lable at ScienceDirect

The Breast 19 (2010) 246e248

Contents lists avai

The Breast

journal homepage: www.elsevier .com/brst

Short Report

Cisplatinegemcitabine therapy in metastatic breast cancer: Improvedoutcome in triple negative breast cancer patients compared tonon-triple negative patients

Nebu Koshy*, Dolly Quispe, Runhua Shi, Richard Mansour, Gary V. BurtonFeist Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA

a r t i c l e i n f o

Article history:Received 28 October 2009Received in revised form22 January 2010Accepted 8 February 2010Available online 15 March 2010

Keywords:Triple negativeCisplatin and gemcitabine chemotherapyMetastatic breast cancer

* Corresponding author.E-mail address: nkoshy@lsuhsc.edu (N. Koshy).

0960-9776/$ e see front matter � 2010 Elsevier Ltd.doi:10.1016/j.breast.2010.02.003

a b s t r a c t

Triple negative or basal-like breast cancers lack expression of estrogen, progesterone and HER2neureceptors. There are no specific treatment guidelines for this group of patients, however, it has beenpostulated that their phenotypic and molecular similarity to BRCA-1 related cancers would confersensitivity to certain cytotoxic agents like cisplatin (CDDP). The aim of the study was to retrospectivelyexamine the clinical outcome at our institution of patients with metastatic breast cancer treated withCDDP and gemcitabine combination chemotherapy who had triple negative breast cancer compared tonon-triple negative breast cancer. Thirty-six patients with metastatic breast cancer were treated withCDDP and gemcitabine combination chemotherapy, 17 of whom were triple negative (47%) and 19 werenon-triple negative (53%). The median progression free survival for triple negative and non-triplenegative metastatic breast cancer patients were 5.3 months and 1.7 months respectively (p ¼ 0.058). Bymultivariate Cox proportional hazard model after adjusting for age, race and menopausal status the riskof progression was reduced by 47% for triple negative compared to non-triple negative metastatic breastcancer patients (HR ¼ 0.53, p ¼ 0.071).Conclusions: Our results suggest an improved outcome for metastatic triple negative breast cancerpatients compared to non-triple negative breast cancer patients when treated with cisplatin andgemcitabine combination chemotherapy.

� 2010 Elsevier Ltd. All rights reserved.

Introduction

Triple negative breast cancers (TNBC) are characterized by lackof expression of estrogen (ER), progesterone (PR) and HER2neureceptors and comprise 15% of all breast cancers. Most TNBC havea basal-like molecular phenotype by gene expression profiling.1,2

TNBC also shares clinical and pathologic features with hereditaryBRCA1 related breast cancers including lack of ER/PR and HER2neu,presence of p53 mutation, basal gene expression patterns andBRCA1 inactivation either by mutation or pathway dysfunction.3e5

Most of these tumors are high grade or poorly differentiatedtumors. Management of these tumors are challenging because of itsrelatively poor prognosis, aggressive behavior and lack of targetedtherapies.6 Standard treatment options are limited for metastaticTNBC as most patients have been treated with adjuvant anthracy-cline, taxane and cyclophosphamide.

All rights reserved.

Cisplatin (CDDP) and gemcitabine combination therapy is aneffective regimen for the treatment of patients with metastaticbreast cancer.7 Studies have suggested that TNBC may be moresensitive to DNA damaging agents like CDDP.8e11 A recent PhaseII clinical trial using CDDPegemcitabine demonstrated superiorresponse in ER/PR negative patients suggesting that TNBC mayin fact be more sensitive to CDDP as compared to non-TNBC.12

We routinely, at our institution, use CDDPegemcitabine combi-nation therapy as 3rd or 4th line therapy in patients with anadequate performance status. To determine if TNBC is prefer-entially sensitive to platinum therapy as compared to non-TNBC,we reviewed the outcome of patients treated with CDDPegem-citabine at our institution.

Methods

This was a single institution retrospective study. Followingapproval by the Louisiana State University Health Sciences CenterInstitutional Review Board, data was collected from the medicalrecords of all patients with metastatic breast cancer treated withCDDP and gemcitabine combination chemotherapy between July,

Table 1Patient characteristics.

