THEMED ARTICLE y Lung Cancer
Review
HER2 and lung cancer Expert Rev. Anticancer Ther. 13(10), 1219–1228 (2013)
Lorenza Landi and Federico Cappuzzo* Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, viale Alfieri 36, 57100 Livorno, Italy *Author for correspondence: Tel.: +39 0586 223 189 Fax: +39 0586 223 457 [email protected]
In non-small-cell lung cancer (NSCLC), the identification of oncogenic driver mutations led to the definition of different clinical entities with different therapeutic opportunities, as demonstrated in patients harboring EGF receptor (EGFR) mutations or anaplastic lymphoma kinase translocations. Human EGFR2 (or HER2) has an established role as a prognostic and predictive factor in breast cancer. Although HER2 deregulation, including overexpression, amplification and mutation, has been described in NSCLC, its role as a therapy biomarker remains undefined. In the last few years, there has been a growing interest on HER2 mutation, with few anecdotal or retrospective studies suggesting a relevant role for this biomarker. This review discusses the prognostic and predictive impact of HER2 deregulation and the clinical implications of anti-HER2 strategies in NSCLC. KEYWORDS: anti-HER2 therapy • EGFR • HER2 • NSCLC • oncogenic driver
In 2013, once again, statistics reaffirmed nonsmall-cell lung cancer (NSCLC) as the leading cause of cancer-related death worldwide [1], with a median survival that rarely exceeds 10 months in unselected patients with metastatic disease treated using conventional chemotherapy [2]. Despite this discouraging picture, today we are used to considering NSCLC as a combination of different clinical entities with different prognoses and therapeutic opportunities. The identification of key genetic events driving tumor growth and metastatic spread led to the postulation of the concept of oncogene addiction. According to this model, the inhibition of certain molecular drivers by targeted agents could be effective in reducing tumor burden and improving patient outcome. In the last few years, collaborative groups conducted extensive analyses of lung cancer tissue specimens using modern techniques of genomic sequencing with the aim of deciphering the complexity of lung tumorigenesis [3,4]. As a result, a potentially actionable driver event can be found in more than 50% of newly diagnosed NSCLCs [3]. During the last few years, many molecular events driving tumor growth have been identified in patients with squamous cell carcinoma, including FGF receptor-1 (FGFR1) amplification or mutations, DDR2 or PIK3CA mutations, thus opening the door for personalized treatment [5–9]. Conversely, several molecular alterations have been described in
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adenocarcinomas, especially but not exclusively, in the never/former smoker population. This is the case of the EGF receptor (EGFR) activating mutations, mainly represented by deletion in exon 19 or the L858R substitution in exon 21, and the EML4-ALK fusion gene [10–12]. Indeed, large randomized trials clearly demonstrated that in presence of EGFR mutations or EML4-ALK translocation, EGFR-tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib or afatinib or the anaplastic lymphoma kinase (ALK) inhibitor crizotinib are the best therapeutic choice we can offer today to our patients [13–21]. More recently, novel ‘biomarker slices’ have been added to the ‘adenocarcinoma pie’ such as RET and ROS1 fusion genes, BRAF, KRAS and HER2 mutations for which many targeted drugs are currently under investigation (FIGURE 1) [4,22,23]. In this context, the HER2 gene represents a relatively new biomarker for NSCLC. HER2 also known as human EGFR2 or ERBB2 or NEU, belongs to the ERBB family, which includes three other members: EGFR (HER1/ERB1), HER3 (ERBB3) and HER4 (ERBB4). The HER family represents an appealing target for anti-cancer strategies due to its central role in tumor growth. Indeed, similar to other receptors, all family members are structurally constituted by three domains: an extracellular domain responsible for ligand binding and homo/heterodimers formation, a transmembrane domain that
2013 Informa UK Ltd
ISSN 1473-7140
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Adenocarcinoma
the last 15 years, several studies investigated the prognostic role of HER2 Squamous cell expression in lung cancer, with discordant carcinoma results [27,36–45]. In order to define whether HER2 levels, assessed using the FGFR FGFR HercepTest, could affect prognosis in amplification mutation NSCLC, in 2002 Hirsch et al. analyzed a EGFR Unknown series of 187 surgically resected lung Unknow tumor specimens. Thirty four tumors DDR2 (18%) showed positivity (2+/3+) on HercepTest, with only 3% having strong posKRAS itivity (3+). According to histological type, 32% of adenocarcinomas were posiPIK3CA BRAF ALK tive, contrasting with only 8% of squaFusion ROS oncogenes ERBB2 mous cell carcinomas. No difference in RET MEK 1 survival was observed among patients MET PIK3CA amplification with positive (HercepTest 2+/3+, n = 34) and negative (HercepTest 0/1+, n = 153) Figure 1. Molecular driver events in non-small-cell lung cancer. tumors, although the median survival for HercepTest 3+ individuals (n = 6) tended makes a single pass through the plasma membrane and a TK to be shorter. Similarly, no difference in survival was observed domain responsible for activation of two key signaling pathways, in patients with positive and negative tumors according to hisnamely, the RAS/RAF/MAPK pathway, which stimulates prolif- tology (adenocarcinoma vs squamous cell carcinoma) [46]. In a eration, and the PI3K/Akt pathway, which promotes tumor cell Japanese study, HER2 immunohistochemical levels were tested survival. Several ligands have been described for HER1, in more than 230 lung tumors obtained from a consecutive HER3 and HER4 including EGF, epiregulin, betacellulin, TGF surgical series. Immunohistochemistry (IHC) score was defined and neuregulins. Ligand binding triggers intracellular signaling as follows: 0 = none, 1 = weak, 2 = 10–30% of stained cells, through the formation of heterodimers or homodimers between ‡3 30% of stained cells. The authors confirmed an overall inciErbB receptors. Due to the lack of innate kinase function, dence of HER2 2+/3+ positivity of around 15%, with adenoHER3 can heterodimerize with other HER family members, carcinoma having the highest frequency rate (10%). especially with EGFR, thus potentiating its activity. Unlike Postoperative 5-year survival rates were 75.3, 77.8, 76.5 and EGFR, HER3 and HER4, HER2 has no known ligand. This 20.0% in patients with adenocarcinoma and HER2 scores were unique characteristic translates in the ability of HER2 to directly 0, 1, 2 and 3, respectively. Moreover, adenocarcinoma patients bind with the other family members including EGFR. On this with an IHC score of >3 had a significantly unfavorable surbasis, HER2 could modulate EGFR signaling. The role of vival compared to those with staining scores of 0–2 [47]. More HER2 as a proto-oncogene has been well defined for two recently, meta-analysis suggested that HER2 overexpression was decades. Its deregulation was detected in several types of malig- a poor prognostic factor in lung cancer, particularly in small nancies including breast cancer, gastric cancer and NSCLC [24–27]. cell lung cancer, adenocarcinoma and early-stage NSCLC In the present review, we critically analyze and report how patients [48]. Overall, based on available data it seems that, in HER2 is dysregulated in NSCLC and how this event could NSCLC, HER2 overexpression is a weak prognostic factor. affect patient prognosis and sensitivity to targeted therapies. HER2 gene amplification is an event occurring in less than 10% of cases. Unlike other cancer types, including breast, ovarPrognostic role of HER2 deregulation ian and gastric cancer, HER2 amplification does not have a Among the different mechanisms potentially responsible for clearly negative prognostic impact in NSCLC, as shown in the gene deregulation, HER2 expression, amplification and muta- previously mentioned meta-analysis [48]. tion have been most extensively investigated. HER2 In 2012, we published the results of a retrospective study overexpression – defined as moderate or strong (2+/3+) mem- evaluating the incidence and prognostic impact of HER2 branous staining – seems the most frequent event, reported in amplification in a cohort of 447 resected NSCLC patients [49]. up to 20% of cases, while HER2 amplification or mutation are HER2 gene copy number (GCN) gain was assessed by FISH. more rare and reported in up to 9 and 3% of cases, respec- No difference in survival was observed between patients with tively [27–35]. or without HER2 amplification (median: 38 vs. 41 months; HER2 overexpression or amplification correlates with poor p = 0.46), thus confirming the lack of prognostic impact for prognosis in different malignancies including breast and ovarian HER2 increased GCN gain in resected NSCLC [49]. cancers [24,25]. Nevertheless, in lung cancer, the role of HER2 The incidence of HER2 mutations ranges from 1 to 6%, overexpression and amplification remains controversial. During with the highest frequency described in a highly selected 1220
