Pharmacogenomics Application In Breast Cancer Personalized Medicine

Abstract

Breast cancer is a worldwide disease that affect about 2.1 million of patients each year and becoming a major challenge in the medical field because of its heterogeneity that makes it difficult to treat. Chemotherapy which is a standard treatment used for breast cancer could have serious side effects on some patients that affect their quality of life. Therefore, there is an urgent need for developing therapeutic breast cancer strategies with high efficacy rate and minimal adverse reaction. Personalised medicine uses pharmacogenomic to provide tailored treatment for each patient according to their genome for an efficient breast cancer therapy. The study of pharmacogenomic explain the impact of genetics variations on drug metabolism in addition to the effect of the entire genome on drug response.

Background

Breast Cancer evolves when cells duplicate, grow out of control and eventually develop into tumour [1]. It is a heterogeneous group of disease that has a distinctive set of biological and clinical activities [2]. Also, it is one of the three most common type of cancer in women worldwide. Breast cancer can be categorised into five different stages including stage one which is non-invasive breast cancer to stage five where it develops into a metastatic cancer. According to the international Agency for Research on Cancer, the total global cancer incidence in 2018 is approximately 18.1 million. Breast cancer is the third leading types of cancer with an estimated new cases of 2.1 million which is about 11.6% of the total cancer incidence globally in 2018 [3].

Figure1. Worldwide cancer rate incidents in 2018.

Figure2. Worldwide cancer death rate in 2018.

Introduction

Due to the distinct biological behaviour of the breast cancer disease, the theory of one size fit all is no longer valid in the field of breast cancer treatment. This has been seen from the unsatisfactory outcomes of chemotherapy treatment, where drugs show a very limited efficacy rate with high toxicity in some patients because of off-target side effects and bypass mechanisms as well as cross-talk across compensatory escape pathways. This happens as a result of genome destabilisation in addition to signalling rewiring. Personalised medicine is aiming to provide the right medicine, in the right dose to the right patient [5]. Patients response to treatments are different and some patients could develop adverse reaction while others are non-responders [31]. Therefore understanding the factors (table 1) that contribute to low efficacy or high toxicity is essential in personalising medicine for breast cancer patients [5].

Adherence

Genetics and gender

Age of patients

Pollutant (smoking)

Disease state

pregnancy

Drug-drug interaction

Route of administration

Food-drug interaction

formulation

Table 1. The main Factors promoting the variability to drug response in patients [31].

lt;/p> lt;/p>The identifications of the recent biomarkers can assist in the prediction of drug response and toxicity. This is useful in recommending the ideal drug and dosage to the right patient which results in more personalised and effective therapy in cancer treatment. Although the survival rate have improved in breast cancer patients, oncologists still find challenges in implementing an effective therapy because of the therapeutic tumour resistance which leads to a low success rate of breast cancer therapies. A study in the UK demonstrated around 2.5% of patients that were exposed to anticancer therapies died after the first month of treatment [6] This essay will focus on the study of the pharmacogenomic biomarkers of breast cancer and different cell mutations that affect the outcome of a treatment in personalised medicine.

Pharmacogenomic

Pharmacogenomic refers to the study of the human genome and the influence of genes on drug efficacy or toxicity rate as well as finding biomarkers (table2) that could be helpful in preventing or treating breast cancer [7]. The characteristics and molecular biology of a tumour cell that can be measured and assessed as an indicator of normal biologic processes or pharmacologic response to a treatment is called biomarker. Biomarkers are valuable for diagnosis, prognosis and in prediction of the therapeutic response.

Prognosis markers can deliver information regarding the outcome of the disease, whereas predictive marker are able to predict the efficacy or the resistance of genes to certain therapies. Pharmacogenomic biomarkers can also predict the adverse reaction or variation response to a drug according to the germline polymorphisms of patients.

Breast Cancer Type

ER

HER2

Ki-67

PR

Luminal A

Positive

Negative

Low level

High level

Luminal B

Positive

Negative

High level

Low level

HER2-positive

Negative

Over-expressed

Unclear

Negative

Triple negative

Negative

Negative

Unclear

Negative

Table 2. Breast cancer subtype categories according to the expression of biomarkers within the tumour [8].

lt;/p> lt;/p> lt;/p>Chemotherapy

One of the standard treatment options for breast cancer is chemotherapy. It is an aggressive type of chemical drug that is designed to destroy the growing cancer cells in the breast. It is usually used with other therapies like endocrine, radiation therapy and surgery depending of the type of cancer and its stage, patients overall health and their personal treatment choice. Chemotherapy is mainly used to reduce the tumour size, decrease the overall number of carcinogenic cells and therefore lower the possibility of cancer spreading in the body. However, it can also have some serious side effects on patients quality of life which will be discussed later on in this essay[4].

