overexpression of human epidermal growth factor receptor 2 ( her2 ) is reported approximately in 1520% primary human breast cancers .
her2 and other member of her superfamily , consist of tyrosine kinase receptors which have roles in the proliferation 's regulation and epithelial cells ' survival .
it is one of the members of her family and has four plasma membrane - bound receptors of tyrosine kinases that transmit extracellular signals to initiate cellular signaling pathways via mitogen - activated protein kinase , phosphoinositide 3-kinase , phospholipase c , protein kinase c , and signal transducer and activator of transcription .
recently , there are some reports that her2 is expressed in many tissues , including the breast , gastrointestinal tract , kidney , and heart .
it has been suggested that possession of her2 lead to cell proliferation and also apoptosis suppression .
patients who suffer her2-positive breast cancer had poor outcome ; however , after introducing trastuzumab , a recombinant humanized monoclonal antibody that binds to the extracellular subdomain of her2 , the destinies have changed .
it is worth noting that not all the patients take advantages of trastuzumab administration , approximately 15% of patients relapse after treatment , indicating trastuzumab resistance eventually emerges in the patients .
several resistance mechanisms have been noted to be responsible including changes in receptor  antibody interaction , induction of the downstream pathways due to increasing in signaling from either other members of the her family or other receptors , and finally constitutive activation of downstream elements .
resistance to trastuzumab as a her2 receptor antagonist , causing concerns , and in recent years , great efforts were applied in developing therapeutic agents to either potentiate the effect of trastuzumab or target cells which have become resistant to trastuzumab .
ado - trastuzumab emtansine ( t - dm1 ) , is an antibody - drug conjugate , in which trastuzumab linked to the fungal cytotoxic agent , mertansine .
antibody - drug conjugate such as t - dm1 are composed of antigen - specific antibodies bounds to cytotoxic agents in order to selectively transfer drugs to tumor cells and minimize systemic toxicity .
t - dm1 consists of the monoclonal antibody trastuzumab linked to a potent microtubule inhibitor ( emtansine ) , leading to a targeted delivery of chemotherapy agent to cells that overexpress her2 .
a derivative of maytansine , emtansine ( also known as dm1 ) , is a cytotoxic agent that its mechanism of action is , microtubule inhibition similar to vinca alkaloids . off note , emtansine are more potent than vincristine and vinblastine in vitro and failed to show therapeutic effect at tolerable doses .
t - dm1 binds to the her2 receptors , and makes the her2 receptor and drug - antibody conjugate internalized via endocytosis .
hence , emtansine binds to its target , tubulin , and causes cell cycle arrest and apoptosis .
the role of trastuzumab is targeted delivery of emtansine and inhibition of her2 signaling pathways .
t - dm1 has primarily been evaluated as a single agent in patients with metastatic her2-positive breast cancer .
there are several phase ii studies on which t - dm1 was administered every 3 weeks as a single agent .
afterwards , the phase iii clinical trial , trastuzumab emtansine for her2-positive advanced breast cancer ( emilia ) , was released .
this study was the only competed phase iii clinical study , in which t - dm1 administration was randomly compared to lapatinib plus capecitabine in patients with her2-positive , unresectable , locally advanced , or metastatic breast cancer who were previously treated with trastuzumab and a taxane .
the results were in favor of the positive effects of t - dm1 administration in overall survival and median duration of response . according to the package labeling ,
appropriate candidates for t - dm1 include patients who have received prior therapy for metastatic disease or those who have developed recurrent disease during or within 6 months of completing adjuvant therapy .
the national comprehensive cancer network has recommended t - dm1 as a preferred agent for patients with her2-positive metastatic breast cancer and prior trastuzumab therapy . according to promising and hopeful results of t - dm1 administration in patients with her2-positive metastatic breast cancer
, this agent attracts attention in using in other her2-positive non - breast cancers . new investigation unleashed the presence of her2 receptors in other malignant organs such as bladder , gastric , and urogenital carcinosarcomas . in this article
, we reviewed the available published data from preclinical and clinical trials over the use of t - dm1 in her2-positive non - breast cancers .
this review focuses on encouraging researchers and clinicians to perform future investigation in this era .
one of the most frequent and fatal human malignancies all over the world is gastric cancer . since it is asymptomatic in preliminary phase ,
many patients suffered from gastric cancer are diagnosed when cancer develop beyond curative strategy . by recent development in molecular biology of her2 and analyses in genomics and proteomics finding , it has now been discovered that her2 is implicated in other severe forms of cancer , especially gastric cancer .
the frequency of her2-positive overexpression in gastric cancer estimated around 20% and is associated with poor clinical outcome .
