As you mentioned, FOLFIRI+Cetuximab+Herceptin is likely to overcome cetuximab-resistant colon adenocarcinoma depending on the presence of EGFR mutation. Herceptin is widely known to be effective for HER-2-overexpressing gastric and breast cancer tissues, so that these days herceptin binding to DM1 promotes the intracellular uptake and exhibits the significant tumor therapeutic effect. After all, DM1 is an antibody-conjugatable maytansinoid that has been developed to overcome systemic toxicity associated with maytansine and to enhance tumor-specific delivery.

Thanks for your answer Mr. Yoshida

EGFR,KRAS,NRAS AND BRAF  is not mutant but there is a polysomy(%40 of Tumor cells) in chromosome 17 and HER2. Some article said that "HER2 amplification causes resistance to anti-EGFR therapy". FOLFIRI+Cetuximab did not affect. If we use FOLFIRI+Cetuximab+Herceptin, can ve overcome EGFR resistance in tumor?

You mean that there is a heterogeneity in the HER2 overexpression in your case? The heterogeneity is one of the most crucial factors for cancer cells to acquire the adaptive resistance or show the Darwinian Evolution under the micro-environmental stress characterized by anti-cancer drugs-induced ROS etc.  

yes there is a heterogenity in our case.

In the setting of HER2 amplification, one would expect so. A small clinical trial evaluated the combination of irinotecan + hercepting and reported very high response rates (7 out 9) if I recollect. The question is therefore how to best target this patient population. At this time, it is unclear that herceptin + cetuximab + chemo will be better than herceptin + chemo or cetuximab plus chemo. Pre-clinical models suggest that cetuximab resistance is associated with increased HER-2 expression/ amplification. However, there is no clinical data to support that anti-EGFR resistance can be overcome with herceptin. You also have to consider the potential of added toxicty of herceptin + anti-EGFR as the safety of this combo has not been shown with FOLFIRI.

More recent data presented this GI ASCO suggests that HER-2 degree of amplification matters in response. The HERCULES clinical trial evaluated responses to lapatinib + pertuzumab in mCRC with HER-amplification and the ORR exceeded 20%. The responses were seen in the highly amplified HER-2 tumors.. Therefore, it is possible that the role of HER-2 targeting in the future of mCRC may not only be limited to FISH positivity but also to highly amplified FISH positive tumors.

In our case, we have two main problem.First one is there is a polysomy for her2. Second is her2 polysomy is not pure for cancer cell. %40 of cancer cells have polysomy. 

You raised an interesting question. I did not notice that there is an undergoing clinical trial for the combination as you mentioned. However, there are several aspects need to be considered in my opinion.

First, what is the differences in EGFR expression between these Her2 polysomy cells (40%) vs. the Her2 amplification-negative cells (60%)? Do the Her2 amplification occur simultaneously with the EGFR overexpression? Or are they exclusive to each other? If the latter is the case, then Her2 might compensate the pro-survival signals of EGFR in this sub-population, and one can predict that Cetuximab+Herceptin would be useless.

Second, other RTKs might also contribute to the cancer cell growth, such as Met as you mentioned. In our studies, we found IGF1R, FGFR, VEGFR, PDGFR, Axl and EphR were also functional relevant in some cases, especially when there is a gene amplification of these receptors. The heterogeneity exists extensively. So very elaborate stratification is needed for every individual cancer.

Last, other downstream mutations, beside KRAS, should be taken into account. For example, BRAF mut is reported to be the reason for 5-10% of CRC cases which are KRAS wild-type but resistant to anti-EGFR therapy.

From a practical point of view I see 3 problems in the combination of Cetuximab and Trastuzumab

First: I think the combination would be biologically redundant (2 drugs for the same target at the same level , EGFR pathway at the extracelular domain) considering that the main activity of cetuximab is in  EGFR signalling (clinically no relevant ADCC activity has been revealed)

Second: From our knowledge of breast cancer polisomy of chr 17 is not associated with response to trastuzumab (in fact is considered a false positive for FISH tests), probably by inactivation of "extra chromosomes"

Third: There is no experience with this combination even in early phase trials

This is how I understand it:

The size of a cell, even a cancer cell, is within a certain limit as it is not possible for a cell to go infinitely big. Hence the surface area also has a certain limit and so do the proteins on the cell membrane. Normally, cetuximab targets patient with EGFR(Her1) expression. However, if a patient has an amplified Her2 gene, the cellular surface expression level of Her1 would definitely drop. And that might be the cause of insensitivity towards anti-Her1 treatment.

Based on that, I would say adding Herceptin will definitely increase the response in those patients. Those cancer cell populations without Her2 amplification would be destroyed by cetuximab as they normally do. And the 40% you mentioned will respond to Herceptin.

Again, it's just my personal thought on this.

Very interesting discussion, I would just like to add besides the discussions above, one may also keep in mind the PI3K, MEK, AKT mutations that may be involved and molecules of other alternative or additional  pathways that may be involved in resistant metastatic colorectal carcnomas. The article below may be of help.

http://tpx.sagepub.com/content/42/1/124.full