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Chemotherapy of metastatic triple negative breast cancer: Experience of using platinum-based chemotherapy

Chemotherapy of metastatic triple negative breast cancer: Experience of using platinum-based... www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 40 Chemotherapy of metastatic triple negative breast cancer: Experience of using platinum-based chemotherapy 1,* 1,* 1 1 1 1 Jian Zhang , Minhao Fan , Jie Xie , Zhonghua Wang , Biyun Wang , Sheng Zhang , 1 1 1 1 1 Leiping Wang , Jun Cao , Zhonghua Tao , Ting Li , Xichun Hu Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China These authors have contributed equally to this work Correspondence to: Xi-chun Hu, e-mail: [email protected] Keywords: platinums, metastatic breast cancer, triple-negative, chemotherapy Received: July 09, 2015 Accepted: September 21, 2015 Published: October 03, 2015 ABSTRACT The results of recent studies investigating the role of platinum-based chemotherapy (PBCT) in metastatic triple-negative breast cancer (mTNBC) were conflicting. We retrospectively investigated a large cohort ( n = 379) of mTNBC to re-evaluate the role of platinums. Longer PFS was found in patients with PBCT than those with non-PBCT (7.8 vs. 4.9 months, P < 0.001) as first-line chemotherapy, but no statistical difference of OS was observed. Compared with other kinds of platinum, cisplatin-based regimens as the rst-line fi chemotherapy showed better PFS (8.0 vs. 4.3 months, P = 0.03) and better ORR. Introduction of ≥2 lines, rather than 1 line, of PBCT can result in better OS when compared with no introduction of PBCT during the whole treatment. If considering the timing of intervention of PBCT, first- line introduction and later line introduction of PBCT did not make any difference in OS among patients with only one line PBCT during the whole treatment. We concluded that PBCT with only 1 line during the whole treatment might not be necessary for unselected mTNBC with the exception of an urgent demand to control disease or symptoms, however, ≥2 lines of PBCT did prolong OS. TNBC varies from 16–42% and IHC-based studies classify INTRODUCTION 80–90% of BRCA1-associated tumors as TNBC and/ or BLBC [13, 14]. Due to these similarities, it has been Triple-negative breast cancer (TNBC) which hypothesized that the DNA repair defects that sensitize accounts for ~12–20% of all breast cancers is a clinical BRCA-mutated and BRCA-like breast cancer tumors to challenge as this subtype is associated with an increased platinum may also be present in TNBC, indicating that rate of recurrence, shorter disease-free intervals (DFI), platinum-based chemotherapy (PBCT) may be an effective earlier visceral metastasis, and poorer survival compared treatment option for this subset of breast cancer [15]. with other breast cancer subtypes [1, 2]. The median During the past few years, several studies have survival for metastatic TNBC (mTNBC) ranges from been conducted to study the role of PBCT in the mTNBC 6 to 13.3 months [3–6]. Cytotoxic chemotherapy is setting, but results were conflicting. Some data support the mainstay treatment for mTNBC and no dedicated the use of platinum (mainly cisplatin-based) [16–18]. biological agents are available. Targeted therapies While some are discouraging, for example, the TNT study including DNA repair agents, PARP or EGFR inhibitors, compared carboplatin to docetaxel therapy in unselectted anti-angiogenic agents, or checkpoint kinase 1 (Chk1) metastatic or recurrent locally advanced TNBC or inhibitors (with or without chemotherapy) have not BRCA1/2 positive breast cancer but similar efficacy substantially improved mTNBC outcomes [7, 8]. was observed in terms of overall response rate (ORR Gene expression analysis demonstrates that the [31.4% vs. 35.6%, p = 0.44]), PFS (3.1 vs. 4.5 months, molecular signature of TNBC generally overlaps with p = 0.29) and overall survival (OS [12.4 vs. 12.3 months, basal-like breast cancer (BLBC), with concordance rates p = 0.31]) [19]. Even with a first-line gemcitabine of 70–90% [9–12], TNBC is also associated with BRCA- and carboplatin combination regimen, PFS was only related breast cancer. The incidence of BRCA mutations in www.impactjournals.com/oncotarget 43135 Oncotarget 4.6 months, which did not appear significantly superior to OS was observed between these two groups (median OS, historical data [6, 20]. Likely, cisplatin is more efficacious 19.6 months vs. 19.2 months, P = 0.82). than carboplatin [21, 22]. We need more evidence in Compared with other forms of platinum, cisplatin- unselected mTNBC patients to confirm that PBCT is based regimens (cisplatin + taxanes/vinorelbine/ more efficacious than non-PBCT, and whether these gemcitabine) as first-line chemotherapy offered better differences are due to types of platinums, and whether PFS (median PFS, 8.0 months vs. 4.3 months, P = 0.03; later-line treatment with platinums influence OS. We Fig. 1C) and better ORR (59.6% vs. 35.0%, P = 0.03), but then retrospectively reviewed a large cohort of mTNBC no benefit to OS was observed (median OS, 25.1 months patients at Fudan University Shanghai Cancer Center vs. 19.6 months, P = 0.69). (FUSCC) to re-evaluate of the role of platinums and A numerical but not a significant difference was compared potential prognostic factors for first-line ORR observed (median OS, 20.3 months vs. 15.7 months, and PFS and OS. P = 0.87) in terms of OS between patients with an introduction and those with no introduction of PBCT during treatment. However, more lines of intervention RESULTS with PBCT offered better OS outcomes. For all 379 patients, those who received 2 or more lines of PBCT Patient characteristics in their metastatic setting had longer OS than those who received none or only one line of PBCT (median Between July 2000 and March 2014, patients OS, 25.1 months vs. 17.2 months, P = 0.02; Fig. 