How organoids can improve personalized treatment in patients with gastro-esophageal tumors

Gastric cancer (GC) is still a big killer, being fifth for incidence and fourth for mortality globally [1]. About 90% of gastric cancers are adenocarcinomas [2]. Localized resectable GC treatment is based on a triplet perioperative chemotherapy based on fluoropyrimidine, platinum, and docetaxel (FLOT regimen) [3] for fit patients. For advanced GC, standard first-line treatment is chemotherapy doublet based on the combination of platinum and a fluoropyrimidine. In patients with human epidermal growth factor receptor 2 (HER2) positive, GC trastuzumab is recommended in combination with chemotherapy, while patients with esophageal adenocarcinoma or of the gatroesophageal junction (GEJ)and with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) >/ = 10 are candidate for pembrolizumab [2]. In second line, ramucirumab combined with paclitaxel (or alone) is recommended. In HER2 positive disease, trastuzumab deruxtecan is an option, while pembrolizumab is recommended for microsatellite instable (MSI)-high GC. TAS-102 (Trifluridine/Tipiracil), a taxane, or irinotecan may be considered in further lines [2].

Esophageal cancer (EC) is the seventh most prevalent cancer and the sixth for cancer-related mortality [1]. Squamous-cell carcinoma accounts for 90% of cases, although the incidence of adenocarcinoma is increasing and, in several regions (especially in North America and Europe), is now more incident than squamous cell carcinoma. Moreover, the incidence of GEJ adenocarcinoma is also increasing [4].

In locally advanced resectable EC, perioperative chemotherapy or chemoradiotherapy is recommended. Squamous cell carcinomas are candidates for chemoradiotherapy followed by surgery or definitive chemoradiotherapy. For locally advanced adenocarcinomas, preoperative chemoradiotherapy or preoperative and perioperative chemotherapy are both valid options. As regards the choice of chemotherapy regimen, for patients with adenocarcinoma or GEJ tumor, neoadjuvant chemoradiotherapy according to the CROSS [5] or FLOT [3] regimens followed by surgery are both valid options. Adjuvant nivolumab (anti-PD 1) should be administered to patients with evidence of residual disease after surgery at pathological evaluation. Unresectable disease should be treated with definitive chemoradiotherapy [4]. As for metastatic disease, a combination of platinum and fluoropyrimidine remains the first-line chemotherapy backbone. Pembrolizumab combined with chemotherapy showed the greatest benefit in patients with PD-L1 CPS >/ = 10, while the combination with nivolumab is approved for those with PD-L1 >/ = 1% [4]. In second line setting, after chemotherapy nivolumab is recommended for squamous histology or pembrolizumab for patients with a PD-L1 CPS >/ = 10. In further lines, a taxane or irinotecan may be considered [4].

In the last decades, a great effort has been carried out to molecularly dissect GC, which moved from the classical Lauren classification [6], based on morphology, to The Cancer Genome Atlas classification [7], based on molecular alterations integrating genomics, transcriptomics, and proteomics. Lauren classification distinguished the intestinal type, associated with intestinal metaplasia and Helicobacter pylori infection, which forms glandular-like structures from the diffuse-type tumors, which tend to early infiltrate peritoneum and are characterized by non-cohesive cells, sometimes associated with the presence of signet-ring cells. These tumors tend to have a lower response to chemotherapy [3,8]. According to the The Cancer Genome Atlas, GC can be classified into four different subgroups: chromosomally instable (CIN), genomically stable, Epstein–Barr Virus (EBV), and MSI. In each of these categories, a relevant number of molecular targetable alterations have been identified [9]. In particular, the chromosomally instable subtype is enriched for copy number changes such as HER2, epidermal growth factor receptor, fibroblast growth factor receptor 2 (FGFR2), and MET genes. Nevertheless, the number of molecularly targeted agents that have been brought into the clinic are somehow disappointing as they include only those against HER2 amplification, MSI, and EBV.

One of the key issues that limit the possibility to bring precision medicine into the clinical practice is represented by GC intrinsic heterogeneity. This heterogeneity occurs both between primary and metastases and within the same tumor. For instance, relevant differences in mutations between primary and metastatic GC reach 20%, increasing up to 30% when it comes to copy number variations [10]. As for intratumor heterogeneity, the example of HER2 expression is paradigmatic, where even different areas of the same primary tumor can exhibit positive areas near to completely negative ones [11].

Moreover, it should be considered that multiple factors can influence the response to a given treatment; therefore, the presence of a genomic alteration does not always translate into a relevant clinical benefit for the patient [12,13].

Recent data from phase III clinical trials opened the way to immunotherapy in GC, such as programmed cell death protein 1 (PD-1) inhibitors [14,15]. Immunohistochemical evaluation of PD-L1 expression based on CPS has been proposed as biomarker of response. Approximately, 50–60% of tumors are PD-L1 positive, although a great interstudy heterogeneity exists on the methodology and staining interpretation [16,17]. Indeed, many efforts are undergoing to find better biomarkers for immunotherapy [18, 19, 20, 21].

In 2017, the authoritative journal Nature elected organoids as method of the year [22]. Some years have passed, and the number of research articles employing this technology for the discovery or validation of biomedical research findings has grown exponentially.

Patient-derived organoids (PDOs) are 3D primary cultures that can be maintained and propagated in vitro keeping the same molecular and phenotypic features of the original tumor. Their most stringent application in precision medicine relies on the possibility to employ them to perform high-throughput drug screening, as a similar phenotype should lead to a similar response to a given treatment [23, 24, 25, 26]. Therefore, they constitute a great opportunity to turn precision medicine into functional precision medicine, as they offer the unprecedent opportunity to anticipate in vitro what could be observed into the patients.

Several studies reported on the possibility to generate organoids from many types of solid tumors [27, 28∗∗, 29, 30, 31, 32, 33, 46].

The aim of this work is to review the state-of-the-art of organoids generated from patients having gastro-EC, with a special focus on their applications for precision medicine.

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