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short review memo https://doi.org/10.1007/s12254-019-00534-7 Molecular profiling in gastroesophageal cancer—clinical routine and future perspective Hannah Christina Puhr · Aysegül Ilhan-Mutlu Received: 29 July 2019 / Accepted: 13 October 2019 © The Author(s) 2019 Summary Although several large clinical trials have treatment response; therefore, these investigations been conducted in order to investigate targeted inhi- are already part of routine diagnostic biomarker in- bition of several molecular pathways in gastric cancer, vestigations in the USA. Potential biomarkers for the only a limited number of targeted therapies have been prediction of successful treatment with immunother- introduced in clinical routine. Besides scientific inter- apy such as EBV are promising; however, clinical est, international guidelines recommend investigation and investigational data are not complete. There are of some distinct molecular alterations, which are as- several clinical trials, which test potential biomark- sociated with therapeutic consequences. These are ers for response prediction to immunotherapy such (i) human epidermal growth factor receptor 2 (HER2), as tumor mutation burden, distinct labor alterations (ii) programmed death receptor 1 (PD-L1) and (iii) mi- (neutrophil/lymphocyte ratio), or content of gut mi- crosatellite instability (MSI). There are some emerg- crobiome. These are investigational biomarkers and ing markers, such as Epstein–Barr virus (EBV), which have no application for the routine assessments. might also be associated with a favorable response to In case of resectable settings, molecular prolin fi g immunotherapy. These routine and potential mark- and biomarker investigations are still in early phases, ers will be further discussed in the scope of this short where no routine recommendation for the diagnostic review. procedures is available. Keywords Gastric cancer · Gastroesophageal Introduction junction cancer · Molecular markers Gastric cancer is a major contributor to global dis- ease burden [1]. Even though survival has steadily Take home message increased during the past decades independent of the Testing for HER2 is an international consensus in tumor stage, the prognosis remains poor [2]. Thus, the diagnostic work-up of metastatic gastrointesti- molecular pathways, which drive tumor progression nal tumors. After the introduction of very promising and metastasis, are of high clinical interest for the de- results with immunotherapy, identifying emerging velopment of new targeted therapeutic approaches. biomarkers for the prediction of treatment response has become of particular interest. In this regard, HER2 analysis of PD-L1 staining with CPS score and in- vestigation of MSI show a strong correlation with Human epidermal growth factor receptor 2 (HER2) is overexpressed in up to 20% of all gastroesophageal (GE) tumors [3]. There exists varying information on H. C. Puhr, MD · A. Ilhan-Mutlu, MD, PhD () the expression of HER2 and its association with the Department of Medicine I, Division of prognosis of this malignant disease. Although HER2 Oncology, Medical University of Vienna, positivity is mainly associated with poorer survival Waehringer Guertel 18–20, 1090 Vienna, Austria [4], comparable survival times with HER2-negative Gastroesophageal Tumors Unit, Comprehensive Cancer patients were also shown [4]. Recently, Gu et al. Center Vienna, Vienna, Austria aysegul.ilhan@meduniwien.ac.at demonstrated a meta-analysis of the prognosis of K Molecular profiling in gastroesophageal cancer—clinical routine and future perspective short review HER2-positive patients, where equal survival rates ful for further treatment decision, when the patients between HER2-negative and -positive patients were relapse. However, therapeutic consequences in the observed [5]. neoadjuvant setting do not exist. The pivotal ToGA (Trastuzumab for Gastric Cancer) trial was the first randomized, prospective, multi- TCGA and molecular characterization center phase III trial to study the efficacy of first-line trastuzumab (a monoclonal antibody against HER2) in Recently, advances in technology and high-through- patients with HER2-positive advanced, metastasized put analysis have improved our understanding of the or relapsed GE tumors [3]. Patients were randomly genetic basis of gastric cancer. To