Determination of HER2 status has become an important part of the workup of patients with advanced esophagogastric cancer, given recent data from a phase III trial (ToGA) indicating that trastuzumab, an anti-HER2 monoclonal antibody, prolongs survival in these patients.
Harry H. Yoon, MD, MHS
Assistant Professor, Division of Medical Oncology,
Mayo Clinic, Rochester, MN;email@example.com
Determination of HER2 status has become an important part of the workup of patients with advanced esophagogastric cancer, given recent data from a phase III trial (ToGA) indicating that trastuzumab, an anti-HER2 monoclonal antibody, prolongs survival in these patients. HER2 positivity is at least as common in esophageal adenocarcinomas as in cancers of the gastroesophageal junction or stomach. It is important to utilize new disease-specific criteria for interpreting HER2 expression by immunohistochemistry, because HER2 overexpression in esophagogastric tumors is distinct from that in breast tumors. It is generally agreed that patients whose esophagogastric tumors show strong HER2 expression (IHC 3+), or weak-moderate HER2 expression (IHC 2+) with gene amplification as measured by fluorescence in situ hybridization, are candidates for trastuzumab. However, it is controversial whether patients whose tumors show only faint or absent HER2 expression (IHC 0 or 1+), despite being gene-amplified, should be trastuzumab-eligible. Concordance of HER2 results between IHC and FISH is high in the IHC 0-1+ and IHC 3+ subgroups, but not the IHC 2+ subgroup. IHC is generally recommended as the initial test to screen for HER2 positivity, with confirmatory testing by FISH for IHC 2+ cases. Given that lapatinib, a small-molecule inhibitor of EGFR and HER2, did not significantly improve overall survival in this malignancy, use of lapatinib is not recommended outside of a clinical trial. Ongoing trials in HER2-positive esophagogastric cancer are evaluating whether trastuzumab improves outcomes perioperatively or in combination with agents that block HER3/ERBB3.
HER2/ERBB2 oncoprotein overexpression is an important therapeutic target in esophagogastric cancer. Trastuzumab, an anti-HER2 monoclonal antibody with known activity in breast cancer, was recently demonstrated to prolong survival in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.1 Because HER2 positivity is a strong predictor of trastuzumab benefit, determination of HER2 status has become integral in the workup of this malignancy worldwide, and its accurate determination is critical. HER2 overexpression in esophagogastric tumors is distinct from that in breast tumors, which influences patient selection for HER2-targeted therapy. Considerations relevant for the practicing physician are discussed here.The benefit of trastuzumab in advanced HER2-positive GEJ/gastric adenocarcinoma was demonstrated in an international phase III trial (ToGA), which compared cisplatin/fluoropyrimidine chemotherapy with and without trastuzumab.1All tumors were screened for HER2 protein expression by immunohistochemistry (IHC), andHER2gene amplification by fluorescence in situ hybridization (FISH). Patients were eligible if their tumor was positive by IHC (ie, showing 3+ expression) or FISH (ie, showing aHER2/CEP17ratio of ≥ 2). Among enrolled patients (n = 594 of the 3807 screened), almost all tumors were FISH-positive, whereas protein expression rates by IHC varied.
At a median follow-up of more than 17 months, median overall survival (OS; the primary endpoint) was significantly better with trastuzumab (13.8 vs 11.1 months). Progression-free survival (PFS) and objective response rate (ORR) also favored trastuzumab. Trastuzumab was well tolerated.
Based on these data, trastuzumab was approved, in combination with cisplatin and a fluoropyrimidine, for the treatment of patients with metastatic HER2-overexpressing gastric or GEJ adenocarcinomas who have not received prior treatment for metastatic disease. The significance of these data are underscored in light of recent phase III trial results showing a failure of multiple biologic agents to prolong survival, including those targeting EGFR (cetuximab,2panitumumab,3gefitinib4), EGFR/HER2 (lapatinib5,6), and VEGF (bevacizumab7).
