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New directions in the medical treatment of gastric cancer

Florian Lordick

Director of the University Cancer Center Leipzig (UCCL) and Professor of Oncology, University of Leipzig, Germany

The current status of treatment and prognosis

Gastric cancer is a highly heterogeneous disease with a high degree of genetic variability, and overall, prognosis remains poor for patients with gastric cancer.

Although, in general, survival of cancer patients is improving in Europe, long-term survival rates for patients with gastro-oesophageal cancer remain low, at only 10–25% [1]. Unlike prostate cancer, for which survival rates have steadily increased throughout Europe since 1999, the age-standardized 5-year relative survival rates for patients with stomach cancer have barely risen in this period [1].

For the curative treatment of gastric cancer, the European Organisation for Research and Treatment of Cancer (EORTC) currently recommends different therapies according to disease stage [2], which should be determined primarily by computed tomography of the chest and abdomen. Endoscopic ultrasonography or laparoscopy may provide additional useful information. For cT1m tumours, endoscopic submucosal resection may be an appropriate primary treatment; gastrectomy is recommended for tumours with diffuse histology or deep submucosal infiltration (cT1sm/2 cN0). For locally advanced (cT3 cNx and cT4 cNx) and possibly also cT2 N0 cancers, perioperative chemotherapy should be considered in addition to gastrectomy.

The choice and timing of chemotherapy differ globally. In Europe, the most widely used chemotherapeutic regimen includes a platin and 5-fluorouracil (5FU), possibly also epirubicin, administered perioperatively. Adjuvant radiochemotherapy (45 Gy radiation + 5FU or leucovorin) has been the mainstay of treatment in North America [3], whereas in Asia, the treatment of choice is adjuvant chemotherapy with S-1 (tegafur, gimeracil, and oteracil) or capecitabine plus oxaliplatin [4,5].

For stage 4 gastric cancer, combination chemotherapy with two or three agents is the norm. Cisplatin is commonly combined with S-1 in Japan and with 5FU in Europe, and cisplatin or oxaliplatin is combined with capecitabine in Korea, the USA, and Europe. Other common doublets are 5FU with oxaliplatin (FOLFOX, used in the USA and Europe) or irinotecan (FOLFIRI, used a lot in France). Cisplatin and 5FU form the basis of triplet combinations with epirubicin (ECF) in the UK and the Netherlands or with docetaxel (DCF) in other European countries; other regimens used in Europe include four agents (5FU, leucovorin, oxaliplatin, and docetaxel: “FLOT”).

These therapies prolong survival by 11–18 months in East Asia and only 8–11 months in Europe and North America. Improvements in therapy are eagerly awaited.

Identification of new drug targets in gastric cancer

Gastric cancer, like other cancers, is associated with multiple genetic alterations. Analysis of the frequency of somatic mutations in different cancers has shown more than a 1,000-fold variation in mutation frequency across cancer types. Mutation frequencies are lowest in haematological and paediatric tumours and highest in tumours caused by carcinogens such as tobacco smoke and ultraviolet light. Gastric cancer falls into this latter category and, of the 27 cancer types, has the 5th highest mutation frequency [6].

Such a high frequency of genetic alterations provides a rich source of potential drug targets. An analysis of genomic alterations in gastric cancer revealed the existence of five distinct subgroups defined by mutually exclusive alterations in the receptor tyrosine kinase (RTK) signalling genes FGFR2, KRAS, EGFR, ERBB2 (also called HER2), and MET. Together, these subgroups account for 37% of gastric cancers and identify patients for whom RTK/RAS-targeted therapies may be effective [7].

One such targeted therapy is trastuzumab, a monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). Trastuzumab has been tested in a phase 3, open-label, randomized controlled trial in patients with HER2-positive gastric cancer [8]. These patients comprised approximately 16% of those screened for inclusion in the trial, and HER2 positivity was more common in proximal than in distal gastric cancer and much more common in intestinal than in diffuse gastric cancer. The findings of this trial showed that targeting HER2-positive gastric cancer with trastuzumab does confer a survival advantage (Figure 1): median overall survival was 11.8 months without trastuzumab and 16.0 months with trastuzumab. The hazard ratio was 0.65 (95% confidence interval 0.51–0.83).

Figure 1. Survival advantage with trastuzumab in patients with HER2+ gastric cancer [8].

