Adjuvant Trastuzumab In The Treatment Of Breast Cancers Biology Essay

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1.0 ABSTRACT

Breast cancer is one of the common cancers in the western world .The Human epidermal growth factor receptor (HER 2) belongs to the tyrosine kinase family that is involved in growth, differentiation and cell survival. Over expression of HER 2 and gene amplification is seen in 20-30% of breast cancers. This represents an aggressive form of the disease

Trastuzumab (herceptin) is a humanised monoclonal antibody that is used in the treatment of breast cancers that overexpress Her 2,if functions by binding to the outside of the cell and causing programmed cell death. HER2, it has shown to be beneficial in patients who over express HER2 when given weekly or every three weeks alone or in combination with chemotherapy. The main adverse effect associated with trastuzumab have been cardio toxicity (mainly congestive heart failure), the development of brain metastasis. In this review I will be looking at the effectiveness of trastuzumab plus chemotherapy in the treatment of breast cancer in comparison to chemotherapy alone.

In summary trastuzumab has shown to be effective in the treatment of breast cancer for women who are HER 2 and so it should be looked as first choice of treatment.

2.0 INTRODUCTION

In breast cancer the cells divide, multiply, and grow uncontrollably and this is referred to as malignant tumour. In normal cells they partition and replicate themselves in an organized and natural manner.

The breast consists of lobules, ducts and stroma .There are different types of breast cancer namely ductal cancer (start in the cells that surround the milk producing areas), lobular cancers (start in cells that surround the lobules) and minute numbers begin in different other tissues. Some breast cancers are carcinoma and a few are adenocarcinomas (cancer .org, 2010)

Figure 1.0 shows the structure of a normal breast

http://www.mentorwwllc.com/global/images/breast-anatomy.jpg(mentorwwllc.2011)

Statistics show that in 2008, around 1.38m women were diagnosed with breast cancer worldwide. In the UK 48,034 new cases of breast cancer were diagnosed around 47,693 (over 99%) in women and 341 (less than 1%) in men. In the UK almost all new cases of cancer are breast and the likely hood of developing cancer in women is very high compared to men. Breast cancer likely hood is strongly associated with age as most cases appear in the over fifties. Figure 1.2

Figures show that incidence rate of female breast cancer is highest in Europe and the lowest incidence rates are in Africa and Asia. Figure 1.3

Figure 1.1 shows the number of breast cancer cases in the UK and its component countries in 2008

Figure 1.1 above shows that the number 0f breast cancer in females is high in the United Kingdom (UK) followed by England then Scotland and the lowest in Wales and Northern Ireland.

Figure 1.1: Shows the number of New Cases and Age-Specific Incidence Rates, of breast cancer in the UK between 2006-2008

(cancerresearchuk.org ,2010)

The figure shows that there are few cases of breast cancer between the age group of 0-34, then between 35-59 reasonably high, the highest at 60-64, followed by 65-69 and it goes down at 70-85.

Figure 1.2: shows World Age-Standardised Incidence and Mortality Rates of breast cancer by World Regions in 2008

Chart showing the age-standardised incidence rates (World) for female breast cancer, 2002 estimates

(Cancer researchuk, 2010)

Figure above shows that the lowest incidence rates are in Africa and Asia and the highest incidence rates are in Europe the lowest mortality rate is in Eastern Asia and Central America and the highest in southern Northern and western Africa Africa

some of these factors have been indentified that make people more susceptible to breast cancer: genetic factor (heritage BCRA 1 and BCRA2 gene that has been identified to cause breast cancer) ,gender,( female have higher chance of developing cancer of the breast than male counterpart), age ( old people are more susceptible to breast cancer), treatment with hormone replacement treatment commonly during menopause treatment, exposure to chemicals that are harmful to DNA, being overweight, smoking and alcohol drinking (cancer research uk,2010)

