Recently, the cholesterol lowering-independent or “pleiotropic” effects of statins have gained greater recognition, particularly in the area of cancer therapeutics . Cumulative in vivo evidence as well as observational clinical studies suggest a therapeutic potential of statins in different cancer models . Nevertheless, translating these findings into clinical studies faces multi-dimensional challenges comprising; which statin to use, the timing (when or at what stage of cancer progression), the temporal frame (short-term versus long-term), and what cytotoxic agents/chemotherapy line, hormonal, or radiotherapy with which should a particular type of statin is co-administered. To our knowledge, this study represents the first clinical trial to utilize short-term simvastatin at therapeutically relevant dose (40 mg) in combination with carboplatin and vinorelbine in metastatic breast cancer patients.
The combination of carboplatin and vinorelbine is a one of the palliative treatments for MBC in Al-Baironi Hospital. Our study confirms the effectiveness of carboplatin plus vinorelbine with an ORR of 33.75%, a median OS of 16 months and 35% grade ≥3 neutropenia for all patients. Iaffaioli et al reported their experience with a same therapy regimen, the ORR was 41%, median OS was 16 months and the principal toxicity was myelotoxicity; grade 3/4 leukopenia in 46% of advanced breast cancer patients .
Expectedly, the lipid lowering effect of simvastatin was evident by a significant decrease in total cholesterol and LDL-C levels compared with placebo. These findings suggest good compliance with the study intervention and confirm the effectiveness of simvastatin in lowering lipids within a short-term (15 days) exposure frame.
Surprisingly, a significant drop in total cholesterol (range -3.26% to -9.43%, p<<0.05) and LDL-C (range -2.82% to -12.73%, p<<0.05) levels was observed between the first and eighth day of each of the treatment cycles in patients who received chemotherapy plus placebo. These observed simvastatin-independent changes in cholesterol levels are consistent with in vitro experiments, where in acute myeloid leukemia (AML) samples exhibited abnormally increased demands for cholesterol following exposure to cytotoxic agents (daunorubicin or cytarabine), a phenomenon described as "defensive adaptation" of cancerous cells to increase chemo-resistance .
Within the 15-day simvastatin exposure in each cycle, no changes in hsCRP level was observed, suggesting that a dose of 40 mg of simvastatin for this short-term duration may not have been sufficient to exhibit anti-inflammatory benefit in MBC patients. These findings contradict others in coronary artery disease (CAD) patients, where short term exposure of simvastatin lowered hsCRP . We should note here that the hsCRP baseline levels are rather different between the two patient populations, (median [lower-upper quartile]; 8.18 [3.93-22.11] in MBC vs. 2.8 [1.3-4.8] mg/l or 1.1 [0.8-2.5] in female and male CAD patients, respectively). A significant reduction in serum CRP in breast cancer patients may demand a higher dose and/or longer duration of statin therapy (e.g. at least 3 months) to demonstrate a similar effect to that observed in CAD patients .
Despite the promising in vitro and in vivo evidence that provided support to anti-tumor effect(s) of statins in a variety of human malignancies , our findings prove that clinically relevant dose of simvastatin, added to carboplatin and vinorelbine course has no clinical benefit in terms of outcome (i.e. ORR and median OS) in MBC patients. However, treatment with simvastatin in MBC proved to be very well tolerated, as no significant chemotherapy toxicity or simvastatin adverse effects were recorded. These findings are in agreement with a study by kim and colleagues that investigated a combination of statins with capecitabine and cisplatinin advanced gastric cancer, as no increase in progression free survival was reported . Similarly, gemcitabine-simvastatin at 40mg daily vs. gemcitabine-placebo resulted in no significant difference in time to progressionin advanced pancreatic cancer patients . The overall null results in our study and others may stem from statins' conflicting properties; on one hand, they have anti-proliferative effects, but on another hand, they exhibit immune tolerance-promoting properties during tumor development. Therefore, statins might be concurrently inhibiting and promoting tumor growth . Another explanation may arise from the pulsatile administration of statin (15 days every cycle), which may not be enough in terms of cholesterol deprivation of cancerous cells.
We decided the dose-level of simvastatin (40 mg) in combination with the carboplatin and vinorelbine course based on an observation that low concentrations of statins were capable of inducing apoptosis of microvascular endothelial cells and lowering VEGF serum levels, implicating a possible anti-angiogenic role for statin in cancer treatment [22, 25]. Of interest, statins were proved to induce apoptosis through activation of the JNK-signaling pathway, and since inhibition of JNK activation is a major mechanism beyond tumor resistance to platinums and Vinca alkaloid, therefore the addition of statins to either of these drugs is speculated to help overcome chemoresistance [26, 27].
There have been only a few reports on prognostic factors in patients with metastatic disease . Notably, not all studies agreed on the same set of risk factors explaining variation in prognosis following breast cancer metastasis . Some studies have shown that age, number of metastatic sites, ER/PR and HER2 status, ECOG-PS and baseline values of CEA and CA15-3 are valuable prognostic factors [28, 29, 30, 31]. Nevertheless, our study did not provide support for a significant influence of any of these factors on survival in multivariate analysis. Variations in prognostic factors in terms of the patients’ selection, presence of clinical covariates, rate of patients’ lost to follow-up, lines of chemotherapy and statistical method for analysis [29, 32] may explain the differences between our results and those from previous ones.
Nevertheless, our findings prove that increased baseline serum concentrations of hs-CRP may serve as a predictor for poor prognosis among MBC patients. This result is consistent with Albuquerque et al study , Al Murri et al study  and Petekkaya et al study .
On another hand, Swenerton et al. was the first to report the clinical importance of serum lactate dehydrogenase in predicting survival of MBC patients . Our results reinforced that elevated serum LDH levels significantly correlate with poorer survival among MBC patients [35, 36].
No global consensus exists regarding the ideal treatment strategy for MBC. Thus, once first line failed, second and later lines are adapted, reflecting the clinically challenging picture of progressive disease . Our data showed that the grade of chemotherapy line had significant impact on survival of MBC patients.