HER2 overexpression therefore provides a means to identify patients for whom first-line treatment with trastuzumab is effective and can be included in treatment algorithms such as that proposed recently (Figure 2) [9].

Figure 2. Algorithm for first-line treatment of stage IV gastric cancer, according to HER2 status [9].

However, testing for HER2 in gastric cancer is a demanding procedure, and immunohistochemistry (IHC) reveals focal staining of HER2 in 33% of gastric cancers [9]. This means that the same tissue sample could be given an IHC score of 3+ in intestinal regions where HER2 staining is intense and 1+ in regions where staining is diffuse or weak (Figure 3).

Figure 3. Focal staining of HER2 in gastric cancer [9].

This issue is being addressed in the VARIANZ study of HER2 expression in gastric cancer [10]. Central pathologists assigned a different HER2 status from that assigned by local pathologists in 36 (34%) of 106 tumour specimens fully characterized to date: 7 judged locally as negative were assigned positive status centrally, and 29 judged locally as positive were assigned negative status centrally. For only 26 patients receiving trastuzumab has the indication been confirmed; the indication is unconfirmed in 24 patients receiving trastuzumab. These kinds of discrepancies are not unique to gastric cancer and can be explained by intratumoral heterogeneity and clonal evolution. The therapeutic target is not only the dominant clone of the primary tumour but also dominant and rare subclones that evolve as the primary tumour progresses and metastasizes. In addition, mechanisms of acquired resistance must be addressed [11]. As the tumour responds and rebounds during the course of the disease and treatment, sequential testing will be needed to identify new clones, and different therapies may be needed as the tumour evolves.

One approach to the treatment of progressive disease is that of anti-angiogenesis. A tumour’s need for perfusion was hypothesized by Judah Folkman (Boston, 1933–2008) several decades ago [12]. More recently, the anti-angiogenic approach (ramucirumab) has been tested as a second-line therapy for gastric cancer and shown to have efficacy comparable to that of chemotherapy (Table 1).

Table 1. Second-line therapy for gastric cancer: randomized studies 

Ramucirumab is a monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR2) (Figure 4) [9].

Figure 4. Therapies targeting angiogenic pathways [9].

In a randomized, placebo-controlled, phase 3 trial of ramucirumab monotherapy for previously treated (with platinum or 5FU), advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD) conducted at 119 centres (355 patients), treatment with ramucirumab significantly improved survival (Figure 5) and resulted in improved quality of life in 10% of patients (compared with 4% in the placebo group) (Figure 6) [16]

Figure 5. Survival benefit with ramucirumab in the REGARD trial [16].

Figure 6. Patient-reported global quality of life 6 weeks after start of treatment [9].

In another randomized, double-blind phase 3 trial (RAINBOW) conducted at 170 centres in 27 countries, ramucirumab was combined with paclitaxel and tested in a similar population (665 patients) [17]. Patients were randomized 1:1 to receive ramucirumab 8 mg/kg, days 1 and 15 every 4 weeks plus placebo or paclitaxel 80 mg/m², days 1, 8, and 15 every 4 weeks until progression. The primary endpoint was survival. The response rate was significantly higher, and progression-free and overall survival were significantly better, with ramucirumab than without (Table 2).

Table 2. Key outcomes from the RAINBOW trial of ramucirumab in second-line treatment of advanced gastric and oesophago-gastric junction adenocarcinoma [17] 

Compared with placebo, ramucirumab treatment maintained quality of life and delayed worsening of symptoms and deterioration of functional status (Figure 7) [18].

Figure 7. Quality of life with and without ramucirumab in second-line therapy in the RAINBOW trial [18].

These findings support the inclusion of ramucirumab in the treatment algorithm for gastric cancer (Figure 8) [9].

Figure 8. Algorithm including ramucirumab for treatment of gastric cancer [9]

Immune therapy

As part of The Cancer Genome Atlas (TCGA) project, 295 gastric adenocarcinomas were analysed to identify mutations, amplifications, methylation, miRNA, mRNA, and their proteomes. This comprehensive molecular characterization allowed classification of the tumours into four subtypes: those that were positive for Epstein–Barr virus (EBV), those with microsatellite instability (MSI), those that were genomically stable (GS), and those with chromosomal instability (CIN) (Figure 9) [19].

Figure 9. The four subtypes of gastric adenocarcinoma identified by comprehensive molecular characterization [9].