Triple negativen ¼ 17

Non-triple negativen ¼ 19

Age (years), mean (range) 47.5 (29e62) 50.2 (32e68)Ethnicity, n (%)Caucasians 7 (41%) 11 (58%)AfricaneAmericans 10 (59%) 8 (42%)

Menopausal status, n (%)Pre-menopausal 10 (59%) 8 (42%)Post-menopausal 7 (41%) 11 (58%

Receptor status, n (%)Her2neu þve 0 (0%) 9 (47%)

ERþve and/or PRþve/HER2neu�ve

0 (0%) 10 (53%)

Metastatic sites, n (%)Lung 11 (65%) 7 (37%)Liver 5 (29%) 12 (63%)Brain 7 (41%) 4 (21%)Bone 11 (65%) 9 (47%)Lymph nodes 12 (71%) 6 (32%)

Prior cytotoxic (non-hormonal) regimens for metastatic disease, n (%)0 0 (0%) 2 (10%)1 2 (12%) 4 (21%)2 6 (35%) 4 (21%)3 6 (35%) 4 (21%)�4 3 (18%) 5 (27%)

Prior cytotoxic agents received, n (%)Doxorubicin 15 (88%) 17 (89%)Cyclophosphamide 15 (88%) 17 (89%)Taxanes (Docetaxel/Paclitaxel) 17 (100%) 19 (100%)Capecitabine 13 (76%) 8 (42%)Vinorelbine 8 (47%) 12 (63%)

0 1 2 3 4 5 6 7 8 9 10 11 12 13

0

10

20

30

40

50

60

70

80

90

100

Non-Trip Neg

Trip Neg

p=0.058, Log rank test

Months

ytili

baborP

Fig. 1. Progression Free survival with CisplatineGemcitabine.

N. Koshy et al. / The Breast 19 (2010) 246e248 247

2000 and June, 2008. The primary inclusion criteria includedmeasurable disease and treatment with CDDPegemcitabinecombination chemotherapy.

Clinical and laboratory information on ER, PR and HER2neureceptor status, age at diagnosis, ethnicity, menopausal status, priorchemotherapy (adjuvant and metastatic disease), performancestatus, sites of disease, tumor radiographic measurements, time toprogression and patient survival were collected. Tumors for allpatients were assessed for ER, PR and HER2neu status by theImmunopathology Laboratory at Louisiana State University HealthSciences Center, Shreveport. The determination of hormonereceptor status was performed by quantitative immunohisto-chemical (IHC) analysis. Negative ER and PR status was defined asnuclear staining of less than 5%. HER2neu status was assessed byimmunohistochemistry (IHC) and/or fluorescence in situ hybrid-ization (FISH). Scores by IHC of 2þ and 3þwere considered positive(overexpression). HER2neu gene amplification by FISH was per-formed for all cases of 2þ or greater by IHC. FISH analysis wasperformed using the Path Vysion HER2neu DNA probe kit (Vysis,Downers Grove, IL). HER2neu negative status was defined as either1þ or no staining by IHC and or absence of gene amplification byFISH. Patients were defined as TNBC if ER, PR and HER2neu were allnegative. If any of the three receptors were positive, patients werecategorized as non-TNBC. Menopausal status was obtained fromthe information recorded in the medical records. Functional statuswas defined using Eastern Co-operative Oncology group (ECOG)score prior to starting CDDPegemcitabine therapy. Tumormeasurement and staging evaluation was performed prior totherapy initiation and every 6e8 weeks until progression.Progression was defined using RECIST criteria.

Chemotherapy, in all patients, consisted of CDDP 25 mg/m2 andgemcitabine 1000mg/m2 both on days 1 and 8 of a 21 day cycle or 1,8 and 15 of 28 day cycle dependent on individual patient recoveryfrom neutropenia and/or thrombocytopenia.

Progression free survival (PFS) from the start of CDDPegemci-tabine chemotherapy, was the primary end point of the study withoverall survival after start of this combination chemotherapy,a secondary end point. Univariate log rank test and multivariateanalysis with Cox proportional hazard model was performed todetermine any association between age, ethnicity, menopausalstatus and treatment outcome.

