Advanced HER2-positive gastric cancer: Current and future targeted therapies

Critical Reviews in Oncology/Hematology 85 (2013) 350–362

Advanced HER2-positive gastric cancer: Current and future targeted therapies Roberto A. Pazo Cid ∗ , Antonio Antón Aragon Institute of Health Sciences, Medical Oncology Department, Miguel Servet University Hospital, Zaragoza, Spain Accepted 29 August 2012 The authors would like to dedicate this paper to the memory of Carla Delibes Senna-Cheribbo, MD.

Contents 1. 2. 3. 4.

5.

6. 7.

8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HER2 in gastric cancer: molecular and pathological features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HER2 overexpression and prognosis of gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Testing HER2 expression in gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Chromosome 17 polysomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. HER2 status in primary and metastatic sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . First-line treatment for HER2-positive AGC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Predictive biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Second-line treatment for HER2-positive AGC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms of trastuzumab resistance in gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Strategies to overcome trastuzumab resistance in gastric cancer: future therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. mTOR inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. HSP90 inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Trastuzumab-emtansine (T-DM1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Pertuzumab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Pan-HER TKIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6. Lapatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7. Met inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.8. Radioimmunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9. HER2 vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract The prognostic value of human epidermal growth factor receptor 2 (HER2) in gastric cancer is controversial. Consensus guidelines have standardized the testing of HER2 status in gastric cancer. Overexpression of this receptor occurs in approximately 20% of gastric and gastroesophageal junction adenocarcinomas, predominantly those of the intestinal type. Recently, trastuzumab has emerged as the first targeted drug to improve overall survival when combined with chemotherapy in advanced HER2-positive gastric cancer. Primary and secondary ∗ Corresponding author at: Medical Oncology Department, Hospital Universitario Miguel Servet, Paseo Isabel la Catolica, 1-3, 50009 Zaragoza, Spain. Tel.: +34 976 765 500x1147; fax: +34 976 359 268. E-mail address: [email protected] (R.A. Pazo Cid).

1040-8428/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.critrevonc.2012.08.008

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resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed. A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy. New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, heat-shock protein 90 (HSP90) inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T-DM1), could offer alternative second-line treatments when trastuzumab-based first-line therapy fails. © 2012 Elsevier Ireland Ltd. All rights reserved. Keywords: Gastric cancer; Human epidermal growth factor receptor; Trastuzumab resistance; Multitargeted tyrosine kinase inhibitors; Second line therapies; Targeted therapies

1. Introduction Gastric cancer is the fourth most commonly diagnosed cancer worldwide and is the second leading cause of cancerrelated deaths [1]. Although there has been a 3.75% annual decrease in mortality since 1997, the survival rate remains poor for this disease [2]. First-line chemotherapy for advanced gastric cancer (AGC) increases overall survival (OS) compared with best supportive care; nonetheless, for many years, no chemotherapy regimen could offer a mean OS of more than 12 months. A meta-analysis showed that a combination of two drugs (usually fluorouracil and cisplatin) was more beneficial than monotherapy [3]. The addition of a third drug, such as anthracycline or docetaxel, to a platinum–fluoropyrimidine combination also improves survival [4,5]. The same analysis indicated that treatment regimens containing irinotecan (CPT-11) offer a non-statistically significant improvement of OS [3]. Finally, both capecitabine and oxaliplatin have been shown to be non-inferior to fluorouracil and cisplatin, respectively, in terms of OS and progression-free survival (PFS) [5,6]. Preclinical studies have demonstrated the antitumor activity of trastuzumab in gastric cancer cell lines overexpressing human epidermal growth factor receptor 2 (HER2) [7,8]. In the Trastuzumab for Gastric Cancer (ToGA) trial, the addition of trastuzumab to chemotherapy significantly improved OS compared with chemotherapy alone in patients with HER2positive AGC, achieving a median OS of 13.8 months in the trastuzumab plus chemotherapy group [9]. Approximately 20% of gastric cancers overexpress HER2 [10]. This review will focus on the diagnosis, outcomes and present and future HER2-targeted therapies for advanced HER2-positive gastric cancer.

