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 Journal of Cancer Therapy, 2012, 3, 777-781 http://dx.doi.org/10.4236/jct.2012.325097 Published Online October 2012 (http://www.SciRP.org/journal/jct) 777 Triple Negative Breast Cancer Treatment: Use of Platinum and Platinum Analogs Manuela Fantini1*, Carlotta Santelmo1, Fabrizio Drudi1*, Claudio Ridolfi1, Eleonora Barzotti1, Lorenzo Gianni1, Valentina Arcangeli1, Alessandra Affatato1, Alberto Ravai o li2 1Oncology Department, Infermi Hospital, Rimini, Italy; 2IRST (Cancer Center of Romagna), Meldola, Italy. Email: [email protected], carlotta.sante[email protected], [email protected], claudi[email protected], eleonora.barzotti@libero.it, Received July 24th, 2012; revised August 27th, 2012; accepted September 9th, 2012 ABSTRACT Triple negative br east cancer (TNBC) is characterized by a high sensitivity to antiblastic drugs and a high pathological complete remission rate after neoadjuvant therapy. In patients showing complete re mission, the probabilit y of develop- ing metastatic disease would seem to be reduced. Nonetheless, this cancer has a high percentage of relapse. Anthracy- clines, taxanes and platinum compounds are the most effective drugs for the treatment of TNBC. There is substantial evidence to support the efficacy of platinum-based chemotherapy, probably attributable to the mechanism of action of such drugs, which react with the DNA repair system. PARP inhibitors would also seem to be very interesting. Despite promising results, TNBC remains a disease with a poor prognosis due to the lack of targeted therapy. The discov ery of new targets and new agents is thus a high prio rity issue for this typ e of breast cancer. In this respect, lipoplatin has been identified as a potentially interesting treatment option to evaluate in both neoadjuvant and advanced settings. Keywords: Breast Cancer; Triple Negative; Treatment; Platinum; Platinum Analogs 1. Introduction Breast cancer is the most common malignancy and lead- ing cause of cancer death in women, both worldwide and in many developed countries, including Italy. It is a heterogeneous disease whose prognosis is re- lated mainly to stage and biological characterization, which defines a variety of conditions ranging from a low risk of relapse and indolent clinical course to a high re- lapse risk and rapid clinical progression, despite aggres- sive therapies [1]. Routine pathological reports, in addi- tion to defining tumor stage and grade, include an as- sessment of proliferation index (Ki-67/MIB-1 immu- nostaining), expression of estrogen (ER) and progestin receptors (PR), and HER-2/neu status (evaluated through protein immunostaining or the study of gene amplifica- tion). Whilst these biological features have some prog- nostic value, they are principally considered as predictors of response to different treatments, especially targeted therapies. Breast cancer can be classified into three large subgroups: hormone receptor-positive, HER-2-positive (which is also hormone-receptor positive in less than half of cases), and the so-called “triple negative” (TN) tumors, where ER and PR are negative and there is no amplifica- tion or overex p ressi o n of HER-2 [2]. Studies of gene expression profiling have confirmed the existence of breast cancer subtypes, leading to a more accurate definition: luminal tumors are typically ER- positive but with different expression of ER-related genes and proliferative genes; HER-2 positive tumors are characterized by the overexpression and/or amplification of HER-2 and other genes; the normal breast-like sub- type and basal-like subtype are usually TN at immu- nostaining studies [3]. This classification has biological and clinical relevance, defining how tumor growth is driven by different pathways, as best exemplified by the luminal and HER2/neu subtypes, and with different prognoses. TN tumors merit special attention because they have a poor prognosis and also because no targeted therapy has been approved as yet for clinical use [4]. TN tumors defined by immunostaining differ somewhat from the basal-like subtype defined by gene profiling, but the latter subtype is the most frequent and most important form of triple negative breast cancer (TNBC) [5]. The most important features of TN/basal-like tumors include a strong expression of basal cytokeratins CK5/6 and CK17 (high molecular weight cytokeratins, found