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Breast cancer is a tumour related to breast tissues and out of total cancer patients in UK 30 percent are females suffered from breast cancer and there is possibility that 1 out of 9 women in UK will get breast cancer once in their life. Chemotherapies are well known treatments for cancer. These techniques are effective but having possible side effect, this project will primarily focus on the finding of the biomarkers in clinical and pathologic response of primary tumour treated with neoadjuvent docetaxal-capecitabine(with or without trasthzumb) chemotherapy. Biomarkers are the basically product of genes whose expression increase or decrease in particular biological state. Chemotherapy is effective way to treat HER2 positive cells with docetaxal-capecitabine-trasthzumb regimen and HER2 negative cancer with docetaxal-capecitabine regimen and show increased death free survival time (D.F.S). But problem associated with chemotherapy is lots of side effects in human and same dose of chemotherapy can't be used for the desired results in each and every patient. This project will try to find out biomarkers in EMBL's ARRAYEXPRESS E-GEOD-22358 dataset in response to chemotherapy by using artificial neural network (A.N.N) technique to analyse this database and try to validate and optimise results statically.
After finding of biomarkers we can personalised this chemotherapy according to individual and screen out group of people on which this therapy will not work effectively and show heightened complete pathological response in patients who takes this therapy. By just taking patient's biopsy sample we can find out whether this therapy is effective and at which level patient will response to therapy.
Background to investigation:
Breast cancer is the state in which uncontrolled growth of breast tissue takes place. Most commonly cancer originates from milk duct's inner linings or lobules of breast. Among all types of cancer breast cancer is the second diagnosed cancer in the world. some of cancerous cell have receptor on surface of cells and respond in specific way according to their receptor like HER2 receptor, ER receptor
HER2 is human epidermal growth factor receptor. This is surface bound receptor help in singal transduction by which cell proliferate and differentiate. But in some cells HER2 gene product(protein ) over express and due to which cell grow in uncontrolled manner and become cancerous. HER2 positive status it means cell have overproduction of HER2 GENE and cell shows cancerous growth, if HER2 negative then HER2 not causing cancer.HER2 belongs to the Human Epidermal Growth Factor Receptor (HER) family of tyrosine kinases conisting of EGFR (HER1, erbB1), HER2 (erbB2, HER2/neu), HER3 (erbB3), and HER4 (erbB4)
30% of breast cancers are due to over expression of HER2 gene. And inhibition of HER2 would be the best treatment for this type of cancers and monoclonal antibodies (AB) found to be an effective treatment for her positive cancer, for this purpose thousands of monoclonal AB find and produced and out of them some are humanised. Some of such humanised clone lost their anti proliferating activity but some retain by selecting from such abs Trastuzumab was prodused. this is an AB which bind specifically to HER2 protein and stop growth of uncontrolled cells in breast tissue.
In intial phase it was difficult to detect HER2 positive cells with immunohistochemical methods but this problem resolve by implementation of a fluorescence in situ hybridization (FISH) assay, this is easy and fast method to detect her2 amplification in cells. this Trastuzumab show good response if it is used as upfront therapy. Patients with metastatic disease not showing response to Trastuzumab even after long treatment cancer come back
And activity of Trastuzumab is only related to HER2 positive cells . this is not working against HER2 negative cells. Mode of action was determined various theories
"trastuzumab binds and internalizes with surface HER2 but re-emerges with HER2 at the surface, merely accompanying HER2 passively along its normal endocytic recycling route". trastuzumab inhibit EGFR-HER2 interaction but not HER2-HER3 interactions.Trastuzumab binding inhibits the proteolytic cleavage and shedding of HER2 by ADAM proteases. Lots of report shows that decreasing in the signalling pathway of HER2 by Trastuzumab
How this trastuzumab show anti proliferating effect. By indusing p27 which induse suppression of cell proliferation and cell cycle at g1 phase ,suppresses Akt signaling in tumor cell, downstream PI3K cascade,by inhibition of CDK2 activity, inhibit the HER2 ectodomain cleavage, trastuzumab response effected by PTEN gene,low or absence of PTEN in tumour cells make them resistant to trastuzumab Nagata et al. 2004; Fujita et al. 2006). Chemotherapy with this drug show good response rate and survival time. Having some significant side effects like not suitable for heart patient and risk of chemotherapy increase when combine with anthracyclin.