1D). having received at least one line of chemotherapy in the This advantage remained with the 309 patients with metastatic setting, including 309 of 379 patients (81.5%) PBCT in the metastatic setting, and better OS was seen who received one or more platinum-based regimens and for those with ≥2 lines of PBCT compared to those with 70 patients (18.5%) who received non-platinum regimens, only one line of PBCT (median OS, 25.1 months vs. were identified from our database. Table 1 depicts their 17.2 months, P = 0.01). Regarding timing of the PBCT characteristics and treatments. Therapies administrated intervention, first-line and later line introduction of PBCT were summarized in Table 2. was not different with respect to OS (20.2 months vs. Among the 364 patients with available PFS data, 15.6 months, P = 0.15) among patients with only one line 218 received PBCT as their first line chemotherapy of PBCT during the treatment. for mTNBC and 146 patients received non-PBCT Other variables significantly influencing PFS correspondingly. The median follow-up was 15.9 months in the univariate analysis included ECOG score, time (range, 2.0–127.4 months) by the time of data lock between breast surgery and number of metastatic organ (March 20, 2014). As the date of data cut off, 319 events sites. Besides receiving ≥2 lines of PBCT, the univariate of disease progression among the 364 patients as first line analysis also indicated that post-menopausal, time between chemotherapy and 267 deaths in total of the 379 had been breast surgery ≥12 months, no visceral metastasis and observed, with 5 patients (1.3%) were lost to follow-up. less number of metastatic organ sites were significantly Ninety percent patients received neo-adjuvant or adjuvant associated with longer OS. Previous use of platinum as chemotherapy. Prior exposure rates were 78.7% to adjuvant or neo-adjuvant did not significantly influence the anthracyclines and 57.0% to taxanes, with 9.5% exposed PFS or ORR of first-line chemotherapy in the metastatic to platinum in the neo-adjuvant or adjuvant setting. setting (median PFS, 5.1 months vs. 6.9 months, P = 0.29; Table 2 summarizes therapies in the metastatic setting with ORR, 47.1% vs. 47.6%, P = 0.95). respect to types and strategies for PBCT used. On average, mTNBC patients received 2.7 lines of chemotherapy in the Factors independently predicting treatment metastatic setting (range, 1–9). outcome Using a binary logistic regression model, only Response and survival first-line PBCT (HR, 0.36, 95% CI 0.21 – 0.61; P < 0.001) By the time of data lock, the median OS of all was identified as independent factors for predicting first- 379 patients was 19.7 months (95% CI, 17.2 to 22.1). line ORR. Among the 364 patients with available first-line data, Cox proportional hazards model was used to the median PFS was 6.9 months (95% CI, 6.1 to 7.7) determine the hazard ratios of the above-mentioned (Fig. 1A), with the ORR of 47.5% (26 CR, 147 PR). variables for predicting the risk of disease progression Longer PFS observed in patients with PBCT compared or death for mTNBC patients in the first-line setting. to those with non-PBCT (median PFS, 7.8 months vs. Event-free survival was set as a dependent variable, and 4.9 months, P < 0.001) as first-line chemotherapy for parameters for which P < 0.1 in the univariate analysis mTNBC (Fig. 1B). The ORR was also statistically higher were independent variables. Forward selection based on a in the first-line PBCT group than in the non-PBCT group maximum likelihood ratio (Forward LR) was used as the (57.3% vs. 32.9%, P < 0.001). No statistical difference in regression method. www.impactjournals.com/oncotarget 43136 Oncotarget Table 1: Patient characteristics at time of metastases diagnosis (n = 379) Characteristics No. % Median age (years, range) 49 (25–76) <40 73 19.3 ≥40 306 80.7 Pathological types Invasive ductal carcinoma 355 93.7 Others 24 6.3 Menstruation status Pre- or peri-menopausal 179 47.2 Post-menopausal 200 52.8 ECOG performance status 0 87 23.0 1 281 74.1 ≥2 11 2.9 Time between breast surgery and recurrent 14.3 (0–217.0) disease(months, range) <12 133 35.1 ≥12 224 59.1 de novo metastatic 22 5.8 Number of metastatic organ sites 1 126 33.2 2 143 37.7 ≥ 3 110 29.0 Metastatic sites Lymph node 230 60.7 Lung 163 43.0 Chest wall 108 28.5 Bone 99 26.1 Liver 76 20.1 Pleura 32 8.4 Brain 11 2.9 Breast 4 1.1 Type of metastasis Visceral 212 55.9 Non-visceral 167 44.1 (Continued ) www.impactjournals.com/oncotarget 43137 Oncotarget Characteristics No. % Adjuvant or neo-adjuvant chemotherapy Yes 341 90.0 Anthracyclines only 106 28.0 Taxanes only 24 6.3 Both Anthracyclines and Taxanes 192 50.7 With Platinum 36 9.5 Without Platinum 305 80.5 No 38 10.0 Abbreviations: ECOG, Eastern Cooperative Oncology Group PBCT used as first-line chemotherapy (HR, 0.63, platinums and different patient ethnicities may contribute 95% CI 0.47 – 0.84; P = 0.002) together with ECOG score, to these differences. Not including the phase II study by number of metastatic organ sites, and time between breast Fan [17] which studied a relatively small sample size, OS surgery were observed to be independent predictive factors benefits were not gained with first-line PBCT in our study for PFS. We also found that cisplatin-based regimens and the TNT trial. For CBCSG006, although OS data were independent predictive factors for first-line PFS are immature, death events were almost equal between in the PBCT subgroup (HR, 0.59, 95% CI 0.35 – 0.99; arms. We do agree that post-progression crossover to the P = 0.046) (Table 3). PBCT might contribute to no differences observed in OS Regarding OS, lines of PBCT (<2 line vs. ≥2 lines, because our study indicated that OS was not significantly HR, 0.73, 95% CI 0.56 – 0.94; P = 0.016) together with influenced by the timing (early or late) of introduction number of metastatic organ sites, and time