Skip to main content

The effect of neoadjuvant platinum-based chemotherapy in BRCA mutated triple negative breast cancers -systematic review and meta-analysis



Triple negative breast cancers (TNBC) are associated with an aggressive clinical course, earlier recurrence and short survival. BRCA – mutated tumours represent up to 25% of all TNBC. BRCA status is being studied as a predictive biomarker of response to platinum agents. However, the predictive role of BRCA status is still uncertain in this setting. Since TNBC is a very heterogeneous group of diseases, it is important to identify subsets of TNBC patients that may benefit from platinum-based therapy. This study aims to establish if the presence of a germline BRCA mutation in women with TNBC improves the pathologic complete response (pCR) after neoadjuvant chemotherapy with platinum compounds.


An extensive literature search was performed in MEDLINE, EMBASE and LILACS databases, WHO (WHO International Clinical Trials Registry Platform) and the Cochrane Controlled Trials Register Database, for online trial registries and conference proceedings. The measurement of pCR was assessed by pathology review of breast specimen and lymph nodes.


The overall OR was computed using random effects models.

Seven studies were included, comprising a total of 808 TNBC patients, among which 159 were BRCA mutated. Among mutated TNBC patients, 93 (93/159; 58.4%) achieved pCR, while 410 wildtype patients (410/808; 50.7%) showed pCR (OR 1.459 CI 95% [0.953–2.34] p = 0.082) although this result did not reach statistical significance.


This meta-analysis shows that the addition of platinum to chemotherapy regimens in the neoadjuvant setting increases pCR rate in BRCA – mutated as compared to wild-type TNBC patients. However, this trend did not achieve statistical significance.

Trial registration


Peer Review reports


Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for approximately 15 to 20% of all breast cancers [1, 2]. TNBC is defined as lacking the expression of both estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This type of breast tumours comprises a matter of clinical interest because no effective targeted therapy is available, being therefore associated with a more aggressive clinical course, earlier recurrence and short survival, when compared with other types of breast cancer [3, 4]. TNBC has close associations with specific subgroups of patients, including premenopausal women and BRCA mutation carriers [5, 6].

The standard treatment for TNBC that has been shown to improve outcomes is chemotherapy. Interestingly, despite the poor prognosis, it is evident that a subset of patients appears to be particularly chemosensitive when compared to ER positive breast cancers [7]. Hence neoadjuvant chemotherapy has become a standard approach to treat patients with TNBC. It is worthy of note that patients who achieve pathologic complete response (pCR) after neoadjuvant treatment have been shown to have improved long-term outcomes when compared to patients with residual invasive disease [8, 9].

The usual combinations of chemotherapy in the treatment of TNBC include anthracycline and taxane-based regimens. Adding platinum derivatives in the neoadjuvant setting has been shown to improve pCR and also disease-free survival (DFS) in TNBC [10, 11]. Despite these promising results, the inclusion of carboplatin as part of neoadjuvant therapy regimens has not been consensually accepted.

There is evidence that TNBC comprises a heterogeneous breast cancer subtype and this heterogeneity may partially explain the lack of success of targeted therapies in unselected patients [12, 13]. TNBC presents as multiple clinically, biologically and molecular subtypes, that are not yet clearly defined and that may differently respond to chemotherapy. Some patients respond very well to neoadjuvant chemotherapy, with high pCR after surgery. Nevertheless, other patients show no response to neoadjuvant treatment and suffer from early relapse [2].

Disappointingly, a predictive factor for patients who will better respond to specific chemotherapy has not been identified. Further research on the heterogeneity within TNBC may lead to different therapeutic strategies. Indeed, 75 to 80% of TNBC belong to the basal-like subtype of breast cancer, which includes specific genomic profiles, being the most frequent mutations in the BRCA1, TP53 and PIK3CA genes [13, 14].

Approximately 60 to 80% of breast cancer patients with BRCA1 germline mutations have triple negative cancers [15, 16]. On the other hand, around 15 to 25% of all TNBC patients harbour a BRCA mutation [17,18,19].

A higher pCR rate was demonstrated in TNBC after neoadjuvant chemotherapy, when compared with others subtypes of breast cancer [8]. Moreover, pCR is considered a predictive factor for future outcomes: patients who achieve pCR with neoadjuvant chemotherapy have significant better overall survival than those with residual disease [9]. These observations suggest pCR to be a prognostic factor for breast cancer and that subgroup of TNBC patients more sensitive to chemotherapy possibly exists.

