Helicobacter pylori: Gastric Cancer and Extragastric Malignancies – Clinical aspects

In 2013, Helicobacter pylori infection is still one of the world's most prevalent infections and accounts for high morbidity and mortality. About 10–20% of subjects infected with the bacterium will develop complications of the infection including peptic ulcer disease and gastric cancer (GC), which accounts annually for at least 738.000 deaths 1. During the past year, new data have been gained concerning GC prevention by eradication of H. pylori. For patients with advanced gastric cancer, ongoing phase II trials are evaluating safety and efficacy of new targeted molecules.

This review summarizes recent clinical advances in the field of H. pylori and GC published between April 2012 and April 2013, including also recent insights concerning the association between H. pylori infection and extragastric malignancies.

Gastric Cancer: Prevention and Screening Strategies

Helicobacter pylori is a group I carcinogen to humans and the major risk factor for the development of sporadic GC of both intestinal and diffuse type. 2. In around 10% of patients, H. pylori-induced chronic active gastritis progresses to severe atrophic changes in gastric mucosa over time, usually many decades 3. Up to 5% of patients with severe gastric atrophy may develop intestinal-type GC 4. The classical Correa cascade concerns approximately one-half of the GC cases worldwide 5. Diffuse-type GC instead arises mostly in H. pylori-infected gastric mucosa without severe atrophic changes. Early treatment for the infection is considered the key to prevent both GC entities 6.

To evaluate the benefit of H. pylori eradication for GC prevention, Lee et al. conducted a mass eradication of H. pylori infection over 4 years (2004–2008) in a Taiwanese population >30 years of age with a high prevalence of H. pylori infection 7. Participants with a positive ¹³C-urea breath test underwent endoscopic screening and 1–2 courses of eradication therapy. The main outcome measures were changes in (i) the prevalence of H. pylori infection, (ii) prevalence and incidence of gastric atrophy, and (iii) GC incidence before (1995–2003) and after (2004–2008) chemoprevention. Eradication therapy was successful in 88.8% of participants. Reinfection/recrudescence rate was 1%. The reduction in H. pylori infection and incidence of gastric atrophy were 78.7% (95% CI 76.8–80.7%) and 61.1% (95% CI 18.5–81.5%), respectively. The prevalence of gastric atrophy was 59.9% in 2004 (immediately before chemoprevention) and 13.7% in 2008 (after chemoprevention), yielding an effectiveness of 77.2% (95% CI 72.3–81.2%) in reducing gastric atrophy. Compared with the 5-year period before chemoprevention and endoscopic screening, the effectiveness in reducing GC incidence during the chemoprevention period was 25% (rate ratio 0.753, 95% CI 0.372–1.524). Side effects of this mass eradication program were a reduction in the prevalence of peptic ulcer disease from 11 to 3.6% and an increased incidence of esophagitis from 13.7 to 27.3% (95% CI 5.1–6.9%) after treatment.

About 40% of the world's total new cases of stomach cancer occur in China 8. In the Shandong intervention trial, the efficacy of a short-term H. pylori eradication treatment with amoxicillin and omeprazole in reducing GC incidence was tested in adults aged 35–64 years from 13 randomly selected villages in Linqu County, Shandong Province, China 9. After a baseline endoscopy in 1994, 2,258 participants with positive H. pylori serology were randomly assigned to capsules containing amoxicillin (1 g) and omeprazole (20 mg) (N = 1,130) or placebo (N = 1,128) to take twice daily for 2 weeks. In patients who received active treatment for H. pylori, GC incidence was reduced by 39% compared with the placebo group after 14.7 years of follow-up (absolute risk 3.0 vs 4.6%; odds ratio 0.61, 95% CI 0.38–0.96; p = .03). A similar but nonstatistically significant reduction was seen for GC mortality. The inclusion of younger participants in such intervention trials is likely to further reduce the burden of GC, the earlier the treatment, the higher the benefit.

