E. Strong (ed.). Gastric cancer. Principles and practice. Springer (2015)
Trastuzumab (Herceptin®, Genentech) is a monoclonal antibody which binds to the extracellular domain of the HER2. It mediates antibodydependent cellular cytotoxicity by inhibiting proliferation of cells that overexpress HER2 protein, resulting in the blockade of receptor dimerization. Trastuzumab is a key component in the treatment of early and metastatic HER2-positive breast cancer [20–22].
The ToGA trial is the first prospective, multicenter, phase III trial to evaluate the efficacy and safety of trastuzumab in patients with HER2-positive gastric and GEJ adenocarcinoma in combination with standard chemotherapy. In this trial, 594 patients with HER2-positive (3 + on IHC or FISH positive HER2:CEP17 ratio = 2) were randomized to receive cisplatin and fluoropyrimidine alone or with trastuzumab. Patients assigned to receive trastuzumab with chemotherapy had a significant improvement in all measures of efficacy including OS (13.8 versus 11.1 months, HR 0.74, 95%CI 0.60–0.91, p = 0.0046), progressionfree survival (PFS, 6.7 versus 5.5 months, HR 0.71, 95%CI 0.59–0.85, p = 0.0002), and overall response rate (47 versus 35%, p = 0.0017) .
Trastuzumab is the first biological agent to show a survival benefit in the treatment of advanced esophagogastric adenocarcinoma. In October 2010, the Food and Drug Administration (FDA) granted approval for trastuzumab in combination with cisplatin and a fluoropyrimidine (either capecitabine or 5-fluorouracil) for the treatment of patients with HER2-positive metastatic gastric or GEJ adenocarcinoma who have not received prior treatment for metastatic disease based on the results of the ToGA trial.
Trastuzumab is administered at an initial dose of 8 mg/kg intravenously (IV) followed by 6 mg/ kg IV every 3 weeks until disease progression or intolerable toxicity. The most common grade 3 or 4 toxicities in patients treated with trastuzumab plus chemotherapy were neutropenia, anemia, diarrhea, nausea, anorexia, and vomiting. Of all patients receiving trastuzumab plus chemotherapy, 37% developed infusion-related reactions. Cardiac adverse reactions were rare, with no difference between the two groups. Cardiac failure occurred in less than 1% of patients.
Predictors of response to trastuzumab
Currently there are no predictive biomarkers of response to trastuzumab. In breast cancer, the level of HER2 amplification has only been shown to be truly predictive in the neoadjuvant setting .
In the post hoc subgroup analysis of the ToGA trial, patients with strongly HER2-positive tumors (IHC 2 +/FISH + or IHC 3 +) derived the greatest OS benefit with the addition of trastuzumab to chemotherapy (16.0 versus 11.8 months, HR 0.68, 95% CI 0.5–0.83). In an exploratory study, Gomez-Martin et al. evaluated 90 patients with metastatic gastric cancer treated with first-line trastuzumab-based chemotherapy to evaluate the relationship between HER2/CEP17 ratio and HER2 gene copy numbers with outcome . Central testing for HER2 status using IHC and dual color silver in situ hybridization (de-SISH) was performed on all tumors. In the study, the authors found that a mean HER2/CEP17 ratio of 4.7 was identified as the optimal cutoff value discriminating trastuzumab sensitive and refractory patients (p = 0.005). The optimal cutoff for predicting survival longer than 12 months was 4.45 (p = 0.005) and for survival longer than 16 months was 5.15 (p = 0.004). For HER2 gene copy numbers, the optimal cutoff values were 9.4, 10.0, and 9.5, respectively for the outcomes (p = 0.02). The relationship between the level of HER2 amplification and outcome of HER2 gastric cancer treated with trastuzumab requires further investigation.
Dose escalation of trastuzumab
It has been suggested that the pharmacokinetics of trastuzumab differ in gastric cancer and breast cancer patients, and higher dosing may be required in gastric cancer patients. Pharmacokinetic data reported from the ToGA study showed that the trastuzumab clearance is 0.378 L day based on the current standard dosing, 70% higher than the clearance rates shown in patients with metastatic breast cancer receiving trastuzumab [25, 26].
In addition, research in breast cancer has shown that patients with greater sites of metastatic disease have faster clearance of trastuzumab . The greater tumor burden seen in metastatic gastric cancer patients may be associated with higher clearance levels of trastuzumab, and thus gastric cancers patients may require higher dosing.