Recent evidence suggests that TNBC and BRCA 1 related DNA- repair defects determine sensitivity to DNA –damaging agents, such as platinum- based chemotherapy and poly (ADP ribose) polymerase (PARP) inhibitors [10, 20, 21]. BRCA mutations are responsible for a defect in DNA double-strand break repair which seems to make this type of breast cancer particularly sensitive to treatment with inter-strand cross-linking agents, including platinum analogues. Despite this apparent sensitivity to neoadjuvant chemotherapy, the exact role of carboplatin is still under debate [22]. The incorporation of platinum compounds increases pCR rates in TNBC and BRCA mutated patients; however, in neoadjuvant setting its use remains controversial and it is not routinely recommended in unselected TNBC or BRCA mutations carriers [23,24,25].

Since TNBC is a very heterogeneous group of diseases, it is urgent to identify subsets of TNBC patients that may benefit from platinum-based therapy and their eventual predictors of response. With this purpose, we have conducted a systematic review of studies including TNBC patients with germline BRCA mutation, in order to determine predictive factors for platinum based therapy response.

Our primary aim was to establish if the presence of a germline BRCA mutation in women with TNBC does improve the pCR after neoadjuvant chemotherapy with platinum compounds. Additionally, we aimed to recognize if the use of platinum compounds could help predict pCR in a subgroup of breast cancer patients in a neoadjuvant setting.

There are several studies and meta-analysis that report the association between neoadjuvant chemotherapy and pCR for TNBC, but until now none has been designed with the specific purpose of comparing pCR in TNBC wild-type and TNBC BRCA mutated tumours, after exposure to the same neoadjuvant platinum-based regimen.

Although numerous clinical studies have reported the superior efficacy of platinum- based treatment for TNBC, most of the results were observed in small samples. Here we present a systematic review with meta-analysis of studies that include a subset of TNBC patients with BRCA mutations.

Material and methods

We have conducted a systematic literature review following both Cochrane and PRISMA-P guidelines [26].

Protocol and registration

Two reviewers (OC and CS) established the protocol for this systematic review, which was published at the International Prospective Register of Systematic Reviews (PROSPERO) in April 2018 with the registration number CRD42018092341.

Eligibility criteria

The following eligibility criteria were defined according to the PICO methodology:

  • Patients: women with non-metastatic TNBC (stage I-III) who have been submitted to neoadjuvant chemotherapy with platinum regimens (including cisplatin or carboplatin) and were previously tested for the BRCA1 mutation.

  • Outcomes: studies must report data on pCR, as determined by histological study after surgery; pCR was defined as the absence of any residual invasive cancer (ypT0/is ypN0) or of any invasive and non-invasive cancer (ypT0 ypN0), on evaluation of the resected breast specimen and of all sampled ipsilateral lymph nodes following completion of neoadjuvant therapy. pCR was used as the indicator of response rate among TNBC with or without BRCA 1 mutation when treated with platinum compounds in a neoadjuvant chemotherapy setting. When described, Residual Cancer Burden index (RCB) was used as a secondary outcome. This index evaluates the extent of residual disease and has been validated as an independent prognostic marker of distant relapse- free survival in patients with breast cancer treated with neoadjuvant chemotherapy (RCB-0 complete pathologic response; RCB-I minimal residual disease; RCB II moderate residual disease; RCB III extensive residual disease). Only RCB 0 and RCB I were included as criteria of response.

  • Studies: we have included phase II and III clinical trials, retrospective studies and cohort studies as long as they include comparison of TNBC BRCA 1 mutated vs TNBC non-mutated subgroups. Single arm trials or case reports were not included. Only studies in English language were considered, published in a time frame of 10 years (2008–2018).

Search strategy and study selection

An extensive bibliographic search was performed in the Medline, EMBASE and LILACS databases, and in WHO (WHO International Clinical Trials Registry Platform) and Cochrane (Cochrane Controlled Trials Register Database). The following Medical Subject Heading terms were used: “breast neoplasm”, “breast cancer”, “breast carcinoma”, “breast tumor” or “breast tumour”, combined with “triple negative” or “TNBC” and “platinum compounds”, “cisplatin”, “carboplatin”, or “platinum”. Furthermore, a search for relevant abstracts was performed in the conference proceedings from the European Society for Medical Oncology (ESMO) congress, the American Society of Clinical Oncology (ASCO) annual meeting, and the San Antonio Breast Cancer Symposium (SABCS).

