The identification of predictive markers remains a challenge in this era of novel molecularly targeted therapeutics. Correlative studies have become an integral part of clinical trials to establish relevant predictors of response to targeted therapies. Our study evaluated the value of EGFR and HER2 gene amplification in predicting outcome for patients with MSGT treated with lapatinib. This is the first study to analyze EGFR and HER2 gene amplification by FISH and to correlate with clinical outcome in this uncommon tumor type. These molecular abnormalities may confer different disease behavior and determine response to targeted therapies.
No EGFR gene amplifications were found in either ACC or non-ACC despite the high proportion of patients with ≥2+ EGFR protein expression by IHC. Although significant discrepancies between publications have been observed, the frequency of EGFR protein overexpression found in our patients with MSGT is similar to previous reports (7
). Not surprisingly, EGFR protein expression did not correlate with tumor response. Most previous studies have shown that expression of EGFR protein in archival tumors by IHC is an unreliable predictor of responsiveness to EGFR inhibitor agents (22
In our study, no HER2 gene amplifications were found in ACC patients. Although only few HER2 gene amplifications were found in non-ACC patients, these patients had better outcome with lapatinib. The HER2 amplified patients all had 3+ EGFR and HER2 staining by IHC, suggesting that HER2 amplification status by FISH based on conventional criteria did not contribute additional predictive or prognostic value in our study. Our findings are consistent with the general observation that EFGR but not HER2 seems to be greater expressed in ACC and vice versa in non-ACC (24
). In our study, 9 of 39 (23%) patients with MSGT presented with 2+ and 3+ HER2 protein expression and higher frequency was observed for non-ACC patients (8/19,42%). Among the 8 non-ACC tumors overexpressing HER2, the histologies were as follows: adenocarcinomas (n=4), salivary duct carcinomas (n=2), undifferentiated carcinoma (n=1) and squamous cell carcinoma (n=1). Recent data indicate that some histologies of MSGT, in particular salivary duct carcinomas, present with higher rates of HER2 positivity either by IHC and FISH (25
), and may be more likely to benefit from agents targeting HER2 such as trastuzumab (27
). Furthermore, a parallel can be drawn between our findings in MSGT and that reported with in patients with metastatic breast cancer treated with lapatinib (28
). In the latter, HER2 overexpression measured qualitatively or quantitatively was more predictive of response with lapatinib than EGFR expression.
From these results, the benefit of adding HER2 gene amplification by FISH as a predictive marker for response to lapatinib seems very limited in MSGT. However, we did observe an interesting relationship between HER2:CEP17 FISH ratio and clinical outcome for both ACC and non-ACC when a non-conventional set of criteria was used. The conventional criteria of HER2:CEP17 ≥ 2 as a cut-off to define amplification status in breast cancer does not necessarily apply to MSGT, as these malignancies likely possess different disease biology. In our exploratory analysis, patients were grouped arbitrarily into moderate versus low/high groups, based on non-conventional cut-off values for the HER2:CEP17 ratio. This subgroup evaluation, intended to be hypothesis generating, may have yielded a relevant marker for MSGT patients treated with agents targeting HER2. Patients with low or high HER2:CEP17 ratios appear to have a longer TTP than those with moderate ratios, reflecting improved clinical outcomes. A low HER2:CEP17 ratio may have prognostic value and reflects patients who have a less aggressive disease biology, whereas a high HER2:CEP17 ratio may have predictive value and reflects patients who benefited most from lapatinib. This finding needs to be confirmed with future larger studies in this disease. Although designing trials to validate these differences is challenging due to the small number of MSGT cases, recent studies have proven that, through collaborative group efforts, accrual can be rapid and optimized. (18