2. HER2 in gastric cancer: molecular and pathological features The HER2 protein is a transmembrane tyrosine kinase (TK) receptor belonging to a family of epidermal growth factor receptors (EGFRs) that comprise four members (HER1 or EGFR, HER2, HER3 and HER4) [11]. HER2

amplification is associated with adverse pathological features, such as increased tumor size, serosal invasion and lymph node metastases [7]. HER2, which has no identified ligand, is the preferred heterodimerization partner of the other HER family members. The HER2-HER3 heterodimer is the most active HER signaling dimer and plays a critical role in oncogenic transformation in HER2-driven tumors [12]. Dimerization precedes the transactivation of the TK part of the receptor, which subsequently activates downstream proteins, including members of the Ras/Raf/mitogen-activated protein kinase (Ras/Raf/MAPK) and phosphatidylinositol3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathways, as well as gene transcriptional programs [13].

3. HER2 overexpression and prognosis of gastric cancer Unlike the poor prognosis associated with HER2 positivity in breast cancer, the prognostic value of HER2 in gastric cancer is a controversial issue. Almost all of the studies published on this subject are retrospective analyses of variably sized series of post-resection gastric cancer patients. Recent studies (published since 2009) may be considered more reliable than the older ones (published from 1991 to 2008) due to the use of more standardized techniques to test HER2 tumor status and the greatly increased sample sizes. Between 1991 and 2008, nine relevant studies (involving a total of 1413 patients) demonstrated a direct association between HER2 overexpression in gastric cancer and significantly worse OS [7,14–21], while only four studies (involving a total of 1037 patients) did not find such a correlation [22–25]. From 2009 to the present, eleven American, European and Asian studies (involving a total of 5869 patients) have found that HER2 overexpression does not impact the prognosis of gastric cancer [26–36], whereas only six studies (involving a total of 3199 patients) have reported HER2 positivity to be a poor prognostic factor [37–42]. Therefore, the role of HER2 overexpression in gastric cancer survival remains unclear; arguably, it has little impact on prognosis.

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4. Testing HER2 expression in gastric cancer HER2 overexpression can be determined by immunohistochemistry (IHC) using a monoclonal antibody or by the detection of HER2 gene amplification through fluorescent in situ hybridization (FISH). Increased expression of HER2 has been detected in 13–23% of patients with gastric cancer [14–42]. The use of IHC to determine HER2 overexpression was recently validated for gastric cancer application [43]. This validation required some adaptations of the HER2 expression scoring system because of the incomplete immunoreactivity of gland cells (which express HER2 predominantly along the basolateral or lateral cell membrane) and/or the greater heterogeneity of HER2 expression/amplification in gastric cancer (found in up to 30–80% of HER2-positive cases), compared with that in breast cancer (Table 1) [43–45]. After these adaptations were made, there was an 87–93% concordance rate between the IHC and FISH results [43,44]. Based on these criteria, studies involving patients from Europe, Latin America and Asia who had AGC or cancer of the gastroesophageal junction (GEJ) confirmed the differences in HER2 expression according to both the histological type (intestinal 34%, diffuse 6%, and mixed 20%) and the location of the primary tumor (GEJ 32% and gastric 18%) [46–48]. Similar HER2 overexpression rates have been observed in esophageal adenocarcinoma and GEJ cancers [46–48]. In Asians, most gastric tumors arise distally to the GEJ. Large, unselected Asian population series show lower HER2 positivity rates (ranging from 6 to 15%) than those from Western countries (ranging from 10 to 23%) [26–42]. Mutation or epigenetic silencing of the E-cadherin gene seems to be a key carcinogenic event in diffuse gastric cancer, but rare in the intestinal-type. E-cadherin mutations are inversely associated with HER2 gene amplification, which may partly explain the correlation between the intestinal-type histology and HER2 overexpression [49]. There is controversy regarding the best system for HER2testing in gastric cancer and whether it should be similar to or different from the system used in breast cancer. This question was recently addressed by the College of American Pathologists and several European groups (Table 1) [44,50,51]. When these new criteria are applied, the HER2 positivity rates in gastric cancer are slightly higher for biopsies than for surgical specimens (positivity rates of approximately 22% and 19%, respectively) [26,46]. IHC appears to be more predictive of truly HER2-driven tumors than FISH; therefore, the latter should be reserved for the reclassification of IHC 2+ cases [44,46,50,51]. 4.1. Chromosome 17 polysomy Chromosome 17 polysomy, defined as ≥3 chromosome 17 signals detected by in situ hybridization techniques, was found in only 4.1% of the gastric cancer tumors screened in the ToGA trial [9]. According to other series data, polysomy

occurred in up to 35% of cases [27]. Sometimes, polysomy may represent a coamplification of the centromere region of chromosome 17 rather than a true polysomy (i.e., an increased copy number of the whole chromosome 17). HER2 copy number may be far more important than chromosome 17 copy number for predicting the benefit of trastuzumab [52]. 4.2. HER2 status in primary and metastatic sites Unlike in breast cancer, there are currently no definitive data available addressing HER2 status in primary and metastatic sites in gastric cancer patients. In three studies, there was a high level of agreement between HER2 status in primary gastric cancers and tumor metastasis, suggesting that the HER2 status remains unchanged during the metastatic process in most cases [53–55].