in the basal layer of stratified epithelia), expression of prolif- eration related genes, high tumor grade, frequent p53 mutations and p63 gene amplification, low expression of BRCA1, frequent expression of EGFR, KIT, v imentin, p- *Corresponding authors Copyright © 2012 SciRes. JCT  Triple Negative Breast Cancer Treatment: Use of Platinum and Platinum Analogs 778 cadherin, fascin, caveolins 1 and 2, alpha-B-crystallin, and genes involved in matrix rem odeling and angi ogenesis. Using univariate analysis, we can define the differ- ences between the two main histological subgroups. In Bertucci and co-workers 2008 study on TNBC, the me- dian age of patients with basal tumors (50 years) was lower than that of patients with other TN types (57 years). Basal tumors exhibited a higher pathological grade: 88% were grade III ver sus only 51% in non basal tumors. The pathological tumor size (pT) was higher in basal tumors: 60% pT2 - pT3 versus 46% in the other group. No corre la- tion was found with pathological axillary lymph node status (pN). There were more medullary breast cancers within the basal tumors, and more lobular breast cancers within the non basal tumors. Five-year metastasis-free survival was 65% in the basal group and 75% in the other group, while 5-year overall survival (OS) was 68% and 78%, respectively. Pathological complete resp onse (p CR) after primary chemotherapy was observed in 59% of basal tumors versus 27% in the other group [6]. TNBC represents a heterogeneous group of tumors that include 70% of basal tumors and 30% of the non basal kind. TN basal tumors are characterized by ER, PR and HER-2 negativity, and EGFR and cytokeratin 5/6 and 17 positivity. In contrast, TN non basal tumors are characterized by ER, PR and HER-2 negativity and EGFR and cytokeratin 5/6 and 17 negativity. Neverthe- less, it is impossible to distinguish between basal and non basal subtypes in the results obtained from the clinical treatment of TN tumors in neoadjuvant, adjuvant and metastatic settings because they are not considered sepa- rately in either clinical practice or in the majority of pub- lished pa p ers. 2. Treatment of TNBC TNBC is characterized by a high sen sitivity to antib lastic drugs. Although an elevated percentage of pCR is ob- served in the neoadjuvant setting and a high remission rate in metastatic disease, this breast cancer subtype shows a high percentage of relapse. Numerous drugs have been evaluated for the treatment of this tumor, the most efficacious being anthracyclines, taxanes (paclitaxel and docetaxel) and platinum compounds. Among the new drugs, PARP-inhibitors would seem to be of par- ticular interest. However, because of the biological het- erogeneity within TNBC, many patients show an excel- lent outcome while others obtain much poorer results, despite the administration of systemic treatments consid- ered effective. 2.1. The Experience in Neoadjuvant Settings In the neoadjuvant treatment of TNBC, the paradox of high sensitivity to anthracyclines and a high percentage of relapse in this poor prognostic subgroup is attributable to the elevated recurrence rate in patients who have re- sidual disease at the time of surgery. Those who achieve pCR in basal-like, HER-2 positive and ER negative tu- mors would seem to show a higher rate of survival, in contrast to patients who do not achieve pCR and appear more likely to experience early relapse and early death. One of the most important studies published to date is by Carey and coworkers who examined the response rate to neoadjuvant anthracycline-based chemotherapy in 34 TN patients, reporting 85% clinical response (complete or partial), more than the value reached in luminal subtypes [7]. pCR to chemotherapy was significantly better among basal-like subtypes (27%) than among other subtypes (7%). Furthermore, the percentage of patients with minimal residual disease after chemotherapy was higher in basal-like (58%) than in luminal A subtypes (21%). Despite sensitivity of basal like-TNBC in Carey’s study, his group still showed very poor prognosis, for the high relapse rates observed among those who do not achieve pCR. In another study by Liedtke and coworkers, response to neoadjuvant chemotherapy and survival was compared in TNBC and non-TNBC patients [8]. 