Toward optimizing outcomes in Her2-positive gastric cancer: timing and genomic context matter
Authors: S.J. Klempner, J. Chao
Journal: Annals of Oncology (2018)

In 2010, the ToGA trial demonstrated a 2.7-month improvement in overall survival (OS) with the addition of the anti-HER2 monoclonal antibody trastuzumab to platinum-5-FU in first-line treatment of advanced HER2-positive gastric cancer [1.Bang Y.J. Van Cutsem E. Feyereislova A. et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.Lancet. 2010; 376: 687-697Abstract Full Text Full Text PDF PubMed Scopus (5171) Google Scholar]. Subsequent attempts to address HER2-directed therapies in first and second lines have been met with largely disappointing results [2.Hecht J.R. Bang Y.J. Qin S.K. et al.Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC – a randomized phase III trial.J Clin Oncol. 2016; 34: 443-451Crossref PubMed Scopus (383) Google Scholar, 3.Thuss-Patience P.C. Shah M.A. Ohtsu A. et al.Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.Lancet Oncol. 2017; 18: 640-653Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar, 4.Satoh T. Xu R.H. Chung H.C. et al.Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN – a randomized, phase III study.J Clin Oncol. 2014; 32: 2039-2049Crossref PubMed Scopus (460) Google Scholar, 5.Shah M.A. Xu R.H. Bang Y.J. et al.HELOISE: phase IIIb randomized multicenter study comparing standard-of-care and higher-dose trastuzumab regimens combined with chemotherapy as first-line therapy in patients with human epidermal growth factor receptor 2-positive metastatic gastric or gastroesophageal junction adenocarcinoma.J Clin Oncol. 2017; 35: 2558-2567PubMed Google Scholar]. In the phase III LOGiC trial, the addition of the small molecule HER2-inhibitor lapatinib to first-line CapeOx failed to improve OS in the primary efficacy population (12.2 versus 10.5, Hazard Ratio (HR) 0.91, P = 0.35), though preplanned subset analysis suggested a benefit with the addition of lapatinib in Asian patients (HR 0.68) and patients < 60 years old (HR 0.69) [2.Hecht J.R. Bang Y.J. Qin S.K. et al.Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC – a randomized phase III trial.J Clin Oncol. 2016; 34: 443-451Crossref PubMed Scopus (383) Google Scholar]. There was no correlation between Immunohistochemistry (IHC)-status and OS benefit in the study population, which were all amplified by FISH. Contemporary with the LOGiC trial was several publications associating magnitude of HER2 amplification with degree of benefit from trastuzumab, as well as the recognition that HER2-positive gastric cancer is a highly heterogeneous disease complicated by chronologic HER2 changes, and inter- and intratumoral variations in molecular features [6.Gomez-Martin C. Plaza J.C. Pazo-Cid R. et al.Level of HER2 gene amplification predicts response and overall survival in HER2-positive advanced gastric cancer treated with trastuzumab.J Clin Oncol. 2013; 31: 4445-4452Crossref PubMed Scopus (153) Google Scholar, 7.Press M.F. Ellis C.E. Gagnon R.C. et al.HER2 status in advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma for entry to the TRIO-013/LOGiC trial of lapatinib.Mol Cancer Ther. 2017; 16: 228-238Crossref PubMed Scopus (26) Google Scholar, 8.Kim J. Fox C. Peng S. et al.Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma.J Clin Invest. 2014; 124: 5145-5158Crossref PubMed Scopus (84) Google Scholar, 9.Lee J.Y. Hong M. Kim S.T. et al.The impact of concomitant genomic alterations on treatment outcome for trastuzumab therapy in HER2-positive gastric cancer.Sci Rep. 2015; 5: 9289Crossref PubMed Scopus (34) Google Scholar]. The incorporation of cell-free DNA (cfDNA) has allowed for perhaps more representative sampling of global tumor makeup, potentially facilitating identification of patient subsets with better or worse outcomes though limited prospective data exist in esophagogastric cancers [10.Schrock A.B. Pavlick D.C. Klempner S.J. et al.Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced cancers of the gastrointestinal tract or anus.Clin Cancer Res. 2018; (Jan 23 [Epub ahead of print] doi 101158/1078-0432CCR-17-3103)Crossref PubMed Scopus (35) Google Scholar]. In the current issue, Kim et al. report parallel biomarker studies associating preexisting genomic alterations detected by cfDNA and tissue with outcomes in a single arm phase II first-line trial of CapOX and lapatinib in advanced HER2 overexpressing gastric adenocarcinoma [11.Kim S.T. Banks K.C. Pectasides E. et al.Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients.Ann Oncol. 2018; 29: 1037-1048Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Key eligibility criteria included treatment naïve, advanced HER2-positive (HER2 IHC3+ or IHC2+ and HER2 SISH positive) gastric adenocarcinoma that was potentially resectable. Resectability was defined as, "patients with liver metastases were limited to those with two to five liver metastases. Cases suspicious of peritoneal seeding by imaging without definite evidence of ascites and/or peritoneal enhancement were allowed to enter the study based on investigator's decision. Isolated metastases were also allowed for study entry." All patients received CapOX (capecitabine 1700 mg/m2/day days 1–4 and oxaliplatin 130 mg/m2 on day 1) plus lapatinib 1250 mg/day days 1–21 of a 21-day cycle for up to eight cycles. Computed tomography was performed every two cycles, and in the event of radiographic partial response (PR) or complete response (CR) patients were assessed for curative intent resection. Blood samples for cfDNA analyses (73-gene panel, Guardant360TM) were collected at pretreatment baseline and at each radiographic assessment, and archival tissue was utilized to determine eligibility and further genomic analyses. The primary end point was the CR rate (RECISTv1.1) with secondary end points including