5. First-line treatment for HER2-positive AGC The humanized recombinant monoclonal antibody trastuzumab exerts its therapeutic effects through two possible mechanisms. The first, a direct mechanism, blocks HER2 signaling pathways and reduces the expression of this receptor, leading to an inhibition of angiogenesis, a reduction in DNA repair and the induction of apoptosis. The second indirect mechanism is mediated by antibody-dependent cellular cytotoxicity (ADCC) (Fig. 1) [56]. The ToGA trial randomly assigned 594 patients (50% of whom were of Asian origin) with HER2-positive gastric adenocarcinomas (80%) or GEJ cancers (20%) into either a control group treated with cisplatin and capecitabine/fluorouracil (CX) or an experimental treatment group in which trastuzumab was added to the aforementioned dual drug combination (T + CX). A significant increase in OS was observed in the T + CX treatment group compared to the CX group (13.8 and 11.1 months, respectively; p = 0.0046) [9]. This implied a 26% reduction in mortality risk for the patients in the T + CX group. The overall response rate was also greater in the antibody-containing treatment arm (T + CX 47% and CX 35%; p = 0.0017). In this trial, the frequency of IHC 0/1 samples that proved to be FISH+ was similar to that of IHC 2+/FISH+ samples (23% and 26%, respectively); however, it should be emphasized that the benefit derived from trastuzumab was negligible in the group of IHC 0/1/FISH+ patients, suggesting that the FISH results for these patients may have been false positives and that their tumors were not driven by HER2 (Fig. 2). The cohort of patients that were IHC 3+ or IHC 2+/FISHpositive, the “strongly HER2-positive” group, exhibited the greatest benefit from trastuzumab in the ToGA trial, with a median OS of 16 months (HR 0.65; 95% CI 0.51–0.83) (Fig. 2) [9]. Of note, the median OS of 11.1 months observed in the CX control group was longer than the 7.2–8.6 months reported with cisplatin-5FU in large randomized trials [57,58]. The high proportion of patients receiving

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Fig. 1. Mechanisms of action of trastuzumab. Source: From Ref. [56], used with permission.

Fig. 2. (A) Exploratory analyses of patients stratified by human epidermal growth factor receptor 2 (HER2) status and (B) overall survival curves in patients with IHC 3+ tumors or IHC 2+ and FISH+ tumors from the ToGA trial. Source: From [9], used with permission.

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Table 1 Comparison of differences in HER2 testing between gastroesophageal and breast cancer. Gastric cancer IHC positive score: number of positive cells

IHC score: in situ component IHC score 3+: pattern of membrane staining Intratumoral heterogeneity of HER2 positivity FISH amplified HER2 gene: HER2:CEP 17 ratio FISH analysis: number of cells required IHC/FISH concordance IHC vs. FISH

Breast cancer

≥5 clustered cells in biopsy ≥10% (≥ 30%)a of tumor cells specimens ≥10% of tumor cells in resection specimens If positive in situ component, the Not scored tumor is classified as HER2+ Allowed for cases with only a lateral Full circumferential staining pattern is required or basolateral staining pattern High Moderate Ratio ≥ 2.0 Ratio ≥ 2.0 (≥2.2)a 20 cohesive tumor cells showing the highest gene count (add 20 new cells if ratio 1.8–2.2) 83% 85–95% IHC is more predictive than FISH: IHC and FISH are equally predictive IHC primary testb ; FISH if IHC 2+

IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor-2; CEP 17, chromosome 17 centromere. a According to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists. b According to approval by the European Medicines Agency.