Due to the severity of the disease, bigger number of people dying death rate, the disease reappearing it posed aquestion to scientists to find out what causes the alteration of the HER gene expression and how to treat this overexpressed gene.that is found with about 20-30% of all diagnosed breast cancers. The most commonly used techniques to determine the level of gene over expression and gene amplification at 3+ levels is immunohistochemistry (IHC) and fluorescence in situ hybridisation respectively. (Ross J.S, 2005)

HER2 is part of the epidermal growth family of the receptor tyrosine kinase.which is made up of her1, her2 ,her3 and her 4 .They are involved in a lot of activities in the body like; they induce signals that regulate how cells multiply, divide, and programmed cell death. Patientswho are her2 positive have a more hostile type of breast cancer. Initially breast cancers that over expressed HER2 were treated with chemotherapy,( chemotherapy is a therapy that uses cytotoxic drugs to kill cancerous cells) or when used alone radiation therapy, surgery but these were not very effective and not specific so there was need to develop a drug that was more effective and specific

Figure 1

Figure1.3 shows members of the HER-2 gene they include ,HER-1,HER -3 HER-4 .it shows how many pathways are affected by the actions of this family of gene(Ross J.S ,2005)

Abbreviations: Amp, amphiregulin; β-cel, β-cellulin; EGF, epidermal growth factor; Epi, epinephrine; HB-GF, heparin-binding growth factor; MAPK, mitogen-activated protein kinase; MEK, MAPK/extracellular signal-related kinase kinase; NRG, neuregulin; PI3K, phosphatidylinositol 3' kinase; SOS, son of sevenless; TGF{alpha}, transforming growth factor {alpha}; VEGF, vascular endothelial growth factor. (Ross J.S, 2005.)

Figure 2

 

Figure 2. Human epidermal growth factor receptor (HER)-2-positive in Paget's disease of the nipple.

Ross J.S ;2009l)

Trastuzumab ( Herceptin) a recombinant humanised (one part of it is from mouse and the other part from human) Immunoglobulin monoclonal antibody which attaches to the outside part of HER2 and stops the growth of malignant cells which show over expression 0f HER2 was invented .trastuzumab can be used in addition with chemotherapy drugs for the treatment of cancer which have metastasized (spread to other parts of the body or women with an early form of the disease and this has shown some positive results .but this has some side effects mostly cardiac toxicity when trastuzumab is used in combination with chemotherapy (chemotherapy is a therapy that uses drugs to kill cancerous cells) or when used alone . (Mckeage K, 2008)it is worth mentioning that there are some drugs that are available to treat other forms of breast cancer for example bevacizumab which is an ( anti vascular endothelial growth factor),Pertuzumab (anti her1/her2 ) ertumaxomab and lapatinib and some clinical trials are going on to see whether they can be used with trastuzumab.

AIM: In this review I will be assessing the effectiveness of trastuzumab in combination with chemotherapy in the treatment of breast cancer compared with the use of chemotherapy alone.

2.0 METHOD:

I gathered information from; American journal of clinical oncology ,the anals of oncology, Medline,

Pubmed, Journal of clinical oncology, cancer research UK. National Institute of Health and Clinical Excellence, Medline The lancet, New England journal.

I looked at journals from 2001-2009 because I wanted to include the five major trials (The HERA, NCCTG, N9831and NSABPB-31, BCIRG 006 and FINHER) which are my basis for analysis,

Key words were trastuzumab, breast cancer, HER-2, meta-analysis, chemotherapy, adjuvant, effectiveness

3.0 RESULTS FROM THE 5 MAJOR TRIALS

These names refer to the chemotherapy drugs used in the different trials doxorubicin, cyclophosphamide, paclitaxel, docetaxel, carboplatin,