1118 patients at M.D. Anderson Cancer Center received neoadjuvant che- motherapy for stage I-III breast cancer from 1985 to 2004. Although patients with TNBC (23%) had higher pCR rates than those with non-TNBC (22% versus 11%), they showed poorer 3-year progression-free (PFS) and overall survival (p < 0.0001 and p < 0.0001, respectively). Recurrence and death rates were higher for the TNBC group, but only in the first three years. When pCR was achieved, patients with TNBC or non-TNBC showed similar survival while those with residual disease had a poorer outcome, especially if they had the TNBC subtype, confirming previous observations in larger groups of patients. 2.2. The Experience in Adjuvant Settings Numerous studies have reported on the adjuvant treat- ment of TNBC basal-like and non basal-like TNBC, the majority concerning retrospective experiences analyzing breast cancer treatments in different subsets. Although locoregional and distant relapse in TNBC occur mainly during the first three years of follow up after the end of therapy, we found few reports on long-term follow up that made a distinction between TN and other kinds of breast cancers. In Voduc and coworkers’s report of 4033 patients followed up for almost ten years after breast- conserving surgery and given post-operative radiotherapy and hormone or antiblastic treatment, regional relapse- free survival (RRFS) was 86% for basal-like breast can- cer and 92% for non basal-like TNBC, while the per- centage of RRFS of luminal A breast cancer was 97% [1]. The observation that TNBCs are especially sensitive to Copyright © 2012 SciRes. JCT  Triple Negative Breast Cancer Treatment: Use of Platinum and Platinum Analogs 779 antiblastic drugs has been made by numerous authors. The Cancer and Leukemia Group B reported a benefit from the addition of a taxane to the adjuv ant treatment of ER, PR and HER-2 negative tumors, whereas no benefit was observed in patients with ER positive tumors [9]. Furthermore, the Breast Cancer Intergroup, in their re- view of 6644 node-positive breast cancer patients, re- ported more important results in those with ER- negative tumor given chemotherapy [9]. Patients with a high pro- liferative index and ER/PR negativity showed very im- pressive results at ten years with CMF chemotherapy. More recently, Colleon i and his co llaborators published a paper on the use of classic CMF in TN node-negative breast cancer patients [10]. They found that CMF che- motherapy produced a stronger effect in patients with TNBC than in those who did not receive the schedule or whose tumors showed ER positivity. New approaches to adjuvant therapy are guided by re- sults from preclinical models, molecular profiling, and findings from trials on metastatic disease. Numerous adjuvant clinical trials are currently ongoing to evaluate the role of ixabepilone, platinum agents and VEGF in this clinical setting [11]. The PACS 08 adjuvant trial [12], built on data from PACS 01 [13,14], is a phase III study of TNBC patients randomized to receive three cycles of FEC followed by three cycles of docetaxel or ixabepilone every three weeks. The phase III adjuvant TITAN trial is evaluating four cycles of standard doxorubicin plus cyclophosphamide followed by four cycles of ixabepi- lone or twelve cycles of weekly paclitaxel [15]. The phase III BEATRICE study is assessing numerous chemother- apy agents with or without bevacizumab at a dosage of 5 mg/Kg weekly for patients with TNBC [16]. Findings are expected in the next year. In conclusion, TN tumors are currently most effect- tively treated with conventional adjuvant or neoadjuvant therapies (anthracyclines and taxanes). Although signifi- cant results have been achieved, TN patients show lower disease-free survival than those with non TN tumors. 2.3. The Experience in a Metastatic Setting Results on the treatment of TNBC in a metastatic setting do not differ from those described in neoadjuvant and adjuvant situations. These tumors only respond to che- motherapy, and although a substantial percentage of complete response (CR) can be achieved, relapse and non clinical response remain high. Whilst anthracyclines and taxanes have proven the most effective drugs in this set- ting, cisplatin also shows very promising results [17]. Among the new products, PARP-inhibitors are consid- ered to be potentially important drugs. Indeed some re- ports suggest that TNBC expresses high levels of poly- merase 1 (PARP-1), a DNA repair enzyme which is the molecular target of PARP inhibitors. In