second-line therapy in this trial may be the confounding factor explaining this result. In addition, given the supposed better prognosis of the intestinal histological subtype as well as the Asiatic population, this result may be due primarily to the high rate of the intestinal-type histology (74%) and secondarily to the large proportion of Asian patients (50%) enrolled into the ToGA trial. Furthermore, the patients treated with T + CX in the ToGA trial demonstrated improvement in all of the secondary efficacy endpoints including PFS (6.7 months vs. 5.5 months), the time to progression (7.1 months vs. 5.6 months), the duration of the response (6.9 months vs. 4.8 months) and the overall response rate (47% vs. 35%); no differences were observed in the quality of life [9,59]. The addition of trastuzumab to CX in the ToGA trial was well-tolerated, with no differences in the incidence of grade 3 and 4 events between the two groups. There were especially few differences in the incidence of cardiac (6% in both treatment arms) and congestive heart failure events (<1% in both arms) [9]. A cost-effectiveness analysis of the Japanese and Korean populations of the ToGA trial concluded that trastuzumab for the IHC 3+ population was cost-effective, whereas the cost-effectiveness of treating IHC 2+/FISH+ patients was debatable [60]. Using trastuzumab to treat the entire HER2positive AGC population may not be cost-effective and deserves further investigation. Trastuzumab was approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for patients with HER2-positive metastatic adenocarcinoma of the stomach or GEJ who have not received previous anticancer therapy for metastatic disease. According to the EMA, HER2 overexpression is defined by IHC2+ and a confirmatory FISH+ result, or IHC3+. Due to limitations in evaluating HER2 status, the FDA has discouraged the use of a single testing method to exclude patients from receiving trastuzumab.

New, cisplatin-free, less toxic, trastuzumab-based firstline therapies are being tested in clinical trials and may be as effective as cisplatin-containing regimens (Table 2) [61]. 5.1. Predictive biomarkers There are no definitive biomarkers that allow the selection of patients who will respond to trastuzumab. Since many molecular pathways are involved in gastric tumor carcinogenesis, it is difficult to find tumors predominantly addicted to a constitutively active HER2 pathway. Levels of HER2 expression might predict the response to trastuzumab, as reported in the post hoc analysis of OS in the “strongly HER2-positive” group in the ToGA trial [9]. Breast cancer patients with low levels of HER2 homodimers and high levels of HER2-HER3 heterodimers exhibit a diminished response to trastuzumab; conversely, high levels of HER2 homodimers correlate with a longer time to progression following trastuzumab therapy [62]. In one study, HER2-HER3 coexpression was observed in 15% of resected gastric tumors and did not correlate with survival [40]. No data are available on gastric cancer response to trastuzumab according to the type of HER heterodimers/homodimers expressed. A phase II trial exploring the efficacy of trastuzumab combined with cisplatin as first-line therapy in HER2-positive AGC reported higher baseline HER extracellular domain (ECD) levels in patients with a better outcome in terms of response, PFS and OS. There were no differences in HER2ECD baseline levels or HER2-ECD dynamics between the responders and non-responders in this study [63]. 5.2. Second-line treatment for HER2-positive AGC In the ToGA study, slightly more than 40% of the patients from Western countries, in both the CX and T + CX groups,

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Table 2 Ongoing clinical trials exploring new first-line trastuzumab-based combination therapies against HER2-positive advanced gastric cancer. Phase

Drugs combined with Tz

PEP

I

Docetaxel, oxaliplatin, capecitabine

MTD

Docetaxel, oxaliplatin, capecitabine, bevacizumab Oxaliplatin, capecitabine, bevacizumab Oxaliplatin, capecitabine Oxaliplatin, capecitabine Oxaliplatin, capecitabine Cisplatin, S1 Cisplatin, capecitabine, pertuzumab

PFS RR RR RR OS RR AEs

Cisplatin–capecitabinec

OS

II

III

Statusa

NCT code/trial name

15

nyo

NCT01295086

80b 36 56 51 51 30 30

r r r r r r r

NCT01359397/B-DOCT NCT01191697 NCT01396707 NCT01364493 NCT01503983/HerXO NCT01228045 NCT01461057

400

r

NCT01450696

Pts

Tz, trastuzumab; PEP, primary end point; Pts, number of patients; NCT, ClinicalTrials.gov registry number; MTD, maximum tolerable dose; nyo, not yet open; PFS, progression-free survival; r, recruiting; RR, response rate; AEs, adverse events. a Available at: http://clinicaltrials.gov (accessed 25.05.12). b A minimum of 20 HER2+ patients is required. c Randomized trial comparing chemotherapy plus either standard dose or high-dose trastuzumab.

received second-line therapy. In contrast, in Japan and Korea, more than 70% of the patients received second-line therapy [9]. In patients with HER2-positive breast cancer, two randomized prospective trials have suggested that it may be beneficial to maintain trastuzumab therapy after tumor progression [64,65]. Currently, there is no standard second-line treatment for AGC, with CPT-11 emerging as the drug of choice. Secondline therapy shows a mean response rate of 13%, a PFS of 2.5–5.0 months, and a mean OS of 5.6 months [66]. In two recently published, small, randomized phase III trials, second-line chemotherapy significantly prolonged OS compared with the best supportive care in AGC patients with unknown HER2 status [67,68].