between of platinum for patients with only one line PBCT during breast surgery were independent predictive factors for OS the whole treatment. However, OS did not differ between (Table 3). groups with PBCT introduced or not during treatment, suggesting that re-evaluating the role of platinums in mTNBC is needed. For mTNBC patients with more DISCUSSION extensive, rapidly progressive, or symptomatic disease, PBCT was preferred because—even without improved The controversy over the role of platinums in OS—PBCT appeared to offer more symptom control and mTNBC persists, so we retrospectively re-evaluated this allowed later line treatments. Identification of predictive concept in a patient population, focusing on first-line markers for PBCT and population enrichment with those and later line therapy. We found that PBCT, especially a who benefit from PBCT should prolong OS for mTNBC cisplatin-based regimen, was significantly more effective patients. than non-PBCT strategies in terms of PFS and ORR during Cisplatin-based regimens appeared to be first-line therapy in a metastatic setting, but OS did not significantly more efficacious than other platinum types as improve. Also, no significant difference was observed in a first-line therapy in our study. Both PFS (8.0 months vs. OS whether PBCT was introduced or not during treatment. 4.3 months) and ORR (59.6% vs. 35%) were comparable Early and late introduction of PBCT did not influence to data from the two phase III trials (TNT and CBCSG006) OS, but more treatment lines (≥2) of PBCT significantly and other previous studies, findings which support our lengthened OS. data. Compared with carboplatin, cisplatin has superior Both BRCA-associated breast cancer and sporadic efficacy as a neo-adjuvant for locally advanced TNBC, triple-negative or basal-like breast cancers have with more patients achieving a pathological complete characteristics consistent with abnormal DNA repair and response and significant improvement in OS [22]. Also in genome-wide instability [23, 24], which lends support to the metastatic setting, more patients respond to cisplatin the use of DNA-damaging compounds such as platinums. than carboplatin [21]. That PBCT yielded higher response and longer PFS than An important finding in our study was that more non-PBCT in our study established this concept and was lines of PBCT improved OS and reduced the risk of in accordance with data from the phase II study by Fan’s death by 27% according to a Cox hazards model. Patients group [17] and the prospective phase III CBCSG006 [18]. who received ≥2 lines of PBCT had a median OS more Similar to our study, these two trials were based on Asian than 2 years (25.1 months), which suggested that the population. Differences in data from the TNT trial [19] cumulative effect of better PFS from different lines of which compared carboplatin with docetaxel and mainly PBCT might ultimately result in longer OS. included western populations suggest different types of www.impactjournals.com/oncotarget 43138 Oncotarget Table 2: Summary of therapies in the metastatic setting No. % Total lines of therapy received (n = 379) 1 83 21.9 2 111 29.3 3 85 22.4 4 50 13.2 ≥5 44 11.6 Uncertain 6 1.6 Total lines of PBCT received (n = 379) Yes 309 81.5 1 195 51.5 2 85 22.4 3 22 5.8 4 7 1.8 No 70 18.5 Line of the first introduction of PBCT ( n = 309) s t 1 218 70.6 nd 2 64 20.7 rd 3 20 6.5 th 4 4 1.3 th ≥5 3 1.0 Regimen of the first introduction of PBCT ( n = 309) Gemcitabine + cisplatin 171 55.3 Vinorelbine + cisplatin 30 9.7 Docetaxel + cisplatin 29 9.4 mFOLFOX6 25 8.1 Vinorelbine + oxaliplatin 19 6.1 Abraxane + cisplatin 16 5.2 Carboplatin-based and Others 19 6.1 Regimen of the second introduction of PBCT (n = 114) mFOLFOX6 29 25.4 Vinorelbine + oxaliplatin 28 24.6 Gemcitabine + cisplatin 9 7.9 Paclitaxel + carboplatin 7 6.1 Abraxane + carboplatin 6 5.3 Others 35 30.7 Abbreviations: PBCT, platinum-based chemotherapy www.impactjournals.com/oncotarget 43139 Oncotarget Figure 1: A. Kaplan-Meier estimates of OS for the whole cohort and PFS for patients with available first-line data B. Kaplan- Meier estimates of PFS for different chemotherapy in the first-line setting (PBCT vs. non-PBCT) C. Kaplan-Meier estimates of PFS for different platinums in first-line PBCT (cisplatin vs. other platinums) D. Kaplan-Meier estimates of OS for different total lines of PBCT (≥ 2 lines vs. 0–1 line). Multivariate analysis confirmed that PBCT used as inclusion of one institution and the fact that different first-line chemotherapy was an independent predictive baseline information as well as various intrinsic molecular factor for PFS. For patients with first-line PBCT, a subtypes of TNBC might lead to clinical heterogeneity. In cisplatin-based regimen was a favorable predictive factor addition, the impossibility to retrieve enough information for longer first-line PFS. These data confirmed a potential to analyze the safety profile and tolerability of these PBCT role for platinums to treat mTNBC but they have not regimens should be considered, with the solely exception been confirmed to predict better OS. Through molecular of a fraction of patients treated in the most recent years, profiling, TNBC was identified to be a disease of many owing to the wide time window considered. Based on intrinsic molecular subtypes (basal-like, claudin-low currently available, albeit incomplete, data we did not or human epidermal growth factor receptor 2 [HER2]- observe any unexpected warnings in terms of toxicity and enriched) [25]. The high heterogeneity of TNBC suggests adherence to these PBCT therapies. Even so, our study is that platinums used to treat unselected mTNBC patients to the first and the largest re-evaluation of the role of PBCT improve OS may not be a good strategy. Application of the in first-line and later line settings. PAM50 intrinsic subtype signature to sub-classify TNBC In