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population (TABLE 1) [4,29–34]. HER2 mutations occur in the first four exons of the TK domain (exons 18–21) and are mainly represented by a 12 bp duplication/insertion of the amino acid sequence YVMA in exon 20 at codon 776 (HERYVMA). Arcila et al. recently published the first largest retrospective study of a series of Caucasian NSCLC patients tested for HER2 and other molecular alterations [33]. The authors reported an unusual incidence of HER2 mutations of 5% in a ‘super-selected’ EGFR/KRAS wild-type population and, more interestingly, this event was mutually exclusive with point mutations in BRAF, PIK3CA, MEK1 and AKT genes [33]. As previously observed in EGFR mutated patients as well as in those carrying an ALK, ROS1 or RET fusion gene, the presence of HER2 mutations seems associated with female gender, adenocarcinoma subtype and never smokers [34]. Importantly, as observed for other biomarkers, clinical characteristics are not sufficient for selecting patient candidates for HER2 mutation screening, as confirmed by the detection of such events in male and heavy smoker patients [34,35]. Because of the low incidence, the prognostic impact of HER2 mutations in the natural history of NSCLC is not fully elucidated and recent literature data are discordant. Arcila et al. analyzed the survival outcome of 468 NSCLC patients with advanced disease according to the presence of EGFR mutations, KRAS mutations, BRAF mutations, ALK translocations or HER2 mutations. Although the overall survival of the HER2 cohort was not statistically different from the other molecularly defined cohorts, the worst survival performance was observed among patients with HER2 or KRAS mutations [33]. On the other hand, Mazie`res and coworkers recently reported a possible indolent outcome of HER2 mutant NSCLC when compared to an unselected NSCLC population [34]. Therefore, the few available data are not enough for defining whether HER2 mutations are prognostic in NSCLC. HER2 dysregulation as predictive of sensitivity to antiEGFR agents
Preclinical findings suggest that HER2 dysregulation could modify tumor sensibility to anti-EGFR agents. In fact, HER2 is the major partner of EGFR and activated heterodimeric complexes containing HER2 are more stable at the cell surface than complexes containing other EGFR family members [50]. In addition, HER2 can decrease the rate of ligand dissociation from the cognate receptor EGFR [51]. Finally, EGFR signaling through phosphorylation of the intracellular TK domain of the protein can be blocked by small-molecule EGFR-TKIs [52–54]. Ten years ago, at the beginning of our studies on the EGFR family, we analyzed a cohort of 63 pretreated NSCLC patients exposed to gefitinib in order to evaluate the correlation between HER2 expression and efficacy to anti-EGFR therapy in terms of response rate (RR), time to progression (TTP) and overall survival (OS) [55]. HER2 levels were assessed by IHC using the 0 to 3+ scale and considering a staining intensity of 2+ or 3+ in more than 10% of cells as positive. We also evaluated the www.expert-reviews.com
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levels of EGFR by IHC. Fifteen (34.8%) out of the 43 patients evaluable for HER2/EGFR status were labeled HER2 2+/3+, while 28 (65.2%) patients were labeled negative. No significant differences were observed in terms of disease control rate (DCR: 40 vs 64.3%), TTP (3.5 vs 3.7 months) and OS (5.7 vs 6.8 months) in HER2 overexpressing and HER2 negative patients, respectively, thus suggesting that HER2 overexpression was not useful for predicting sensitivity to gefitinib in unselected NSCLC patients [55]. To further evaluate the role of HER2 dysregulation in modulating sensitivity to EGFR-TKIs, 2 years later we investigated whether HER2 genomic gains, assessed using FISH, were associated with sensitivity to gefitinib in 102 pretreated advanced NSCLC patients [28]. HER2 amplification was detected in 9% of cases and we considered as positive all patients with high polysomy or gene amplification, using the same criteria adopted for EGFR [56]. HER2 FISH positive patients had better outcome than HER2 FISH negative individuals, probably because HER2 GCN gain was associated with the major predictors for gefitinib sensitivity, which are EGFR mutations. More recently, Takezawa et al., showed that high levels of HER2 amplification contribute to acquired resistance to EGFR-TKIs in approximately 12% of cases [57]. Overall, all these data suggest a strong predictive role of HER2 GCN gain. Indeed, in presence of HER2 increased copy number, EGFR and HER2 cooperate leading tumor cells to be highly dependent on the HER axis and more vulnerable to anti-EGFR treatment. Conversely, in the presence of high levels of HER2 amplification, HER2 becomes an essential driver for tumor growth and metastatic spread, irrespective of EGFR inhibition. Similar findings have been observed in metastatic colorectal cancer (mCRC) treated with anti-EGFR monoclonal antibody. At the preclinical level, the amplification of the HER2 gene has been correlated with cetuximab resistance due to the continued activation of EGFR downstream pathways when cetuximab is bound to EGFR [58,59]. Our group evaluated the HER2 gene status by FISH in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab alone or in combination with chemotherapy in different lines of treatment [60]. According to HER2 GCN status, 4% of patients had HER2 gene amplification, 61% had HER2 gain due to polysomy or gene amplification in minor clones and 35% had no or slight HER2 gain. HER2 amplified patients had the worst outcome in terms of RR (p = 0.0006), progression-free survival (PFS; p = 0.0001) and OS (p = 0.0001). Conversely, patients with HER2 polysomy had the highest survival probability [60]. Although HER2 mutations have been described in 2004, the interest in translational research in this defined molecular setting emerged only in the last few years. The presence of mutation translates into a conformational change in the kinase domain of the receptor, leading to an increased kinase activity compared to the wild-type form. HERYVMA is able to activate EGFR in a ligand-independent fashion and irrespective of the presence of an activating EGFR mutation [61,62]. In vitro studies demonstrated that HERYVMA clones are resistant to reversible 1221
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Table 1. HER2 mutant lung cancers: clinical characteristics and incidence in recent trials. Study (year)
Patients (n)
Stage
Ethnicity
Incidence (n/%)
Female (%)
Histology
Never smoker (%)
Stephens et al. (2004)
120
NR
NR
5/4
NR
ADC
NR
[30]
Shigematsu et al. (2005)
671
Resected
Asian/Caucasian
11/1.6
63.6
ADC
81.8
[29]
Buttitta et al. (2006)
403
Resected
Caucasian
9/2.2
66.6
ADC
33.3
[32]
Sasaki et al. (2006)
95
All
Asian
1/1.0
100
ADC
100
[31]
Tomizawa et al. (2011)
504
Resected
Asian
13/2.6
77
ADC/AS
84.6
[35]
Cappuzzo
42†
III/IV
Caucasian
2/5.4
100
ADC
100
[79]
‡
Ref.
Arcila et al. (2012)
560
All
Asian/Caucasian
25/4.4
68
ADC
68
[33]
Barlesi et al. (2013)
10,000
All
Caucasian
NR/0.9
NR
ADC
NR
[4]
†
37/42 evaluated patients. EGFR/KRAS wild-type population. ADC: Adenocarcinoma; AS: Adenosquamous; NR: Not reported.
