paper5-13.doc

A Meta­Analysis of Platinum­Based Treatments

on Triple Negative Breast Cancer

By Kevin Blackwell

Abstract

TNBC is an aggressive form of breast cancer that is completely absent of the three receptors commonly found within the tumors: estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth receptor 2 receptor (HER2). TNBC is untreatable by hormone therapies or by drugs that target abnormal ER, PR, and HER2 receptors. Currently, chemotherapy using harmful drugs, e.g., Gemcitabine or Paclitaxel, are the only available treatments for triple negative breast cancer. However, there are increasing numbers of studies on the effectiveness, of platinum­based chemotherapy. A meta­analysis was performed to determine the effectiveness of platinum­based chemotherapies, e.g., Carboplatin or Cisplatin, on TNBC. Effectiveness of platinum­based chemotherapies was determined based on survival rate, as compared to survival rate when patients were treated with traditional chemotherapies alone. Data from numerous sources, e.g., Springer Link, the US National Library of Medicine, clinicaltrials.gov, and Mendeley, were extrapolated. As described here, the data was processed to determine the effectiveness of platinum­based treatment. The variables tested were the pathological complete response rates (pCr) and the objective response rate (ORR). A qualitative analysis was performed on the remaining data to ensure validity; a quantitative analysis was performed to determine variability. The data that fit the criteria were ran through Prism 6.0. If samples had a significant heterogeneity (I^2>50%) a random­effects model was used. If samples did not have a significant heterogeneity (I^2<50%) was ran through a fixed­effects model.

The means of platinum pCr rates were significantly higher than non­platinum pCr rates at the 95% confidence interval. Also, the means of the platinum oRr rates were significantly higher than non­platinum oRr rates at the 95% confidence interval. Based on the forest plots, the cancerous cells exposed to the platinum­based chemotherapies underwent apoptosis, reducing the size of the tumors. The cancerous cells exposed to non­platinum­based chemotherapies underwent apoptosis, but not to the degree of the regimens containing platinum. Platinum­based chemotherapies encourage triple negative breast cancer tumors to undergo apoptosis more than non­platinum­based chemotherapies.

Introduction/Background

The purpose of this study was to determine whether platinum­based chemotherapy treatments were more effective in extending the life rates of metastatic triple negative breast cancer patients than non­platinum­based chemotherapy treatments. In triple negative breast cancer, the tumors are absent of all receptors treatable by hormone therapies: estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth receptor 2 (HER2) (Katakkar et al., 2012). Due to the absence of receptors, patients are subjected to harmful chemotherapy treatments that aren’t necessarily designated for breast cancer, which leads to apoptosis of non­cancer cells. The more well­known platinum­based chemotherapy treatments (oxaliplatin, cisplatin, carboplatin) are neutral platinum II complexes that consist of two amine ligands and two extra ligands that can be used for extra DNA binding (Afghahi et al., 2014). Platinum­based chemotherapy treatments have the ability to inhibit gene transcription, which increases the rate of cellular apoptosis (cell death). This class of chemotherapy treatments is also nonspecific, making it universal in all treatments of cancer (Khalaf et al., 2014). Experimental Description

In the meta­analysis, numerous sources were obtained from the US National Library of Medicine, clinicaltrials.gov, Springer Link, and Mendeley. Each source obtained underwent a qualitative analysis as well as a quantitative analysis. For the qualitative analysis, the average patient tested in the study must have fit a certain criteria: each patient must be a woman, in between the ages of 40 to 50 years of age, suffering from triple negative breast cancer, and had their cancer metastasized. For the quantitative analysis, the source must have at least 100 sources. In the studies used in the meta­analysis, the average patient fit the criteria, and each source had about 200 pieces of data each, making the overall sample size about 1000. To conduct the meta­analysis, the software Prism 6.0 was used to build funnel plots and forest plots. The funnel plots were used to determine publication bias, whereas the forest plots were used to visually show means and their confidence intervals. A sample T­Test was also conducted on SPSS 21.0 to compare the uppers and lowers of the means to determine significant differences. The variables compared in the study were the pathological complete response rate (pCr), which is the complete absence of any inflicted tumor cells, and the objective response rate (ORr), which is a combination of the pCr and the partial response rate, which is when at least 50% of the inflicted cells experience apoptosis.

Results

Table 1 shows the T­Test results from the combined platinum pCr rates and the combined non platinum pCr rates. The pCr rates of the Platinum­Based chemotherapy treatments is significantly higher than the pCr rates of the Non Platinum­Based chemotherapy treatments at the 95% confidence interval. Table 1. T­Test Results: Combined Platinum pCr v.s. Combined Non Platinum pCr

Combined Platinum pCr v.s. Combined Non Platinum pCr Test Value = 1.4

T df Sig.

(2­tailed)

Mean

Difference

95% Confidence

Interval of the

Difference

Lower Upper

Combined Platinum

Based pCr

.000 54 1.000 .0000 ­.134 .134

Combined

Non­Platinum Based

pCr

­3.757 45 .000 ­.29043 ­.8461 ­.4134

Table 2 shows the comparison of the uppers and lowers of the combined platinum oRr rates and the combined non platinum oRr rates. The oRr rates of the Platinum­Based chemotherapy treatments is significantly higher than the oRr rates of the Non Platinum­Based chemotherapy treatments at the 95% confidence interval. Table 2. T­Test Results: Combined Platinum oRr v.s. Combined Non Platinum oRr

Combined Platinum oRr v.s. Combined Non Platinum oRr Test Value = 7.5

t df Sig.

