1. 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.

2. 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.

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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.

12. 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.

13. Literature Cited
Afghahi, Anosheh, and Melinda L. Telli. "The Role of Platinum Therapy in Triple­negative Breast
Cancer." ​Breast Cancer Management​ 3.4 (2014): 377­85. Print.
Biersack, Bernhard, and Rainer Schobert. "Platinum and Ruthenium Complexes for the Therapy
of Breast Cancer Diseases." ​Breast Cancer Metastasis and Drug Resistance​ (2012):
275­90. Print.
Desai, Kartik Aysola Akshata. "Triple Negative Breast Cancer – An Overview." ​Hereditary
Genetics​ (2012). Web.
"Triple Negative Breast Cancer." ​Encyclopedia of Cancer​: 3055. Print.
Fantini, Manuela, Carlotta Santelmo, Fabrizio Drudi, Claudio Ridolfi, Eleonora Barzotti, Lorenzo
Gianni, Valentina Arcangeli, Alessandra Affatato, and Alberto Ravaioli. "Triple Negative
Breast Cancer Treatment: Use of Platinum and Platinum Analogs." ​JCT Journal of
Cancer Therapy​ 03.05 (2012): 777­81. Print.
Graña, Begoña, Natalia Fernández, and Judith Balmaña. "The Role of Platinum Compounds for
the Treatment of Breast Cancer." ​Current Breast Cancer Reports Curr Breast Cancer
Rep​ 5.1 (2013): 11­22. Print.
Hastak, K., E. Alli, and J. M. Ford. "Synergistic Chemosensitivity of Triple­Negative Breast
Cancer Cell Lines to Poly(ADP­Ribose) Polymerase Inhibition, Gemcitabine, and
Cisplatin." ​Cancer Research​ 70.20 (2010): 7970­980. Web.
Ibrahim, Toni. "Cisplatin in Combination with Zoledronic Acid: A Synergistic Effect in
Triple­negative Breast Cancer Cell Lines." ​Int J Oncol International Journal of Oncology
(2013). Web.
Katakkar, Suresh. "A Triple Negative Breast Cancer: What It Is Not!" ​Breast Cancer: Targets
and Therapy BCTT​ (2012): 21. Web.

14. Khalaf, Daniel. "Investigating the Discernible and Distinct Effects of Platinum​‑​based
Chemotherapy Regimens for Metastatic Triple​‑​negative Breast Cancer on Time to
Progression." ​Oncology Letters Oncol Lett​ (2014). Web.
Mcwhinney, S. R., R. M. Goldberg, and H. L. Mcleod. "Platinum Neurotoxicity
Pharmacogenetics." ​Molecular Cancer Therapeutics​ 8.1 (2009): 10­16. Web.
Muscella, A., C. Vetrugno, F. P. Fanizzi, C. Manca, S. A De Pascali, and S. Marsigliante. "A
New Platinum(II) Compound Anticancer Drug Candidate with Selective Cytotoxicity for
Breast Cancer Cells." ​Cell Death Dis Cell Death and Disease​ 4.9 (2013). Web.
"Chemotherapy of Metastatic Triple Negative Breast Cancer: Experience of Using
Platinum­based Chemotherapy." ​Oncotarget​ (2015). Web.
Reddy, Kaladhar. "Cisplatin and TRAIL Enhance Breast Cancer Stem Cell Death." ​Int J Oncol
International Journal of Oncology​ (2011). Web.
Telli, Melinda. "Optimizing Chemotherapy in Triple­Negative Breast Cancer: The Role of
Platinum." ​American Society of Clinical Oncology Educational Book​ 34 (2014). Print.
Tian, Muyou, Yahua Zhong, Fuxiang Zhou, Conghua Xie, Yunfeng Zhou, and Zhengkai Liao.
"Platinum­based Therapy for Triple­negative Breast Cancer Treatment: A
Meta­analysis." ​Mol Clin Onc Molecular and Clinical Oncology​ (2015). Web.