conclusion, compared with non-PBCT, PBCT groups as basal- and non-basal-like, or a determination especially cisplatin-based regimens using at the first of the status of BRCA1, BRCA2 and BRCAness may be line can significantly improve ORR and PFS, but cannot better for testing platinums but this requires future study. improve OS. PBCT with only 1 line during the whole Our study is limited by its retrospective nature treatment might not be necessary for unselected mTNBC and potential patient and treatment selection biases, its with the exception of an urgent demand to control disease www.impactjournals.com/oncotarget 43140 Oncotarget Table 3: Factors independently predicting PFS and OS Cox regression results of PFS (n = 364) Independent predictive Hazard ratio (HR) 95% CI P value factors ECOG 0 Ref 1–2 1.53 1.12 – 2.09 0.008 Number of metastatic organ sites 1 Ref 2 1.21 0.89 – 1.65 0.224 ≥3 1.78 1.30 – 2.44 <0.001 Time between breast surgery and recurrent disease <12 months Ref ≥12 months 0.58 0.44 – 0.75 <0.001 PBCT used as first-line chemotherapy No Ref Yes 0.63 0.47 – 0.84 0.002 Cox regression results of PFS in subgroup of PBCT as the first line chemotherapy (n = 218) ECOG 0 Ref 1–2 1.52 1.06 – 2.18 0.022 Number of metastatic organ sites 1 Ref 2 1.47 1.01 – 2.13 0.045 ≥3 2.23 1.53 – 3.25 <0.001 Time between breast surgery and recurrent disease <12 months Ref ≥12 months 0.63 0.46 – 0.86 0.004 Type of PBCT Non-cisplatin-based Ref Cisplatin-based 0.59 0.35 – 0.99 0.046 Cox regression results of OS (n = 379) Number of metastatic organ sites 1 Ref 2 1.32 0.94 – 1.86 0.108 (Continued ) www.impactjournals.com/oncotarget 43141 Oncotarget Cox regression results of PFS (n = 364) Independent predictive Hazard ratio (HR) 95% CI P value factors ≥ 3 2.67 1.92 – 3.71 <0.001 Time between breast surgery and recurrent disease < 12 months Ref ≥ 12 months 0.43 0.32 – 0.57 <0.001 Total lines of PBCT received < 2 Ref ≥ 2 0.73 0.56 – 0.94 0.016 Abbreviations: PBCT, platinum-based chemotherapy; PFS: progression-free survival; OS: overall survival; CI: confidence interval; Ref: reference category. or symptoms, however, ≥2 lines of PBCT did prolong OS. the first-line treatment to death by any cause or censored at A better future strategy may be identification of predictive the last date the patient was known to be alive. markers of PBCT for mTNBC patients. One of the objectives of this study was to establish prognostic factors for outcomes in TNBC patients who received PBCT. Data for clinical variables identified through PATIENTS AND METHODS literature review were collected as potential important predictors of ORR, PFS and OS in mTNBC patients. Patient selection Potential prognostic variables collected at the time of diagnosis of distant metastases or the beginning of treatment Retrospective analysis was conducted within a included age, menstruation status, details about neo-adjuvant cohort of mTNBC patients who received PBCT or non- and adjuvant chemotherapy administered, distant disease- PBCT at FUSCC between July 2000 and March 2014. free interval, and number and sites of metastatic disease. Data were collected from electronic patient records and hospital charts. Study procedures were approved by institutional ethical board of FUSCC. The eligible Statistical analysis patients were ≥ 18 years old and had TNBC histologically Results were analyzed using SPSS 16.0 (SPSS, confirmed at the primary tumor, with clinical, imaging, Chicago, IL). Binary logistic regression model was histological or cytological evidence of metastatic disease. used to identify the factors that independently influence Patients were classified as TNBC based on their surgical or first-line ORR. Cox proportional hazards models were biopsy results, histologically confirmed estrogen receptor used to estimate adjusted hazard ratios (HRs) and 95% CIs (ER)-, progesterone receptor (PR)-, and HER2- were of disease progression or death. The models were adjusted defined as follows: ER- and PR- were defined as < 1% for age, menstruation status, prior adjuvant and neo-adjuvant positive tumor cells immunohistochemical nuclear chemotherapy, site and extent of first distant relapse, and staining and HER2- was defined as having an IHC score presence of visceral metastasis. Median PFS and OS were of 0 or 1+ or a FISH non-amplified score according to all estimated by the Kaplan–Meier method and compared ASCO guidelines. Patients with incomplete receptor status using a log-rank test. Response rates of different regimens or changed status in metastatic lesions inconsistent with were compared using a chi-squared test or Fisher’s exact the definition described above were excluded. test. All P values were two sided, P < 0.05 was considered to indicate a statistically significant difference. Data collection The efficacy of PBCT and non-PBCT was analyzed Abbreviations according to ORR, PFS, and OS. Tumor response was evaluated in accordance with the Response Evaluation TNBC, triple-negative breast cancer; ER, estrogen Criteria in Solid Tumors (RECIST 1.1) guidelines by receptor; PR, progesterone receptor; HER2, human computed tomography scanning or magnetic resonance epidermal growth factor receptor 2; DFI, disease-free imaging if indicated. The date of disease progression interval; BLBC, basal-like breast cancer; PBCT, platinum- was determined from the clinical notes. PFS was defined based chemotherapy; ORR, overall response rate; PFS, as the time from the start of the treatment until disease progression-free survival; OS, overall survival; FUSCC, progression or death. OS was calculated from the start of Fudan University Shanghai Cancer Center; RECIST, www.impactjournals.com/oncotarget 43142 Oncotarget Response Evaluation Criteria in Solid Tumors; SPSS, 11. Bertucci F, Finetti P, Cervera N, et al. 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Clin Cancer Res. 2004; 10:5367–5374. cancers. Oncologist. 2011; 16:61–70. www.impactjournals.com/oncotarget 43143 Oncotarget http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oncotarget Unpaywall