6. Mechanisms of trastuzumab resistance in gastric cancer In the ToGA trial, the addition of trastuzumab to chemotherapy for patients with HER2-positive gastric cancer led to an additional absolute increase in response rate of only 12% [9]. This indicates the existence of a high intrinsic or primary trastuzumab resistance in this subpopulation. Furthermore, the majority of patients who had initially responded to treatment developed acquired or secondary resistance. In the clinical setting of HER2-positive metastatic breast cancer, trastuzumab “resistance” may be defined as progression at the first radiological reassessment within 3 months after first-line trastuzumab-based therapy, while trastuzumab “refractoriness” may be described as disease progression after two or more lines of trastuzumab-containing regimens that initially achieve response or stabilization [69]. This clinical distinction could reflect different molecular mechanisms: in trastuzumab-resistant tumors, intrinsic resistance plays a dominant role, whereas in trastuzumab-refractory tumors, acquired resistance is more important.

Intratumoral heterogeneity of gastric cancer may contribute to trastuzumab resistance [45,70]. In initially sensitive disease, selection of a non-sensitive clone with continued trastuzumab therapy may give rise to acquired resistance. The molecular mechanisms underlying trastuzumab resistance are not yet well-characterized. Activation of the downstream PI3K/Akt signaling pathway, which is often caused by mutations in the genes encoding the PI3K catalytic domain (reported in 13% and 6% of gastric and esophageal cancer cases, respectively), could contribute to trastuzumab resistance of gastro-esophageal cancer cells due to the activation of HER2-related receptors and/or non-HER receptors, such as the insulin-like growth factor 1 receptor (IGF1R) [71,72]. In some studies, IGF1R overexpression has been linked to poor outcomes in gastric cancer patients [25]. HER2 and IGF1R physically interact in trastuzumab-resistant breast cancer cells and are involved in cross-talk that results in p27 downregulation [73,74]. Additionally, the loss of the phosphatase and tensin homolog (PTEN) tumor suppressor gene, which occurs in over 50% of AGC cases, correlates with poor outcome and results in heightened Akt/mTOR signaling, which leads to a decreased sensitivity to trastuzumab [75–77]. Cell surface proteins such as mucins decrease the interaction between trastuzumab and the HER2 receptor, thereby blocking the inhibitory actions of the drug [78]. Recent studies have shown upregulation of mucin-1 (MUC1), a protein with growth factor receptor-like activity that mediates the growth of tumor cells, in trastuzumab-resistant HER2-positive breast cancer cells. The addition of MUC1 antagonists reverses trastuzumab-resistance in these cells [79]. Chaperone proteins, such as heat-shock protein 90 (HSP90), are critical for the stability of both the nascent and mature forms of the HER2 protein. HSP90 inhibitors have been shown to inhibit gastric cancer cell growth in preclinical models [80,81]. Exploratory clinical data have supported the hypothesis that the extreme overexpression of HER2 on the surfaces of breast cancer cells may contribute to the primary resistance

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complex inhibitors and the combination of mTOR inhibitors with HER2- and IGF1R-targeted drugs should be clinically evaluated in HER2-positive gastric cancer patients [94]. 7.2. HSP90 inhibitors

Fig. 3. The sites of action of selected, potentially useful, new targeted drugs in HER2-positive gastric cancer. HER, human epidermal growth factor receptor; PI3K, phosphatidylinositol-3 kinase; AKT, serine/threonine protein kinase; mTOR, mammalian target of rapamycin; HSP90, heat-shock protein 90; DM1, emtansine 1. Source: From [87], adapted with permission.

Preclinical data have demonstrated the potent activity of NVP-AUY922, a novel inhibitor of HSP90, against gastric cancer cells and a synergistic effect when combined with cytotoxic chemotherapeutic agents such as 5-fluorouracil and oxaliplatin [95]. A phase II clinical trial is planned to evaluate the efficacy and safety of NVP-AUY922 combined with trastuzumab as a second-line treatment regimen in patients with HER2-positive AGC who progress after trastuzumabbased first-line therapy [96]. 7.3. Trastuzumab-emtansine (T-DM1)

to trastuzumab observed in HER2-positive tumors by restricting the access of this drug to its epitope or by other complex, unknown mechanisms [82,83]. In breast cancer preclinical models, the accumulation of a constitutively active form of HER2, the loss of a binding site on truncated HER2 receptors (p95-HER2), the incomplete inhibition of the EGFR/HER2 TK domain, EGFR overexpression, and cross-talk between HER2 and other growth factor receptors such as the mesenchymal–epithelial transition factor (MET) receptor, are other proposed mechanisms underlying tumor resistance to HER2-targeted agents [84–88].