The HELOISE study is an ongoing study designed to compare standard versus escalated dose of trastuzumab in HER2-positive metastatic gastric and GEJ cancers in combination with cisplatin-based chemotherapy . In this phase III multicenter study, patients are randomized to either standard dosing or higher dosing arm (trastuzumab given at 8 mg/kg loading dose followed by 10 mg/kg every 3 weeks). The accrual goal is for 400 patients, with primary endpoint of overall survival and secondary endpoints evaluating safety, trastuzumab concentrations, PFS, and response rates. At present time, only the standard dosing of trastuzumab is approved for advanced or metastatic gastric and GEJ cancers.
Trastuzumab in the adjuvant or neoadjuvant setting
Unlike in breast cancer, currently trastuzumab is only indicated in the setting of HER2-positive advanced or metastatic disease in gastric cancer. Given the success of HER2 directed therapies in both neoadjuvant and adjuvant breast cancer, the use of trastuzumab in the adjuvant and neoadjuvant setting is an area of active investigation in gastric cancer research.
There is a small ongoing phase II study planning to accrue 45 patients with resectable HER2positive gastric or GEJ adenocarcinoma to receive three cycles of neoadjuvant chemotherapy with oxaliplatin, capecitabine, and trastuzumab. Patients achieving R0 or R1 resection will receive a further three cycles of the same chemotherapy regimen postoperatively with trastuzumab continuing for 12 months . RTOG 1010 trial is a phase III trial evaluating radiation, paclitaxel, and carboplatin with or without trastuzumab in locally advanced HER2 overexpressing esophageal and GEJ adenocarcinoma with a planned enrollment of 160 patients with the anticipation of screening 480 patients .
In the adjuvant setting, there is an active phase II study of oxaliplatin, capecitabine, trastuzumab, and chemoradiotherapy in patients with curatively resected HER2-positive gastric or GEJ adenocarcinoma (TOXAG study) . It is hoped that these studies will provide data regarding the efficacy of trastuzumab for resectable gastric cancer.
Mechanisms of trastuzumab resistance
Resistance to trastuzumab is now emerging in HER2-positive esophagogastric cancers after median of 6.7 months . There is no standard of care second-line therapies for HER2-positive gastric cancer after progression on trastuzumab. Mechanisms of resistance are being actively investigated.
Several putative models of resistance have been described in HER2-positive breast cancer . Activation of PI3K-AKT-mTOR signaling pathway by loss of phosphatase and tensin homolog (PTEN) suppressor and mutation activation of PI3K has been demonstrated to confer resistance to trastuzumab in preclinical studies . Increased signaling from HER family receptors (including overexpression of HER3 and formations of high levels of HER2-HER3 heterodimers) and insulin-like growth-like growth factor-1 receptor (IGF-1R) are also associated with PI3K-AKT activation and trastuzumab resistance . Another proposed mechanism is the accumulation of a truncated form of the HER2 receptor, p95, which lacks the extracellular domain needed for trastuzumab binding .
EGFR plays a significant role in trastuzumab resistance. Work by Ritter and colleagues demonstrated that trastuzumab resistant cell lines and xenograft models overexpress phosphorylated EGFR, EGFR/HER2 heterodimers, and HER family ligand EGFR, heparin-binding EGF, and heregulin . Furthermore, the addition of dual EGFR/HER2 kinase inhibitors was shown to lead to diminished HER2 phosphorylation and cellular proliferation .
The role of EGFR/HER2 cross-talk in transformation and tumor progression is supported by multiple examples in mouse models and primary human tumors. For example, co-expression of the EGFR ligand TGFα and Neu in the mammary gland of transgenic mice markedly accelerates tumor onset and progression compared with mice expressing the TGFα or Neu transgenes alone. In this model, bitransgenic mice exhibited increased tyrosine phosphorylation of both EGFR and HER2 and tumor latency was markedly delayed by the administration of the EGFR tyrosine kinase inhibitor (TKI). [35, 36]. Analysis of breast tumor specimens revealed that the majority of breast tumors with phosphorylated HER2 at Y1248 exhibited detectable EGFR and the combination of Y1248 phosphorylated HER2 together with the co-overexpression of HER2 and EGFR is associated with the shortest patient survival . In esophagogastric cancers, EGFR is commonly overexpressed and may signify worse prognosis [38, 39]. Although EGFR overexpressing MKN7 gastric cancer cells are insensitive to trastuzumab, in these cells, submicromolar concentrations of an EGFR TKI, gefitinib, inhibit p-EGFR and restore sensitivity to trastuzumab . Combined blockade for EGFR and HER2 may be a viable strategy to overcome trastuzumab resistance.
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