Chemotherapy of metastatic triple negative breast cancer: Experience of using platinum-based chemotherapy

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www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 40 Chemotherapy of metastatic triple negative breast cancer: Experience of using platinum-based chemotherapy 1,* 1,* 1 1 1 1 Jian Zhang , Minhao Fan , Jie Xie , Zhonghua Wang , Biyun Wang , Sheng Zhang , 1 1 1 1 1 Leiping Wang , Jun Cao , Zhonghua Tao , Ting Li , Xichun Hu Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China These authors have contributed equally to this work Correspondence to: Xi-chun Hu, e-mail: [email protected] Keywords: platinums, metastatic breast cancer, triple-negative, chemotherapy Received: July 09, 2015 Accepted: September 21, 2015 Published: October 03, 2015 ABSTRACT The results of recent studies investigating the role of platinum-based chemotherapy (PBCT) in metastatic triple-negative breast cancer (mTNBC) were conflicting. We retrospectively investigated a large cohort ( n = 379) of mTNBC to re-evaluate the role of platinums. Longer PFS was found in patients with PBCT than those with non-PBCT (7.8 vs. 4.9 months, P < 0.001) as first-line chemotherapy, but no statistical difference of OS was observed. Compared with other kinds of platinum, cisplatin-based regimens as the rst-line fi chemotherapy showed better PFS (8.0 vs. 4.3 months, P = 0.03) and better ORR. Introduction of ≥2 lines, rather than 1 line, of PBCT can result in better OS when compared with no introduction of PBCT during the whole treatment. If considering the timing of intervention of PBCT, first- line introduction and later line introduction of PBCT did not make any difference in OS among patients with only one line PBCT during the whole treatment. We concluded that PBCT with only 1 line during the whole treatment might not be necessary for unselected mTNBC with the exception of an urgent demand to control disease or symptoms, however, ≥2 lines of PBCT did prolong OS. TNBC varies from 16–42% and IHC-based studies classify INTRODUCTION 80–90% of BRCA1-associated tumors as TNBC and/ or BLBC [13, 14]. Due to these similarities, it has been Triple-negative breast cancer (TNBC) which hypothesized that the DNA repair defects that sensitize accounts for ~12–20% of all breast cancers is a clinical BRCA-mutated and BRCA-like breast cancer tumors to challenge as this subtype is associated with an increased platinum may also be present in TNBC, indicating that rate of recurrence, shorter disease-free intervals (DFI), platinum-based chemotherapy (PBCT) may be an effective earlier visceral metastasis, and poorer survival compared treatment option for this subset of breast cancer [15]. with other breast cancer subtypes [1, 2]. The median During the past few years, several studies have survival for metastatic TNBC (mTNBC) ranges from been conducted to study the role of PBCT in the mTNBC 6 to 13.3 months [3–6]. Cytotoxic chemotherapy is setting, but results were conflicting. Some data support the mainstay treatment for mTNBC and no dedicated the use of platinum (mainly cisplatin-based) [16–18]. biological agents are available. Targeted therapies While some are discouraging, for example, the TNT study including DNA repair agents, PARP or EGFR inhibitors, compared carboplatin to docetaxel therapy in unselectted anti-angiogenic agents, or checkpoint kinase 1 (Chk1) metastatic or recurrent locally advanced TNBC or inhibitors (with or without chemotherapy) have not BRCA1/2 positive breast cancer but similar efficacy substantially improved mTNBC outcomes [7, 8]. was observed in terms of overall response rate (ORR Gene expression analysis demonstrates that the [31.4% vs. 35.6%, p = 0.44]), PFS (3.1 vs. 4.5 months, molecular signature of TNBC generally overlaps with p = 0.29) and overall survival (OS [12.4 vs. 12.3 months, basal-like breast cancer (BLBC), with concordance rates p = 0.31]) [19]. Even with a first-line gemcitabine of 70–90% [9–12], TNBC is also associated with BRCA- and carboplatin combination regimen, PFS was only related breast cancer. The incidence of BRCA mutations in www.impactjournals.com/oncotarget 43135 Oncotarget 4.6 months, which did not appear significantly superior to OS was observed between these two groups (median OS, historical data [6, 20]. Likely, cisplatin is more efficacious 19.6 months vs. 19.2 months, P = 0.82). than carboplatin [21, 22]. We need more evidence in Compared with other forms of platinum, cisplatin- unselected mTNBC patients to confirm that PBCT is based regimens (cisplatin + taxanes/vinorelbine/ more efficacious than non-PBCT, and whether these gemcitabine) as first-line chemotherapy offered better differences are due to types of platinums, and whether PFS (median PFS, 8.0 months vs. 4.3 months, P = 0.03; later-line treatment with platinums influence OS. We Fig. 1C) and better ORR (59.6% vs. 35.0%, P = 0.03), but then retrospectively reviewed a large cohort of mTNBC no benefit to OS was observed (median OS, 25.1 months patients at Fudan University Shanghai Cancer Center vs. 19.6 months, P = 0.69). (FUSCC) to re-evaluate of the role of platinums and A numerical but not a significant difference was compared potential prognostic factors for first-line ORR observed (median OS, 20.3 months vs. 15.7 months, and PFS and OS. P = 0.87) in terms of OS between patients with an introduction and those with no introduction of PBCT during treatment. However, more lines of intervention RESULTS with PBCT offered better OS outcomes. For all 379 patients, those who received 2 or more lines of PBCT Patient characteristics in their metastatic setting had longer OS than those who received none or only one line of PBCT (median Between July 2000 and March 