In xenograft tumor models, the antibody-drug conjugate T-DM1, which combines trastuzumab with the targeted delivery of the antimicrotubule agent DM1, has demonstrated a promising anti-tumor effect in HER2-positive gastric cancer cells, even in tumors with developed resistance to trastuzumab [97]. Robust single-agent activity (a PFS of 9.6 months and a 43.6% objective response rate) has been recently reported for T-DM1 in heavily pretreated HER2positive trastuzumab-refractory/resistant advanced breast cancer patients; however, no clinical trials have yet been conducted for the treatment of gastric cancer with T-DM1 [98].

7. Strategies to overcome trastuzumab resistance in gastric cancer: future therapies

7.4. Pertuzumab

Most HER2-positive gastric tumors exhibit dependency on signaling pathways downstream of the HER2 TK receptor, even after developing resistance to anti-HER2 drugs. A number of strategies for overcoming trastuzumab resistance have been proposed (Fig. 3 and Tables 2 and 3). 7.1. mTOR inhibitors mTOR inhibition appears to be particularly important for optimizing the effects of HER2 inhibitors in cell culture models [89]. In phase I/II trials, treatment with everolimus elicited clinical benefits and disease response in patients with trastuzumab-resistant HER2-positive advanced breast cancer [90,91]. Nevertheless, in the recently reported GRANITE-1 randomized phase III trial involving AGC patients who were neither selected for HER2 status nor previously treated with HER2-targeted therapies, the use of everolimus as second- or third-line therapy did not improve OS compared to placebo, despite a significantly better PFS with everolimus [92]. In preclinical models, blocking mTOR protein complex-1 induced an upregulation of IGF1R and HER2 expression mediated by mTOR protein complex-2 [93]. Hence, new pan-mTOR

The formation of HER2-HER3 heterodimers is indispensable for the growth and proliferation of HER2-driven cancer cells [12]. Trastuzumab binds to domain IV of the HER2 extracellular domain and does not inhibit the dimerization of HER2 with ligand-activated HER3 [56]. In contrast, pertuzumab, a humanized monoclonal antibody directed against the extracellular heterodimerization domain II of HER2, effectively blocks HER2/HER3 heterodimerization. In preclinical models of HER2-overexpressing gastric cancer cells, pertuzumab displays efficacy when combined with trastuzumab and T-DM1 [99,100]. In the clinical setting, pertuzumab treatment of trastuzumab-resistant HER2-positive gastric cancers may be particularly effective, as reported for HER2-positive breast cancer patients who progress on trastuzumab therapy [101,102]. 7.5. Pan-HER TKIs Irreversible pan-HER TKIs such as PF-00299804 and HM781-36B cause marked tumor regression in HER2overexpressing human gastric cancer xenograft models by inhibiting the phosphorylation of HER family receptors and downstream signaling pathways, as well as blocking

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357

Table 3 Ongoing clinical trials exploring new therapies against HER2-positive advanced gastric cancer. T Line

Phase

Drugs

PEP

Pts

Statush

NCT code/trial name

1st

II

III

Lapatinib, capecitabine Lapatinib, carboplatin, paclitaxel Lapatinib, epirubicin, cisplatin, fluorouracil/capecitabine Oxaliplatin, capecitabine, lapatinib [112]

RR AEs/RR RR OS

76 43 192 535

r r r anr

NCT01145404 NCT01395537 NCT01123473 NCT00680901/LOGiC

Ii

212 Pb-TCMC-trastuzumabk

AEs AEs MTD IR IR/AEs IR/AEs AEs MTD PFS RR RR RR OS

36 50 ns 5–25 12 40 15

r r nyo ns ns nyo anr anr anr r r r anr

NCT01384253 NCT01148849 NCT01598077 NCT00005956 NCT00017537 NCT01526473 NCT01171924 NCT00313599 NCT01152853 NCT01522768 NCT01402401 NCT01145404/GastroLap NCT00486954/TYTAN

2nd OR further

II

III

[119] MGAH22a LJM716b HER2 intracellular domainc MVF-HER2 vaccine HER2-ECD vaccine CUDC-101d Lapatinib, Nab-paclitaxele Dacomitinib (PF-00299804)f [104] Afatinib (BIBW 2992)f [105] AUY92,g trastuzumab [96] Lapatinib, capecitabinej Lapatinib, paclitaxelj [109]