hence , inhibiting the her family signal transduction is likely contribute to improved survival of patients surfed from gastric cancer .
one of the milestone studies over the use of anti - her2 antibody in the treatment of gastric cancer is trastuzumab for gastric cancer ( toga ) study .
toga was an open - label , international , phase iii , randomized controlled trial undertaken in 122 centers worldwide . in this study , patients with gastric or gastro - esophageal junction cancer who have overexpression of her2 protein were included .
participants were randomly assigned to receive a standard chemotherapy regimen or chemotherapy in combination with intravenous trastuzumab .
the toga trial is a landmark in the treatment of gastric cancer , since following the successful completion of the study , trastuzumab , in combination with chemotherapy , approved for this indication .
results showed that median overall survival was 138 months ( 95% confidence interval [ 95% ci ] 1216 ) in those received trastuzumab plus chemotherapy compared to 111 months in those received chemotherapy alone ( hazard ratio 074 ; 95% ci 060091 ; p = 00046 ) .
prolonged overall survival in trastuzumab administrated group , led to the guidelines recommendation that her2 testing should be routinely performed in patients with metastatic or recurrent gastric cancer .
due to promising results by trastuzumab combination therapy in her2-positive gastric cancer , consequently t - dm1 became the corn stone of consideration .
in gastric cancer , t - dm1 has been evaluated in several preclinical , in vitro and in vivo , her2 positive cell culture .
for the first time in 2011 , barok et al . studied the effects of t - dm1 on her2-positive human gastric cancer cells and xenograft tumors . in vitro study , four her2-positive gastric cancer cell lines including ( n-87 , oe-19 , snu-216 , and mkn-7 ) were applied .
results showed that except in snu-216 cells , t - dm1 has superior inhibitory activity against cancer cells in comparison to trastuzumab . in vivo study , using same cell lines in xenograft tumors , similar positive antitumor effects was found by t - dm1 . in this study ,
t - dm1 has a promising antitumor effect in her2-positive gastric cancer cell lines by direct effects including apoptotic cell death and improper mitosis as well as antibody - mediated cellular cytotoxicity , even in tumors which had developed resistance to trastuzumab . in another preclinical study , t - dm1 as a single agent showed statistically significant antitumor activity in three her2-rich expression tumor models evaluated ( nci - n87 , sch and 4 - 1st ) .
in addition , the combination of t - dm1 and pertuzumab , a her2 dimerization inhibitor , in xenografted gastric tumors induced significant tumor regression .
the possible mechanisms involved in tumor regression of combination treatment are enhancement of antibody - dependent and increase in cellular cytotoxicity by akt , v - akt murine thymoma viral oncogene homolog 1 , and signal inhibition . nowadays , in a clinical trial which is underway ,
the efficacy and safety of t - dm1 compared with standard taxane therapy in patients with her2-positive advanced gastric cancer was examined . in this multicenter , randomized , adaptive phase ii / iii study
, patients will be randomized to one of the three arms , 3.6 mg / kg t - dm1 every 3 weeks , 2.4 mg / kg t - dm1 every week , or taxane therapy ( docetaxel or paclitaxel per investigator choice ) , for at least four cycles ( 12 weeks ) .
patients will receive study protocol treatment until disease progression , unacceptable toxicity , or withdrawal .
considered endpoints of the study are overall survival , progression free survival , duration of response , and time to gastric cancer symptom progression , as well as safety .
using t - dm1 in her2-positive gastric cancer is in infancy , lots of well - designed randomized control trials must be handled to clarify the real indication , proper doses , and duration of treatment by this agent .
urothelial bladder carcinoma is a major global health concern responsible for 165,000 deaths annually . over the two past decades
, there has been no statistically significant improvement in 5-year patients ' survival rates for locally advanced and metastatic condition . in recent study ,
several mutations in the extracellular and tyrosine kinases domains of her2 , was reported in urothelial bladder cancers .
it has been suggested that having her2 expression correlated with inferior recurrence - free survival .
furthermore , identifying of her2 mutations and the role of this pathway in bladder carcinogenesis is desirable .
more heavily reason back to the use of anti - her2 agents , ( e.g. , trastuzumab , lapatinib , ado - trastuzumab emtansine , and pertuzumab ) in the bladder carcinoma 's treatment . in a phase ii study done by hussain et al . , the safety and efficacy ( response rates , time to disease progression , survival ) of trastuzumab , carboplatin , gemcitabine , and paclitaxel in advanced urothelial carcinoma with her2 over - expression were evaluated .
these patients achieved a remarkable response rate of 70% ( 31 out of 44 patients ; 5 complete responses , and 26 partial responses ) , and a median time to progression and overall survival of 9.3 and 14.1 months , respectively .