2014, patients OS, 25.1 months vs. 17.2 months, P = 0.02; Fig. 1D). having received at least one line of chemotherapy in the This advantage remained with the 309 patients with metastatic setting, including 309 of 379 patients (81.5%) PBCT in the metastatic setting, and better OS was seen who received one or more platinum-based regimens and for those with ≥2 lines of PBCT compared to those with 70 patients (18.5%) who received non-platinum regimens, only one line of PBCT (median OS, 25.1 months vs. were identified from our database. Table 1 depicts their 17.2 months, P = 0.01). Regarding timing of the PBCT characteristics and treatments. Therapies administrated intervention, first-line and later line introduction of PBCT were summarized in Table 2. was not different with respect to OS (20.2 months vs. Among the 364 patients with available PFS data, 15.6 months, P = 0.15) among patients with only one line 218 received PBCT as their first line chemotherapy of PBCT during the treatment. for mTNBC and 146 patients received non-PBCT Other variables significantly influencing PFS correspondingly. The median follow-up was 15.9 months in the univariate analysis included ECOG score, time (range, 2.0–127.4 months) by the time of data lock between breast surgery and number of metastatic organ (March 20, 2014). As the date of data cut off, 319 events sites. Besides receiving ≥2 lines of PBCT, the univariate of disease progression among the 364 patients as first line analysis also indicated that post-menopausal, time between chemotherapy and 267 deaths in total of the 379 had been breast surgery ≥12 months, no visceral metastasis and observed, with 5 patients (1.3%) were lost to follow-up. less number of metastatic organ sites were significantly Ninety percent patients received neo-adjuvant or adjuvant associated with longer OS. Previous use of platinum as chemotherapy. Prior exposure rates were 78.7% to adjuvant or neo-adjuvant did not significantly influence the anthracyclines and 57.0% to taxanes, with 9.5% exposed PFS or ORR of first-line chemotherapy in the metastatic to platinum in the neo-adjuvant or adjuvant setting. setting (median PFS, 5.1 months vs. 6.9 months, P = 0.29; Table 2 summarizes therapies in the metastatic setting with ORR, 47.1% vs. 47.6%, P = 0.95). respect to types and strategies for PBCT used. On average, mTNBC patients received 2.7 lines of chemotherapy in the Factors independently predicting treatment metastatic setting (range, 1–9). outcome Using a binary logistic regression model, only Response and survival first-line PBCT (HR, 0.36, 95% CI 0.21 – 0.61; P < 0.001) By the time of data lock, the median OS of all was identified as independent factors for predicting first- 379 patients was 19.7 months (95% CI, 17.2 to 22.1). line ORR. Among the 364 patients with available first-line data, Cox proportional hazards model was used to the median PFS was 6.9 months (95% CI, 6.1 to 7.7) determine the hazard ratios of the above-mentioned (Fig. 1A), with the ORR of 47.5% (26 CR, 147 PR). variables for predicting the risk of disease progression Longer PFS observed in patients with PBCT compared or death for mTNBC patients in the first-line setting. to those with non-PBCT (median PFS, 7.8 months vs. Event-free survival was set as a dependent variable, and 4.9 months, P < 0.001) as first-line chemotherapy for parameters for which P < 0.1 in the univariate analysis mTNBC (Fig. 1B). The ORR was also statistically higher were independent variables. Forward selection based on a in the first-line PBCT group than in the non-PBCT group maximum likelihood ratio (Forward LR) was used as the (57.3% vs. 32.9%, P < 0.001). No statistical difference in regression method. www.impactjournals.com/oncotarget 43136 Oncotarget Table 1: Patient characteristics at time of metastases diagnosis (n = 379) Characteristics No. % Median age (years, range) 49 (25–76) <40 73 19.3 ≥40 306 80.7 Pathological types Invasive ductal carcinoma 355 93.7 Others 24 6.3 Menstruation status Pre- or peri-menopausal 179 47.2 Post-menopausal 200 52.8 ECOG performance status 0 87 23.0 1 281 74.1 ≥2 11 2.9 Time between breast surgery and recurrent 14.3 (0–217.0) disease(months, range) <12 133 35.1 ≥12 224 59.1 de novo metastatic 22 5.8 Number of metastatic organ sites 1 126 33.2 2 143 37.7 ≥ 3 110 29.0 Metastatic sites Lymph node 230 60.7 Lung 163 43.0 Chest wall 108 28.5 Bone 99 26.1 Liver 76 20.1 Pleura 32 8.4 Brain 11 2.9 Breast 4 1.1 Type of metastasis Visceral 212 55.9 Non-visceral 167 44.1 (Continued ) www.impactjournals.com/oncotarget 43137 Oncotarget Characteristics No. % Adjuvant or neo-adjuvant chemotherapy Yes 341 90.0 Anthracyclines only 106 28.0 Taxanes only 24 6.3 Both Anthracyclines and Taxanes 192 50.7 With Platinum 36 9.5 Without Platinum 305 80.5 No 38 10.0 Abbreviations: ECOG, Eastern Cooperative Oncology Group PBCT used as first-line chemotherapy (HR, 0.63, platinums and different patient ethnicities may contribute 95% CI 0.47 – 0.84; P = 0.002) together with ECOG score, to these differences. Not including the phase II study by number of metastatic organ sites, and time between breast Fan [17] which studied a relatively small sample size, OS surgery were observed to be independent predictive factors benefits were not gained with first-line PBCT in our study for PFS. We also found that cisplatin-based regimens and the TNT trial. For CBCSG006, although OS data were independent predictive factors for first-line PFS are immature, death events were almost equal between in the PBCT subgroup (HR, 0.59, 95% CI 0.35 – 0.99; arms. We do agree that post-progression crossover to the P = 0.046) (Table 3). PBCT might contribute to no differences observed in OS Regarding OS, lines of PBCT (<2 line vs. ≥2 lines, because our study indicated that OS was not significantly HR, 0.73, 95% CI 0.56 – 0.94; P = 0.016) together with influenced by the timing (early or late) of