Introduction

Cancer is a state of abnormal, uncontrolled multiplication of cells, which results in the formation of tumors. The tumor can be of two types – benign and malignant. Benign tumors are localized tumors associated with much lesser aggressive symptoms. It restricts its influence in its tissue or organ of origin (Rosenzweig et al. 2017). While benign tumors are less aggressive, have better prognosis and can be managed well with medical interventions – the malignant tumors exhibit metastasis that is an extensive process of aggressive invasion and infiltration of the normal cells of the body (Bu et al. 2019). Metastasis is a core characteristic of malignancy and the level or extent of involvement of the lymph nodes – is often indicative of its progression. Malignant cancer has two types of spread – haematogenous (Gasparri et al. 2016) and lymphatic (Holm-Rasmussen et al. 2015). Blood cancer have a hematogenous influence. And breast cancer is a classic example of lymphatic spread where higher the severity of the breast cancer, the more number of lymph nodes are involved. TNM is the most commonly used grading throughout the globe. Biopsy and imaging are important techniques to understand the features of the tumor (Polifka et al. 2019). In this essay, two different cases of cancer – a breast cancer and chronic lymphocytic leukemia has been discussed with respect to the pathogenesis, prognosis, target therapy and biomarkers.

Response to Case study 1

Chronic lymphocytic leukemia is a very usual form of leukemia in Western world (Thompson et al. 2018). It has an incidence of 5.5 cases per lakh men in Italy and 4 cases per 1lakh women. Australia, Ireland and United states have a higher incidence from 7 to 10. Risk diagnosis of chronic lymphocytic leukemia have been reported to increase significantly with the age. Population above 70 years age show an incidence rate of twenty cases every one-lakh people. Prevalence data is available for the country Italy that is calculated from men survival. Performing census of CLL patients ideates from the critical need of estimating the affected population and the census serves an alternative purpose of analyzing the different ways of treating the same disease, prevalent in different countries. CLL have been reported as the most usual form of leukemia in United States that has a higher incidence in the Caucasians when compared to the population of African Americans (Robbins et al. 2015). Although having a lower rate in African Americans, many studies have reported that the disease progresses more rapidly in African Americans than the Caucasians. Genetic variation play an important role in incident rates of CLL.

Different cell types, over the years, is recognized as the normal counterparts of chronic lymphocytic leukemia. The complex suggestions reflected on sophistication in technology not available or available during that time. CLL affects the immunological system by accumulating the incompetent cells, which in microscopy analyses revealed that, the cells are of uniform size that fits the clinical observations of slow, unavoidable elevation in lymphocyte numbers. Advent of the flow cytometer, availability of safer and the convenient ways that label the multiplication of cells – have made the critical understandings feasible. CLL clones begin from follicular mantle B lymphocyte cells that is based on the shared surface expression (membrane) of CD23 and CD5 (Maďarová et al. 2018). This was then altered when the scrutiny of DNA sequencing determine the fifty percent of Chronic lymphocytic leukemia. CLL is involved with IGHV mutations and follicular B cells and IGVs. CLL is considered as a one-cell disease and the fact being researched vigorously nowadays.

Among the various prognostic markers that are reviewed, the chromosomal aberrations are validated mostly to predict the CLL prognosis. Patients who have a 17p13.1 chromosome deletion shows a poor response when given with chemotherapy and hence, for a better prognosis, the patient must be treated with an allogeneic transplantation in the first remission. In Jacob, the deletion is present and allogeneic transplantation can be considered. As because ZAP-70 status in Jacob is positive and he is also diagnosed with unmutated IGHV, this might have an adverse prognosis. As Jacob has been diagnosed with Rai stage 1, it means the subject exhibits enlarged lymph nodes and lymphocytosis, the liver and spleen is not enlarged yet and red blood cells and thrombocyte count is normal. Because of lymphocytosis – the immunological prognosis can be poor, if not treated properly. Otherwise, the normal thrombocyte and erythrocyte count will stabilize the positive prognostic outcomes effectively. Ibrutinib treatment over a longer time, have been reported to increase the complete response with time. Deletion of chromosome 13 parts (Stilgenbauer et al. 2016) without any chromosome abnormalities, have been reported as the more suitable prognostic factor for CLL. Deletion of chromosome 17 or 11 parts is considered as a less suitable prognostic factor. Again, the pro-lymphocytes numbers in blood that indicates a prolymphocytic transformation is a less suitable or favourable prognosis. Lymphocyte doubling time if more than 6 months have a better prognosis.