Vinorelbine, fluorouracil and epirubicin

The HERA (Herceptin Adjuvant) trial enrolled 5102 women; it looked at women who had received chemotherapy that involved radiotherapy or without radiotherapy so these were given trastuzumab while the observation group was not(those that had received chemotherapy) so after one year the number of patients free of the disease was in favour of trastuzumab than observation. The results showed that a large number of women who had received showed no signs of the disease reappearing after one year (Mckeage K, 2008) The number of women showing no reappearance of the disease was 1703 compared to the observation which was 1698 this was at 23month after treatment. The number of women being reported not to have the disease was 218 for trastuzumab and 321 for the observation with a relative risk that that the disease would occur of 0.64 in the trastuzumab group.it was estimated that the percentage of persons staying absolutely free of the disease was 6.3% that is 80.6% compared to 74.3% at three year follow up when using trastuzumab or no trastuzumab respectively. At one year provisional analysis the number of people staying free of the disease was 127 for trastuzumab and 22o for the observation taking into account that the number of people for trastuzumab was 1694 and 1693 for the observation with unchanged relative risk that the disease would occur of 0.5 and the person staying completely free of the disease when using trastuzumab was 8.4%at 24 months. General survival was good in the trastuzumab group than in the control at 24 months. The numbers of death were 59 in the trastuzumab and 90 in the observation. The overall benefit of not dying from the disease was 2.7% that is 92.4% in the trastuzumab group compared with 89.7%in the observation and this was at three years. There was a lower reaperance of the disease in the trastuzumab group than in the observation group at 2 years .There was a 6.3% advantage of staying free from the disease reappearing in the trastuzumab that equates to 85.7% compared to 79.4% at 3 years in the trastuzumab and observation respectively.

(Mckeage K, 2008)

The combined NCCTG (North Central Cancer Treatment Group) N9831 and NSABP (National surgical adjuvant breast and bowel project) B-31 trials This trial looked at the difference of action on her 2 positive patients who were given different types of chemotherapy drugs alone or chemotherapy with trastuzumab. So patients were given standard regimen of chemotherapeutic drugs which include an anthracycline-doxorubicin and cyclophosphamide for every three weeks followed by four cycles of paclitaxel for three weeks or 12 cycles of paclitaxel every week which contained trastuzumab or which did not have trastuzumab every week for 52 weeks. The NCCTG N9831, trial looked at weekly trastuzumab given after paclitaxel.( Mckeage K .2008) the results showed that patients who received trastuzumab plus chemotherapy showed better results compared to those who received chemotherapy, At a two year follow up it showed that he percentage of being completely free from the disease was much higher in the trastuzumab than chemotherapy alone. That is 94.3% for trastuzumab compared with 91.7% in the observation

(Mckeage K .2008)

In the BCIRG 006 study, the first regimen in this trial consisted of an anthracycline doxorubicin which was given with cyclophosphamide plus trastuzumab and docetaxel, then another group was given doxorubicin and cyclophosphamide plus docetaxel and this would act as the control. In the last group they were given docetaxel plus carbopltin and trastuzumab. In this trial part of the aim was to evaluate how safe it is when trastuzumab is given with different forms of chemotherapy that is the ones that containing anthracycline and a non anthracycline regimen, because these anthracyclines have been associated with heart problems it was important to get to the root of it. so their findings were that the two groups which were given trastuzumab were the same in terms of the ratio of people free from the disease that is o.49 for the group that contained anthracycline-doxorubicin and cyclophosphamide plus trastuzumab and the group that contained docetaxel plus carboplatin and trastuzumab. Their findings revealed that there were less heart problems with the group who were given no anthracycline (Viani .AG, 2007)

Last but not least was the Fin her trial, the main aim of the trial was to compare the use of docetaxel with vinorelbine patients were given three cycles of docetaxel or vinorelbine followed by three cycles of fluorouracil,cyclophosphamide plus epirubicin,women who were her-2 positive (n=232 ) were divided so that some received trastuzumab and others didn't for nine weeks together with the first three cycles of vinorelbine . The end point was recurrence-free survival, adverse events, time to distant recurrence, effect on LVEF and overall survival. The DFS was better in those treated with trastuzumab (89 vs 78 percent) there was better overall survival (96 vs 90 percent).The size of the benefits is relatively the same as those seen in other trials that extend to two years. (Viani .AG, 2007l)

4.0 DISCUSSION

4.1 The characteristics of Her-2 over expressing tumors

Even with increased improvements in the management of breast cancer that is diagnosis awareness and treatment some people who are found to have breast cancer do not completely recover from the disease and the disease still reappea. HER 2 which belongs to the epidermal growth factor family, over expressed in some breast cancers which brings about greater cell survival, resistance to apoptosis (programmed cell death) and propagation.