Strategies Improving The Efficacy Rate of Chemotherapy

The demand for developing new strategies in personalised medicine to improve the efficacy rate of breast cancer therapy and decrease the duration of chemotherapy is high. Age and the stage of cancer both play an important role in cancer treatment. Older patients and patients with advanced breast cancer are more susceptible to the undesired side effects cause by chemotherapeutic drugs because of pharmacokinetics changes that occur with advance aging [15]. Patients who have undergone chemotherapy treatment were identified with 38 common symptoms which were classified under symptom clusters like psychological, hormonal, nutritional, gastrointestinal, and epithelial [16].

Chemotherapy Side Effects and Associated Biomarkers

Premature menopause of chemotherapy-induced menopause

Premature menopause can occur in 13.3% of young women below 40 after undergoing a chemotherapy treatment due to oestrogen deficiency which diminishes the ovaries functions. Recent studies have shown that SNPs in the genes coding for oestrogen receptors ESR1 and ESR2 biomarkers were linked to premature ovarian declining [17].

Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Patients may experience CIPN during their therapeutic period and could have a long term effect in some cases. A rate of 45% of patients would feel numbness within their peripheral limbs even for 6 year following a chemotherapy treatment. These patients are more vulnerable to falls and at risk of developing bone fractures [18]. Some Biomarkers associated with CIPN were found to be useful in reducing the neurotoxicity of chemotherapeutic drugs. 3435TT genotype of ABCB1, a gene coding that relates to the ATP family can results to a high risk of neurotoxicity in patients. NDRG1 is another useful genetic biomarker for CIPN because of its negative link among the expression level of gene and CIPN severity [19].

Depression

A mild to moderate depression levels were noticed in half of the patients who underwent chemotherapy. This symptom was found to be associated with cognitive dysfunction. About 22% of Indian patients have shown moderately severe to severe levels of depression which leads to a poor quality of life for the patients [21]. A recently discovered biomarker for depression symptom is gene coding for brain-derived neurotrophic factor (BDNF) which contains Val66Met polymorphisms. This finding could identify patients who would suffer from depression and benefits from anti-depression therapies for a better therapeutic outcomes (22).

In order to minimise the aforementioned side effects of the chemotherapy, it is essential to develop more personalised according to patients gender, age and cancer stage. The pharmacogenomic biomarkers that have been discovered so far are a great start in personalisation of more effective cancer treatment and the future hold promise for reducing these side effects. For example, the discovery of ESR1 and ESR2 biomarkers have increased the possibility of understanding the SNPs that leads to premature menopause. Also, the discovered biomarkers in CIPN can reduce the neurotoxicity caused by the chemotherapeutic drugs which leads to a better management of neurotoxicity during treatment.

Although, choosing the right drug and recommending the right dosage to each patient for a safe and effective treatment is still a challenge for oncologists and doctors. The current knowledge of genomic could assist in personalising more effective treatments for breast cancer patients throughout and after chemotherapy in order to reduce the chemotherapy duration and hence reducing its side effects. This is can be done throughout the discovery of predictive biomarkers that can predict the efficacy and the toxicity rate of a treatment.

lt;/p> lt;/p> lt;/p> lt;/p> lt;/p> lt;/p>Predicting Response to HER2-targeted Therapy

HER2 is part of the EGF receptor family and generally the human tissues contain low expression of HER2 in their normal state. However, in breast cancer cells HER2 is being overexpressed by 20 to 25% which is the main cause of aggressive biological behaviour in the tumour. HER2 is considered to be an exceptional treatment s target due to the presence of variations in the expression of HER2 in the normal and breast cancer cells. Over 14% of breast cancer are found with HER2 amplification that are related to cell multiplications, angiogenesis invasion as well as decreased apoptosis [9].

In HER2- tumours the presence of the driver genes such as BRF2 and DSN1 is found to be an advantage as they reduce the overexpression and development of a tumour. The first personalised monoclonal antibody drug that was approved by FDA as a targeted drug for breast cancer is trastuzumab [10]. Trastuzumab and lapatinib have demonstrated a dramatic movement in the therapy of HER2 overexpressing tumours in metastatic and adjuvant setting. It has been shown that the addition of Trastuzumab to adjuvant chemotherapy reduces the probability of cancer recurrence by 20% with an enhanced the survival rate for up to 2 years. However, patients with HER2+ demonstrated sensitivity to HER3 antibody drugs like lapatinib, pertuzumab, trastuzumab, ado-trastuzumab and emtansine [2].