Targeted therapies has found great emphasis over the last decades and it comprises of the drugs that particularly targets the cancer cells. Unlike the standardized chemotherapy drugs, that attacks the normal cells and the oncology cells together. These drugs attack the major proteins in CLL cells. In CLL, target therapy is a priority line of oncology treatment (Byrd et al. 2016). The kinase inhibitor relay grow signals that aid cells to grow. Using, Venetoxac in a relapsed chronic lymphocytic leukopenia achieving a complete remission have shown the most durable responses.

Chronic lymphocytic leukaemia has different clinical courses. The clinical variability in CLL’s clinical course have an intensified effort in identification of molecular markers for chronic lymphocytic leukaemia prognostication. There are many reasons that affects the wide applicability of the CLL biomarkers are: 1. lack in independent results of individual markers for prognosis, 2. Using arbitrary cut-offs in continuous variables. 3. Technical challenges prevalent in reproducibility, validity, reliability and 4. The lack of marker validation in cohort studies. CLL interphase FISH, snap array based markers can used in case of Jacob.

Response to CASE 2:

Breast cancer has a high malignancy amongst United States woman but a significant disparity exist between the incidence rates in African American and Caucasian women. African American women exhibits the prevalence of breast cancer from younger age. They have a higher incidence under fifty years; they show aggressive tumors (histological) presenting at advanced stage. The African American women have worsened survival rates than the Caucasian women. The primary tumor’s biological characteristics has been reported to play a very important role in determination of incident rates. Cultural factors like discrimination and disparity play a critical role in outcomes of African American and Caucasian women (Ademuyiwa et al. 2017). The oncological progress associated with signaling of steroid receptor, the growth factor, cell cycle mutations, the chromosomal abnormalities (Malmgren et al. 2016) the tumor suppressor and signaling of different cancer genes. The results of biological factors affected by non-biological factors – the socioeconomic, the healthcare access, the reproductive and the confounding factors (Brunault et al. 2016). Non-biological factors directly affect biological consequences and it indirectly influences the facilitation of disparity outcomes.

Amongst the hormonal influences influencing the progression of breast cancer – elevated oestrogens levels have been shown to underpin various types of gynaecological cancers like vaginal, cervical and breast carcinomas (Heong, Ngoi and Tan 2016). Although sometimes considered as idiopathic, the molecular origin of breast cancer but over the years, oestrogens have been regarded as carcinogenic to breast tissue. Different contemporary understandings underling oestrogens carcinogenicity is associated with a higher risk of neoplasia and endometrial hyperplasia with oestrogen supplementation and these findings were based out of experimental data. Three mechanisms responsive for carcinogenicity related with oestrogens are – 1. Broadly recognized concept of hormonal activity (cell mediated) – related to cellular proliferation, genetic damage accumulation and finally causing carcinogenesis. Second molecular mechanism that is globally considered over the decades is – cytochrome P450-driven metabolic activation that directly causes various genotoxic effects by elevating the cellular level mutation rates (Wilsher et al. 2016). The third postulate on molecular basis of breast cancer is relate to DNA repair mechanism (Day et al. 2015) – that in turn causes lesion accumulation in genome that is essential to the oestrogen-mediated tumorogenesis (Ding 2018). Initiation of breast cancer is pointed at an uncontrolled proliferation of cells followed by apoptosis as cumulative consequence of genetic injury followed by genetic repair, remodelling and activation of proto-oncogenes along with suppressor genes inactivation. Genetic alterations are then inherited or passed over to progeny through germinal lines.

A prognostic factor of breast cancer or any cancer acts a predictive factor that predicts the influence of response of a drug in a particular situation. There are certain indicators and factors that can identify the prognosis of breast cancer. Stage – earlier the stage, better the prognosis, as Monica tumour has been diagnosed to be in stage 2 – the chances of having a positive prognosis is higher. As per the researches and scientific literatures, a tumour of five centimetres or bigger has a higher relapse than breast tumours of smaller size. As Monika’s tumour is of 3cm in size, the prognosis will be good with lesser chances of relapse. Tumour grade have a great influence on the patient prognosis and low grade tumours such as that of Monica has a better prognosis and positive outcome. Stats of hormone status is highly important and hormone receptor (+) tumours generally show a good prognosis. As Monica is oestrogen hormone receptor positive, she must have a better prognosis and respond fine to the prescribed hormonal therapy. The concern is that Monica is HER2 positive that means she will have a HER2 positive progression (Ferraro et al. 2016) which is very aggressive in nature as compared to patients with HER2 negative expression. From this perspective, the prognosis can be poor and hence, it has to be controlled by medications and interventions accordingly. As shown by the researchers – the post-menopausal women have more recurrence rates. Monica is 65 years old and is post-menopausal – hence, the prognosis may be poor from this aspect. Recurrence of tumour and the time-period between the periods of relapse play a very vital role in prognosis of breast cancer. The timeline of her occurrence and recurrence play a pivotal role in Monica’s prognosis. Monica’s overall prognosis hangs on a fine line intersecting the chances of positive and negative outcomes. There are certain factors identified, in favour of a positive outcome and there are certain factors especially her age and related physiological changes that relates to a poor prognosis.