(Dahabreh .I J, 2008) Patients who have HER2 positive breast cancer have some of these features: they have an aggressive form of the disease ,metastatic HER2 positive breast do not lose the biochemical make up of the original tumour in HER2 grade and is oestrogen receptor negative ,DNA malfunction , tumour grade is moderate to high .HER2 positive breast cancer is more likely to spread to other parts of the body like; the ovaries bone marrow ,liver .lungs, axillary lymph node , adrenal glands and the chance of recurrence is high and survival time is shorter. (Dahabreh L.J 2008)

4.2 Trastuzumab actions and its pharmacokinetics

Trastu zumab stimulates HER2 receptor down modulation and this leads to the inhibition of the signalling pathways (P13k/ AKt and ras-Raf-MaPK) and stops the cell cycle by stirring up the creation of p27/cdk2 linkages. Trastuzumab in vivo reduces the growth of new blood vessels from pre existing ones and bring about antibody dependent cellular cytotoxicity.Trastuzumab is involved in inhibiting the cleavage of HER2 and preceding antibody induced receptor downmodultion. (Peintinger F: 2008)

Trastuzumab has a low volume of distribution, low all over the body clearance, and a long half life of 28 days. Whether trastuzumab is given in adjuvant setting or for the treatment of metastatic disease the recommended dose remains the same after giving a loading dose, trastuzumab is given by intravenous perfusion according to your body weight. (Ross J.S, 2009)

It is given weekly or every three weeks according to neoadjuvant, adjuvant metastatic disease protocols and (adjuvant protocols) respectively. In cases where the disease has spread Trastuzumab does not have to be stopped until time of disease progression. National comprehensive cancer network (NCCN) suggests that the regimen for HER-2 positive metastatic breast cancer is trastuzumab and single agent either paclitaxel (every weekly or three weekly), docetaxel (every weekly or three weekly) or vinorelbine weekly. NCCN suggests for combination therapy trastuzumab plus paclitaxel and carboplatin every three weeks or docetaxel plus carboplatin.

(Ross J.S, 2009)

4.3 Evidence of its effectiveness in comparison with chemotherapy

Trastuzumab has clearly demonstrated its effectiveness in the treatment of breast cancer as seen in the HERA trial here trastuzumab was given after completion of chemotherapy and radiotherapy compared with the observation (no trastuzumab) the results tend to favour trastuzumab than chemotherapy alone with overall longer survival after one year and 2 year follow up .(Smith I, 2007)this is the same for all the all the trials where trastuzumab was added to chemotherapy except that the endpoints differ

In the combined NSABP B-31 and NCCTG N9831 trials after a 2 year follow patients treated with trastuzumab experienced a significantly longer DFS time, lower risk of distant recurrence, longer overall survival compared with control.

The BCIRG 006 trial confirmed the efficacy of trastuzumab at a 2 year follow up as trastuzumab containing arms showed lower DFS compared to control (AC followed by docetaxel)

The FinHer trial after a 3 year follow up recurrence free survival was significantly improved in patients who received trastuzumab compared with the control (Baselga J.2006l)

Trastu zumab used as a single agent has shown to induce programmed cell death in the preoperative setting. (Peintinger F, 2008) In a study that was carried out by Vogel and Cobleigh ,2002 regarding "the safety and efficacy of trastuzumab as a single agent "the response rate was 26% .It showed that the use of trastuzumab as a single agent is efficient and active for women with whose cancer has spread. (Vogel .C.L, 2002)

Data from the five published Clinical trials have shown that trastuzumab can be used in adjuvant after (chemotherapy, radiotherapy or surgery) or neoadjuvant setting (preoperative) so this gives clinician a wide range of treatment options above all its shown to be effective in treatment of her2 positive breast cancer. (Dahabreh, L.J 2008).