‡
EGFR-TKIs such as gefitinib and erlotinib, while they remain sensitive to HER2 and dual EGFR/HER2 inhibitors [61]. Clinical impact of anti-HER2 strategies in NSCLC
Trastuzumab, the humanized monoclonal IgG1 targeting the extracellular domain of HER2, has already had an impact on the treatment of 20% of breast cancer patients with HER2 protein overexpression and recently it also gained niche status in the treatment of patients with HER2 overexpressing gastric cancer [63,64]. In NSCLC patients, pivotal Phase II studies demonstrated only modest activity and results were disappointing [65–70]. Efficacy results of published trials evaluating the efficacy of anti-HER2 monoclonal antibodies in NSCLC are summarized in TABLE 2. In the first-line setting, adding trastuzumab to standard platinum-based chemotherapy in NSCLC HER2 IHC positive patients did not translate into improvement in terms of RR, PFS and OS, although the small fraction of IHC 3+ or HER2 FISH amplified patients tended to have a longer duration of response when treated with trastuzumab [65]. Overall, three main issues were noted from these trials. First, it is unknown whether this effect was related to trastuzumab or to chemotherapy, considering that HER2 amplification is frequently associated with EGFR gene amplification and mutation – a biological event increasing sensitivity to antiEGFR agents as well as to chemotherapy. Second, it is reasonable to assume that in lung cancer HER2 amplification could be clinically irrelevant and other molecular abnormalities, such as HER2 mutation, could be responsible for the sensitivity of trastuzumab. Third, there is no consensus on the IHC scoring system for considering a patient as ‘HER2 positive’, thus 1222
resulting in some imbalance in comparing efficacy data. Also pertuzumab, a monoclonal antibody that binds the dimerization domain of HER2 and inhibits HER2 signaling, failed to demonstrate any benefit (RR: 0%) when used as a single agent in an unselected NSCLC population [70]. In a prematurely closed trial, we tried to assess the efficacy of trastuzumab in HER2 amplified or HER2 mutated pretreated NSCLC (NCT00758134). No response was observed among the 10 HER2 FISH amplified patients included in the study, while no HER2 mutated individuals were enrolled (UNPUBLISHED DATA). The demonstration that HER2-mutant transgenic mice rapidly developed lung cancer [71] led to the proposition that HER2 mutation is more relevant than HER2 amplification or overexpression as an oncogenic driver as well as a predictive factor for sensitivity to anti-HER2 therapy. Moreover, preclinical experiences revealed that NSCLC cell lines harboring HER2 mutations are sensitive to trastuzumab therapy [62] and anecdotal cases confirmed this assumption [34,35,72]. In 2006, we firs reported the clinical case of a woman with lung adenocarcinoma who failed to respond to three lines of therapy including an EGFR-TKI and was successfully treated with the paclitaxel–trastuzumab combination. The genetic make-up of her disease consisted of a mutation in exon 20 of the HER2 gene, but surprisingly FISH analysis also revealed increased numbers of copies of both HER2 and EGFR genes [72]. A similar experience had been described by Tomizawa and colleagues, who observed a long-lasting remission in a HER2 mutated female adenocarcinoma patient treated with trastuzumab and vinorelbine as third-line therapy [35].
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Table 2. Published trials evaluating anti-HER2 monoclonal antibodies in advanced non-small-cell lung cancer. Study (year)
Phase
Patients (n)
Treatment
HER2 status
RR (%)
mPFS (months)
mOS (months)
Gatzemeier et al. (2004)
IIR
103
Langer et al. (2004)
II
Lara et al. (2004)
Ref.
Cddp/gem + trastuzumab‡
IHC/FISH†
36 41
6.1 7.0
NR 12.2
[65]
56
Cbdca/paclitaxel + trastuzumab‡
IHC
24.5
3.3
10.1
[66]
II
13
Docetaxel + trastuzumab
IHC
8
NR
5.7
[68]
Zinner et al. (2004)
II
21
Cddp/gem + trastuzumab‡
IHC/ELISA§
8
9.0
NR
[69]
Krug et al. (2005)
IIR
65
Docetaxel + trastuzumab‡ Paclitaxel + trastuzumab‡
IHC
23 32
NR NR
16 14
[67]
Herbst et al. (2007)
II
43
Pertuzumab
IHC
0
1.5
NR
[70]
†
FISH test was performed only in IHC 3+ patients. First-line treatment. Serum Her2 shed antigen level of at least 15 ng/ml by ELISA. Cbdca: Carboplatin; Cddp: Cisplatin; gem: Gemcitabine; IHC: Immunohistochemistry; mOS: Median overall survival; mPFS: Median progression-free survival; NR: not reported; R: Randomized; RR: Response rate. ‡ §
In the retrospective series published by Mazie`res and coworkers [34], 16 patients received an HER2 targeted therapy, including trastuzumab, lapatinib, afatinib or masatinib, after first-line conventional platinum doublet chemotherapy with or without bevacizumab failure. Because 6 patients received up to four additional anti-HER2 drugs, a final cohort of 22 patients was evaluable for activity. Overall, the RR was 50% with a DCR of 82%. The greatest benefit was obtained for the combination of trastuzumab and chemotherapy (15 treated patients; DCR: 96%) and afatinib monotherapy (4 treated patients; DCR: 100%), while no benefit was observed for lapatinib or mosatinib therapy [34]. Several kinase inhibitors are under investigation in HER2driven lung adenocarcinoma, including irreversible TKIs targeting HER2 and EGFR, such as dacomitinib (PF-00299804), afatinib (BIBW-2992) and neratinib (HKI-272) [73–75]. In preclinical models, these agents effectively inhibited the growth of HER2-mutant lung cancer clones [76]. Dacomitinib (PF-00299804) covalently binds the ATP domain of each of the three kinase active members of the HER family: EGFR/HER1, HER2 and HER4, and in preclinical studies it showed greater antitumor activity in gefitinib-resistant NSCLC in vitro and in vivo models [76]. More recently, Kris and colleagues reported the results of the 1017 trial, a Phase II study exploring the efficacy in terms of PFS rate at 4 months (PFS at 4 M), PFS and partial response of dacomitinib at the dose of 30–45 mg daily in two different cohorts: the EGFR cohort included never or light former smoker (24 weeks) was observed in 43% of refractory NSCLC patients [75]. Neratinib was also evaluated in combination with temsirolimus in adenocarcinoma patients carrying the HER2 mutation [78]. The rationale for 1223
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Table 3. Ongoing trials with anti-HER agents in non-small-cell lung cancer. Trial
Phase
Patients (n)
LUX-Lung 5 (NCT01085136)
III
1021
NCT00818441
II
114
NCT01827267
IIR
84
Treatment
Molecular selection
Setting
Primary end point
Status
Afatinib vs afatinib/paclitaxel
NR
Third line
PFS
Active, not recruiting
Dacomitinib
Cohort A: EGFR mutated Cohort B: HER2 FISH +ve or HER2 mutation +ve
First line†
PFS
Active, recruiting
Neratinib vs neratinib + temsirolimus
HER2 mutation +ve
Second line and subsequent
RR
Recruiting
† Only for cohort B. NR: Not required; PFS: Progression-free survival; R: Randomized; RR: Response rate.