Results

A total of 36 patients met the inclusion criteria. The patientcharacteristics are shown in Table 1. There were 17 patients withTNBC with a mean patient age of 47.5 years (range: 29e62 years)and 19 patients with non-TNBC with a mean age of 50.2 years(ranging: 32e68 years). Ten patients (59%) in the triple negativegroup and eight patients (42%) in the non-triple negative groupwere AfricaneAmerican. Seven of the ten (70%) AfricaneAmericanpatients in the triple negative group were pre-menopausal.CisplatineGemcitabine was given as a 3rd, 4th, or 5th linechemotherapy for metastatic disease in 90% of the TNBC group and75% of the non-TNBC group. All the patients had an ECOG perfor-mance status of 2 or less when combination chemotherapy wasfirst started.

Nine of the 19 patients in the non-TNBC group were HER2neureceptor positive and all received trastuzumab either before orduring cisplatin and gemcitabine chemotherapy. The medianprogression free survival (primary end point) for TNBC was 5.3months compared to 1.7 months in non-TNBC (p ¼ 0.058) (Fig. 1).By multivariate Cox proportional hazard model after adjusting forage, race and menopausal status. The risk of progression wasreduced by 47% for metastatic TNBC compared to non-TNBC

patients treated with the CDDP and gemcitabine combination(HR ¼ 0.53, p value ¼ 0.071). The median overall survival after thestart of CDDPegemcitabine chemotherapy was 10.8 months inTNBC patients compared to 4.3 months in non-TNBC patients (pvalue ¼ 0.109) (Fig. 2). Overall survival from date of breast cancerdiagnosis for the TNBC group was 47.8 months compared to 66.8months in non-TNBC (p value ¼ 0.25).

Discussion

Triple negative or basal-like breast cancers have a moreaggressive clinical course than other forms of breast cancer.13

Population based studies have shown a higher prevalence ofthese tumors among pre-menopausal AfricaneAmerican

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 35.0

0

10

20

30

40

50

60

70

80

90

100

Non-triple Negative

Triple Negative

p=0.109, Log Rank Test

Months

ytili

baborP

Fig. 2. Overall survival after start of CisplatineGemcitabine.

N. Koshy et al. / The Breast 19 (2010) 246e248248

patients.14 Our small population of patients also had a slightpredominance of TNBC in AfricaneAmerican patients most ofwhom were pre-menopausal.

Treatment options for TNBC have been limited by the lack oftargeted therapies. However, recent strategies to target DNArepair mechanisms mediated by BRCA1 and PARP (poly-ADPribose polymerase) are promising.15e18 The vast majority of breastcancers occurring in. BRCA1 germ-line mutation carriers aretriple negative and have a basal-like phenotype. While mostpatients with sporadic TNBC are not carriers of BRCA1 mutation,there is evidence of BRCA1 pathway dysfunction in these tumors.Studies have shown that down regulation of BRCA1 function ismediated by epigenetic mechanisms, such as gene promotermethylation and/or transcriptional silencing of BRCA1 and byoverexpression of negative regulators of BRCA1 such as ID4.5

When DNA double strand breaks occur, either spontaneously orin response to DNA damaging agents, like cisplatin, the preferredmechanism of repair involves BRCA1 repair via homologousrecombination. When BRCA1 function is affected as in TNBCeither by mutation or pathway dysfunction, homologous recom-bination is impaired and cell death occurs. The associationbetween TNBC and BRCA-1 mutation status has led to severalstudies showing the activity of platinum based regimens inTNBC.8e11 Gemcitabine and platinum agents have shownpreclinical evidence of synergistic antitumor activity that resultsin interstrand DNA crosslinks and double strand DNA breaks bothof which are preferentially repaired by homologous recombina-tion. Both agents have demonstrated activity in metastatic breastcancer with response rates ranging from 26 to 50%.7

In this study we report the improved outcome for metastaticTNBC patients compared to non-TNBC patients when treated withCDDP based chemotherapy. The combination of CDDPegemcita-bine resulted in a 3.7 months progression free survival differencebetween the two groups. Despite the small sample size, progressionfree survival difference almost reached statistical significance(p ¼ 0.058). The overall survival did not reach statistical signifi-cance (p ¼ 0.109) but there was a definite trend toward improvedsurvival in the TNBC group (10.8 months vs. 4.3 months). Similarbenefits were demonstrated in a recent Phase II trial withCDDPegemcitabine in patients with minimal prior therapy. ER/PRnegative patients had a response rate of 43% as compared to 8% inER/PR positive patients (HER2neu status was not defined). Therewas, however, no difference in response in heavily chemotherapytreated patients.12 We, however, did see an improved outcome inour heavily treated TNBC patient population.

