Breast Cancer Treatment

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 estrogen deficiency which diminishes the ovaries functions. Recent studies have shown that SNPs in the genes coding for estrogen 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 the 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.

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 was 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,80). 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.