28 27 48 76 273

T line, therapy line; PEP, primary end point; Pts, number of patients; NCT, ClinicalTrials.gov registry number; 1st, first-line therapies; 2nd, second-line therapies; AEs, adverse events; RR, response rate; MTD, maximum tolerable dose; IR, immune response; PFS, progression-free survival; OS, overall survival; r, recruiting; anr, active but not recruiting; nyo, not yet open for recruitment; ns, not specified; HER2-ECD, HER2 extracellular domain. a Anti-HER2 antibody. b Anti-HER3 antibody. c HER2 intracellular domain protein-pulsed, autologous, cultured dendritic cells. d Multitargeted inhibitor of HER2, EGFR and histone deacetylase. e Paclitaxel albumin-stabilized nanoparticle formulation. f Irreversible pan-HER inhibitor. g HSP-90 inhibitor. h Available at: http://clinicaltrials.gov (accessed 25.05.12). i Open to HER2-positive gastric cancer and other HER2-positive tumors. j Previous trastuzumab therapy not required. k Intraperitoneally administered.

EGFR/HER2, HER2/HER3 and HER3/HER4 heterodimerization. In preclinical models, both drugs exert synergistic effects with chemotherapeutic agents or molecular targeted agents, including trastuzumab [103,104]. These drugs are second generation inhibitors that have more attractive pharmacokinetic properties, a longer half-life and lower clearance than the first generation pan-HER TKIs. Two separate phase II clinical trials indicated clinical benefits with the new pan-HER TKIs dacomitinib and afatinib, respectively, in trastuzumab-refractory HER2-positive AGC patients [105,106]. 7.6. Lapatinib Lapatinib, a reversible dual TKI that affects both HER2 and EGFR, has demonstrated a lack of cross-resistance with trastuzumab, and preclinical models have shown that lapatinib is effective in restoring trastuzumab sensitivity [107]. Another mechanism of trastuzumab resistance is the accumulation of the truncated form of HER2, p95-HER2, which lacks the trastuzumab binding site. p95-HER2 can maintain its TK activity despite the absence of an extracellular domain. A potential advantage of lapatinib is its inhibition of p95-HER2 phosphorylation, which results in reduced cellular growth in HER2-driven tumors [84]. In trastuzumab-resistant

breast cancer cell lines treated with lapatinib, decreased signaling through IGF1R has also been observed [108]. A phase III trial demonstrated that lapatinib was effective in patients with HER2-positive breast cancers who progressed on trastuzumab therapy [65]. In esophageal and gastric adenocarcinoma cell lines overexpressing HER2, lapatinib has shown activity and additive or synergistic effects when combined with chemotherapy [109]. Despite a lack of clinical data on the efficacy of lapatinib in trastuzumab-refractory HER2-positive gastric cancer patients, preliminary results have indicated the efficacy and safety of lapatinib for gastric cancer treatment in the Asian phase III TYTAN trial, which is examining the combination of paclitaxel and lapatinib as a second-line treatment for HER2-positive trastuzumab-naive gastric cancer patients [110]. The ongoing German randomized phase II GastroLap trial is comparing lapatinib to a lapatinib/capecitabine combination as a second-line therapy in a trastuzumab-naïve cohort. Lapatinib plus CPT-11 is another attractive potential second-line combination therapy that deserves to be explored [111]. In the phase II SWOG0413 trial, lapatinib administered as first line monotherapy to AGC patients not selected by HER2 status demonstrated limited activity (overall response rate, 11%; OS, 4.8 months) [112]. The phase III LOGiC trial

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is currently evaluating the capecitabine/oxaliplatin combination with or without lapatinib as a first-line therapy for HER2-positive AGC patients [113].

7.7. Met inhibitors MET receptor activation induces resistance to both trastuzumab-mediated inhibition of HER2-overexpressing breast cancer cells and lapatinib-elicited inhibition of HER2amplified gastric cancer cells through reactivation of the downstream signaling pathways MAPK and AKT [114,115]. A recent report of a large series of 489 gastroesophageal tumors suggested that amplification of MET and HER2 were mutually exclusive events and may represent distinct molecular phenotype populations [116]. Nevertheless, MET pathway dysregulation can occur by other mechanisms different from MET gene amplification, including paracrine and autocrine activation, activating mutations, chromosomal rearrangement or MET transcriptional upregulation. In some series of unselected gastric cancer patients, MET and HER2 are coexpressed in 9–12% of tumors, and in 24% of the intestinal subtype [117,118]. Rilotumumab, a monoclonal antibody directed against the ligand of the MET receptor, has shown clinical activity in gastric cancer patients not selected by HER2 status [118]. Foretinib (GSK1363089), an oral multiTKI of MET and vascular endothelial growth factor receptors (VEGFRs), has shown synergistic effects with lapatinib in MET-overexpressing HER2-positive gastric cancer cell lines [119]. These data suggest that combination therapy with a MET-inhibitor and a HER2-targeted agent should be clinically tested in HER2-positive patients who progress on either trastuzumab or lapatinib.

