Molecular profiling in gastroesophageal cancer—clinical routine and future perspective

Programmed cell death ligand 1 (PD-L1) is a 40-kDA transmembrane protein that is activated among many cancer types and leads to an immunosuppressive tumor microenvironment. Thus, inhibition of PD-L1 and its receptor PD‑1 have been intensively studied as novel treatment concepts in various cancer types [15]. A phase Ib clinical trial showed a promising overall response in gastric cancer when treated with the anti-PD‑1 antibody pembrolizumab [16]. A further phase II trial emphasized this response in PD-L1 combined positive score (CPS) ≥1% patients; thus, pembrolizumab was approved in the USA for this indication [17]. Furthermore, a recent phase III trial in heavily pretreated patients with gastric cancer demonstrated an efficacy with another PD‑1 inhibitor, nivolumab, in an Asian population, which led to its approval as salvage treatment in Japan [18]. Median OS was 5.26 months in the nivolumab group and 4.14 months in the placebo group (hazard ratio 0.63, 95% CI 0.51–0.78; p < 0.0001). Interestingly, pembrolizumab demonstrated different results in recent phase III trials in second line settings. In the Keynote-61 trial, pembrolizumab was not effective as second-line treatment option in PD-L1-positive preselected patients [19]. However, in the Keynote-181 trial, pembrolizumab was demonstrated to be effective in both adenocarcinoma and squamous cell carcinoma in second line, when CPS was ≥10% [20]. The Keynote-62 trial was presented within the ASCO 2019 [21]. The results of this study, which tested pembrolizumab as first-line treatment in advanced and metastasized gastroesophageal cancer, might indicate a survival benefit of patients with a CPS ≥10%. However, further investigation is necessary, since some subgroups developed a rapid progress despite having a CPS ≥10%.

According to National Comprehensive Cancer Network (NCCN) guidelines, CPS should be investigated in gastroesophageal carcinoma patients if metastatic disease is suspected. It is, however, important to mention that neither pembrolizumab nor nivolumab has treatment approval by European authorities; thus, no evident recommendation for CPS testing can be made. Nevertheless, in many large European centers CPS is investigated routinely in metastatic settings.

In gastric cancer, many studies have been conducted concerning the clinical and pathological characteristics of MSI. The majority of these studies show an association of a high MSI (MSI-H) with older age, female gender, distal third of the stomach, intestinal pathology, lower pTNM stage and lower number of infiltrated lymph nodes [22‐26]. MSI‑H gastric cancer is generally characterized by some distinct genetic features including increased number of tumor infiltrating lymphocytes and PD-L1 positivity [22, 26]. It is surmised that around 20% of all western gastric tumor cases are MSI‑H [22, 26].

In 2017 immunotherapy with pembrolizumab was approved by the Food and Drug Administration (FDA) for the treatment of unresectable or metastatic, MSI‑H solid tumors that have progressed following prior treatment and which have no satisfactory alternative treatment options [27]. Based on this “tissue agnostic approval”, investigation of MSI in tissues of all tumor types might have a therapeutic consequence. However, it is again important to mention that this kind of treatment has not been approved by European authorities.

The British MAGIC trial demonstrated a survival benefit for patients with resectable cancer when treated perioperatively with the chemotherapy combination epirubicin, oxaliplatin, and capecitabine [28]. However, a recent post hoc investigation of the tissue samples of the MAGIC trial suggested that those patients with MSI‑H tumors benefited less from chemotherapy, indicating other treatment strategies should be offered for this selected patient group [29]. The post hoc investigation of the CLASSIC trial, where Asian patients were randomized to adjuvant chemotherapy versus surgery alone, did again show no survival benefit for patients with MSI‑H, when postoperative treatment is given [30]. Randomized prospective trials with MSI‑H patients, where chemotherapy in the resectable setting is omitted, are under investigation and will show us whether we could treat these patients solely with surgery or with an alternative therapy, such as immunotherapy. Therefore, it is too early now to say that MSI should be routinely tested in resectable settings.

Tumor Epstein–Barr virus (EBV) positivity is an emerging marker, which might be introduced in personalized treatment for gastric cancer. A positivity rate of 8–10% in gastroesophageal cancers is estimated [31]. Unlike other EBV-associated malignancies, the distribution of EBV-associated gastric carcinoma worldwide is approximately even. The prognostic value of EBV on the survival is not fully clarified; however, several studies indicate a better prognosis associated with EBV positivity [32‐34]. Additional studies show an enhancement of PD-L1 expression in EBV-positive gastroesophageal tumors, which might suggest that immunotherapy targeting the PD-L1/PD‑1 axis might be of benefit in this subgroup [35, 36]. Recently, a phase II biomarker trial demonstrated a 100% overall response rate in gastroesophageal cancer patients with EBV positivity, when treated with pembrolizumab in a second-line setting [37]. Due to the lack of evidence in large clinical trials, investigation of EBV is not routinely recommended in international guidelines. Nevertheless, testing for EBV is already part of routine diagnostics in many large academic hospitals.