introduction number of metastatic organ sites, and time between of platinum for patients with only one line PBCT during breast surgery were independent predictive factors for OS the whole treatment. However, OS did not differ between (Table 3). groups with PBCT introduced or not during treatment, suggesting that re-evaluating the role of platinums in mTNBC is needed. For mTNBC patients with more DISCUSSION extensive, rapidly progressive, or symptomatic disease, PBCT was preferred because—even without improved The controversy over the role of platinums in OS—PBCT appeared to offer more symptom control and mTNBC persists, so we retrospectively re-evaluated this allowed later line treatments. Identification of predictive concept in a patient population, focusing on first-line markers for PBCT and population enrichment with those and later line therapy. We found that PBCT, especially a who benefit from PBCT should prolong OS for mTNBC cisplatin-based regimen, was significantly more effective patients. than non-PBCT strategies in terms of PFS and ORR during Cisplatin-based regimens appeared to be first-line therapy in a metastatic setting, but OS did not significantly more efficacious than other platinum types as improve. Also, no significant difference was observed in a first-line therapy in our study. Both PFS (8.0 months vs. OS whether PBCT was introduced or not during treatment. 4.3 months) and ORR (59.6% vs. 35%) were comparable Early and late introduction of PBCT did not influence to data from the two phase III trials (TNT and CBCSG006) OS, but more treatment lines (≥2) of PBCT significantly and other previous studies, findings which support our lengthened OS. data. Compared with carboplatin, cisplatin has superior Both BRCA-associated breast cancer and sporadic efficacy as a neo-adjuvant for locally advanced TNBC, triple-negative or basal-like breast cancers have with more patients achieving a pathological complete characteristics consistent with abnormal DNA repair and response and significant improvement in OS [22]. Also in genome-wide instability [23, 24], which lends support to the metastatic setting, more patients respond to cisplatin the use of DNA-damaging compounds such as platinums. than carboplatin [21]. That PBCT yielded higher response and longer PFS than An important finding in our study was that more non-PBCT in our study established this concept and was lines of PBCT improved OS and reduced the risk of in accordance with data from the phase II study by Fan’s death by 27% according to a Cox hazards model. Patients group [17] and the prospective phase III CBCSG006 [18]. who received ≥2 lines of PBCT had a median OS more Similar to our study, these two trials were based on Asian than 2 years (25.1 months), which suggested that the population. Differences in data from the TNT trial [19] cumulative effect of better PFS from different lines of which compared carboplatin with docetaxel and mainly PBCT might ultimately result in longer OS. included western populations suggest different types of www.impactjournals.com/oncotarget 43138 Oncotarget Table 2: Summary of therapies in the metastatic setting No. % Total lines of therapy received (n = 379) 1 83 21.9 2 111 29.3 3 85 22.4 4 50 13.2 ≥5 44 11.6 Uncertain 6 1.6 Total lines of PBCT received (n = 379) Yes 309 81.5 1 195 51.5 2 85 22.4 3 22 5.8 4 7 1.8 No 70 18.5 Line of the first introduction of PBCT ( n = 309) s t 1 218 70.6 nd 2 64 20.7 rd 3 20 6.5 th 4 4 1.3 th ≥5 3 1.0 Regimen of the first introduction of PBCT ( n = 309) Gemcitabine + cisplatin 171 55.3 Vinorelbine + cisplatin 30 9.7 Docetaxel + cisplatin 29 9.4 mFOLFOX6 25 8.1 Vinorelbine + oxaliplatin 19 6.1 Abraxane + cisplatin 16 5.2 Carboplatin-based and Others 19 6.1 Regimen of the second introduction of PBCT (n = 114) mFOLFOX6 29 25.4 Vinorelbine + oxaliplatin 28 24.6 Gemcitabine + cisplatin 9 7.9 Paclitaxel + carboplatin 7 6.1 Abraxane + carboplatin 6 5.3 Others 35 30.7 Abbreviations: PBCT, platinum-based chemotherapy www.impactjournals.com/oncotarget 43139 Oncotarget Figure 1: A. Kaplan-Meier estimates of OS for the whole cohort and PFS for patients with available first-line data B. Kaplan- Meier estimates of PFS for different chemotherapy in the first-line setting (PBCT vs. non-PBCT) C. Kaplan-Meier estimates of PFS for different platinums in first-line PBCT (cisplatin vs. other platinums) D. Kaplan-Meier estimates of OS for different total lines of PBCT (≥ 2 lines vs. 0–1 line). Multivariate analysis confirmed that PBCT used as inclusion of one institution and the fact that different first-line chemotherapy was an independent predictive baseline information as well as various intrinsic molecular factor for PFS. For patients with first-line PBCT, a subtypes of TNBC might lead to clinical heterogeneity. In cisplatin-based regimen was a favorable predictive factor addition, the impossibility to retrieve enough information for longer first-line PFS. These data confirmed a potential to analyze the safety profile and tolerability of these PBCT role for platinums to treat mTNBC but they have not regimens should be considered, with the solely exception been confirmed to predict better OS. Through molecular of a fraction of patients treated in the most recent years, profiling, TNBC was identified to be a disease of many owing to the wide time window considered. Based on intrinsic molecular subtypes (basal-like, claudin-low currently available, albeit incomplete, data we did not or human epidermal growth factor receptor 2 [HER2]- observe any unexpected warnings in terms of toxicity and enriched) [25]. The high heterogeneity of TNBC suggests adherence to these PBCT therapies. Even so, our study is that platinums used to treat unselected mTNBC patients to the first and the largest re-evaluation of the role of PBCT improve OS may not be a good strategy. Application of the in first-line and later line settings. PAM50 