8. Conclusions Despite its controversial prognostic role, HER2 has emerged as a new key therapeutic target in gastric cancer. Routine HER2 testing should be included in the diagnostic workup of patients with advanced forms of this disease. Trastuzumab added to a platinum/fluoropyrimidine combination is a new standard first-line therapeutic regimen for patients with HER2-positive AGC. The predictive value of HER2 overexpression is greater than that of HER2 amplification; however, HER2 overexpression is clearly not a robust predictive biomarker because trastuzumab-based therapy produces no response in many patients. Furthermore, the majority of patients develop resistance to this therapy. Preclinical models have identified multiple mechanisms underlying trastuzumab resistance in HER2-driven gastric cancer, as well as potential predictors of the response to HER2-targeted drugs. These support the development of rational second-line therapies to overcome trastuzumab resistance based on the concept that HER2 is the main oncogenic driver in these tumors. Due to the cross-talk between pathways and the coexistence of many mechanisms of resistance in the same cell population, combinations of targeted therapies may provide maximal therapeutic benefits. New biomarkers are urgently needed to predict HER2-targeted therapy resistance and guide the selection of a potentially drug-sensitive cohort when designing new clinical trials.

Funding sources The authors received no external financial or grant support.

Conflict of interest 7.8. Radioimmunotherapy A currently recruiting phase I clinical trial will evaluate lead-212 (212 Pb)-trastuzumab in patients with HER2-positive intraperitoneal cancers, using an isotope with a short path length that is targeted to malignant cells by the trastuzumab antibody, which will be delivered intraperitoneally [120].

7.9. HER2 vaccines Active immunotherapy against the HER2 protein has been attempted. In pilot phase I clinical trials, HER2 vaccines have elicited prolonged, robust, antigen-specific immune responses in patients with HER2-positive metastatic breast tumors; however, no confirmed objective tumor responses or clinical benefits have yet been achieved using this method [121]. Combining HER2 vaccines with other HER2-targeted therapies, such as trastuzumab, in patients with low disease burdens could provide the optimal clinical setting for testing this innovative therapeutic strategy.

The authors declare no conflicts of interest relating to the publication of this manuscript.

Reviewers Professor Hans-Joachim Schmoll, MD, Martin-LutherUniversitat, Halle-Wittenberg, Innere Med. IV, Ernst-GrubeStrasse 40, D-06120 Halle, Germany.

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Biographies Roberto A. Pazo-Cid, M.D., M.A.S., is a medical oncologist in the Department of Medical Oncology at the Miguel Servet University Hospital and Associate Researcher at the Aragon Institute of Health Sciences, Zaragoza, Spain. He received his M.D. in 1998 at the University of Santiago de Compostela, Spain, and then joined the Son Dureta University Hospital to complete residency in oncology. Master of Advanced Studies by the Alcalá de Henares University in 1999. Master of Advanced Studies by the Zaragoza University in 2006. Posgraduate Certificate in Applied Statistics for Health Sciences in 2006. Postgraduate Certificate in cell growth and cancer in 2007. Dr Pazo-Cid research is focused in antiangiogenic therapy in hepatocellular carcinoma, targeted drugs in gastic cancer and predictive biomarkers in the context of gastrointestinal tumors. Antonio Antón Torres, M.D., Ph.D., currently serves as Chairman of the Medical Oncology Department at the Miguel Servet University Hospital, Zaragoza, Spain. He also holds a faculty position as Associate Professor of Medicine at the Zaragoza University. Dr Antón received his M.D. in 1980 and PhD in 1983, both at the Valencia University, Valencia, Spain. He then completed a medical oncology residency at the Hospital Clínico de Valencia, Valencia, Spain. Dr Antón is a principal investigator in several ongoing clinical trials in breast cancer and he has published numerous articles in such journals as the New England Journal of Medicine, Journal of Clinical Oncology, The Oncologist and Annals of Oncology. Current areas of research interest include new drugs and predictive biomarkers in breast and gastrointestinal tumors.