Data extraction

Two researchers (OC and CS) performed the search independently and any discrepancies during the process were resolved by discussion with a third reviewer (TAS).

Studies were screened for inclusion over three phases, using EndNote® software: 1) duplicates were searched and deleted; 2) the two reviewers OC and CS screened the results first by title and then by abstract; when a title seemed relevant, the abstract was reviewed for eligibility; 3) if any doubt remained, the full text of the article was retrieved and discussed. Arbitration by a third author (TAS) was applied in case of persistent disagreement. The reasons for exclusion were recorded and present in (Fig. 1).

Fig. 1

Flowchart of the literature search

Data extraction was performed between April 2017 and June 2018. The following information was independently extracted from each article: 1) basic information, including year of publication and first author’s name; 2) study information, including setting, sample size, study design, inclusion and exclusion criteria, number of TNBC wild-type patients and number of TNBC patients with BRCA mutation; 3) treatment information, including neoadjuvant platinum-based regimens and number of cycles, type of surgery; 4) outcomes of interest: number of patients achieving pCR in the TNBC wildtype and BRCA mutated subgroups; number of patients with RCB 0 or 1in the same subgroups. A funnel-plot was performed to assess the potential publication bias (Fig. 2).

Fig. 2

Funnel plot of publication bias for Odds Ratio meta-analysis

Statistical analysis

The primary outcome measure was pCR assessed by pathologic review of breast specimen and lymph nodes. Study-specific Odds Ratio (OR) of pCR/RCB was estimated indirectly from the total number of patients and the number of patients with pCR/RCB 0 or 1 in each arm (wildtype TNBC/BRCA mutated TNBC).

The overall OR was reported with a measure of precision (confidence interval or standard error). Statistical analysis was performed using the software R®, version 3.5.0. The software Medcalc was also used for forest- plots and funnel plot generation. Meta-analysis was conducted using a random effects model. Statistical heterogeneity was assessed with a chi-square test. The significance level adopted was 0.05.


A total of 362 references were identified through database search. Eighty-seven articles were assessed for eligibility, among them 82 were excluded, mainly because they did not report pCR or did not specifically discriminate the presence of BRCA mutation in TNBC. Among these, five studies were selected for the review and two new publications were added later on, during the execution of this systematic review (Table 1).

Table 1 Characteristics of the studies included in this work

One study [27] that assessed pCR in TNBC BRCA mutated patients only included one patient submitted to neoadjuvant chemotherapy with cisplatin and was excluded from the study.

Studies and outcomes

Most of the studies only presented pCR rate and/or RCB as efficacy outcomes. In the study by Hannen et al. [21], disease free survival (DFS) was also reported. Loibl and colleagues [28] indicated that results on event –free survival (EFS) and overall survival (OS) were ongoing.

Pathologic complete response (pCR) rate

Overall, seven studies were included, comprising a total of 808 TNBC patients, among which 159 were BRCA mutated (Table 2).

Table 2 Detailed characteristics of studies included regarding treatment regimens, efficacy (pCR) outcomes and safety outcomes in BRCA-mutated and wild-type TNBC groups

Among mutated TNBC patients, 93 (93/159;58.4%) achieved pCR, whereas 410 wildtype patients (410/808; 50.7%) showed pCR (OR = 1.459 CI [95% 0.953–2.34] p = 0.082) although this result did not reach statistical significance (Fig. 3).

Fig. 3

Forest plot of odds ratio for pathologic complete response of BRCA – mutated and BRCA wild-type TNBC after neoadjuvant platinum- based chemotherapy

No significant heterogeneity was found between studies (I2 = 18.54%; p = 0.2884). The symmetric funnel plot for this meta-analysis is an additional indicator of the absence of publication bias and study heterogeneity [29].

Residual cancer burden (RCB) rate

Three of the included studies evaluated RCB as an outcome. From a total of 233 TNBC patients in which RCB was evaluated, 47 patients were BRCA-mutated. In mutated TNBC patients, 34 (34/47; 72.3%) achieved RCB 0/1, while 141(141/233; 60.5%) wild type TNBC attained RCB. Figure 4 shows an OR 1.68 (CI 95% [0.777–3.657], p = 0.186) favoring the use of platinum-based therapy in the mutated TNBC group, although this result was not statistically significant. No significant heterogeneity among studies was observed (I2 = 12.19%; p = 0.320).