Clinical Studies showed that combined therapies of trastuzumab and chemotherapy has resulted in a better response in comparison to the chemotherapy drug alone, however, some patients have developed resistance to this therapy [2]. HER2 signalling pathway that is related to the activation of PIK3CA, RAS, Src, NFKB and also inactivation mutations in PTEN seems to be the main mechanisms of patients resistance to trastuzumab [11] .

Trastuzumab-DM1 is an antibody that is combined with maytansine (fungal toxin). In order to achieve a maximum level of efficacy with this drug, it demands a great amount of HER2 expression on the cancer cells. low intra-tumour levels of HER2 expression as well as inadequate internalisation of HER2-drug which can be related to the poor intracellular expression of DM1, appeared to be the main reason for the drug resistance [12]. Clinical trials shown that only 30% of patients benefit from trastuzumab monotherapy and resistance development to this therapy is still a challenge. Therapeutic resistance has been investigated and it appears that mutations in the PIK3CA gene, loss of PTEN, overexpression of IGFR in addition to HER2 truncation might predict resistance to trastuzumab.

There are a number of strategies that could be employed to control the resistance to trastuzumab drug, including the usage of pan PI3K inhibitor, speci c PIK3CA inhibitors, AKT inhibitors, and mTOR inhibitors if the resistance is from PIK3CA variations. Using the Lapatinib chemotherapy to control the high amount of p95HER2, MET inhibitors to control MET variations in addition to the immune checkpoints inhibitors to manage the low immune response [13]. Pertuzumab administration could contribute in reversing resistance to trastuzumab in metastatic breast cancer. The mechanism of this drug involves preventing hetero and homodimerization of HER2 which could be useful for overcoming the lapatinib resistance. One way of targeting the intracellular and also extracellular region of HER2 is by administrating a combination of lapatinib and trastuzumab drugs. Lapatinib is an inhibitor of tyrosine kinase receptor in which inhabits the autophosphorylation of EGFR and HER2 [14].

Although a combination of Trastuzumab and Lapatinib appear to be effective in targeting HER2 overexpression and showed to reduce the cancer recurrence by 20%, it is not very effective in treating HER2+ due to the genes resistance to HER3 antibodies. Also, the efficacy rate of Trastuzumab-DM1 on patients seems to be fairly low (30%) due to the genes resistant to this therapy. Therefore, the genes resistance seems to be a critical issue in the treatment of cancer due to its complicated mechanisms in the tumour genes and the oncologists still find it challenging to develop a therapy to overcome this resistant. Therefore, more research need to be done in the field of breast cancer pharmacogenomics in order to develop new personalised treatment for an effective and safe therapy.

Predicting Response to Endocrine Therapy, ER and PR Biomarkers

Oestrogen plays an important role in developing ER-positive breast cancer cells. There are two types of ER biomarkers, including Er and ER . Generally, about 50 to 70% of breast cancer express ER and 50% PR, therefore, the clinical testing for these biomarkers during the initial diagnosis of breast cancer is essential. Several researches have been carried out on the effect of endocrine therapy on breast cancer. It has been revealed that the endocrine therapy is less effective in patients with ER- and PR-positive cancer [23]. Tamoxifen is an anti-estrogenic drug that is explored as an adjuvant in the therapy of breast cancer and has demonstrated to decrease the mortality because of the presence of malignant cells with oestrogen receptor- (R ) [24]. ER has been used to predict response to endocrine therapy in early breast cancer in several trials involving 37,000 patients in the early stages of breast cancer with ER-positive tumours. It revealed that five years of adjuvant tamoxifen treatment have reduced the cancer recurrence for 10 years by 47% and improved the overall survival rate by 26%.

Trials illustrated that the adjuvant tamoxifen therapy was also effective in women with ER-negative, PR-positive cancer tumours. Similarly, ER-positive tumours have benefited from this treatment irrespective of PR expression. Bardou et al. showed that the presence of PR biomarker is the main factor for making the hormone therapy ineffective in some cases and therefore, these patients may also benefit from an additional chemotherapy treatment [25]. Some of the factors that could contribute to endocrine resistance are listed below:

mutation rate,

methylation,

acetylation and downregulation of ER ,

and overexpression of ER ,

ARN810 is found to be an effective drug in degrading ER and showed efficacy on tumours containing ESR1 mutation, if conventional endocrine treatment is ineffective. Studies showed that occurrence of ESR1 is high in metastatic breast cancer and therefore, testing the plasma of DNA could be useful in choosing therapeutic strategies. For example, Fulvestrant which could be used in combination with Palbociclib drug has proven to increase the tumour free survival in patients with ESR1 mutation. The mechanism associated to the effect of these drugs is not clear yet but patients with metastatic cancer can benefit from this treatment [14].