testing the dual inhibition of Akt/mTOR and HER pathways was derived from a preclinical transgenic mouse model in which the antitumor activity of afatinib was potentiated by the addition of rapamycin [71]. In this Phase I trial, the treatment combination produced a partial response in two out of six enrolled patients [78]. Some of the ongoing trials exploring anti-HER2 strategies in NSCLC are reported in TABLE 3. Expert commentary
The treatment of NSCLC has dramatically changed with the identification of key genetic driver alterations. Furthermore, two important issues were derived from this translational revolution. First, the knowledge of genetic makeup of a metastatic lung tumor at baseline can allow the assignment of patients to target treatment according to the specific profile of their tumor. Indeed, large clinical trials confirmed that targeted therapies are the best treatment option only when the target is present, with no benefit or even a detrimental effect when a targeted agent is given in unselected populations [12–21]. Second, the use of sophisticated genomic techniques allows, today, the identification of many potentially driving events, for which often the proper agent is not available in clinical practice. Therefore, in clinical practice, also considering the difficulties in obtaining tumor tissue in NSCLC, priority should be given to standard biomarkers, such as EGFR mutations and ALK translocations, and all other biomarkers, including HER2, remain under investigation. HER2 represents an old biomarker, since its prognostic and predictive role has been extensively evaluated for many years. Although up to 30% of NSCLC cases display HER2 overexpression, amplification or mutation, the prognostic significance of HER2 dysregulation remains undefined [33–48]. Conversely, preclinical and clinical data suggest that HER2 gene amplification plays an important predictive role [56–58]. Low levels of HER2 amplification seems predictive for sensitivity to reversible EGFR-TKIs, although in clinical practice the only validated biomarker for EGFR-TKI naive patients still remains EGFR mutations. By contrast, in the presence of high HER2 genomic gain, the tumor became HER2 addicted and therefore resistant to EGFR inhibition [56–58]. Therefore, the 1224
combination of anti-EGFR and anti-HER2 agents should be investigated as a potential strategy to overcome the acquired resistance to EGFR-TKIs. Moreover, based on these observations it is not possible to exclude that the apparent superiority of irreversible EGFR-TKIs versus reversible EGFR-TKIs in terms of PFS observed in large studies of chemonaive EGFR mutant NSCLC could in some way be related to the ability of afatinib and dacomitinib to interfere with HER2 function. HER2 mutations seem a relevant target in advanced NSCLC, and small studies reported encouraging results of antiHER2 agents, particularly for trastuzumab-based therapy. HER2 mutations are mutually exclusive with other genetic alterations and they identify a distinct group of NSCLC, mainly represented by subjects of female gender, never smokers and with adenocarcinoma [29–35]. Early anecdotal reports highlighted the anti-tumor activity of trastuzumab in combination with chemotherapy in heavily pretreated HER2 mutant lung cancer [35,72]. In the largest published series, Mazie`res et al. reported an impressive RR of nearly 60% for HER2 mutation positive subjects receiving trastuzumab and chemotherapy [34], quite similar to the one observed in EGFR mutant or ALK positive patients treated with an EGFR-TKI and crizotinib, respectively [13–21]. Although the retrospective and preliminary nature of this work requires us to interpret these results with caution, they deserve a deeper reflection. First, it is reasonable to consider this alteration as a real oncogenic driver [71]. Second, although the detection of HER2 mutation is a rare event occurring in less than 3% of cases [29–35], considering the annual incidence of NSCLC [1], targeting HER2 mutations could be beneficial for thousands of patients each year in Western countries and elsewhere. Third, testing for HER2 mutations should be routinely included in the panel of molecular assessment of advanced NSCLC. Finally, from a practical point of view, while waiting for confirmatory data, the treatment with a drug that is already available such as trastuzumab could represent a valid therapeutic option to be discussed with HER2 mutant patients excluded from clinical trials. In breast cancer, new anti-HER2 agents, such as pertuzumab or TDM1, demonstrated efficacy in HER2 amplified patients. We believe that these agents could play an important role even Expert Rev. Anticancer Ther. 13(10), (2013)
HER2 & lung cancer
in NSCLC only if they are properly investigated, avoiding some methodological issues such as the lack of any selection criterion, which so far has probably precluded the approval of any anti-HER2 agent in lung cancer. Five-year view
The story of NSCLC treatment is rapidly changing over the years. The discovery of actionable drivers have led to novel and more effective drugs, but only for a small fraction of patients. In this scenario, HER2 is emerging as a ‘vintage’ target in NSCLC, and among its abnormalities, HER2 mutations surely represent an oncogenic druggable driver. In the coming years, the development of anti-HER2 targeted agents will offer the opportunity for improving patient outcomes, but careful biological selection will remain crucial for better defining which patients will most benefit from such treatment. As demonstrated for other targeted therapies, the availability of anti-
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HER2 agents and a growing knowledge of the HER2 pathway will uncover mechanisms responsible for acquired resistance to such agents. Last but not the least, another key challenge in the near future will be to develop efficient assays for identifying a wide spectrum of genomic alterations, in order to understand all of the mechanisms correlated with drug sensitivity and, more importantly, to ensure that the best therapeutic option is available to patients. Financial & competing interests disclosure
Supported in part by the Italian Association for Cancer Research (AIRC) and Associazione Oncologia Traslazionale (AOT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Oncogenic driver mutations identify different lung cancers subtypes. • In non-small-cell lung cancer (NSCLC), HER2 is one of the more interesting biomarkers that is considered to play a central role in cancer proliferation. • HER2 is overexpressed, amplified or mutated in a significant fraction of lung adenocarcinomas. • The prognostic significance of HER2 dysregulation remains undefined. • HER2 gene copy number seems to affect sensitivity to anti-EGFR agents. • HER2 amplification is one of the mechanisms responsible for acquired resistance to reversible EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs). • A combination of anti-EGFR and anti-HER2 agents should be considered in order to overcome acquired resistance to reversible EGFRTKIs. • Anti-HER2 agents, and in particular the combination of trastuzumab and chemotherapy, seem effective in HER2 mutant NSCLC. • Systematic genotyping testing should include detection of HER2 mutations.
EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts). J. Clin. Oncol. 31(Suppl.), Abstract 8000 (2013).
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Brabender J, Danenberg KD, Metzger R et al. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival. Clin. Cancer Res. 7, 1850–1855 (2001). Cappuzzo F, Varella-Garcia M, Shigematsu H et al. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. J. Clin. Oncol. 23(22), 5007–5018 (2005).
••
The results of this study highlight the mechanisms of sensitivity to EGF receptor-tyrosine kinase inhibitors (EGFRTKIs).
29
Shigematsu H, Lin L, Takahashi T et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J. Natl Cancer Inst. 97, 339–346 (2005).
30
Stephens P, Hunter C, Bignell G et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004).
31
32
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Arcila ME, Chaft JE, Nafa K et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin. Cancer Res. 18(18), 4910–4918 (2012).
34
Mazie`res J, Peters S, Lepage B et al. Lung cancer that harbors a HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J. Clin. Oncol. 31(16), 1997–2003 (2013).
••
First study reporting important insights of HER2-driven non-small-cell lung cancer (NSCLC).
35
Tomizawa K, Suda K, Onozato R et al. Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer 7, 139–144 (2011).
•
Early segnalation of trastuzumab activity in HER2 mutant NSCLC.
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39
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40
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Cantero R, Torres AJ, Maestro M, et al. Prognostic value of the quantified expression of p185 in non-small cell lung cancer. J. Thorac Cardiovasc. Surg. 119, 1119–1125 (2000).
44
Schneider PM, Praeuer HW, Stoeltzing O et al. Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer. Br. J. Cancer 83, 473–479 (2000).
45
46
47
48
49
50
51
52
53
overexpressing breast cancer cells in vitro and in vivo. Cancer Res. 61, 8887–8895 (2001). 54
55
Anido J, Matar P, Albanell J et al. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin. Cancer Res. 9, 1274–1283 (2003). Cappuzzo F, Gregorc V, Rossi E et al. Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J. Clin. Oncol. 21(14), 2658–2663 (2003).
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activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10, 25–38 (2006). 63
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. 344, 783–792 (2001).
64
Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376, 687–697 (2010).
65
Gatzemeier U, Groth G, Butts C et al. Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann. Oncol. 15, 19–27 (2004).
Carbognani P, Tincani G, Crafa P et al. Biological markers in non-small cell lung cancer. Retrospective study of 10 year follow-up after surgery. J. Cardiovasc. Surg. 43, 545–548 (2002).
56
Hirsch FR, Varella-Garcia M, Franklin WA et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br. J. Cancer 86, 1449–1456 (2002).
Cappuzzo F, Hirsch FR, Rossi E et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J. Natl Cancer Inst. 97(9), 643–655 (2005).
66
57
Takezawa K, Pirazzoli V, Arcila ME et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discovery 2, 922–933 (2012).
Langer CJ, Stephenson P, Thor A et al. Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598. J. Clin. Oncol. 22, 1180–1187 (2004).
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First trial describing in detail the role of HER2 amplification in acquired resistance to reversible EGFR-TKIs.
58
Yonesaka K, Zejnullahu K, Okamoto I et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3(99), 99ra86 (2011).
Krug LM, Miller VA, Patel J et al. Randomized phase II study of weekly docetaxel plus trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously untreated advanced nonsmall cell lung carcinoma. Cancer 104, 2149–2155 (2005).
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Zinner RG, Glisson BS, Fossella FV et al. Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease. Lung Cancer 44(1), 99–110 (2004).