the primary end point of the study was cardiac toxicity that was higher than projected .
today , it is believed that novel strategies targeting her2 lead to outcomes of her2 positive bladder cancer 's improvement .
an encouraging preliminary study was designed by the aim of evaluating the effect of t - dm1 compared to trastuzumab in different cell lines and xenograft models of her2 over expressing in bladder cancer . in this study ,
rt4v6 cell line was used as a highest her2 expressing bladder cancer cell line . in comparison to trastuzumab
t - dm1 made apoptosis of rt4v6 cells after g2/m arrest on cell cycle analysis .
the most interesting finding was that her2 expression was higher in cell lines with acquired cisplatin resistance 's cell line .
moreover , in an orthotopic bladder cancer xenograft model , tumor growth of cisplatin resistant cells , rt112 , was significantly inhibited by t - dm .
these inhibitory effects are suggested to be via the induction of apoptosis compared to treatment with control igg or trastuzumab . taken together , although there is a paucity of data around the administration of her2-possitive bladder cancer , but when we want to looking for emerging strategy , in bladder cancer treatment , targeting this pathway must be considered . however , t - dm1 showed promising antitumor effects in preclinical models of her2 over expressing bladder cancer , but running several well - designed clinical trial is warranted to prove the potential positive effects of t - dm in affected patients .
carcinosarcoma , also characterized as malignant mixed mllerian tumors , are one of the rarest and challenging tumors among all gynecological malignancies .
these tumors compromise in any genital tract anatomical organs of the female body such as endometrium , ovary , cervix , vulva , vagina or fallopian tube . but among that , endometrium is the most common affected site . on the other hands ,
uterine sarcoma accounts for 35% of all corpus uteri malignancies with an incidence in the united states of 14/100,000 women . on the other hands ,
ovarian carcinosarcoma has a worse prognosis than uterine carcinosarcoma , with a median survival rate of 832 months and recurrence rates of 50100% .
this high rate of tumor recurrence , resistance to therapy , and the poor median survival of patients suffered from carcinosarcoma propose a need to identify more effective treatment modalities . by identifying carcinomatous component - induced tumor growth ,
it is suggested that therapeutic interventions targeting cellular pathways that drive epithelial cell proliferation may potentially be beneficial against these kind of tumor .
it has been reported that her2/neu is overexpressed and amplification in uterine carcinosarcoma ranged from 17% to 43% .
having her2 , raising the possibility that anti - her2 therapies may be an effective modalities in the treatment of carcinosarcoma .
for the first time , english et al . evaluated the t - dm1 against her2-positive uterine serous carcinoma in vitro followed by developing a supportive carcinosarcoma in vivo model . in this study , fifteen primary uterine serous carcinoma cell lines were assessed for her2 protein expression by the aim of immunohistochemistry and flow - cytometry .
they found that near 33% of uterine serous carcinoma were positive for her2 gene amplification and protein overexpression . in vitro , t - dm1 , and
trastuzumab cytostatic and apoptotic activities were evaluated by flow - cytometry - based proliferation assays and showed that t - dm1 was notably more effective than trastuzumab in inhibiting cell proliferation and inducing apoptosis in her2 overexpression 's cell line . moreover , in mice model , t - dm1 treatment led to highly reduction in tumor size and longer survival comparing to trastuzumab and control group .
furthermore , t - dm1 showed effective antitumor activity in both xenograft and cell lines models .
it may represent a novel treatment option for her2-positive uterine serous carcinoma patients with disease refractory to trastuzumab and traditional chemotherapy .
the positive effects of t - dm1 against primary her2 positive and her2 negative carcinosarcoma cell lines were documented in another report .
nicoletti et al . in 2015 , in a similar experimental study noted that t - dm1 was dramatically more effective than trastuzumab in inhibiting cell proliferation and in inducing g2/m phase cell cycle arrest in the her2 expressing cell lines in vitro and in vivo . according to new and promising finding from these two study
, we can conclude that t - dm1 at least may represent a novel treatment option for the subset of her2 positive carcinosarcoma patients with disease refractory to chemotherapy .
antibody - mediated therapy for the treatment of various human malignancies has proved efficacy in the past 30 years , and it is now one of the most successful strategies for targeted treatment of patients suffering from hematological malignancies and solid tumors .
not so far days , when trastuzumab , as a recombinant humanized monoclonal antibody , has been introduced to her2 positive breast cancer treatment , hope opens door for these group of poor prognosis cancers .
but todays concerns were raised along to trastuzumab resistance that was induced by malignant cells .
evidence suggests that combinations of her2-directed agents by other cytotoxic ones may show additive or synergistic effects and lead to improving outcome . by developing the antibody 
drug conjugates technique , the opportunity came up to take advantage of selectively delivery of potent cytotoxic drugs by monoclonal antibodies to antigen - expressing tumor cells .