This is specialised term used for treatment of cancer cells. Chemotherapy chemicals introduce in to blood stream and kill cancerous cell by Cell apoptosis, Mutation in DNA /RNA of cell, freezing of mitosis, stopping growth of new blood vessels that supply tumour. Chemotherapy could be given by single or group of chemicals depend upon the type of therapy and stage of cancer.
Chemical used in chemotherapy:
These are chemical compound which produce naturally by genre "taxus" and causing less cytotoxicity then anthracyclin. Most commonly used taxane are paciltaxal, dociltaxal etc. taxane report very good in anthracyclin resistant patients. Taxane are radiosenstizing and cause appotosis of cancerous cell in radiotherapy. Taxane cause apoptosis, frozen mitosis. Taxane bind reversibly to beta microtubule to stabilise microtubule complex, this caused microtubule polymerisation, arrest cell cycle and cause apoptosis(REF R MIX 3).paciltaxal used as adjuvant therapy for early and advance state breast cancer?(r mix r2).Taxane can be used alone or in combination of chemotherapeutic agents. Taxane also used in the treatment of metastasis breast cancer in which HER2 gene is over expressed. Response rate is high with paciltaxal used in combination or alone and in neo adjuvant therapy. Some Problems associated with taxane: Worse emotional and mental quality of life throughout adjuvant treatment, High risk of psychological problem, Rate of recovery is very slow(r mix r2).Chemotherapy known for tumor size reduction and incrase survival in case of breast cancer so it is substitute treatment for harmone resistant cancer cells due to high response rate abthracyclin used as treatment for cancer but many patient have recurret disease which already treated with anthracyclin and for that type of patient taxane treatment is used
Ghersi et al research daw an comparision between taxane and non taxane based regimen and showed that patient treatd with taxane regimen show improved overall survival, time of progression and overall response rate and showed chemotherapy with taxane based regimen show improved overall survival rate . patient treated with taxane show higher survival rate of 40-68% and in anthracycin resistant patient alone 52- 57%.
capecitabine is oral anticancer drug used for mylosupression and monotherapy with this useful to treat advance stage metastatic breast cancer.capecitabine is a thymidine phosphorylase activated fluropyrimidine and used to genrate 5 flurouracil at tumour site. Many chemicals like taxanes,cyclophosphoamidee, mytomycin are used in combination with cepecitabine and show synergic effect, docetaxal and capecitabine is extensively used combination because of low price of treatment as compare to chemotherapeutic agents. Cepecitabine is useful anticancer agent in breast cancer and show equal cytotoxic effects as like other drugs used for cancer treatment and inhibit growth of cancerous cells by inducing apoptosis .capecetabine is a drug having less side effect as compare to other chemotherapeutic agents
P53 is protein having tumour suppressing activity which is prodused by tp53 gene located on chromosome 17.this protein regulate cell cycle and prevent camcer. This have anti cancer role and cause apoptosis. Cancer occure due to faulty copy fo tp53 of mutation by any chemical , radiation or any other mean due to which p53 lost his activity and cell start to grow in uncontrolled fashion and this is known as primary cause of cancer.
Drugs in combinations:
Combination of docetaxal and capecitabine show positive response in locally advance breast cancer. this combination make surgery possible and increase diseased free survival time. docetaxal and capecitabine is highly active combination in metastatic breast cancer and this is good alternative for non anthracycline based treatments. Study done by Stefan gluck et al shows that 3 cycles of Docetaxal, capecitabine as neoadjuvan therapy gives hightend pCR and this pCR achived by this combination is equal to 3 cycles anthracyclin and taxane combination which shows that this is better alternative to non anthracyclin based chemo therapy and this study also shows that HER2 positive/ HER2 negative patient should treat with not more then four cycle of this combination. side effects of Docetaxal, capecitabine are: gastroinstestinal side effects and hard foot syndrome
. This combination frequently used in treatment of HER2 POSITIVE breast cancer treatment because of less cardiotoxicity and can be used with trastuzumab .Trastuzumab have high clinical and pathological response in treatment of HER2 positive cancer. some study shows that pre-operative treatment with docetaxal and trastuzumab should be used as standard treatment.Trastuzumab in combination with docetaxal and capecitabine show good response in HER2 positive patient breast cancer patient
Combination of docetaxal ,capecitabine,trastuzumab:
This is good to used this combination because of less cardio toxicity. docetaxal ,capecitabine,trastuzumab combination show more progression free survival timein HER2 positive patients as compare to docetaxal ,capecitabine. Glueket et al study shows more promising result with this combination In locally advanced breast cancer in HER2 positive type cancer and they also show that this combination is less cardiotoxic,
Combination of Docetaxal, capecitabine and trastuzumabused used as preoperative breast cancer treatmenat for HER2 positive and Docetaxal, capecitabine for HER negative breast cancer.