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71
Perera SA, Li D, Shimamura T et al. HER2YVMA drives rapid development of adeno-squamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin
Takenaka M, Hanagiri T, Shinohara S et al. The prognostic significance of HER2 overexpression in non-small cell lung cancer. Anticancer Res. 31(12), 4631–4636 (2011). Liu L, Shao X, Gao W et al. The role of human epidermal growth factor receptor 2 as a prognostic factor in lung cancer: a meta-analysis of published data. J. Thorac Oncol. 5, 1922–1932 (2010). Cappuzzo F Cho YG, Sacconi A et al. p95HER2 truncated form in resected non-small cell lung cancer. J. Thorac Oncol. 7(3), 520–527 (2012).
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Lenferink AE, Pinkas-Kramarski R, van de Poll ML et al. Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J. 17, 3385–3397 (1998).
This work demonstrated the role of HER2 amplification in determining resistance to cetuximab in metastatic colorectal cancer.
59
Karunagaran D, Tzahar E, Beerli RR et al. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J. 15, 254–264 (1996).
Bertotti A, Migliardi G, Galimi F et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 1, 508–523 (2011).
60
Martin V, Landi L, Molinari F et al. HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients. Br. J. Cancer 108, 668–675 (2013).
Moasser MM, Basso A, Averbuch S et al. The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res. 61, 7184–7188 (2001). Moulder SL, Yakes FM, Muthuswamy SK et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-
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61
Agus DB, Akita RW, Fox WD et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2, 127–137 (2002).
62
Wang SE, Narasanna A, Perez-Torres M et al. HER2 kinase domain mutation results in constitutive phosphorylation and
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combination therapy. Proc. Natl Acad. Sci. USA 106, 474–479 (2009). ••
First clinical evidence for targeting HER mutant lung cancer.
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Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N. Engl. J. Med. 354(24), 2619–2621 (2006).
•
75
Cases of efficacy of afatinib-based therapy in pretreated NSCLC patients harboring HER2 mutations. Gandhi L, Bahleda R, Cleary JM et al. Two-dimensional phase I study of neratinib (NER) combined with temsirolimus (TEM) in patients (Pts) with solid tumors. J. Clin. Oncol. 29(Suppl.), Abstract 3027 (2011).
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Anecdotal case of efficacy of trastuzumab-based therapy in a heavily pretreated HER2 mutated NSCLC patient.
76
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Kris MG, Mok T, Ou S-HI et al. First-line dacomitinib (PF-00299804), an irreversible pan-HER tyrosine kinase inhibitor, for patients withEGFR-mutant lung cancers. J. Clin. Oncol. 30(Suppl.), Abstract 7530 (2012).
Engelman JA, Zejnullahu K, Gale CM et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 67, 11924–11932 (2007).
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Miller VA, Hirsch V, Cadranel J et al. Afatinib versus placebo for patients with advanced, metastatic non-small cell lung
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De Gre`ve J, Teugels E, Geers C et al. Clinical activity of afatinib (BIBW 2992) in
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cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 13, 528–538 (2012).
patients with lung adenocarcinoma with mutations in the kinase domain of HER2/ neu. Lung Cancer 76(1), 123–127 (2012). 78
Wong KK, Fracasso PM, Bukowski RM et al. A phase I study with neratinib (HKI272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin. Cancer Res. 15, 2552–2558 (2009).
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Cappuzzo F, Ligorio C, Janne PA et al. Prospective Study of Gefitinib in Epidermal Growth Factor Receptor Fluorescence In Situ Hybridization–Positive/Phospho-Akt– Positive or Never Smoker Patients With Advanced Non–Small-Cell Lung Cancer: The ONCOBELL Trial. J Clin Oncol. 2007; 25(16): 2248-2255
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Review
HER2 and lung cancer Expert Rev. Anticancer Ther. 13(10), 1219–1228 (2013)
Lorenza Landi and Federico Cappuzzo* Medical Oncology Department, Istituto Toscano Tumori, Ospedale Civile, viale Alfieri 36, 57100 Livorno, Italy *Author for correspondence: Tel.: +39 0586 223 189 Fax: +39 0586 223 457 [email protected]
In non-small-cell lung cancer (NSCLC), the identification of oncogenic driver mutations led to the definition of different clinical entities with different therapeutic opportunities, as demonstrated in patients harboring EGF receptor (EGFR) mutations or anaplastic lymphoma kinase translocations. Human EGFR2 (or HER2) has an established role as a prognostic and predictive factor in breast cancer. Although HER2 deregulation, including overexpression, amplification and mutation, has been described in NSCLC, its role as a therapy biomarker remains undefined. In the last few years, there has been a growing interest on HER2 mutation, with few anecdotal or retrospective studies suggesting a relevant role for this biomarker. This review discusses the prognostic and predictive impact of HER2 deregulation and the clinical implications of anti-HER2 strategies in NSCLC. KEYWORDS: anti-HER2 therapy • EGFR • HER2 • NSCLC • oncogenic driver
In 2013, once again, statistics reaffirmed nonsmall-cell lung cancer (NSCLC) as the leading cause of cancer-related death worldwide [1], with a median survival that rarely exceeds 10 months in unselected patients with metastatic disease treated using conventional chemotherapy [2]. Despite this discouraging picture, today we are used to considering NSCLC as a combination of different clinical entities with different prognoses and therapeutic opportunities. The identification of key genetic events driving tumor growth and metastatic spread led to the postulation of the concept of oncogene addiction. According to this model, the inhibition of certain molecular drivers by targeted agents could be effective in reducing tumor burden and improving patient outcome. In the last few years, collaborative groups conducted extensive analyses of lung cancer tissue specimens using modern techniques of genomic sequencing with the aim of deciphering the complexity of lung tumorigenesis [3,4]. As a result, a potentially actionable driver event can be found in more than 50% of newly diagnosed NSCLCs [3]. During the last few years, many molecular events driving tumor growth have been identified in patients with squamous cell carcinoma, including FGF receptor-1 (FGFR1) amplification or mutations, DDR2 or PIK3CA mutations, thus opening the door for personalized treatment [5–9]. Conversely, several molecular alterations have been described in
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10.1586/14737140.2013.846830
adenocarcinomas, especially but not exclusively, in the never/former smoker population. This is the case of the EGF receptor (EGFR) activating mutations, mainly represented by deletion in exon 19 or the L858R substitution in exon 21, and the EML4-ALK fusion gene [10–12]. Indeed, large randomized trials clearly demonstrated that in presence of EGFR mutations or EML4-ALK translocation, EGFR-tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib or afatinib or the anaplastic lymphoma kinase (ALK) inhibitor crizotinib are the best therapeutic choice we can offer today to our patients [13–21]. More recently, novel ‘biomarker slices’ have been added to the ‘adenocarcinoma pie’ such as RET and ROS1 fusion genes, BRAF, KRAS and HER2 mutations for which many targeted drugs are currently under investigation (FIGURE 1) [4,22,23]. In this context, the HER2 gene represents a relatively new biomarker for NSCLC. HER2 also known as human EGFR2 or ERBB2 or NEU, belongs to the ERBB family, which includes three other members: EGFR (HER1/ERB1), HER3 (ERBB3) and HER4 (ERBB4). The HER family represents an appealing target for anti-cancer strategies due to its central role in tumor growth. Indeed, similar to other receptors, all family members are structurally constituted by three domains: an extracellular domain responsible for ligand binding and homo/heterodimers formation, a transmembrane domain that
2013 Informa UK Ltd
ISSN 1473-7140
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Others
Adenocarcinoma
the last 15 years, several studies investigated the prognostic role of HER2 Squamous cell expression in lung cancer, with discordant carcinoma results [27,36–45]. In order to define whether HER2 levels, assessed using the FGFR FGFR HercepTest, could affect prognosis in amplification mutation NSCLC, in 2002 Hirsch et al. analyzed a EGFR Unknown series of 187 surgically resected lung Unknow tumor specimens. Thirty four tumors DDR2 (18%) showed positivity (2+/3+) on HercepTest, with only 3% having strong posKRAS itivity (3+). According to histological type, 32% of adenocarcinomas were posiPIK3CA BRAF ALK tive, contrasting with only 8% of squaFusion ROS oncogenes ERBB2 mous cell carcinomas. No difference in RET MEK 1 survival was observed among patients MET PIK3CA amplification with positive (HercepTest 2+/3+, n = 34) and negative (HercepTest 0/1+, n = 153) Figure 1. Molecular driver events in non-small-cell lung cancer. tumors, although the median survival for HercepTest 3+ individuals (n = 6) tended makes a single pass through the plasma membrane and a TK to be shorter. Similarly, no difference in survival was observed domain responsible for activation of two key signaling pathways, in patients with positive and negative tumors according to hisnamely, the RAS/RAF/MAPK pathway, which stimulates prolif- tology (adenocarcinoma vs squamous cell carcinoma) [46]. In a eration, and the PI3K/Akt pathway, which promotes tumor cell Japanese study, HER2 immunohistochemical levels were tested survival. Several ligands have been described for HER1, in more than 230 lung tumors obtained from a consecutive HER3 and HER4 including EGF, epiregulin, betacellulin, TGF surgical series. Immunohistochemistry (IHC) score was defined and neuregulins. Ligand binding triggers intracellular signaling as