(2­tailed)

Mean

Difference

95% Confidence

Interval of the

Difference

Lower Upper

Combined

Non­Platinum Based

oRr

­2.022 27 .053 ­1.74750 ­3.5204 .0254

Combined Platinum

Based oRr

4.790 45 .000 5.23957 3.0366 7.4425

Figure 1 shows the means of each measured variable as a forest plot. The combined rates for both of the platinum pCr and oRr rates were significantly different than the pCr and oRr rates of the non­platinum chemotherapy treatments at the 95% confidence interval. Figure 1: Overall Combined pCr and oRr

Figure 2 shows the comparison of the platinum pCr rates from each individual study. Although one of the studies are overlapping with the null hypothesis, the other four statistics were significantly higher than the null hypothesis at the 95% confidence interval. Figure 2: Individual Platinum pCr Rates

Figure 3 shows the comparison of the non­platinum pCr rates over each individual study. The results, although scattered throughout various positions in the graph, show that the non­platinum chemotherapy treatments have no trend, which on a standalone study, is insignificant at the 95% confidence interval.

Figure 3: Individual Non­Platinum pCr Rates

Figure 4 shows the comparison of the platinum oRr rates from each individual study. All of the studies demonstrate a high oRr among platins at the 95% confidence interval. Figure 4: Individual Platinum oRr Rates

Figure 5 shows the comparison of the non­platinum oRr rates from each individual study. There was high variability among each of the studies, showing insignificant results to the 95% confidence interval. Figure 5: Individual Non­Platinum oRr Rates

Discussion The results of this meta­analysis indicated that platinum based chemotherapy treatments exhibited higher pathological complete response rates over non­platinum based chemotherapy treatments. Platinum based chemotherapy treatments also exhibited higher objective response rates over non­platinum­based chemotherapy treatments. There was a normal distribution of patient data among each of the studies, which suggests that the data follows the bell curve model. Based on t­tests, the two sets of variables, the platinum objective response rate vs. the non­platinum objective response rate and the platinum pathological complete response rate vs. the non­platinum pathological complete response rate, were compared against each other. The means of platinum pCr rates were significantly higher (3.745 nodes ± 2.134) than the non­platinum pCr rates (0.281 nodes ± 0.1461) at the 95% confidence limit. The platinum oRr rates were significantly higher (3.356 nodes ± 1.0366) than non­platinum oRr rates (0.511 nodes ± 0.3204) to the 95% confidence limit. Based on the non­platinum meta­analysis, there was high variability in the means between pCr and oRr; there is no significant effect of non­platinum­based chemotherapy treatments on cancerous cells. The means of oRr and pCr of the non­platinum­based treatments were also variable. In other studies concerning platinum­based chemotherapy treatments and triple negative breast cancer, the same trends have been found. In combination with PARP inhibitors and gemcitabine, cisplatin was proven to be more effective than cisplatin alone (Hastak et al., 2010). In another study, anthracycline drugs, i.e. epirubicin, combined with carboplatin, proved to be more effective in improving pCr rates. (Telli et al., 2014) Cisplatin, along with TRAIL (Tumor Necrosis Factor (TNF)­Related Apoptosis Inducing Ligand) helped to eliminate tumor­causing cancer stem cells (CSCs) and reduce the self­renewal complex of these CSCs (Reddy et al., 2011). Hence, platinum­based chemotherapy treatments have a significant effect on cancerous cells and induce cellular apoptosis.

Conclusion The introduction of platinum­based chemotherapy treatments can prove to be extremely beneficial to patients who suffer from triple negative breast cancer. There is no treatment that is specifically designed for this type of cancer. However, platinum­based chemotherapy treatments are often looked over, as they severely increase the toxicity of the patient, leading to extremely harmful side effects. (McWhinney et al., 2009) Platins can cause neurotoxicity, which can lead to renal failure, as well as neutropenia. If there is a way that platinum can be optimized for patient use, triple negative breast cancer patients will be able to live longer, happier lives. This study provided statistical evidence that platinum­based chemotherapy treatments were more effective in extending the life expectancy rates of metastatic triple negative breast cancer patients than the non­platinum­based chemotherapy treatments. The patients exposed to platinum­based chemotherapy treatments exhibited higher pathological complete response rates and objective response rates, whereas the non­platinum­based chemotherapy treatments did not. Thus, platinum­based chemotherapy treatments appear to induce apoptosis in cancer cells at higher rates than occurs when non­platinum­based chemotherapy treatments are used. To further the study of triple negative breast cancer, as well as its treatment, this meta­analysis should be expanded to investigate possible differences on the effect of platinum­based chemotherapy treatments due to ethnicity, gender and age. Other types of chemotherapy, e.g., silver versus platinum, should also be explored for triple negative breast cancer. Alternatives to traditional chemotherapy, e.g., immunotherapy, also should be investigated.

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