Fig. 4

Forest plot of odds ratio for residual cancer burden of BRCA – mutated and BRCA wild-type TNBC after neoadjuvant platinum-based chemotherapy

Safety outcomes

An overview of the most common adverse events after treatment with the different platinum-based chemotherapy regimens is presented in Table 2. The BRCA status of patients experiencing adverse events was not identified in any of the included studies.


In this systematic review with meta-analysis, we intended to clarify the role of platinum- based chemotherapy as neoadjuvant treatment in a very well-established subgroup of TNBC patients. Our results are in line with most of the studies published in the literature, supporting a benefit in pCR from the inclusion of platinum compounds to neoadjuvant regimens [30].

Since BRCA- mutated tumours represent up to 25% of all TNBC [19], it would be important to establish predictive factors that allow for patient selection for platinum- based treatment. BRCA status is being studied as a predictive biomarker of response to platinum agents, based on preclinical evidence that tumours harbouring BRCA deficiency are homologous recombination deficient and consequently, more sensitive to DNA damaging agents like platinum salts. Nevertheless, the predictive role of BRCA status is still uncertain in this setting. Recent evidence suggests favourable results in treating BRCA patients with platinum chemotherapy agents: the use of neodjuvant chemotherapy with cisplatin in BRCA 1 mutation TNBC patients accomplished a pCR rate of 61% [30]. Another recent study, which included neoadjuvant chemotherapy with anthracycline and taxane- containing regimens in TNBC women, has shown a pCR rate of 53.8%. Of the patients achieving pCR, 60.6% were BRCA negative and 39.4% BRCA positive [31]. This difference in pCR rates reveals the low efficacy of traditional chemotherapy regimens in this sub group of patients. Previous results of meta-analyses evaluating pCR in TNBC after platinum –based neoadjuvant chemotherapy have shown a beneficial effect [32, 33].

This meta-analysis is innovative as it compares the effect of platinum- based chemotherapy in TNBC patients with and without BRCA mutations. We found a trend towards higher efficacy of platinum-based regimens in mutated TNBC compared to non-mutated patients.

This result is in line with a recent randomized phase II trial, ADAPT TN, which has shown higher pCR in the neoadjuvant setting with the addition of carboplatin to a taxane based regimen in TNBC (45.9% vs 28.7%) [34], but that did not indicate the BRCA status. Other published results support a statistically significant benefit in TNBC pCR with the addition of a platinum agent to standard chemotherapy; [10, 11] however, once again the subpopulation of BRCA mutated patients was not discriminated in the studies.

On the other hand, the secondary analysis of GeparSixto trial showed that the response to carboplatin was independent from germline BRCA status [21]. When comparing pCR rates in the non-carboplatin arm the results were 66.7% vs 36.4% (OR = 3.50; 95% CI [1.39–8.84]; p = 0.008) for germline BRCA mutation patients and wild-type patients respectively. Surprisingly, the addition of platinum did not increase pCR rate in the germline BRCA group (65.4%); in contrast, carboplatin increased response rates in patients without BRCA mutations (55.0%), (OR = 1.55; 95% CI [0.64–3.74]; p = 0.33). In addition a recent meta-analysis [35] which included the GeparSixo study [21] and also the BrighTNess trial [28] compared platinum-based vs platinum- free neoadjuvant chemotherapy in TNBC patients. A total of 96 BRCA- mutated patients was included, but contrary to our results, the addition of carboplatin was not associated with a significant increase in pCR rate (OR = 1.17; 95% CI [0.51–2.67], p = 0.711). Unexpectedly, among patients without BRCA mutations there was an advantage in the use of platinum based chemotherapy (OR = 2.72, 95%CI [1.71–4.32], p < 0.001). Nonetheless, the authors stated that no conclusions could be drawn because of the small number of patients included. Furthermore, this study was designed to evaluate the effect of platinum-based versus platinum-free neoadjuvant chemotherapy in TNBC patients, and not the effect of platinum compounds in mutated vs non-mutated patients.

When searching for relevant abstracts in the conference proceedings from ESMO and ASCO, we have found reports of many ongoing studies on the subject. Fontaine et al. [36] in ESMO 2017 concluded that the addition of platinum to neoadjuvant treatments presented a pCR rate in the breast and axilla as high as 60% in early TNBC patients is obtained. Correlation with genomic homologous recombination deficiency HRD is ongoing.