Endocrine or hormone therapy is proved to be one of the important treatment of breast cancer as it decreased the cancer recurrence for 10 years by 47% and improved the survival rate by 26%. The pharmacogenomic biomarkers ER and PR have shown to be great predictors of early breast cancer to endocrine therapy response. The overall efficacy rate of the PR, ER-negative tumours is significantly lower than ER-positive due to the PR expression which is the primary reason for an ineffective hormonal therapy. This means that the endocrine therapy is still ineffective in some patients and further studies is still needed in order to establish an effective personalised therapy according to each patient s need.

lt;/p> lt;/p> lt;/p> lt;/p>Pharmacogenomics in Drug Discovery and Drug Development

The pharmaceutical industry has realised the importance of pharmacogenomic is drug discovery and development, therefore, the study of the human genome allows for new drugable and non-drugable targets. It is clear that gene identification and proteins in the pathogenesis of disease would lead to new drug targets and hold promises in the field of personalised medicine in the future [30].

Challenges of Personalised Medicine

Personalised medicine involves tailoring medical treatments according to the patients genetic profile. The patients have to conduct a genetic test to detect and target specific individual profiles in order to prescribe the right drug to the right patient for a maximum efficacy rate [26][27]. Tumour heterogeneity affects the outcome of a particular therapy and the combinational treatment that target different cancer cells makes it difficult to predict the outcome of a treatment. This is because there are a minimum of 18 different breast cancer subtypes have been diagnosed and personalised medicine aims to tailor therapies according to the patients tumour subtype in order to enhance the efficacy of anticancer agents besides minimising the toxicity rate that are significant concern in the oncology field. Similarly, the lack of safe and effective drug that could contribute to more personalised medicine remains a big challenge [28].

Although, personalised medicine has shown improvement in the efficacy rate of treating breast cancer, one of the main challenges that patients might face is the high cost involves with the treatment of personalised medicine in comparison to the standard therapy. On the other hand, the cost of receiving ineffective standard therapy that could be associated with loss of patients life is also high. Therefore, establishments like European Personalised Medicine Association and personalised medicine coalition have suggested the need of delivering personalised medicine in Europe, revaluation of the current assessment as well as the payment scheme. The major challenge however is providing evidence to show that personalised medicine can improve the treatment benefits to patients and at the same time reducing the overall treatment expenses. Identification of the genes participating in the interaction between drug and the body means that breast cancer pharmacogenomic study can have a positive outcome on the way that pharmaceutical industry develops cancer drugs [24].

lt;/p>Several resources have been developed by bioinformatics, cheminformatics and pathway analysis for the purposes of speeding up the detection of gene targets that can help with the discovery of suitable drugs as well as the new molecular targets with high-throughput drug screens. Furthermore, finding new pharmacogenomic variants has shown enhancement and optimisation in the clinical trials design [29] which can give hope for the discovery of new potential drugs that can specifically target certain cancer calls, improve the efficacy and reduce the toxicity of receiving cancer treatment.

Conclusion

Breast cancer develops as a results of cell growth and duplications. Different factors such as inherited genes or environmental impacts can contribute to the occurrence of breast cancer. The worldwide data shows that about 2.1 million people are effected by breast cancer annually. Although chemotherapy can be effective in destroying cancer cells it does not work for every patient and sometimes can also have severe side effects on patients which can affect their quality of life. The application of pharmacogenomic in personalised medicine aims to treat individuals according to their cancer molecular genomic profile in order to improve the efficacy rate of a treatment. The genetics changes helps in the identification of biomarkers like ER and PR that can be employed to determine the right drug in a right dose to the right patient. However, there are still challenges involved and more research needs to be done in the field of pharmacogenomic in order to understand the mutational resistance that occurs in the tumour to a particular therapy. With the current knowledge of human genome it is anticipated that a considerable amount of biomarkers will emerge in the future which will improve the efficacy rate of pharmacogenomic in the field of breast cancer personalised medicine.

lt;/p>

lt;/span>