Our results support the contention that CDDPegemcitabinecombination chemotherapy is an effective regimen for patientswithmetastatic TNBC. This substantial improvement in progressionfree survival was seen in a small sample population despite havingprogressed on multiple different chemotherapy agents. Confirma-tion of this benefit in TNBC patients will require a larger prospectivetrial, preferably as a first line regimen for metastatic disease.

Conflicts of interest

All the authors of this manuscript disclose that they have nofinancial and personal relationships with other people ororganizations that could inappropriately influence the results ofthis study.

Funding source

None.

Ethical approval

Louisiana State University Health Sciences Center InstitutionalReview Board approved the study.

References

1. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecularportraits of human breast tumors. Nature 2000;406:747e52.

2. Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H,et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 2007;9:R65.

3. Turner N, Tutt A, Ashworth A. Hallmarks of BRCAness in sporadic cancers. NatRev Cancer 2004;4:814e9.

4. Turner NC, Reis-Filho JS. Basal-like breast cancer and the BRCA 1 phenotype.Oncogene 2006;25:5846e53.

5. Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, et al. BRCA1dysfunction in sporadic basal e like breast cancer. Oncogene 2007;14:2126e32.

6. Mersin H, Yildirim E, Berberoglu U, Gülben K. The prognostic importance oftriple negative breast carcinoma. Breast 2008;17:341e6.

7. Heinemann V. Gemcitabine plus cisplatin for the treatment of metastatic breastcancer. Clin Breast Cancer 2002;3(Suppl. 1):24e9.

8. Garber J, Richardson A, Harris L,Miron A, Silver D, GolshanM, et al. Neo-adjuvantcisplatin(CDDP) in triple negative breast cancer. Breast Cancer Res Treat 2006;100(Suppl. 1). Abstract 3074.

9. O’ Shaughnessy J, Weckstein D, Vukejlja S, Mclntyre K, Krekow L, Holmes F,et al. Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breastcancer. Breast Cancer Res Treat 2007;106(Suppl. 1):S32. Abstract 308.

10. Sirohi B, Arnedos M, Popat S, Ashley S, Nerurkar A, Walsh G, et al. Platinumbased chemotherapy in triple negative breast cancer. Ann Oncol 2008;20:1e6.

11. Yi S, Uhm J, Cho E, Lee S, Park M, Jun H, et al. Clinical outcomes of metastaticbreast cancer patients with triple negative phenotype who received platinumcontaining chemotherapy. J Clin Oncol 2008;26(Suppl. 15):43s. Abstract 1008.

12. Chew HK, Doroshow JH, Frankel P, Margolin KA, Somlo G, Lenz HJ, et al. Phase IIstudies of gemcitabine and cisplatin in heavily and minimally pretreatedmetastatic breast cancer. J Clin Oncol 2009;27:2163e9.

13. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triplenegative breast cancer: clinical features and patterns of recurrence. Clin CancerRes 2007;13:4429e34.

14. Carey LA, Perou CM, Livsay CA, Dressler LG, Cowan D, Conway K, et al. Race,breast cancer subtypes and survival in the Carolina Breast Cancer Study. JAMA2006;295:2492e502.

15. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Tar-geting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature 2005;434:917e21.

16. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specifickilling of BRCA2edeficient tumors with inhibitors of poly(ADP-ribose) poly-merase. Nature 2005;434(7035):913e7.

17. O'Shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, Monaghan G, et al.Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, incombination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol2009;27(Suppl. 18):793s. Abstract 3.

18. Tutt A, Robson M, Garber JE, Domchek S, Audeh MW, Weitzel JN, et al. Phase IItrial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breastcancer. J Clin Oncol 2009;27(Suppl. 18):803s. Abstract CRA 501.