Figure 3

Figure 1.4 Shows the rate of recurrence, end point process and their effectiveness in the Herceptin® Adjuvant (HERA) trial (Baselga J et al, 2006)

The graph above shows that in the observation (no trastuzumab) the distant event loco-regional event, contra-lateral breast cancer second non breast malignancy is high while central nervous system and death as first event is low while in the trastuzumab containing group the distant event, loco-regional events, contra-lateral breast cancer second non breast malignancy and death as first event is low but central nervous event and death as first event is slightly high.

In a study which compared trastuzumab plus docetaxel versus docetaxel alone in patients who are HER2 positive they found that docetaxel plus trastuzumab gives much better results than docetaxel alone.(Marty M,2005 )

In another study it showed that combining paclitaxel and trastuzumab induced cellular and humoral HER2 specific immune responses that showed good clinical outcomes in patients with advanced breast cancer. (Weiner M. L .2010)

The initiation of HER2 specific CD4+Tcells and humoral responses showed that an adaptive immune response against HER2 was induced by this treatment (Weiner M. L .2010)

Evidence is clear that when trastuzumab is added to chemotherapy there is significant benefits for the patient than chemotherapy alone, this is due to the fact that with chemotherapeutic drugs are not explicit and don't differentiate between tumor and normal cells. They are effective against constantly dividing neoplasm while their effectiveness against non dividing tumours is confined. This means that when they kill off both the normal cell and abnormal cell which leaves the individual more exposed to infection.

Chemotherapy destroys both good and bad cells and this causes serious side effects as will be discussed later. (www.cancer researchuk.org)

Studies have shown that trastuzumab combined with chemotherapy has a generally higher rate of l response of 50% than chemotherapy alone which is 32%,longer time of treatment failure, and a longer duration of response(Smith I, 2007)

In a report by smith and Procter it showed that after a 2 year follow up there was a greater general survival. This benefit after 2 years gives trastuzumab the first place in the treatment of breast as the results from the clinical trial (The HERA) which were used for it to be licensed were initially from one year follow up.

(Smith I, 2007)

The use of trastuzumab is said to be cost effective after one year compared to chemotherapy alone. Because with the addition of trastuzumab especially during early breast cancer it will prevent the disease from progressing to metastasis and also there is better disease free survival. Overall it reduces constant medical treatment and also loss of productivity which affects society (Mckeage K .2008)

The use and benefits of trastuzumab in adjuvant, neoadjuvant setting for the treatment of her2 positive breast cancer

Data from the five published Clinical trials have shown that trastuzumab can be used in adjuvant after (chemotherapy, radiotherapy or surgery) or neoadjuvant setting (preoperative) so this gives clinician a wide range of treatment options above all its shown to be effective in treatment of her2 positive breast cancer. (Dahabreh, L.J 2008).

In a study carried out by Piccart-Gebhart and Procter 2005, it showed that trastu zumab given after completion of adjuvant chemotherapy can benefit HER-2 positive breast cancer .Trastuzumab given after primary therapy reduced the rate of recurrence that is distant recurrence by 50% compared with observation after primary therapy

In the preoperative setting it has shown a great improvement in the time of pathologic complete response. (PCR) (it means that there is no clinical sign of the disease) .The advantage of adding trastuzumab in the preoperative setting seems to b e self-regulating or enhanced by the oestrogen receptor being evident. (Weiner M. L .2010)

HER-2 positive tumors that are treated with trastuzumab are highly sensitive to chemotherapy in preoperative setting due to the fact that HER2 gene amplification is related to how the breast cancer cells survive and grow. (Weiner M. L .2010)

The reason why there is elevated PCR rates in HER-2 positive breast cancers treated with neoadjuvant trastuzumab is because the progenitor stem cell is blocked, cell proliferation and invasion mechanisms are removed or her2 mediated growth signals are down regulated. (Mittendorf E.A, 2008)