Ramucirumab, an anti-VEGFR-2 monoclonal antibody, is the second biologic agent to demonstrate improved OS in this malignancy in a phase III trial (REGARD8). According to preliminary results presented at the 2013 Gastrointestinal Cancers Symposium (ASCO), 355 patients with previously treated metastatic gastroesophageal cancer were randomized (2:1) in the REGARD trial to receive ramucirumab or placebo. The study reached its primary endpoint: median OS was higher in ramucirumab-treated patients (5.2 vs 3.8 months, respectively; HR = 0.776; 95% CI, 0.603-0.998;P=.0473).8While ORRs were similar between arms, ramucirumab-treated patients had significantly improved median PFS (2.1 vs 1.3 months; HR = 0.483;P<.0001) and disease control rate (49% vs 23%;P<.0001). Ramucirumab was well tolerated, and no unexpected safety findings were noted. Further data from other ongoing ramucirumab trials are awaited.Patients with advanced esophagogastric cancer who are potential candidates for trastuzumab should be screened to determine HER2 status. Approximately 7% to 22% of esophagogastric cancers overexpress HER2, a similar percentage to that seen in breast cancer.2,3,9,10-15Of note, HER2 positivity is at least as common in esophageal9,16,17as in gastric adenocarcinomas, and has a predilection for intestinaltype (rather than diffuse-type) gastric cancers. In our study of 713 surgically resected esophageal or GEJ adenocarcinomas, HER2 overexpression and/or gene amplification was significantly more frequent in low- (vs high-) grade tumors, and in tumors with (vs without) adjacent pathologic Barrett’s metaplasia.9As in breast cancer, there appears to be a high concordance between HER2 results obtained from the primary tumor and metastatic sites.12In contrast to breast cancer, the association between HER2 expression/ amplification and prognosis in esophagogastric cancer remains unknown.2,3,9,11-15,18
HER2 status in esophagogastric cancers can be assessed using the same FDA-approved HER2 assays as for breast tumors, which typically includes IHC and FISH. Protein expression by IHC is categorized into one of four levels (0, 1+, 2+, 3+) based on a composite score that incorporates the intensity of staining and the percentage of cancer cells demonstrating that intensity (Table 11,19,20). However, interpretive criteria for determining the IHC score in esophagogastric cancers are distinct in two ways from breast tumors, underscoring the importance of utilizing tumor-specific criteria in clinical practice:
Surgical resection or biopsy specimen
Surgical resection specimen
Uniform intense membrane staining in >30% tumor cells
Strong complete, basolateral, or lateral membrane staining in ≥10% cancer cells
Strong complete, basolateral, or lateral membrane staining in a tumor cluster of ≥5 cancer cells
Weak or nonuniform complete membrane staining in ≥10% tumor cells
Weak-to-moderate complete, basolateral, or lateral membrane staining in ≥10% cancer cells
Weak-to-moderate complete, basolateral, or lateral membrane staining in a tumor cluster of ≥5 cancer cells
Weak, incomplete membrane staining in any proportion of tumor cells
Faint membrane staining in ≥10% cancer cells
Faint membrane staining in a tumor cluster of ≥5 cancer cells
No staining or staining in <10% of cancer cells
aAdapted from 2007 ASCO/CAP guidelines.20
bAdapted from criteria developed for gastric cancer and utilized in the phase III ToGA trial.1,19
These modified criteria for interpreting HER2 by IHC in esophagogastric cancers were developed and validated by an international oncology and pathology panel19,21and utilized to assess eligibility for the ToGA trial. Data suggest that applying breast cancer criteria to esophagogastric tumors may result in an underestimation of HER2 expression.19,21,23Guidelines for selecting patients with esophagogastric cancer for trastuzumab treatment based on HER2 test results are not uniform worldwide. European regulators approved trastuzumab only for tumors that show IHC 3+ expression, or IHC 2+ expression with amplification (FISH-positive). This limited approval was based on an exploratory analysis of the ToGA trial, which showed that trastuzumab was most effective in prolonging survival in the subgroup of patients whose tumors were IHC 3+ or IHC 2+ with amplification (median OS, 16.0 vs 11.8 months in trastuzumab vs non-trastuzumab arms, respectively; HR = 0.65; 95% CI, 0.51-0.83).1By contrast, patients with FISH-positive IHC 0-1+ tumors, which represented 22% of the enrolled population, did not appear to benefit from trastuzumab (median OS, 10.0 vs 8.7 months in trastuzumab vs non-trastuzumab arms, respectively; HR = 1.0; 95% CI, 0.70-1.62). Preliminary data suggest that these FISH-positive IHC 0-1+ tumors have “low-level” amplification,24and the potential cost-ineffectiveness in treating IHC 0-1+ FISH-positive cases has been raised.25,26However, given the exploratory post-hoc nature of these analyses, the FDA approved trastuzumab for patients whose HER2 status meets the eligibility criteria of the ToGA trial (ie, FISH-positive or IHC 3+).27
In other words, it is widely accepted that patients whose tumors are IHC 3+ or IHC 2+ with amplification are candidates for trastuzumab. However, controversy exists on whether to recommend trastuzumab in FISH-positive cases with IHC 0-1+ scores; exploratory analysis from ToGA suggests that these patients do not benefit from trastuzumab, but benefit has not been definitively ruled out.