follows: 0 = none, 1 = weak, 2 = 10–30% of stained cells, through the formation of heterodimers or homodimers between ‡3 30% of stained cells. The authors confirmed an overall inciErbB receptors. Due to the lack of innate kinase function, dence of HER2 2+/3+ positivity of around 15%, with adenoHER3 can heterodimerize with other HER family members, carcinoma having the highest frequency rate (10%). especially with EGFR, thus potentiating its activity. Unlike Postoperative 5-year survival rates were 75.3, 77.8, 76.5 and EGFR, HER3 and HER4, HER2 has no known ligand. This 20.0% in patients with adenocarcinoma and HER2 scores were unique characteristic translates in the ability of HER2 to directly 0, 1, 2 and 3, respectively. Moreover, adenocarcinoma patients bind with the other family members including EGFR. On this with an IHC score of >3 had a significantly unfavorable surbasis, HER2 could modulate EGFR signaling. The role of vival compared to those with staining scores of 0–2 [47]. More HER2 as a proto-oncogene has been well defined for two recently, meta-analysis suggested that HER2 overexpression was decades. Its deregulation was detected in several types of malig- a poor prognostic factor in lung cancer, particularly in small nancies including breast cancer, gastric cancer and NSCLC [24–27]. cell lung cancer, adenocarcinoma and early-stage NSCLC In the present review, we critically analyze and report how patients [48]. Overall, based on available data it seems that, in HER2 is dysregulated in NSCLC and how this event could NSCLC, HER2 overexpression is a weak prognostic factor. affect patient prognosis and sensitivity to targeted therapies. HER2 gene amplification is an event occurring in less than 10% of cases. Unlike other cancer types, including breast, ovarPrognostic role of HER2 deregulation ian and gastric cancer, HER2 amplification does not have a Among the different mechanisms potentially responsible for clearly negative prognostic impact in NSCLC, as shown in the gene deregulation, HER2 expression, amplification and muta- previously mentioned meta-analysis [48]. tion have been most extensively investigated. HER2 In 2012, we published the results of a retrospective study overexpression – defined as moderate or strong (2+/3+) mem- evaluating the incidence and prognostic impact of HER2 branous staining – seems the most frequent event, reported in amplification in a cohort of 447 resected NSCLC patients [49]. up to 20% of cases, while HER2 amplification or mutation are HER2 gene copy number (GCN) gain was assessed by FISH. more rare and reported in up to 9 and 3% of cases, respec- No difference in survival was observed between patients with tively [27–35]. or without HER2 amplification (median: 38 vs. 41 months; HER2 overexpression or amplification correlates with poor p = 0.46), thus confirming the lack of prognostic impact for prognosis in different malignancies including breast and ovarian HER2 increased GCN gain in resected NSCLC [49]. cancers [24,25]. Nevertheless, in lung cancer, the role of HER2 The incidence of HER2 mutations ranges from 1 to 6%, overexpression and amplification remains controversial. During with the highest frequency described in a highly selected 1220
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population (TABLE 1) [4,29–34]. HER2 mutations occur in the first four exons of the TK domain (exons 18–21) and are mainly represented by a 12 bp duplication/insertion of the amino acid sequence YVMA in exon 20 at codon 776 (HERYVMA). Arcila et al. recently published the first largest retrospective study of a series of Caucasian NSCLC patients tested for HER2 and other molecular alterations [33]. The authors reported an unusual incidence of HER2 mutations of 5% in a ‘super-selected’ EGFR/KRAS wild-type population and, more interestingly, this event was mutually exclusive with point mutations in BRAF, PIK3CA, MEK1 and AKT genes [33]. As previously observed in EGFR mutated patients as well as in those carrying an ALK, ROS1 or RET fusion gene, the presence of HER2 mutations seems associated with female gender, adenocarcinoma subtype and never smokers [34]. Importantly, as observed for other biomarkers, clinical characteristics are not sufficient for selecting patient candidates for HER2 mutation screening, as confirmed by the detection of such events in male and heavy smoker patients [34,35]. Because of the low incidence, the prognostic impact of HER2 mutations in the natural history of NSCLC is not fully elucidated and recent literature data are discordant. Arcila et al. analyzed the survival outcome of 468 NSCLC patients with advanced disease according to the presence of EGFR mutations, KRAS mutations, BRAF mutations, ALK translocations or HER2 mutations. Although the overall survival of the HER2 cohort was not statistically different from the other molecularly defined cohorts, the worst survival performance was observed among patients with HER2 or KRAS mutations [33]. On the other hand, Mazie`res and coworkers recently reported a possible indolent outcome of HER2 mutant NSCLC when compared to an unselected NSCLC population [34]. Therefore, the few available data are not enough for defining whether HER2 mutations are prognostic in NSCLC. HER2 dysregulation as predictive of sensitivity to antiEGFR agents
Preclinical findings suggest that HER2 dysregulation could modify tumor sensibility to anti-EGFR agents. In fact, HER2 is the major partner of EGFR and activated heterodimeric complexes containing HER2 are more stable at the cell surface than complexes containing other EGFR family members [50]. In addition, HER2 can decrease the rate of ligand dissociation from the cognate receptor EGFR [51]. Finally, EGFR signaling through phosphorylation of the intracellular TK domain of the protein can be blocked by small-molecule EGFR-TKIs [52–54]. Ten years ago, at the beginning of our studies on the EGFR family, we analyzed a cohort of 63 pretreated NSCLC patients exposed to gefitinib in order to evaluate the correlation between HER2 expression and efficacy to anti-EGFR therapy in terms of response rate (RR), time to progression (TTP) and overall survival (OS) [55]. HER2 levels were assessed by IHC using the 0 to 3+ scale and considering a staining intensity of 2+ or 3+ in more than 10% of cells as positive. We also evaluated the www.expert-reviews.com
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levels of EGFR by IHC. Fifteen (34.8%) out of the 43 patients evaluable for HER2/EGFR status were labeled HER2 2+/3+, while 28 (65.2%) patients were labeled negative. No significant differences were observed in terms of disease control rate (DCR: 40 vs 64.3%), TTP (3.5 vs 3.7 months) and OS (5.7 vs 6.8 months) in HER2 overexpressing and HER2 negative patients, respectively, thus suggesting that HER2 overexpression was not useful for predicting sensitivity to gefitinib in unselected NSCLC patients [55]. To further evaluate the role of HER2 dysregulation in modulating sensitivity to EGFR-TKIs, 2 years later we investigated whether HER2 genomic gains, assessed using FISH, were associated with sensitivity to gefitinib in 102 pretreated advanced NSCLC patients [28]. HER2 amplification was detected in 9% of cases and we considered as positive all patients with high polysomy or gene amplification, using the same criteria adopted for EGFR [56]. HER2 FISH positive patients had better outcome than HER2 FISH negative individuals, probably because HER2 GCN gain was associated with the major predictors for gefitinib sensitivity, which are EGFR mutations. More recently, Takezawa et al., showed that high levels of HER2 amplification contribute to acquired resistance to EGFR-TKIs in approximately 12% of cases [57]. Overall, all these data suggest a strong predictive role of HER2 GCN gain. Indeed, in presence of HER2 increased copy number, EGFR and HER2 cooperate leading tumor cells to be highly dependent on the HER axis and more vulnerable to anti-EGFR treatment. Conversely, in the presence of high levels of HER2 amplification, HER2 becomes an essential driver for tumor growth and metastatic spread, irrespective of EGFR inhibition. Similar findings have been observed in metastatic colorectal cancer (mCRC) treated with anti-EGFR monoclonal antibody. At the preclinical level, the amplification of the HER2 gene has been correlated with cetuximab resistance due to the continued activation of EGFR downstream pathways when cetuximab is bound to EGFR [58,59]. Our group evaluated the HER2 gene status by FISH in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab alone or in combination with chemotherapy in different lines of treatment [60]. According to HER2 GCN status, 4% of patients had HER2 gene amplification, 61% had HER2 gain due to polysomy or gene amplification in minor clones and 35% had no or slight HER2 gain. HER2 amplified patients had the worst outcome in terms of RR (p = 0.0006), progression-free survival (PFS; p = 0.0001) and OS (p = 0.0001). Conversely, patients with HER2 polysomy had the highest survival probability [60]. Although HER2 mutations have been described in 2004, the interest in translational research in this defined molecular setting emerged only in the last few years. The presence of mutation translates into a conformational change in the kinase domain of the receptor, leading to an increased kinase activity compared to the wild-type form. HERYVMA is able to activate EGFR in a ligand-independent fashion and irrespective of the presence of an activating EGFR mutation [61,62]. In vitro studies demonstrated that HERYVMA clones are resistant to reversible 1221
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Table 1. HER2 mutant lung cancers: clinical characteristics and incidence in recent trials. Study (year)
Patients (n)
Stage
Ethnicity
Incidence (n/%)
Female (%)
Histology
Never smoker (%)
Stephens et al. (2004)
120
NR
NR
5/4
NR
ADC
NR
[30]
Shigematsu et al. (2005)
671
Resected
Asian/Caucasian
11/1.6
63.6
ADC
81.8
[29]
Buttitta et al. (2006)
403
Resected
Caucasian
9/2.2
66.6
ADC
33.3
[32]
Sasaki et al. (2006)
95
All
Asian
1/1.0
100
ADC
100
[31]
Tomizawa et al. (2011)
504
Resected
Asian
13/2.6
77
ADC/AS
84.6
[35]
Cappuzzo
42†
III/IV
Caucasian
2/5.4
100
ADC
100
[79]
‡
Ref.