4.5 The side effects of trastuzumab treatment and chemotherapy

However there have been a number of adverse effects associated with the use of trastuzumab and these include:

Agitation, exhaustion, diarrhoea, vomiting, fever cough, pain in the joint headaches, back pain, rise in body temperature, fluid accumulation in the tissues, and have been reported. (Mckeage K .2008)

Cardio toxicity has been reported in fewer patients who were receiving a combination of anthracycline and trastuzumab .In the HERA trial because the problem was so bad some of the patients (around 4%) had to discontinue the treatment. In the HERA (Herceptin Adjuvant) trial there was an association between increased cardiac toxicity with the use of trastuzumab than in the group who did not receive trastuzumab. (Mckeage K, 2008)

But patients with cardiac dysfunction related to trastuzumab treatment who received treatment recovered . This shows that with proper patient management the problem can be put under control.

The problem of cardio toxicity related to the use of trastuzumab still occurs even when the drug is used singly.

(Mckeage K, 2008)

Intermittent use of anthracycline- doxorubicin, cyclophosphamide and trastuzumab amplified the risk of cardiac dysfunction compared with treatment that consisted an anthracycline-doxorubicin and cylophosphamide .The addition of trastuzumab and paclitaxel generated a smaller cardiac dysfunction than the use of paclitaxel singly. (Salmon D, 2001). It is worth knowing that, older people (>60 years) had an increased risk of cardiac failure, if they had taken hypertensive drugs before or were at the time (Mckeage K, 2008). Proposals have been put forward to explain why trastuzumab treatment causes cardio toxicity as the way it comes about is not really known (Salmon D, 2001,) and these include, destruction of heart muscle cells, alterations in cardio toxicity that is brought about by chemotherapeutic drugs.. Information from experiments that were carried in rats and mice show that there is a direct toxic effect of her obstruction because Her 2 signalling plays a role in the development of embryonic heart. Evidence has shown that cardio toxicity caused by trastuzumab is not due to the amount of drug administered or induced by the immune system. (Viani G A, 2007)

The use of anthracycline and trastuzumab have shown an increased risk of cardio toxicity and trastuzumab has brought about the need to look at regimens that do not include anthracycline and trastuzumab , especially now that information has come up showing the effectiveness of nonanthracycline regimens in adjuvant set up. (Dahabreh L.J, 2008)

Figure

shows the number of Cardiac death in the five major trials

The growth of brain metastases has been seen in patients treated with trastuzumab. Some studies have shown that patients treated with trastuzumab alone or trastuzumab and chemotherapy who had Her2 overexpressing breast cancer, 34% of patients had been diagnosed with central nervous system (CNS) metastases. This has been attributed to the fact that the drug is more functional in opposition to metastases affecting the entire system but not so much efficient on metastases affecting the brain and this is due to its poor -blood brain infiltration. (Dahabreh I. J, 2008)

Chemotherapy

These are some of the side effects associated with chemotherapy and they include, loss of hair, tiredness which is attributed to the damage of cells made in the bone marrow (B cells) and those in the thymus (T cells) leaves the patient more susceptible to infections, vomiting, loss of fertility, nausea, development of cancer in lining of the uterus especially with the use of tamoxifen (side effects of chemotherapy, 2010)

Conclusion

Research shows that the use of trastuzumab in the treatment of breast cancer should not be underestimated as the clinical benefits are clearly outlined as it improves survival without the disease, improves quality of life, prolongs life and is cost effective compared to chemotherapy . Some of the questions that puzzle clinicians are timing of administration, how long to administer the drug. With cardiac toxicity, proper screening and better patient management can help to improve the problem but the growth of brain metastases still poses a big risk.

From a" magic bullet" as proposed by Paul Ehrlich in 1908 to clinical reality clearly shows how things have evolved over the years, but still more research needs to be carried out to address the question of what causes breast cancer so that the treatment is more specific to the cause and it is accessible to everyone who needs it.

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