The risk of GC is further increased in H. pylori-infected relatives of patients with GC 10. In a Portuguese case-control study on 103 first-degree relatives of patients with early-onset gastric carcinoma (i.e., diagnosed before 45 years) and 101 age- and gender-matched controls undergoing upper GI endoscopy, severe atrophy (OLGA stage III–IV) and noninvasive neoplasia were identified only in cases (n = 19, p < .001 and n = 7, p = .007, respectively) 11. Considering the high prevalence of severe gastric atrophy and even noninvasive neoplasia in first-degree relatives of patients with early-onset GC, accurate endoscopic investigation and follow-up are mandatory in these patients.

Novel Aspects in the Treatment of Gastric Cancer

In the 1st St. Gallen EORTC Gastrointestinal Cancer Conference 2012, controversial issues with limited or conflicting evidence which could not be easily answered through the study of existing data or guidelines were discussed and treatment recommendations were developed 12. The most controversial issue in GC was the use of staging endosonography and/or laparoscopy to determine the preoperative stage. As endosonographic N staging is not always reliable, most participants recommended its use mainly for staging of small mucosal tumours which can be eventually resected endoscopically. The clinical value of staging laparoscopy for patients with GC has not been addressed in randomised clinical trials so far. Staging laparoscopy for cT3 and cT4 tumours was judged useful by many participants, as early detection of peritoneal carcinomatosis would switch the treatment strategy to a palliative one. Because preoperative staging was deemed highly unreliable, a majority of panelists voted for combined pre- and postoperative chemotherapy (even in localized cancers without lymph node involvement, T2N+ or T2N0), combined with a modified D2 resection (i.e., without resection of the pancreatic tail and without routine splenectomy). Adjuvant chemotherapy or radiochemotherapy was considered for patients who had not received perioperative treatment. There were comments that radiochemotherapy should be preferred in patients with lymph node involvement or inadequate lymphadenectomy.

For pre- or perioperative treatment, a doublet of fluoropyrimidine/platinum was the most widely recommended regimen (e.g., cisplatinum/5-FU, cisplatinum/capecitabine and oxaliplatin/capecitabine). Some considered the addition of taxane as appropriate for the preoperative induction regimen.

Future Therapies for Advanced Gastric Cancer

The addition of trastuzumab to a platinum/fluoropyrimidine combination is a new standard first-line therapeutic regimen for patients with advanced HER2-positive GC. Trastuzumab is a monoclonal antibody that interferes with the HER2/neu receptor. In the ToGA trial, trastuzumab in addition to chemotherapy prolonged the median overall survival from 11.8 months to 16.0 months in a selected group of patients with advanced GC overexpressing the HER-2 protein 13. However, the addition of trastuzumab to chemotherapy in patients with HER2-positive GC led to an additional absolute increase in response rate of only 12%, indicating the existence of a high primary trastuzumab resistance in this subpopulation. Furthermore, the majority of patients who had initially responded to the treatment developed acquired or secondary resistance. The molecular mechanisms underlying trastuzumab resistance are not yet well characterized. New targeted therapies to overcome trastuzumab resistance as well as to improve the outcome of patients with HER2-negative GC are currently being evaluated in clinical trials.

HER2 is the preferred heterodimerization partner of the other HER family members, and the HER2-HER3 heterodimer is the most active HER signaling dimer, playing a critical role in oncogenic transformation in HER2-driven tumors 14. Dimerization is followed by transactivation of the receptor, which subsequently activates downstream proteins, including members of the Ras/Raf/mitogen-activated protein kinase (Ras/Raf/MAPK) and phosphatidylinositol-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathways, as well as gene transcriptional programs 15.

Trastuzumab binds to domain IV of the HER2 extracellular domain and does not inhibit the dimerization of HER2 with ligand-activated HER3 16. In contrast, pertuzumab, a humanized monoclonal antibody directed against the extracellular heterodimerization domain II of HER2, effectively blocks HER2/HER3 heterodimerization. In preclinical models of HER2-overexpressing GC cells, pertuzumab displays efficacy when combined with trastuzumab 17. In the clinical setting, pertuzumab treatment for trastuzumab-resistant HER2-positive GCs may be particularly effective, as reported for HER2-positive breast cancer patients who progress on trastuzumab therapy 18. A currently recruiting trial will evaluate the efficacy and safety of pertuzumab in patients with HER2-positive metastatic GC 19.