The EBV-positive tumours were found to undergo recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274, and PDCD1LG2. CD274 encodes the programmed cell death protein 1 ligand 1 (PD-L1), and PDCD1LG2 encodes PD-L2. PD-L1 and PD-L2 are proteins that have key roles in suppressing the immune anti-tumour response. By binding to the T-cell receptors PD-1 and B7, PD-L1 deactivates cytotoxic T cells to invoke the immune checkpoint. Thus expression of PD-L1 by tumour cells facilitates the continued survival of the tumour [20]. This finding provides a rationale for targeting PD-1 and PD-L1 and inhibiting the immune checkpoint in EBV-positive gastric cancer.

This so-called cancer immunotherapy was hailed by Science magazine as “Breakthrough of the Year” as recently as December 2013. Now, in 2016, cancer immunotherapy has been named ASCO’s clinical cancer “Advance of the Year”.

In the first studies of checkpoint inhibitors, however, response rates were in the region of only 20% [21]. Improving upon this response rate may require identification of better selection criteria or biomarkers.

Some clues to appropriate biomarkers may come from worldwide studies of the geographic variations in outcomes of gastric cancer treatment, by teams led by Patrick Tan (Singapore) and Heike Grabsch (UK and Netherlands). They recently reported their findings from nine expression profiling studies of 1,016 patients: 890 of Asian origin (6 studies) and 126 of non-Asian origin (3 studies), whose survival after surgery differs significantly (Figure 10) [22].

Figure 10. Kaplan-Meier estimates of 5-year overall survival in Asian and non-Asian cohorts [22].

The tumours from Asian and non-Asian patients had distinct immune signatures. Those from non-Asian patients were significantly enriched in T-cell signatures, including signalling by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a B7 ligand and another key player in the immune checkpoint (Figure 11). CTLA-4 is the target of the antibody ipilimumab, a potential cancer immunotherapy.

Figure 11. Immune signatures in the Asian and non-Asian cohorts [22].

This T-cell enrichment of tumours of non-Asian patients was confirmed by immunohistochemical staining of the T-cell marker CD3 (Figure 12).

Figure 12. T-cell enrichment of tumours of non-Asian patients as shown by immunohistochemical staining of CD3 [22].

Immune therapy is on the horizon – but biomarkers and patient selection are yet to be determined.

We look forward to new insights at the 13th International Gastric Cancer Congress (IGCC), to be held in Prague, 8–11 May 2019.

References

1. De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study. Lancet Oncol 2014;15:23–34.

2. Lutz MP, Zalcberg JR, Ducreux M, Ajani JA, Allum W, Aust D, et al. Highlights of the EORTC St. Gallen International Expert Consensus on the primary therapy of gastric, gastroesophageal and oesophageal cancer - differential treatment strategies for subtypes of early gastroesophageal cancer. Eur J Cancer 2012;48:2941–53.

3. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–30.

4. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–20.

5. Bang Y-J, Kim Y-W, Yang H-K, Chung HC, Park Y-K, Lee KH, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012;379:315–21.

6. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214–8.

7. Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 2012;61:673–84.

8. Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki 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;376:687–97.

9. Lordick F, Janjigian YY. Clinical impact of tumour biology in the management of gastroesophageal cancer. Nat Rev Clin Oncol 2016;13:348–60.

10. Haffner I, Luber B, Maier D, Geier B, Theis F, Meyer-Hermann M, et al. Clinical validation of response and resistance factor candidates to targeted therapy in gastric cancer (GC). Oncol Res Treat 2016;39:abstract 0287.

11. Meric-Bernstam F, Mills GB. Overcoming implementation challenges of personalized cancer therapy. Nat Rev Clin Oncol 2012;9:542–8.

12. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182–6.

13. Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et al. Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 2011;47:2306–14.

14. Kang JH, Lee SI, Lim DH, Park K-W, Oh SY, Kwon H-C, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 2012;30:1513–8.

15. Ford HER, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al. Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol 2014;15:78–86.

16. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014;383:31–9.

17. Wilke H, Muro K, Van Cutsem E, Oh S-C, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224–35.

18. Al-Batran S-E, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, et al. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol 2016;27:673–9.

19. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202–9.

20. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1–10.

21. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016;17:717–26.

22. Lin SJ, Gagnon-Bartsch JA, Tan IB, Earle S, Ruff L, Pettinger K, et al. Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut 2015;64:1721–31.


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