The concordance between IHC and FISH is high in the IHC 0-1+ and 3+ subgroups, but not in the IHC 2+ subgroup. The largest studies to date are shown inTable 2.10,13,23,28,29These concordance data, together with the exploratory analysis from ToGA, support the use of IHC as the initial screening test for HER2, as recommended by the European Medicines Agency and others.30 The following points integrate best available evidence, and may assist clinicians in interpreting IHC test results with regard to further testing by FISH and patient selection for treatment:
HER2 Protein Expression (IHC Score)
ToGA 2009b 29
N = 3,280
Kim et al 2011a 10
N = 575
Park et al 201223
Terashima et al 201213
N = 829
Yoon et al 2013b 28
N = 673
Amp, gene amplification; GEJ, gastroesophageal junction; IHC, immunohistochemistry; NR, not reported.
aIn this study, the number of patients by IHC category was not reported, and amplification rates refer to the percentage of tissue microarray cores that were gene-amplified.
bData have been reported in abstract form.
At the time of disease progression on a first-line trastuzumab-containing regimen for HER2-positive disease, there are no data addressing the benefit of continuing trastuzumab with the second-line regimen. However, extrapolating from the experience in breast cancer, many oncologists appear to continue trastuzumab as long as it is well tolerated. Although trastuzumab was studied with fluoropyrimidine/ cisplatin regimens in ToGA, many clinicians incorporate trastuzumab into their first-line regimen of choice (eg, 5FU/oxaliplatin).34Dual EGFR/HER2 inhibition using lapatinib did not yield positive results in two recent phase III trials of patients withHER2-amplified esophagogastric adenocarcinoma. In an international trial in the first-line setting (LOGiC),5 the addition of lapatinib to capecitabine/oxaliplatin in 545 patients with advanced HER2-positive (IHC 3+ or gene-amplified) adenocarcinoma of the upper gastrointestinal tract did not improve the primary endpoint of OS (median 12.2 vs 10.5 months in lapatinib vs non-lapatinib arms; HR = 0.91; 95% CI, 0.73-1.12;P=.35). However, a significant improvement in OS was observed in Asian patients (HR = 0.68) and those under age 60 years (HR = 0.69). Notably, there was no association between IHC and OS.
In a second-line trial (TyTAN)6 conducted in Asia and restricted to patients with gastric cancer (N = 430), the addition of lapatinib to weekly paclitaxel did not improve OS at a statistically significant level (11.0 vs 8.9 months; HR = 0.84;P= .208). However, in a preplanned analysis of the subgroup of patients (n = 261) whose tumors showed strong (3+) HER2 expression, median OS was higher in the lapatinib versus non-lapatinib arm (14.0 vs 7.6 months; HR = 0.59;P= .0176). PFS (5.6 vs 4.2 months; HR = 0.54;P= .0101) and ORR (27% vs 9%) were also better with versus without lapatinib among patients in the IHC 3+ subgroup.
Although lapatinib is not indicated outside of a clinical trial, these data suggest the possibility that some subpopulations, as yet undefined, may benefit from combined inhibition of EGFR and HER2.HER2 status should be examined in all patients with advanced adenocarcinoma of the esophagus, in addition to those with GEJ or gastric cancer. IHC is generally recommended as the initial test to screen for HER2 positivity, with confirmatory testing by FISH for IHC 2+ cases. IHC should be interpreted using criteria specific to gastroesophageal cancer. Patients with IHC 3+ or IHC 2+ with FISH-positive tumors are candidates for trastuzumab therapy, whereas it is controversial to administer trastuzumab in FISH-positive IHC 0-1+ cases. Use of lapatinib outside of a clinical trial is not recommended.
In HER2-positive disease, current research efforts include the determination of whether blockade of HER3/ERBB3, an important heterodimerization partner of HER2, adds clinical benefit when added to trastuzumab. Agents under study in esophagogastric cancer include pertuzumab (phase III, NCT01774786), which inhibits HER2/HER3 dimerization, and MM-111 (phase II, NCT01774851), which docks to HER2 and inhibits HER3 signaling. Although trastuzumab therapy is not indicated perioperatively or in combination with radiotherapy, the question of whether trastuzumab adds benefit to preoperative chemoradiotherapy in locally advanced esophageal or GEJ adenocarcinoma is being examined in an ongoing phase III trial (RTOG-1010, NCT01196390).
Dr. Yoon has received research grants from Genentech/Roche and Eli Lilly and Company.