provide a roadmap assigned to receive the standard chemotherapy com- for patient stratification and trials of targeted thera- bination of cisplatin plus fluorouracil/capecitabine pies, the Cancer Genome Atlas (TCGA) Research Net- with or without trastuzumab. Median overall survival work has characterized 295 primary gastric adenocar- (OS) was 13.8 months in the trastuzumab group, com- cinomas and proposed a new classification of four dif- pared with 11.1 months in the control group (hazard ferent tumor subtypes consisting of Epstein–Barr virus ratio 0.74; 95% confidence interval [CI] 0.60–0.91; positive, microsatellite instability (MSI), genomically p = 0.0046). The longest survival (median 16 months) stable and chromosomal instability subtypes [14]. was seen in patients with the highest HER2 protein overexpression (defined by 3+ positive) and HER2 PD-L1 amplification. On the basis of this study, trastuzumab in combination with cisplatin and a fluoropyrimidine Programmed cell death ligand 1 (PD-L1) is a 40-kDA has been approved for the first-line treatment of ad- transmembrane protein that is activated among many vanced, metastasized or relapsed HER2-positive GE cancer types and leads to an immunosuppressive tu- tumors. Consequently, an international consensus on mor microenvironment. Thus, inhibition of PD-L1 the investigation of HER2 expression in advanced or and its receptor PD-1 have been intensively stud- metastatic settings was reached. ied as novel treatment concepts in various cancer Two retrospective patient series investigating be- types [15]. A phase Ib clinical trial showed a promis- yond progression trastuzumab continuation sug- ing overall response in gastric cancer when treated gested a benefit in terms of an extension of overall with the anti-PD-1 antibody pembrolizumab [16]. survival and progression-free survival [6, 7]. How- A further phase II trial emphasized this response in ever, two large clinical phase III trials investigating PD-L1 combined positive score (CPS) ≥1% patients; the anti-HER2 tyrosine kinase inhibitor lapatinib and thus, pembrolizumab was approved in the USA for chemotherapy/trastuzumab conjunction drug T-DM1 this indication [17]. Furthermore, a recent phase III in second-line treatment of HER2-positive patients, trial in heavily pretreated patients with gastric cancer who received trastuzumab previously, failed to show demonstrated an efficacy with another PD-1 inhibitor, a survival benefit in further lines [8, 9]. A possible nivolumab, in an Asian population, which led to its reason for this failure was potentially the conversion approval as salvage treatment in Japan [18]. Me- of HER2 positivity to a negative state. A phase II trial dian OS was5.26 monthsin the nivolumabgroup from Japan evaluated trastuzumab treatment beyond and 4.14 months in the placebo group (hazard ra- progression and showed that HER2 positivity is lost tio 0.63, 95% CI 0.51–0.78; p < 0.0001). Interestingly, in up to 70% of patients, which might lead to an pembrolizumab demonstrated different results in re- anti-HER2 treatment inefficiency [10]. There is lack cent phase III trials in second line settings. In the of evidence whether patients with maintained HER2 Keynote-61 trial, pembrolizumab was not effective positivity in second-line settings would benefit from as second-line treatment option in PD-L1-positive an anti-HER2 treatment. preselected patients [19]. However, in the Keynote- HER2 inhibition in combination with neoadjuvant 181 trial, pembrolizumab was demonstrated to be treatment is currently under investigation in three effective in both adenocarcinoma and squamous cell large clinical trials. The HER-FLOT trial is a phase II carcinoma in second line, when CPS was ≥10% [20]. trial, where HER2-positive resectable GE tumor pa- The Keynote-62 trial was presented within the ASCO tients receive a combination of trastuzumab and the 2019 [21]. The results of this study, which tested pem- chemotherapy regimen FLOT (5-flurourocil, leucov- brolizumab as first-line treatment in advanced and orin, oxaliplatin, docetaxel) [11]. This trial published metastasized gastroesophageal cancer, might indicate the interim results in ASCO 2014, where a pathological a survival benefit of patients with a CPS ≥10%. How- complete response rate of 22% could be achieved. In ever, further investigation is necessary, since some two further phase II