Targeted therapy has found a great use in treatment of HER2 positive breast cancer. The gene is overexpressed as 1 out of 5 women and Monica is diagnosed with an overexpression. These HER2 + breast cancers (Swain et al. 2015) are likely to spread and grow very aggressively. There are certain proteins like Trastuzumab (or Herceptin) which is quite useful in treatment of Monica. It is a monoclonal antibody – a rare human made form of particular immunological protein. Lapatinib (or Tykerb) is a kinase inhibitor and can be considered for Monica as well, the drug has to be taken daily. Anastrozole advised to Monica, is a drug that reduces the levels of oestrogen synthesized in body. The breast cancers increases by increase in hormone oestrogen levels and this drug acts in an antagonistic way. They are the suitable target drugs for ER positive breast cancers. They belong to the class of aromatase inhibitors. Targeted therapy, on contrary to the chemotherapy, affects only the disease specific cancer cells with minimal or no effect on the normal cells. Hence, the level of side effects produced is much lesser as compared to the chemotherapy and if gives, the patients and the doctors – a better chance of recovering and a better prognosis.

There are certain biomarkers that are involved in testing for breast cancers. Oestrogen receptor or ER, progesterone receptor or PR is commonly used biomarkers in these cases. Cancer cells or the oncogenes use a particular hormone-signalling path to spread to other parts or grow its spread. In ER positive situations such as that of Monica – the cancer requires the hormone progesterone to spread. Hormonal therapy is also known as endocrinal therapy. Aromatase inhibitors such as anastrozole (or Arimidex), Femara and Aromasin are useful. Human epidermal growth factor receptor 2 is an important biomarker and can be used to track the progression of the pathogenesis (Hecht et al. 2016). Higher the expression, higher and faster is the progression of breast cancer. The metastasis rate is higher and is of critical importance when it comes to be marked by biomarkers. Biomarkers overall, can reveal the intrinsic pathways of oncogenesis, hyperplasia and metaplasia. The pathways, the neuronal signalling and the signal transduction can be of various order and types and each type can be related or causative of particular metastatic developmental stage of breast cancer. Hence, it becomes increasingly important, to scrutinize and analyse the exact the routes taken by the carcinogenesis process. While the traditional scanning, imaging and biopsy are pertinent to the planning of interventions but it is also critical to receive real time or rapid reports on to how the cancer is progressing or remitting – is important as well. Biomarkers and genetic studies, on contrary to the vague reports put forward by other investigation techniques, produces the exact information and detailed ‘picture’ of the present and future of the breast cancer situation. It gives a clearer picture of the stage and state of cancer and how it is going to behave in the near future. Hence, biomarkers can be useful in planning of the cancer intervention and in planning of the treatment goals.

Conclusion

Hence, after scrutinizing each aspect of the two cases – it can be concluded saying that although the molecular basis of breast cancer and CLL is elusive and more researches have to be done in the future in order to find out the exact the structures and cells involved in the oncogenesis process. In the current situation, the markers and the prognostic factors has to be determined very well in order to gain a precise but vivid insight to the situation. The first case of CLL is found to be less aggressive on analysis, as compared to the second case where certain aspects of prognosis is inclined towards the adverse. Hence, comprehending both the situations in regards to its molecular or cellular basis and in accordance to the patient’s demographics and history – the right targeted therapy has to be planned out. As per the information given in the case study, the drugs and therapies have been rightly chosen for the cause. The other therapies and drugs that has shown to act positively on the cancer stage has been elucidated as well and can be considered as further recommendations to the case. The biomarkers are of utmost importance and has to be incorporated in each intervention, imperatively.

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