base on the success results from experimental studies , recently , food and drug administration was approved brentuximab vedotin ( adcetris ) and t - dm1 ( kadcyla ) , for clinical applications of cancer treatment .
the clinical studies demonstrated that t - dm1 is associated with improved efficacy and safety compared with traditional chemotherapy .
several clinical trials showed the beneficiary effects of t - dm1 in the her2-positive metastatic setting and in patients with prior exposure to trastuzumab and lapatinib .
the use of t - dm1 in other malignances with her2 overexpression and gene - amplification except than breast cancer is of key interest .
new technical development has demonstrated that her2 overexpression is seen in some other malignancies such as gastric cancer , bladder cancer , uterine and ovarian carcinosarcomas .
it has suggested that up to 20% , 9% , 30% of gastric , bladder , and uterine carcinosarcomas , respectively , overexpress her2 and is associated with significantly worse outcomes . in comparison to her2 positive breast cancer by near 30% overexpression , these quantities are large enough to be considering in treatment modalities . by developing the new concern around trastuzumab resistance and on the other hand , documented efficacy of t - dm1 as better therapeutic option , t - dm1 is now in the spotlight .
this review has discussed just some of the limited data showing the preclinical benefits of t - dm1 for treating her2-positive non - breast cancer .
all in vitro and in vivo study confirmed that t - dm1 administration led to prolonging overall survival and progression - free survival .
hence , by considering these promising results , it is time to assessed clinical responses by designing phase i / ii clinical trials . if future clinical results can demonstrate the similar results as preclinical data , then new era in the treatment of any her2-positive non - breast cancer and survival prolongation will be created . in march 2011 ,
based on the results of the toga trial , trastuzumab was intensively approved in gastric cancer .
the introduction of trastuzumab made new term in gastric cancer entitled  her2-positive gastric cancer ,  similar to her2-positive breast cancer .
this discovery gives us a clue that her2-positive non - breast cancers are developing and identifying .
finding new agents for treatment of them are important future issues . as an example , new advancing in the knowledge of urothelial carcinoma pathophysiology and underlying molecular mechanisms showed the most relevant molecular pathways that might demonstrate therapeutic potential .
the most important relevant overactive signaling networks are fibroblast growth factor receptor , pi3k / akt / mtor , and her2 .
any development in identifying the signaling networks on each cancer types leads to use of another possible effective treatment modality in the future . furthermore , if clinical trials reach to same prominent results as we reviewed . in the near future
, we will see the routine use of trastuzumab conjugated agents such as t - dm1 in chemotherapy regime of other her2-positive non - breast malignancies .
we strongly recommend managing well - designed control trials to clarified future additional data , over the more precise number and roles of her2 receptors as a therapeutic target in her2-positive non - breast malignancies .
we need to know many details about the best administrated regime in her2-positive non - breast malignancies . while we are in the beginning of way and it is soon for any important decision .
azadeh moghaddas was responsible for literature review , data collection , and preparing and editing the manuscript draft .
a part of this study was presented in 18th international conference on non communicable diseases ( icncd 2016 ) which was held in amsterdam , the netherlands .
a part of this study was presented in 18th international conference on non communicable diseases ( icncd 2016 ) which was held in amsterdam , the netherlands .
 the national comprehensive cancer network ( nccn ) has recommended ado - trastuzumab emtansine ( t - dm1 ) as a preferred agent for patients with human epidermal growth factor receptor-2 ( her2)-positive metastatic breast cancer and prior trastuzumab therapy . 
 overexpression of her2 was reported in other cancer types such as bladder , gastric and urogenital carcinosarcomas similar to what is discovered in breast cancer . 
 some preclinical studies demonstrated the potential anti - tumor effects of t - dm1 in her2-positive non - breast cancers . there is a paucity of data over the clinical evaluation of t - dm1 in human studies of non - breast cancer patients . 
 we review some preclinical and ongoing clinical studies that assessed the efficacy of t - dm1 administration in the treatment of non - breast her2 positive malignancies . performing large and well - designed trials in this area 
 is matter of interest and highly recommended . 
INTRODUCTION
ADO-TRASTUZUMAB EMTANSINE IN HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-POSITIVE GASTRIC CANCER
ADO-TRASTUZUMAB EMTANSINE IN HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-POSITIVE BLADDER CANCER
ADO-TRASTUZUMAB EMTANSINE IN HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-POSITIVE UTERINE AND OVARIAN CARCINOSARCOMAS
CONCLUSION
AUTHORS' CONTRIBUTION
Financial support and sponsorship
Conflicts of interest