, et al. Phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 2012; 30:3234–3241.
55▪▪. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367:1783–1791.
A large phase III study that demonstrates that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.
56▪▪. Hurvitz S, Dirix L, Kocsis J, et al. Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H + T) in previously untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study. Eur J Cancer 2011; 47(S330):abstract 5001.
The first study that demonstrates that T-DM1 is superior to docetaxel plus trastuzumab in the first-line treatment of patients with HER2-positive metastatic breast cancer.
57. 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.
58. Extra JM, Antoine EC, Vincent-Salomon A, et al. Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the observational Hermine Study. Oncologist 2010; 15:799–809.
59. Yerushalmi R, Gelmon K. Treatment beyond progression: is it moving from belief to evidence? Oncologist 2010; 15:796–798.
60. Pegram MD, Lopez A, Konecny G, et al. Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin Oncol 2000; 27 (6 Suppl. 11):21–25.
61. Pegram MD, Konecny GE, O’Callaghan C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96:739–749.
62. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004; 64:2343–2346.
63. Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 2009; 69:9330–9336.
64. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 2009; 15:429–440.
65. Xia W, Liu LH, Ho P, et al. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 2004; 23:646–653.
66. Molina MA, Codony-Servat J, Albanell J, et al. Trastuzumab (herceptin), a humanized anti-HER2 receptor monoclonal antibody, inhibits basal and activated HER2 ectodomain cleavage in breast cancer cells. Cancer Res 2001; 61:4744–4749.
67. Kaufmann M, von Minckwitz G, Bear HD, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Oncol 2007; 18:1927–1934.
68. Kuerer HM, Newman LA, Smith TM, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999; 17:460–469.
69▪▪. 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.
A large study that demonstrated that pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease, but not for those with luminal B/HER2-positive or luminal A tumors.
70. Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups. J Clin Oncol 2011; 29:3351–3357.
71. 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.
72. 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.
73. Yen L, You XL, Al Moustafa AE, et al. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 2000; 19:3460–3469.
74. Epstein M, Ayala R, Tchekmedyian N, et al. HER-2/neu-overexpressing human breast cancer xenografts exhibit increased angiogenic potential mediated by vascular endothelial growth factor (VEGF). Breast Cancer Res Treat 2002; 76 (Suppl. 1):S143.
75. Konecny GE, Meng YG, Untch M, et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res 2004; 10:1706–1716.
76. Pegram M, Chan D, Dichmann RA. Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer. Breast Cancer Res Treat 2006; 100 (Suppl. 1):S28[abstract 301].
77. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010; 28:1075–1083.
78. Johnston S, Trudeau M, Kaufman B, et al. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 2008; 26:1066–1072.
79. Gardner H, Nuciforo P, Liu W-H, et al. PI3 kinase pathway analysis in tissue microarrays using laser capture microdissection and immunohistochemistry. Cancer Res 2009; 69(24s):abstract 4043.
80. Eichhorn PJ, Gili M, Scaltriti M, et al. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVPBEZ235. Cancer Res 2008; 68:9221–9230.
81. Shattuck DL, Miller JK, Carraway KL, et al. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 2008; 68:1471–1477.
82. Browne BC, Crown J, Venkatesan N, et al. Inhibition of IGF1R activity enhances response to trastuzumab in HER-2-positive breast cancer cells. Ann Oncol 2011; 22:68–73.
83. Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol 2010; 28:92–98.
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