HER2-low gastric cancer: is the subgroup targetable?

Therapeutic developments in the targeting of human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer have followed the dramatic success of HER2-expressing breast cancer treatment, which has facilitated the expansion of indications for anti-HER2 agents to include not only conventional HER2-positive breast cancer, but also HER2-low and HER2-ultralow subgroups. The targetability of HER2-low gastric cancer, however, has yet to be established. Hence, further studies are needed to comprehensively understand the clinicopathological features, specific gene alterations, and distinct tumor immune microenvironment of HER2-low gastric cancer and compare them with those for HER2-positive or -negative gastric cancer. Antibody-drug conjugates for HER2 play an important role in making HER2-low gastric cancer targetable. In this context, a deeper understanding of the novel anti-HER2 agents, including antibody-drug conjugates, bispecific T-cell engager antibodies, and a combination of these agents, as well as new forms of immunomodulatory agents are also required. Redefining and re-categorizing HER2 status through not only immunohistochemistry/fluorescence in situ hybridization but also evaluating ERRB2 copy number gain or protein overexpression levels measured using DNA or RNA sequencing might be helpful for identifying populations with HER2-expressing tumors who would ideally benefit from anti-HER2 treatment. The current paper reviewed recent clinical trials, focusing particularly on HER2-low gastric cancer together with basic/translational findings, and discuss perspectives on further therapeutic development in the treatment of this distinct subgroup.

Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. PATIENTS AND METHODS: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). RESULTS: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843). CONCLUSIONS: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.

A novel clinical prognostic index for patients with advanced gastric cancer: possible contribution to the continuum of care.

BACKGROUND: The Japan Clinical Oncology Group (JCOG) prognostic index, consisting of performance status, primary tumor resected, number of metastases, and serum alkaline phosphatase, has been one of the robust prognostic indices for patients with advanced gastric cancer on the basis of which clinical trials have stratified prognosis. Only a few studies, however, have utilized the JCOG prognostic index in daily practice. METHODS: We conducted a retrospective study on patients with advanced gastric cancer who received first-line platinum-containing chemotherapy at a single institute between 2011 and 2017. Prognostic factors were evaluated using a Cox proportional regression model. RESULTS: A total of 608 patients were enrolled. Multivariate analysis showed that performance status ≥1, presence or absence of primary tumor, serum alkaline phosphatase, neutrophil-to-lymphocyte ratio ≥4, and diffuse-type histology were significantly associated with worse prognosis, whereas the number of metastases was not. Although the original prognostic index could not adequately stratify patients into three risk groups, the modified index (good: 0 and 1, moderate: 2 and 3, poor: 4-6), which was established by incorporating diffuse-type histology and high neutrophil-to-lymphocyte ratio, demonstrated excellent stratification. The median overall survival of the good (n = 315), moderate (n = 243), and poor (n = 54) risk groups was 20.5, 13.5, and 10.2 months, respectively. Hazard ratios (HRs) were 1.69 [95% confidence interval (CI), 1.40-2.04; good versus moderate] and 1.52 (95% CI, 1.11-2.08; moderate versus poor). This novel index also demonstrated a statistically significant stratification of survival after progression following first-line chemotherapy (good versus moderate: HR, 1.41; 95% CI, 1.16-1.70; moderate versus poor: HR, 2.00; 95% CI, 1.45-2.74). CONCLUSIONS: The modified JCOG prognostic index showed excellent stratification of overall survival in real-world patients, which could also help determine the need for treatment changes throughout the continuum of chemotherapy.

Genomic gain of the PRL-3 gene may represent poor prognosis of primary colorectal cancer, and associate with liver metastasis.

PRL-3 genomic copy number is increased in colorectal cancer (CRC), and PRL-3 expression is closely associated with lymph node and liver metastasis of CRC. However, the clinical significance of PRL-3 genomic gain for CRC remains obscure. Here, PRL-3 genomic status in 109 primary CRC tumors and in 44 CRC tumors that had metastasized to the liver, was quantified using real time PCR. Association of PRL-3 genomic status with clinicopathological factors and prognosis was assessed in detail. PRL-3 genomic gain was identified in 31 primary CRC (27.4 %) and was more frequently seen in stage III than in stage II (p = 0.025). Among the clinicopathological factors assessed, PRL-3 genomic gain was significantly associated with poorly differentiated histology (p = 0.0039). Moreover, CRC patients with PRL-3 genomic gain exhibited poorer prognosis than those with no gain in stage II-IV CRC (p = 0.017). PRL-3 genomic gain was identified in 18 (41 %) of the liver metastasis tumors, and this frequency of gain was significantly increased as compared to that of the corresponding primary CRCs (11 %) (p = 0.001). Our findings suggested that PRL-3 genomic gain may represent an aggressive phenotype of primary CRC, and may associate with liver metastasis.

Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer.

HOP homeobox (HOPX) is an unusual homeobox gene encoding three spliced transcript variants, among which the only HOPX-beta promoter harbors CpG islands. The characteristics of its promoter methylation was analyzed using bisulfite sequencing and quantitative-methylation-specific polymerase chain reaction (Q-MSP), and the effects of HOPX expression were also examined. HOPX-beta expression was silenced in all gastric cancer cell lines tested; its expression could be restored by treatment with demethylating agent. On Q-MSP, HOPX-beta hypermethylation (cut-off value of 3.55) was found in 84% (67 out of 80) of primary tumor tissues and 10% (8 out of 80) of the corresponding normal tissues and could discriminate normal from tumor tissues (P<0.0001). The prognosis of the advanced cases with HOPX-beta hypermethylation was as poor as those with stage IV disease when cut-off value was set at 11.28. This finding was validated in an independent cohort of 90 advanced gastric cancers. The HOPX-beta hypermethylation was also an independent prognostic factor (P=0.029) on multivariate analysis. Exogenous HOPX expression significantly inhibited cell proliferation, colony formation and invasion as well as enhanced apoptosis. Taken together, HOPX-beta promoter methylation is a frequent and cancer-specific event in gastric cancer. Quantitative assessment of HOPX-beta methylation has great clinical potential as a marker of tumor aggressiveness.