**5. General conclusion**

66 Biomarker

584 patients received treatment with trastuzumab plus chemotherapy (5FU or capecitabine and cisplatin) for six cycles or chemotherapy alone (Lorenzen & Lordick, 2011). The primary objective was to compare overall survival in both treatment arms, and the secondary objectives were to compare progression-free survival, time to progression, overall response rate, control disease, duration of response, and quality of life (Gravalos & Jimeno, 2008). The primary endpoint of the study was met: trastuzumab significantly improved overall survival by nearly 3 months (median 11.1 vs 13.8 months) (Lorenzen & Lordick, 2011). In addition, an exploratory post-hoc analysis showed that trastuzumab plus chemotherapy substantially improved overall survival in patients with high expression of HER2 protein (IHC2+/FISH+ or IHC3+, 16 months) compared with patients with low expression of HER2 protein (IHC0 or 1+ and FISH+) (Bang et al., 2010). The secondary endpoints also showed significant improvements when trastuzumab was added to chemotherapy. The addition of trastuzumab to chemotherapy did not increase toxic effects associated with standard fluoropyrimidine-based and platinum-based chemotherapy and therefore trastuzumab can be combined with standard chemotherapy without affecting the overall safety profile. On the basis of these findings, trastuzumab can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer when combined with a chemotherapy regimen consisting of capecitabine plus cisplatin or

On the basis of this evidence, in January 2010 the EMEA and on 20 October 2010, the US FDA granted approval for trastuzumab in combination with cisplatin and fluoropyrimidine (either capecitabine or 5FU), for the treatment of metastatic HER-2 positive gastric or gastrooesophageal junction adenocarcinoma who have not received prior treatment for metastatic

Further studies are necessary to investigate the role of trastuzumab in curative gastric cancer treatment, as well its role as monotherapy, maintenance therapy and second line treatment in the palliative setting. Furthermore, additional predictive markers are needed besides a HER2-positive status. In addition, there is an urgent need to improve the knowledge of the mechanisms involved in anti-HER2 sensitivity or resistance, in order to develop other

Since there is no internationally accepted standard of care for gastric or gastro-esophageal cancer patients and survival remains poor, new therapeutic strategies are needed. There is mounting evidence of the role of HER2 overexpression in patients with gastric cancer. HER2 overexpression has been correlated to poor outcome and more aggressive disease. Furthermore, the positive results of the randomized phase III ToGA trial have opened up new frontiers. Trastuzumab not only represents a new and effective therapeutic option, but has also stimulated the search for predictive marker in order to refine patient selection (Fornaro et al., 2011). Trastuzumab represents a new reference treatment for patients with HER2-positive metastatic gastric or gastro-esophageal cancer. Routine HER2 testing is suggested for all patients with advanced disease. Other agents directed against members of the HER family (like lapatinib) are currently under investigation (Lorenzen & Lordick,

rationally targeted agents in the near future (Fornaro et al., 2011).

fluorouracil plus cisplatin (Bang et al., 2010).

disease (Lorenzen & Lordick, 2011).

**4.5 Conclusion** 

2011).

Ample data shows that only a limited portion of patients may benefit from anti-cancer treatments currently used in the clinic. Personalized cancer medicine, based on genetic profiling of individual tumors and biomarkers, is regarded as the treatment strategy of the future. In this review the most promising biomarkers in colorectal, pancreatic and gastric cancer were discussed (table 2). Currently, the only biomarker that has made it into clinical practice for colorectal cancer is *KRAS* mutation for the selection of patients eligible for cetuximab therapy. Furthermore, evidence shows that other molecular alterations, such as *BRAF*, *PIK3CA* (exon-20) mutations or loss of PTEN expression, could preclude response to EGFR moAb.


Table 2. The most promising biomarkers in colorectal, pancreatic and gastric cancer summarized.

Improved screening for early diagnosis is essential in order to increase the rate of curatively resectable pancreatic carcinomas, thereby ameliorating patient's prognosis. A relatively noninvasive, cost efficient possibility could be provided by the measurement of disease-specific markers in peripheral blood. However, only a few markers have shown promising results in recent studies with CA19-9 being the most widely investigated and evaluated single marker (Bünger et al., 2011).

In patients with gastric cancer there is mounting evidence of the role of HER2 overexpression since it has been correlated to poor outcome and more aggressive disease. Furthermore, HER 2 overexpression was found to be predictive for treatment of gastric cancer patients with trastuzumab. Routine HER2 testing is now suggested for all patients with advanced disease.

Given the importance of biomarkers in this era of targeted therapies more and especially prospective randomized trials are necessary.