Arcila et al. (2012)
560
All
Asian/Caucasian
25/4.4
68
ADC
68
[33]
Barlesi et al. (2013)
10,000
All
Caucasian
NR/0.9
NR
ADC
NR
[4]
†
37/42 evaluated patients. EGFR/KRAS wild-type population. ADC: Adenocarcinoma; AS: Adenosquamous; NR: Not reported.
‡
EGFR-TKIs such as gefitinib and erlotinib, while they remain sensitive to HER2 and dual EGFR/HER2 inhibitors [61]. Clinical impact of anti-HER2 strategies in NSCLC
Trastuzumab, the humanized monoclonal IgG1 targeting the extracellular domain of HER2, has already had an impact on the treatment of 20% of breast cancer patients with HER2 protein overexpression and recently it also gained niche status in the treatment of patients with HER2 overexpressing gastric cancer [63,64]. In NSCLC patients, pivotal Phase II studies demonstrated only modest activity and results were disappointing [65–70]. Efficacy results of published trials evaluating the efficacy of anti-HER2 monoclonal antibodies in NSCLC are summarized in TABLE 2. In the first-line setting, adding trastuzumab to standard platinum-based chemotherapy in NSCLC HER2 IHC positive patients did not translate into improvement in terms of RR, PFS and OS, although the small fraction of IHC 3+ or HER2 FISH amplified patients tended to have a longer duration of response when treated with trastuzumab [65]. Overall, three main issues were noted from these trials. First, it is unknown whether this effect was related to trastuzumab or to chemotherapy, considering that HER2 amplification is frequently associated with EGFR gene amplification and mutation – a biological event increasing sensitivity to antiEGFR agents as well as to chemotherapy. Second, it is reasonable to assume that in lung cancer HER2 amplification could be clinically irrelevant and other molecular abnormalities, such as HER2 mutation, could be responsible for the sensitivity of trastuzumab. Third, there is no consensus on the IHC scoring system for considering a patient as ‘HER2 positive’, thus 1222
resulting in some imbalance in comparing efficacy data. Also pertuzumab, a monoclonal antibody that binds the dimerization domain of HER2 and inhibits HER2 signaling, failed to demonstrate any benefit (RR: 0%) when used as a single agent in an unselected NSCLC population [70]. In a prematurely closed trial, we tried to assess the efficacy of trastuzumab in HER2 amplified or HER2 mutated pretreated NSCLC (NCT00758134). No response was observed among the 10 HER2 FISH amplified patients included in the study, while no HER2 mutated individuals were enrolled (UNPUBLISHED DATA). The demonstration that HER2-mutant transgenic mice rapidly developed lung cancer [71] led to the proposition that HER2 mutation is more relevant than HER2 amplification or overexpression as an oncogenic driver as well as a predictive factor for sensitivity to anti-HER2 therapy. Moreover, preclinical experiences revealed that NSCLC cell lines harboring HER2 mutations are sensitive to trastuzumab therapy [62] and anecdotal cases confirmed this assumption [34,35,72]. In 2006, we firs reported the clinical case of a woman with lung adenocarcinoma who failed to respond to three lines of therapy including an EGFR-TKI and was successfully treated with the paclitaxel–trastuzumab combination. The genetic make-up of her disease consisted of a mutation in exon 20 of the HER2 gene, but surprisingly FISH analysis also revealed increased numbers of copies of both HER2 and EGFR genes [72]. A similar experience had been described by Tomizawa and colleagues, who observed a long-lasting remission in a HER2 mutated female adenocarcinoma patient treated with trastuzumab and vinorelbine as third-line therapy [35].
Expert Rev. Anticancer Ther. 13(10), (2013)
HER2 & lung cancer
Review
Table 2. Published trials evaluating anti-HER2 monoclonal antibodies in advanced non-small-cell lung cancer. Study (year)
Phase
Patients (n)
Treatment
HER2 status
RR (%)
mPFS (months)
mOS (months)
Gatzemeier et al. (2004)
IIR
103
Langer et al. (2004)
II
Lara et al. (2004)
Ref.
