Our HER2 is same as yours

Despite its declining incidence, gastric cancer remains the third most common cancer worldwide (1), with the highest incidence in East Asian and the lowest in North America (2). As compared to non-Asians, although this may represent more than a few different clinical presentations between ethnicities, Asian gastric cancer patients consistently have increased survival rate (3). The ethnic differences might be due to a chance or different tumor biology between Asian and Western patients, or to a different pharmacogenomics in drug metabolism leading to a different drug exposure. The disparity between Asian and non-Asian gastric cancer survival is not explained by the hypothesis of differences in tumor biology (4), in which Asian ethnicity was not independently associated with survival [hazard ratio (HR), 0.89; 95% confidence interval (CI), 0.74-1.08] if adjusted for other patient and disease characteristics.

During the past decade, there have been major advancements in gastric cancer treatment, such as the incorporation of trastuzumab, a monoclonal antibody against HER2, to cytotoxic chemotherapy (5). In the pivotal Trastuzumab for Gastric cancer (ToGA) trial (6), addition of trastuzumab improved progression-free survival (PFS, 6.7 vs. 5.5 months) and overall survival (OS, 13.8 vs. 11.1 months) compared with chemotherapy alone. An exploratory analysis demonstrated that tumors with strong HER2 expressions [i.e., HER2 positivity defined as immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH) positive] were more likely to draw benefit with the addition of trastuzumab (OS, 16.0 vs. 11.8 months). In contrast, OS benefit was not observed in Asian patients, while those from America and Europe benefited from the treatment. In addition, patients with diffuse type gastric cancer, a more common histologic type in Asians and known to seldom harbor HER2 overexpression (7), did not show benefit from the addition of trastuzumab. We already know that HER2 amplification is reported in 7-34% of gastric cancer (6,8), with varying rates according to ethnicity and location of primary tumor.

Recently, in a large, prospective multi-center observational cohort study in Japanese patients (9), Matsusaka and colleagues have presented the clinicopathological factors associated with HER2 status in gastric cancer. The researchers recruited 1,461 patients with gastric cancer in whom 1,427 patients were evaluated for HER2 status. The results showed that the rate of HER2 IHC 3+/FISH positive in Japanese patients was 15.6%, in line with similar studies done in Asian patients (10,11). Multivariate analyses identified intestinal type, liver metastasis and the absence of peritoneal metastasis as independent factors related to HER2 positivity. We should consider several issues raised by this and other studies. The results confirm that the HER2 positivity in Asian patients is comparable to that in other ethnic populations. Any oncologists who do not order HER2 testing prior to starting first-line chemotherapy for gastric cancer should change their practice immediately. The benefit of trastuzumab-based therapy in Asian gastric cancer patients has been suggested in other clinical trials. In a Japanese phase II study (12), 53 HER2 positive patients were treated with trastuzumab plus S-1/cisplatin combination chemotherapy, showing median PFS and OS of 7.8 and 16.0 months, respectively. Korean researchers tested trastuzumab in combination with capecitabine plus oxaliplatin in 55 patients with HER2 positive gastric cancer (13), leading to a remarkable outcome of PFS 9.8 months and OS 21.0 months. Obviously, patients with HER2 positive gastric cancer should receive trastuzumab plus chemotherapy, with best supportive care reserved for those with a poor performance status. We should remember, at the same time, the role of chemotherapy in this setting remains strictly palliative, in terms of its ability to substantially improve OS and to maintain patients’ quality of life.

HER2 evaluation in gastric cancer differs from the traditional assessment used in breast cancer. Current standard scoring of HER2 by IHC and FISH is based on that used to assign HER2 status in ToGA trial. As stated above, the benefit of adding trastuzumab to chemotherapy was greatest in the patient subset defined as HER2 IHC 3+ or IHC 2+ along with a positive FISH test (HER2/CEP17 ratio ≥2). This was the same definition used to define HER2 positivity by Matsusaka and colleagues (9).

In treating patients with HER2 positive gastric cancer, we have to remember that more than half of patients fail to achieve clinical response to trastuzumab-based treatment and, even in the responders, the duration of responses is as short as a few months. Therefore, the knowledge of prognostic or predictive markers that may contribute to the identification of the subset of patients with a greater likelihood of a clinical benefit from trastuzumab would be helpful in clinical setting. While the mechanisms of resistance to trastuzumab are not yet fully understood, histologic type of gastric cancer is one of the interesting issues in HER2 positive gastric cancer. Studies indicated that diffuse type gastric cancer is associated with a poorly-differentiated histology, poor response to treatment and a worse survival (7). In the perspective of the rate of HER2 positivity, unfortunately, it is believed that diffuse type gastric cancer is rarely HER2 positive (6). Among others, a HER2/CEP17 ratio was suggested as a predictive marker for trastuzumab efficacy (14,15). Tumor heterogeneity regarding the HER2 amplification could also be another factor (16). It is also suggested that other additional genetic alterations than HER2 might influence the trastuzumab mode of actions in gastric cancer (17). Experience with other types of cancer had taught us that a substantial improvement in the treatment of gastric cancer could be achieved with individualized therapy strategies (18), including the identification of genetic alterations and the study of the molecular biology of therapeutic agents.

As stated above, Matsusaka and colleagues concluded that the HER2 positivity in Japanese gastric cancer patients was comparable to that in other populations examined (9). Irrespective of ethnicity or histologic subtypes, patients with HER2 positive gastric cancer should receive trastuzumab-based therapy. Not all patients will benefit, nevertheless, there is no prospective analyses to examine prognostic or predictive factors for the addition of trastuzumab. The wealth of evidence for efficacy of trastuzumab in HER2 positive gastric cancer, along with studies on HER2 status in multiple ethnicities, warrants further analyses to explore predictive biomarkers for trastuzumab activity.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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