a randomized phase II study in patients with metastatic TN disease, the PARP inhibitor BSI-201 significantly improv ed objective response rates (48% vs 16%, p = 0.002), PFS (6.9 vs 3.3 months, p < 0.0001) and median OS (9.2 vs 5.7 months, p = 0.0005) when added to carboplatin and gemcitabine [11]. However, despite such encouraging findings, prog- nosis in TNBC patients with advanced disease (apart from those with accurately verified CR), remains very poor. 2.4. Platinum and Lipoplatinum Experience Although cisplatin is one of the oldest and more effective anticancer drugs, its use may be limited by adverse events, mainly nephrotoxicity and neurotoxicity. A number of studies evaluating platinum agents in pa- tients with metastatic TNBC have been carried out. A retrospective study by Uhm and coworkers comparing outcome in patients with TNBC with th at of p atients with other BC subtypes, all treated with a taxane-platinum regimen, did not highlight a difference in response rates between these two groups [18]. A similar experience from the UK showed that patients with advanced TNBC treated with platinum-based chemotherapy had ORRs similar to those with non-TN tumors [17]. Favorable results have also been obtained with cis- platin in a metastatic setting. A single institution ph ase II study on weekly cisplatin and metronomic cyclophos- phamide reported that such a regimen appeared to be safe and effective, with an ORR of 63% and median time to progression of 13 months in contrast to 33% and 7 months, respectively, in patients no t treated with cisplatin [19,20]. The association of carboplatin with paclitaxel [21] or irinotecan [22] in pretreated metastatic patients with TN tumours has also shown good response rates (57% and 30%, respectively). A study conducted at the Royal Marsden Institute also supported the hypothesis that patients with TN tumors have a significantly longer PFS compared with that of other histological subtypes, with a trend towards an improved OS when treated with platinum. Very few studies have been conducted on lipoplatinum in advanced TNBC. Only recently Farhat and coworkers reported the results of their phase II trial of lipoplatin and vinorelbine combination in patients with HER-2 negative metastatic breast cancer who had not received prior treatment in an advanced setting [23]. A 53.1% ORR was reported (CR in 3 patients, 9.4%) and 37.5% patients showed stable disease. The majority of adverse events were mild or moderate. For this reason lipoplatin would seem to be an attractive treatment option for these pa- tients. Lipoplatin is a novel liposomal formulation of cis- platin, designed to increase safety and tolerability by decreasing toxicity and nephrotoxicity. It decreases the Copyright © 2012 SciRes. JCT  Triple Negative Breast Cancer Treatment: Use of Platinum and Platinum Analogs 780 exposure of organs to cisplatin, whilst effectively deliv- ering the drug to the tumor. The formulation comprises cisplatin and liposomes based on 1,2 dipalmitoyl-sn- glycero-3-phospho-rac-1-glycerol (sodium salt) (DPPG, mw 745), soy phosphatidyl choline (SPC-3, mw 790), cholesterol (CHOL, mw 386.66) and methoxy-polyeth- ylene glycol-distearoyl phosphatidyl-etha-nolamine lipid conjugate (mMPEG2000-DSPE, mw 2807). At steady state, particles have a weight ratio of 8.9% cisplatin to 91.1% lipids (0.9:9 .1). The total lipid to cisplatin ratio in lipoplatin is 10 mg lipid/mg cisplatin. The cholesterol content of lipoplatin is 11.6% of the total lipids. It is cal- culated that 1.3 mg of cholesterol is injected per mg of cisplatin [24]. There are numerous indications that point towards the potential usefulness of lipoplatin as treatment of TNBC. Consequently, our group is currently planning a new trial on patients with TNBC who have become resis- tant to anthracyclines and taxanes, offering lipoplatin as second-line treatment following progression after first- line therapy. 3. Conclusion TNBC is a very serious illness and conventional treat- ments only obtain partial control of the disease, and normally for a short period of time. The search for new treatments is urgently needed and lipoplatin could be potentially useful in advanced disease and could also represent a new possible treatment in the future in neo- adjuvant and ad juvant settings. REFERENCES [1] K. D. Voduc, M. C. U. Cheang, S. 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