exploratory biomarker analysis between responder and nonresponders. Thirty-two Korean patients were enrolled at a single institution, with 28 of 32 having HER2 IHC3+ and 4 patients having IHC2+/SISH+ gastric adenocarcinomas. At a median of 22.9-month follow-up, the CR rate was 21.8% among assessable patients (n = 29) with 46.8% (15/29) PR rate for an Overall Response Rate of 68.6%. Among the 22 responders, 2 of the CR patients underwent R0 surgical resection with pCR observed on histopathologic examination. Among 32 enrolled patients, 16 patients had baseline tissue sufficient for tissue-based genomic profiling (243-gene NGS panel), and serial cfDNA was collected for 9 of 32 patients. In addition, paired primary/metastatic tissue was available for 10 of 32 patients and a postprogression biopsy was available for all 7 nonresponders. While the clinical outcomes are themselves interesting, the correlative studies are equally important. Consistent with prior reports, the mean tissue-derived HER2 predicted copy number was significantly higher among responders (mean 24.17) versus nonresponders (mean 3.3). Members of the current publication have previously reported on CCNE1 amplification as a negative predictor of response to trastuzumab and among the relatively small number of patients with baseline tissue profiling, there was a nonsignificant trend (P = 0.08) toward lack of response with concurrent CCNE1 amplification at baseline [9.Lee J.Y. Hong M. Kim S.T. et al.The impact of concomitant genomic alterations on treatment outcome for trastuzumab therapy in HER2-positive gastric cancer.Sci Rep. 2015; 5: 9289Crossref PubMed Scopus (34) Google Scholar]. Among the 10 paired primary/met samples 6 patients had concordant HER2 and 4 patients had discordant results, with 5 of 6 concordant patients achieving response (4 PR and 1 CR). The authors attempted to address baseline intratumoral HER2 IHC heterogeneity, noting that among the 27 patients whose primary tumor was tested, 5 of 7 patients achieving CR had homogeneous HER2 staining whereas 5 of 7 nonresponders (PD + SD) had heterogeneous HER2 staining. Similarly, three of seven postprogression biopsies of the primary from the nonresponders had lost HER2 expression. In the pilot cfDNA group (n = 9, eight assessable), six of eight patients had cfDNA-detected HER2 amplification and all of these patients responded to therapy, though there was no relationship between plasma-derived predicted Her2 copy number and depth of response. In serial plasma cfDNA sampling, a decrease in somatic alteration burden (highest variant allele fraction at a given time point) was observed in all responding patients. The authors should be commended for their efforts toward simultaneously addressing multiple putative biomarkers in a prospective trial setting. While significantly limited by small sample size and lack of multiplatform testing amongst all patients, several important themes still emerge. The manuscript supports a potential utility of composite biomarkers to identify subsets of HER2-positive advanced GC most (or least) likely to benefit from HER2-directed therapy. Are we moving toward a situation analogous to some of the immunotherapy data in non-small-cell lung cancer suggesting composite PD-L1+/tumor-mutation burden high (TMB-H) biomarkers identify optimal responders? Perhaps the HER2 high amp/CCNE1 nonaltered/cfDNA HER2+ profile is a more optimal response biomarker? Unfortunately, similar correlative analyses from larger previously conducted trials (LOGiC, TyTAN, and ToGA) are not available and may be plagued by problems of timing of tissue sampling with respect to treatment. In fact, three recent manuscripts in gastroesophageal adenocarcinomas (GEA) highlight the heterogeneous landscape of gastric cancer, and the importance of analysis from metastatic lesions to enhance efficacy [10.Schrock A.B. Pavlick D.C. Klempner S.J. et al.Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced cancers of the gastrointestinal tract or anus.Clin Cancer Res. 2018; (Jan 23 [Epub ahead of print] doi 101158/1078-0432CCR-17-3103)Crossref PubMed Scopus (35) Google Scholar, 12.Janjigian Y.Y. Sanchez-Vega F. Jonsson P. et al.Genetic predictors of response to systemic therapy in esophagogastric cancer.Cancer Discov. 2018; 8: 49-58Crossref PubMed Scopus (199) Google Scholar, 13.Pectasides E. Stachler M.D. Derks S. et al.Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma.Cancer Discov. 2018; 8: 37-48Crossref PubMed Scopus (189) Google Scholar]. In a cohort of advanced GEA (including some untreated) discordance between concurrently sampled primary tumor and metastatic lesions approached 40% for insertion-deletion and single nucleotide variants, and 60% for amplifications, including HER2 [13.Pectasides E. Stachler M.D. Derks S. et al.Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma.Cancer Discov. 2018; 8: 37-48Crossref PubMed Scopus (189) Google Scholar]. Another recent large NGS-based analysis (abstract only) confirmed a significant portion of HER2-amplified GEA patients harbor genomic alterations predicted to decrease trastuzumab responsiveness, consistent with the observations reported by Kim et al. [11.Kim S.T. Banks K.C. Pectasides E. et al.Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients.Ann Oncol. 2018; 29: 1037-1048Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 14.Klempner S.J. Chao J. Bailey M. et al.Genomic alterations (GA) predicted to confer lack of benefit from trastuzumab in advanced esophagogastric cancers: analysis of 527 Her2 amplified cases.J Clin Oncol. 2018; 36(Suppl 4S; abstr 44)Google Scholar]. We should not be discouraged by the apparent natural heterogeneity in gastric cancer, but rather build on the work presented here and recognize GEA as an ideal model to approach issues of heterogeneity in precision medicine. None declared.