Heat shock protein 90 (HSP90) is critical for the stability of both the nascent and mature forms of the HER2 protein. Most recently, it has become clear that cancer cells in particular express increased levels of active HSP90 and that mutated oncogenic proteins are more reliant on the function of HSP90, and therefore more susceptible to its inhibition 20. In particular, gastric adenocarcinomas have been shown to express higher levels of HSP90 especially in those tumors with lymph node metastasis 21. In cell lines, AUY922, a potent HSP90 inhibitor, has shown a potent antiproliferative effect, whereas in a trastuzumab-resistant xenograft model, the combination of AUY922 and trastuzumab showed greater antitumor efficacy than either drug alone 22, 23. Results from two phase II trials evaluating the efficacy and safety of AUY922 in patients with advanced GC have not been published so far 24, 25. In particular, a trial compared AUY922 with docetaxel or irinotecan in patients with advanced GC showing progress after one line therapy, whereas the other assessed the efficacy and safety of AUY922 administered in combination with trastuzumab in patients with HER2-positive advanced GC who had received trastuzumab plus chemotherapy in the first line.

The PI3K/AKT/mTOR signaling pathway, which is also activated through the HER2 pathway, plays a crucial role in mediating multiple cellular functions including cell growth, proliferation, metabolism, survival, and angiogenesis. The direct activation of the downstream PI3K/AKT/mTOR signaling pathway, which is often caused by mutations in the genes encoding the PI3K catalytic domain, may represent another mechanism of trastuzumab resistance 26. A currently recruiting trial will evaluate the efficacy and safety of the PI3K Inhibitor BYL719 in combination with AUY922 in patients with advanced or metastatic GC 27.

Helicobacter pylori and Extragastric Malignancies

Over the last years, H. pylori infection has been linked more and more often to extragastric malignancies including pancreatic, lung, hepatocellular, and pharyngeal carcinoma 28-32. However, association studies reported often controversial and inconclusive results. The most interesting and so far best analyzed association between H. pylori infection and extragastric malignancies concerns colonic neoplasms.

Helicobacter pylori and Colon Neoplasms

The first reports showing that colon neoplastic lesions, especially adenomas, are associated with an increased prevalence of H. pylori infection date back to the late 90s 33. Later reports further strengthening this association were not able to identify the underlying causal relationship between H. pylori infection and colonic neoplasms 34, 35. Most studies used a positive serology for anti-H. pylori antibodies as a marker for H. pylori infection. A very recent study (by far the largest one) including 156,000 subjects that underwent gastroscopy and colonoscopy has confirmed a strong association between H. pylori-induced gastritis and various forms of colonic neoplasms including hyperplastic polyps, adenomas and colorectal cancer 36. The most interesting aspect of this study is that several H. pylori-induced gastric pathologies, such as intestinal metaplasia, gastric adenomas, gastric lymphoma, and gastric adenocarcinoma, were also associated with colonic neoplasms. However, in spite of a clear association between H. pylori and colon neoplasms a causal relationship is not given. As H. pylori is uniquely adapted to colonize the gastric mucosa, a direct effect of the bacterium to the colon mucosa is unlikely 37. The most favoured hypothesis proposed is that H. pylori-induced hypergastrinemia may contribute to the colon carcinogenesis. Indeed, H. pylori-induced gastritis leads in some patients to increased levels of serum gastrin by negative feedback to the antral G-cells. Gastrin is a stimulating growth factor, and therefore, hypergastrinemia may promote colorectal neoplasia in humans. This hypothesis is supported by in vitro experiments, showing that high gastrin levels are associated with growth and proliferation of colon cancer cells 38, 39. Further investigations are warranted to better clarify this intriguing results.

Conclusions

Prevention is the best strategy to heal the world from the GC burden. Ideally, an effective vaccine would have the potential to reach this high hope, but in the last year, no clinical data have been published on this field. New evidence shows that H. pylori eradication has the potential to reduce GC incidence, the earlier the treatment, the higher the benefit. New targeted molecules for palliative therapy of advanced GC are under scrutiny. Recent data confirmed the association between H. pylori infection and colonic neoplasms, but the causality for this intriguing association has still to be clarified.