Cddp/gem + trastuzumab‡
IHC/FISH†
36 41
6.1 7.0
NR 12.2
[65]
56
Cbdca/paclitaxel + trastuzumab‡
IHC
24.5
3.3
10.1
[66]
II
13
Docetaxel + trastuzumab
IHC
8
NR
5.7
[68]
Zinner et al. (2004)
II
21
Cddp/gem + trastuzumab‡
IHC/ELISA§
8
9.0
NR
[69]
Krug et al. (2005)
IIR
65
Docetaxel + trastuzumab‡ Paclitaxel + trastuzumab‡
IHC
23 32
NR NR
16 14
[67]
Herbst et al. (2007)
II
43
Pertuzumab
IHC
0
1.5
NR
[70]
†
FISH test was performed only in IHC 3+ patients. First-line treatment. Serum Her2 shed antigen level of at least 15 ng/ml by ELISA. Cbdca: Carboplatin; Cddp: Cisplatin; gem: Gemcitabine; IHC: Immunohistochemistry; mOS: Median overall survival; mPFS: Median progression-free survival; NR: not reported; R: Randomized; RR: Response rate. ‡ §
In the retrospective series published by Mazie`res and coworkers [34], 16 patients received an HER2 targeted therapy, including trastuzumab, lapatinib, afatinib or masatinib, after first-line conventional platinum doublet chemotherapy with or without bevacizumab failure. Because 6 patients received up to four additional anti-HER2 drugs, a final cohort of 22 patients was evaluable for activity. Overall, the RR was 50% with a DCR of 82%. The greatest benefit was obtained for the combination of trastuzumab and chemotherapy (15 treated patients; DCR: 96%) and afatinib monotherapy (4 treated patients; DCR: 100%), while no benefit was observed for lapatinib or mosatinib therapy [34]. Several kinase inhibitors are under investigation in HER2driven lung adenocarcinoma, including irreversible TKIs targeting HER2 and EGFR, such as dacomitinib (PF-00299804), afatinib (BIBW-2992) and neratinib (HKI-272) [73–75]. In preclinical models, these agents effectively inhibited the growth of HER2-mutant lung cancer clones [76]. Dacomitinib (PF-00299804) covalently binds the ATP domain of each of the three kinase active members of the HER family: EGFR/HER1, HER2 and HER4, and in preclinical studies it showed greater antitumor activity in gefitinib-resistant NSCLC in vitro and in vivo models [76]. More recently, Kris and colleagues reported the results of the 1017 trial, a Phase II study exploring the efficacy in terms of PFS rate at 4 months (PFS at 4 M), PFS and partial response of dacomitinib at the dose of 30–45 mg daily in two different cohorts: the EGFR cohort included never or light former smoker (24 weeks) was observed in 43% of refractory NSCLC patients [75]. Neratinib was also evaluated in combination with temsirolimus in adenocarcinoma patients carrying the HER2 mutation [78]. The rationale for 1223
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Landi & Cappuzzo
Table 3. Ongoing trials with anti-HER agents in non-small-cell lung cancer. Trial
Phase
Patients (n)
LUX-Lung 5 (NCT01085136)
III
1021
NCT00818441
II
114
NCT01827267
IIR
84
Treatment
Molecular selection
Setting
Primary end point
Status
Afatinib vs afatinib/paclitaxel
NR
Third line
PFS
Active, not recruiting
Dacomitinib
Cohort A: EGFR mutated Cohort B: HER2 FISH +ve or HER2 mutation +ve
First line†
PFS
Active, recruiting
Neratinib vs neratinib + temsirolimus
HER2 mutation +ve
Second line and subsequent
RR
Recruiting
† Only for cohort B. NR: Not required; PFS: Progression-free survival; R: Randomized; RR: Response rate.
testing the dual inhibition of Akt/mTOR and HER pathways was derived from a preclinical transgenic mouse model in which the antitumor activity of afatinib was potentiated by the addition of rapamycin [71]. In this Phase I trial, the treatment combination produced a partial response in two out of six enrolled patients [78]. Some of the ongoing trials exploring anti-HER2 strategies in NSCLC are reported in TABLE 3. Expert commentary
The treatment of NSCLC has dramatically changed with the identification of key genetic driver alterations. Furthermore, two important issues were derived from this translational revolution. First, the knowledge of genetic makeup of a metastatic lung tumor at baseline can allow the assignment of patients to target treatment according to the specific profile of their tumor. Indeed, large clinical trials confirmed that targeted therapies are the best treatment option only when the target is present, with no benefit or even a detrimental effect when a targeted agent is given in unselected populations [12–21]. Second, the use of sophisticated genomic techniques allows, today, the identification of many potentially driving events, for which often the proper agent is not available in clinical practice. Therefore, in clinical practice, also considering the difficulties in obtaining tumor tissue in NSCLC, priority should be given to standard biomarkers, such as EGFR mutations and ALK translocations, and all other biomarkers, including HER2, remain under investigation. HER2 represents an old biomarker, since its prognostic and predictive role has been extensively evaluated for many years. Although up to 30% of NSCLC cases display HER2 overexpression, amplification or mutation, the prognostic significance of HER2 dysregulation remains undefined [33–48]. Conversely, preclinical and clinical data suggest that HER2 gene amplification plays an important predictive role [56–58]. Low levels of HER2 amplification seems predictive for sensitivity to reversible EGFR-TKIs, although in clinical practice the only validated biomarker for EGFR-TKI naive patients still remains EGFR mutations. By contrast, in the presence of high HER2 genomic gain, the tumor became HER2 addicted and therefore resistant to EGFR inhibition [56–58]. Therefore, the 1224
combination of anti-EGFR and anti-HER2 agents should be investigated as a potential strategy to overcome the acquired resistance to EGFR-TKIs. Moreover, based on these observations it is not possible to exclude that the apparent superiority of irreversible EGFR-TKIs versus reversible EGFR-TKIs in terms of PFS observed in large studies of chemonaive EGFR mutant NSCLC could in some way be related to the ability of afatinib and dacomitinib to interfere with HER2 function. HER2 mutations seem a relevant target in advanced NSCLC, and small studies reported encouraging results of antiHER2 agents, particularly for trastuzumab-based therapy. HER2 mutations are mutually exclusive with other genetic alterations and they identify a distinct group of NSCLC, mainly represented by subjects of female gender, never smokers and with adenocarcinoma [29–35]. Early anecdotal reports highlighted the anti-tumor activity of trastuzumab in combination with chemotherapy in heavily pretreated HER2 mutant lung cancer [35,72]. In the largest published series, Mazie`res et al. reported an impressive RR of nearly 60% for HER2 mutation positive subjects receiving trastuzumab and chemotherapy [34], quite similar to the one observed in EGFR mutant or ALK positive patients treated with an EGFR-TKI and crizotinib, respectively [13–21]. Although the retrospective and preliminary nature of this work requires us to interpret these results with caution, they deserve a deeper reflection. First, it is reasonable to consider this alteration as a real oncogenic driver [71]. Second, although the detection of HER2 mutation is a rare event occurring in less than 3% of cases [29–35], considering the annual incidence of NSCLC [1], targeting HER2 mutations could be beneficial for thousands of patients each year in Western countries and elsewhere. Third, testing for HER2 mutations should be routinely included in the panel of molecular assessment of advanced NSCLC. Finally, from a practical point of view, while waiting for confirmatory data, the treatment with a drug that is already available such as trastuzumab could represent a valid therapeutic option to be discussed with HER2 mutant patients excluded from clinical trials. In breast cancer, new anti-HER2 agents, such as pertuzumab or TDM1, demonstrated efficacy in HER2 amplified patients. We believe that these agents could play an important role even Expert Rev. Anticancer Ther. 13(10), (2013)
HER2 & lung cancer
in NSCLC only if they are properly investigated, avoiding some methodological issues such as the lack of any selection criterion, which so far has probably precluded the approval of any anti-HER2 agent in lung cancer. Five-year view
The story of NSCLC treatment is rapidly changing over the years. The discovery of actionable drivers have led to novel and more effective drugs, but only for a small fraction of patients. In this scenario, HER2 is emerging as a ‘vintage’ target in NSCLC, and among its abnormalities, HER2 mutations surely represent an oncogenic druggable driver. In the coming years, the development of anti-HER2 targeted agents will offer the opportunity for improving patient outcomes, but careful biological selection will remain crucial for better defining which patients will most benefit from such treatment. As demonstrated for other targeted therapies, the availability of anti-
Review
HER2 agents and a growing knowledge of the HER2 pathway will uncover mechanisms responsible for acquired resistance to such agents. Last but not the least, another key challenge in the near future will be to develop efficient assays for identifying a wide spectrum of genomic alterations, in order to understand all of the mechanisms correlated with drug sensitivity and, more importantly, to ensure that the best therapeutic option is available to patients. Financial & competing interests disclosure
Supported in part by the Italian Association for Cancer Research (AIRC) and Associazione Oncologia Traslazionale (AOT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Oncogenic driver mutations identify different lung cancers subtypes. • In non-small-cell lung cancer (NSCLC), HER2 is one of the more interesting biomarkers that is considered to play a central role in cancer proliferation. • HER2 is overexpressed, amplified or mutated in a significant fraction of lung adenocarcinomas. • The prognostic significance of HER2 dysregulation remains undefined. • HER2 gene copy number seems to affect sensitivity to anti-EGFR agents. • HER2 amplification is one of the mechanisms responsible for acquired resistance to reversible EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs). • A combination of anti-EGFR and anti-HER2 agents should be considered in order to overcome acquired resistance to reversible EGFRTKIs. • Anti-HER2 agents, and in particular the combination of trastuzumab and chemotherapy, seem effective in HER2 mutant NSCLC. • Systematic genotyping testing should include detection of HER2 mutations.
EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts). J. Clin. Oncol. 31(Suppl.), Abstract 8000 (2013).
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••
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