intrinsic subtype signature to sub-classify TNBC In conclusion, compared with non-PBCT, PBCT groups as basal- and non-basal-like, or a determination especially cisplatin-based regimens using at the first of the status of BRCA1, BRCA2 and BRCAness may be line can significantly improve ORR and PFS, but cannot better for testing platinums but this requires future study. improve OS. PBCT with only 1 line during the whole Our study is limited by its retrospective nature treatment might not be necessary for unselected mTNBC and potential patient and treatment selection biases, its with the exception of an urgent demand to control disease www.impactjournals.com/oncotarget 43140 Oncotarget Table 3: Factors independently predicting PFS and OS Cox regression results of PFS (n = 364) Independent predictive Hazard ratio (HR) 95% CI P value factors ECOG 0 Ref 1–2 1.53 1.12 – 2.09 0.008 Number of metastatic organ sites 1 Ref 2 1.21 0.89 – 1.65 0.224 ≥3 1.78 1.30 – 2.44 <0.001 Time between breast surgery and recurrent disease <12 months Ref ≥12 months 0.58 0.44 – 0.75 <0.001 PBCT used as first-line chemotherapy No Ref Yes 0.63 0.47 – 0.84 0.002 Cox regression results of PFS in subgroup of PBCT as the first line chemotherapy (n = 218) ECOG 0 Ref 1–2 1.52 1.06 – 2.18 0.022 Number of metastatic organ sites 1 Ref 2 1.47 1.01 – 2.13 0.045 ≥3 2.23 1.53 – 3.25 <0.001 Time between breast surgery and recurrent disease <12 months Ref ≥12 months 0.63 0.46 – 0.86 0.004 Type of PBCT Non-cisplatin-based Ref Cisplatin-based 0.59 0.35 – 0.99 0.046 Cox regression results of OS (n = 379) Number of metastatic organ sites 1 Ref 2 1.32 0.94 – 1.86 0.108 (Continued ) www.impactjournals.com/oncotarget 43141 Oncotarget Cox regression results of PFS (n = 364) Independent predictive Hazard ratio (HR) 95% CI P value factors ≥ 3 2.67 1.92 – 3.71 <0.001 Time between breast surgery and recurrent disease < 12 months Ref ≥ 12 months 0.43 0.32 – 0.57 <0.001 Total lines of PBCT received < 2 Ref ≥ 2 0.73 0.56 – 0.94 0.016 Abbreviations: PBCT, platinum-based chemotherapy; PFS: progression-free survival; OS: overall survival; CI: confidence interval; Ref: reference category. or symptoms, however, ≥2 lines of PBCT did prolong OS. the first-line treatment to death by any cause or censored at A better future strategy may be identification of predictive the last date the patient was known to be alive. markers of PBCT for mTNBC patients. One of the objectives of this study was to establish prognostic factors for outcomes in TNBC patients who received PBCT. Data for clinical variables identified through PATIENTS AND METHODS literature review were collected as potential important predictors of ORR, PFS and OS in mTNBC patients. Patient selection Potential prognostic variables collected at the time of diagnosis of distant metastases or the beginning of treatment Retrospective analysis was conducted within a included age, menstruation status, details about neo-adjuvant cohort of mTNBC patients who received PBCT or non- and adjuvant chemotherapy administered, distant disease- PBCT at FUSCC between July 2000 and March 2014. free interval, and number and sites of metastatic disease. Data were collected from electronic patient records and hospital charts. Study procedures were approved by institutional ethical board of FUSCC. The eligible Statistical analysis patients were ≥ 18 years old and had TNBC histologically Results were analyzed using SPSS 16.0 (SPSS, confirmed at the primary tumor, with clinical, imaging, Chicago, IL). Binary logistic regression model was histological or cytological evidence of metastatic disease. used to identify the factors that independently influence Patients were classified as TNBC based on their surgical or first-line ORR. Cox proportional hazards models were biopsy results, histologically confirmed estrogen receptor used to estimate adjusted hazard ratios (HRs) and 95% CIs (ER)-, progesterone receptor (PR)-, and HER2- were of disease progression or death. The models were adjusted defined as follows: ER- and PR- were defined as < 1% for age, menstruation status, prior adjuvant and neo-adjuvant positive tumor cells immunohistochemical nuclear chemotherapy, site and extent of first distant relapse, and staining and HER2- was defined as having an IHC score presence of visceral metastasis. Median PFS and OS were of 0 or 1+ or a FISH non-amplified score according to all estimated by the Kaplan–Meier method and compared ASCO guidelines. Patients with incomplete receptor status using a log-rank test. Response rates of different regimens or changed status in metastatic lesions inconsistent with were compared using a chi-squared test or Fisher’s exact the definition described above were excluded. test. All P values were two sided, P < 0.05 was considered to indicate a statistically significant difference. Data collection The efficacy of PBCT and non-PBCT was analyzed Abbreviations according to ORR, PFS, and OS. Tumor response was evaluated in accordance with the Response Evaluation TNBC, triple-negative breast cancer; ER, estrogen Criteria in Solid Tumors (RECIST 1.1) guidelines by receptor; PR, progesterone receptor; HER2, human computed tomography scanning or magnetic resonance epidermal growth factor receptor 2; DFI, disease-free imaging if indicated. The date of disease progression interval; BLBC, basal-like breast cancer; PBCT, platinum- was determined from the clinical notes. PFS was defined based chemotherapy; ORR, overall response rate; PFS, as the time from the start of the treatment until disease progression-free survival; OS, overall survival; FUSCC, progression or death. OS was calculated from the start of Fudan University Shanghai Cancer Center; RECIST, www.impactjournals.com/oncotarget 43142 Oncotarget Response Evaluation Criteria in Solid Tumors; SPSS, 11. Bertucci F, Finetti P, Cervera N, et al. 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