Introduction
Gastric cancer is the third leading cause of cancer-associated mortality, with an estimated 723,027 mortalities worldwide in 2012 (1). Compared with the best supportive care, first-line chemotherapy for advanced gastric cancer (AGC) improves survival time and quality of life (2–4); however, the median overall survival (OS) time is short (9–13 months) (5–7). Several previous studies have demonstrated that second-line chemotherapy confers a significant survival benefit over best supportive care in AGC, with median OS time ranging from 4 to 9.5 months (8–11).
Among patients with AGC, the rate of human epidermal growth factor receptor 2 (HER2) positivity reportedly ranges from 8.2 to 23.0% as assessed by immunohistochemistry (IHC), and from 7.1 to 27.1% when assessed by fluorescence in situ hybridization (FISH) (12–15). On the basis of the Trastuzumab for Gastric Cancer (ToGA) trial results, addition of trastuzumab to platinum-based chemotherapy has become the standard first-line therapy for HER2-positive AGC (16). However, in the second-line setting, the Tykerb with Taxol in Asian ErbB2+ Gastric Cancer (TyTAN) trial did not demonstrate a survival benefit from the addition of lapatinib, a small-molecule tyrosine kinase inhibitor targeting HER2, to paclitaxel for the treatment of HER2-positive AGC (17). Preliminary evidence from a small phase II study demonstrated that a trastuzumab plus docetaxel-containing regimen was well tolerated and effective for HER2-positive AGC previously treated with fluorouracil-based chemotherapy; however, in this study, the patients had received no previous therapy with trastuzumab (18). On the other hand, several studies have reported that continued therapy with trastuzumab beyond progression (TBP) improves the survival outcome of patients with metastatic HER2-positive breast cancer (19,20), and represents a practical therapeutic option. However, there is currently no clinical data regarding the efficacy of trastuzumab for HER2-positive AGC progressing during trastuzumab-based chemotherapy. The aim of the present, retrospective study was to assess the clinical benefit of the continuation of trastuzumab for HER2-positive AGC patients who progressed during trastuzumab-based chemotherapy.
Discussion
To the best of our knowledge, the present study is the first to evaluate a TBP strategy in second-line chemotherapy for HER2-positive AGC. There were two major findings. Firstly, the trastuzumab-combined therapy was numerically superior to chemotherapy alone for PFS, particularly in the subgroups with HER2 IHC 3+ tumors, histology of intestinal type, or a longer first PFS time (>6 months). Secondly, there was no significant difference in toxicity identified between the two groups, including cardiac dysfunction. These results suggest that the TBP strategy may be a second-line treatment option for patients with HER2-positive AGC.
Compared with the results from a prospective large observational study and a randomized phase III study involving metastatic breast cancer, which showed that the continued therapy with TBP improves the survival outcome of patients with metastatic HER2-positive breast cancer (19,20), the results of the present study did not demonstrate a clear survival time benefit associated with trastuzumab therapy following first disease progression. However, the magnitude of unadjusted HR (0.63) for PFS in the present study was of the same order as that (0.69) in a German phase III trial comparing trastuzumab plus capecitabine vs. capecitabine alone in HER2-positive breast cancer patients whose disease had progressed during trastuzumab therapy (20), a finding which justified further investigation of HER2-positive AGC. The phenomenon of clinically relevant improvement of PFS time in the subgroup of patients with HER2 IHC 3+ tumors is congruent with the exploratory findings from the ToGA and TyTAN trials (16,17). The preplanned analyses of the ToGA trial revealed the greatest survival time gain in the subgroup of patients with HER2 IHC 3+ tumors, and in the TyTAN trial, the subgroup analysis based on HER2 IHC status identified significant survival time improvement only in the IHC 3+ subgroup.
Furthermore, the present study identified that patients with histology of intestinal-type demonstrated increased PFS time with trastuzumab treatment, which supported the subgroup result from the ToGA study in which patients with intestinal-type tumors had increased survival rates on trastuzumab-based chemotherapy (HR, 0.69; 95% CI, 0.54–0.88). The differences in efficacy according to HER2 IHC status and histological type may be partly explained by HER2 heterogeneity, which is more frequent in gastric cancer than in breast cancer (25). Previously, Lee et al (25) reported that only 8 (32.0%) of the patients studied exhibited heterogeneous HER2 overexpression in the IHC 3+ subgroup whereas, in the IHC 2+ subgroup, it was identified in 46 (95.8%) of the 48 cases. Furthermore, only 3 (14.3%) of 21 patients with diffuse or mixed types exhibited homogeneous HER2 overexpression vs. 16 (30.8%) of the 52 cases with histology of intestinal type (25). Presumably, selection of subclones lacking HER2 overexpression is likely to confer resistance to anti-HER2 therapy in tumors with HER2 heterogeneity, and verification of this hypothesis is required in the future. In the present study, patients who had a longer first PFS (>6 months) benefited from continuing TBP, and this result is in accord with that of a previous study on metastatic breast cancer, in which patients with a longer first time-to-progression (≥8.6 months) had significantly improved survival times following first progression compared with those who had a shorter first time-to-progression (median, 24.3 vs. 15.4 months, respectively; P=0.024) (26). The dose of trastuzumab was 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks, and this dose was representative of doses used by other studies (26). In the current study, it is unclear why OS time was not statistically different between the two groups, but it may be due to a high percentage of third-line or later treatment and trastuzumab use following second progression in the non-TBP group.
The limitations of this study are its retrospective nature and small sample size. In addition, the TBP strategy involves the additional cost of trastuzumab, and the current standard care in second-line treatment for gastric cancer is paclitaxel plus ramucirumab regardless of HER2 status (27); consequently, a certain degree of prudence is required when adapting this strategy to patients. Therefore, these findings require confirmation in a well-designed prospective study.
There was no significant difference in toxicity identified between the two groups, a finding that is consistent with the results of the ToGA trial, in which the addition of trastuzumab did not increase the toxic effects associated with standard chemotherapy (16). In addition, no cardiac dysfunction was observed in either group, in contrast to the findings from a previous study of breast cancer (28) and the ToGA trial. In the study of breast cancer, the incidence rates of cardiotoxicity were 27% for patients who received trastuzumab combined with anthracyclines and 13% for those who received paclitaxel (28). In the ToGA trial, the incidence rate of cardiac events was as low as 6% for AGC patients (16). The lack of previous treatment with anthracyclines, the short duration of exposure to trastuzumab, and underestimation of cardiac dysfunction due to less-frequent evaluation may lead to a lack of detection of cardiac events.
To summarize, although the retrospective nature of this study and the small number of patients analyzed are major limitations, these findings indicate that trastuzumab-combined therapy provided a possible benefit of improved PFS time for subgroups of AGC patients with HER2 IHC 3+ tumors, histology of intestinal type, or a longer first PFS time (>6 months). An ongoing randomized phase II study (UMIN000009297; target sample size, n=90) comparing trastuzumab plus paclitaxel vs. paclitaxel-only following disease progression in patients treated with trastuzumab as first-line chemotherapy for HER2-positive AGC is likely to provide further insights into this strategy.