Principle of DNA micro array is "affinity and specificity of cdna molecules to complementary base pairing and involve in the hybridisation of cdna molecules to the dna template from which they were originated" and detection is fluorophore base.
How A.NN was used in breast cancer treatment:
In 1995: a.n.n was designed in which input was histological data of patient to detect breast cancer and this was best method to detect breast cancer among the existing methods.
In 1999: A.n.n was trained on family history of cancer, dietary variable, socio demographic, gyneco-obstetric factors. On this basis this a.n.n was able to separate group of women who have high chance of having breast cancer.
In 2001: a.n.n was designed to analyse quantitative data from M.R.I(magnetic resolution imaging). In this quantitative parameters from time-intensity profile were used as input. These factors were size of tumour, age, area under time intensity curve etc. and this a.n.n was capable to separate malignant to benign tumour.
In 2004: in this a.n.n was used with M.R.A.S(multivarient adopted regression). In this MRAS used in modelling breast cancer diagnostic problem and obtain variable as input of a.n.n, this improve classification efficiency of a.n.n model .this a.n.n input was taken from FNAC database of cancer patient. This a.n.n help to find important predictor variable which may provide information in further diagnostic purpose.
In 2010: a.n.n was used for estimation of tumour parameter in cancerous breast with thermogram. this approach can adopt to retrieve tumour location and radious with reasonable accuracy and patient may refer to higher level treatment or diagnosis like C.T(computerised tomography) scan, M.R.I(magnetic resolution imaging) scan
Recently, a.n.n also used to find biomarkers in the different cancers.
Artificial neural network (A.N.N):
This is computer based model of human brain which works in similar manner to biological neural network but much faster than the human brain. A.N.N have three layers; input, middle and outer layer. Signal is enter through input layer then come to middle layer and processing
of the input data take place and finally result from middle layer transfer to output layer and result comes out from outer layer. In this all nodes are connected with each other and having an assign value or weight. If input signal having that value then this will pass forward and finally come in form of output.
Methods of learning:
In this type of learning A.N.N is trained by some special programmes to withdraw desired output from given set of data. In this we have the output value which we want and A.N.N adjusts the input values according to that and produce desired value.
In this we don't have any special programme through which our A.N.N learn. In this a.n.n mode of learning based upon previous experience and this will learn as much this will entertain with new type of data for example. If A.N.N found new pattern which belong to previous cluster then this inclusion of this pattern take i to existing cluster and change in weight take place .which will characterise A.N.N. If this pattern does not belong to existing cluster then this will accommodate in to new class.
Problem associated with A.N.N
Difficult to interpret how this reach to optimal solution
Suffered from dimensionality problem when used to solve complex problem having large linear data
But in case of non linear data set dimensionality is not any problem and work well with such type of dataset. by the use of A.N.N we will find which set the genes are up/down-regulated. This group of certain gene would be biomarkers which show response it terms of chemotherapy.
We will use various statistical tools to validate and optimise results drawn from A.N.N. Tools selection will depend upon data generated from a.n.n . Primarily, these will include correlation, regression, t test and probalistic approach may be used.
These tests are used for
To check cause and effect relationship.
To check whether two variables are associated.
To estimate value of one variable corresponding to another variable.
Time guidelines for project:
This is six month project. In first month data mining take place along with different modelling pathways. In next three months I will do validation of data and finding of the result. In next one month of analysis of result and validation of result the final month will spent in preparing thesis and poster presentation.