trials, trastuzumab together with subgroups developed a rapid progress despite having pertuzumab, another monoclonal antibody directed aCPS ≥10%. against HER2, and chemotherapy will be investigated According to National Comprehensive Cancer Net- in HER2-positive GE tumor patients [12, 13]. No work (NCCN) guidelines, CPS should be investigated data from these trials are available yet. Testing for in gastroesophageal carcinoma patients if metastatic disease is suspected. It is, however, important to men- HER2 expression in resectable settings might be use- Molecular profiling in gastroesophageal cancer—clinical routine and future perspective K short review tion that neither pembrolizumab nor nivolumab has estimated [31]. Unlike other EBV-associated malig- treatment approval by European authorities; thus, no nancies, the distribution of EBV-associated gastric evident recommendation for CPS testing can be made. carcinoma worldwide is approximately even. The Nevertheless, in many large European centers CPS is prognostic value of EBV on the survival is not fully investigated routinely in metastatic settings. clarified; however, several studies indicate a bet- ter prognosis associated with EBV positivity [32–34]. Additional studies show an enhancement of PD-L1 MSI expression in EBV-positive gastroesophageal tumors, In gastric cancer, many studies have been conducted which might suggest that immunotherapy targeting concerning the clinical and pathological characteris- the PD-L1/PD-1 axis might be of benefit in this sub- tics of MSI. The majority of these studies show an group [35, 36]. Recently, a phase II biomarker trial association of a high MSI (MSI-H) with older age, fe- demonstrated a 100% overall response rate in gastroe- male gender, distal third of the stomach, intestinal sophageal cancer patients with EBV positivity, when pathology, lower pTNM stage and lower number of treated with pembrolizumab in a second-line setting infiltrated lymph nodes [22–26]. MSI-H gastric can- [37]. Due to the lack of evidence in large clinical trials, cer is generally characterized by some distinct genetic investigation of EBV is not routinely recommended features including increased number of tumor infil- in international guidelines. Nevertheless, testing for trating lymphocytes and PD-L1 positivity [22, 26]. It is EBV is already part of routine diagnostics in many surmised that around 20% of all western gastric tumor large academic hospitals. cases are MSI-H [22, 26]. Funding Open access funding provided by Medical Univer- In 2017 immunotherapy with pembrolizumab was sity of Vienna. approved by the Food and Drug Administration (FDA) Conflict of interest H.C. Puhr received travel support from for the treatment of unresectable or metastatic, MSI-H Eli Lilly and Roche. A. Ilhan-Mutlu participated in advisory solid tumors that have progressed following prior boards from Merck Sharp & Dohme and Servier, received lec- treatment and which have no satisfactory alternative ture honoraria from Eli Lilly and Servier, is the local princi- treatment options [27]. Based on this “tissue agnostic ple investigator for clinical trials sponsored by Bristol-Myers approval”, investigation of MSI in tissues of all tumor Squibb and Astellas. types might have a therapeutic consequence. How- Open Access This article is distributed under the terms of ever, it is again important to mention that this kind the Creative Commons Attribution 4.0 International License of treatment has not been approved by European (http://creativecommons.org/licenses/by/4.0/), which per- authorities. mits unrestricted use, distribution, and reproduction in any The British MAGIC trial demonstrated a survival medium, provided you give appropriate credit to the origi- benefit for patients with resectable cancer when nal author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. treated perioperatively with the chemotherapy com- bination epirubicin, oxaliplatin, and capecitabine [28]. However, a recent post hoc investigation of References the tissue samples of the MAGIC trial suggested that 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, those patients with MSI-H tumors benefited less from Rebelo M, et al. 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memo - Magazine of European Medical Oncology – Springer Journals
Published: Nov 8, 2019
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