A randomized phase III trial (PEARLY) [37] compared anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as neoadjuvant therapies in patients with early triple-negative breast cancer. This study is expected to be published in 2023, with the patients being randomized on BRCA status.

At ESMO 2018 the results of the GeparOcto study [38] were presented, which evaluated the germline mutation status and therapy response in patients with TNBC. In this phase III study the patients with TNBC were randomized to receive treatment with intensified dose-dense epirubicin, paclitaxel, and cyclophosphamide, or weekly paclitaxel/liposomal doxorubicin, plus carboplatin. They concluded that BRCA1/2 germline mutations represent a predictive biomarker for the achievement of pCR after neoadjuvant anthracycline-taxane-containing chemotherapy.

The PARTNER study [39] presented at ASCO 2017 which intended to evaluate the efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative breast cancer and/or germline mutated BRCA. Patients were randomised (1,1:1) to either control carboplatin and paclitaxel or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib.

Frovola et al. [40] presented at ASCO 2016, studied the role of different germline BRCA mutations in response to platinum-based chemotherapy in patients with triple-negative breast cancer. Early and locally advanced TNBC BRCA mutated cancers were treated with dose-dense combination of doxorubicin, cisplatin and paclitaxel followed by surgery and the study concluded that BRCA mutations may predispose different responses to platinum-based chemotherapy.

All of these recent preliminary and unpublished studies attest the relevance of the topic and the continuum debate on the field.

There are some limitations in our review. First, there was wide variation in the chemotherapy regimens regarding number of cycles, frequency, and agents used other than platinum compounds. Different types of treatments were included, such as eribulin, a non-taxan microtubule dynamics inhibitor, [41] or iniparib, a PARP 1 inhibitor [42].

Another limitation concerns to the small number of RCTs that have been included, only two studies [21, 28], which however comprise an evaluation of a significant number or patients. Furthermore, as we have selected only subgrups of the overall samples we have obtained homogeneity.

We must emphasize that our study only included patients with germinal mutation on BRCA1/2. Other putative “BRCAness” subgroups such as basal phenotypes, homologous recombination (HR) deficiency, BRCA1 methylation or low levels of BRCA1 mRNA were not assessed. However, a recent phase III trial in advanced TNBC showed a positive effect of carboplatin on germline BRCA1 mutation patients but not on the BRCA1 methylation, BRCA1 mRNA –low levels or HR deficiency subgroups [43]. Moreover, in the total population of TNBC patients, no evidence of a superior response to carboplatin was observed, when compared with the standard of care. In contrast, the subgroup of patients with germline BRCA 1 mutation showed a clear benefit of carboplatin, which doubled the effect of docetaxel [43].

The main strength of our review was the choice of a specific population of TNBC, resulting in a small publication bias and low heterogeneity of the sample, confirmed both by the value of the I2 heterogeneity statistics and the funnel-plot.

Despite the differences between studies regarding chemotherapy drugs, dose, number of cycles, patients’ age, tumour stage and study design, our results highlight the benefit of platinum in a selective subgroup of TNBC.

It is important to point out that TNBC constitutes a heterogeneous group of diseases so future studies are required in order to further individualize treatment.


This meta-analysis shows that the addition of platinum to chemotherapy regimens in the neoadjuvant setting tend to increase pCR rate in BRCA-mutated as compared to wild-type TNBC patients (OR = 1.459 CI 95% [0.953–2.34] p = 0.082). The OR obtained indicates a clinical benefit on the addition of platinum compounds in BRCA mutated TNBC patients, but due to the small number of patients was not possible to achieve statistical significance and more studies are needed to definitely confirm the utility of platinum compounds in this setting.



Confidence interval


Odds ratio


Pathologic complete response


Triple negative breast cancer


  1. 1.

    Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329–34.

    CAS  Article  Google Scholar 

  2. 2.

    Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.

    Article  Google Scholar 

  3. 3.

    Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat. 2009;115(2):423–8.

    Article  Google Scholar 

  4. 4.

    Boyle P. Triple-negative breast cancer: epidemiological considerations and recommendations. Ann Oncol. 2012;23(Suppl 6):vi7–12.

    Article  Google Scholar 

  5. 5.

    Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, Malone KE. Risk factors for triple-negative breast cancer in women under the age of 45 years. Cancer Epidemiol Biomark Prev. 2009;18(4):1157–66.

    Article  Google Scholar 

  6. 6.

    Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008;52(1):108–18.

    CAS  Article  Google Scholar 

  7. 7.

    Colleoni M, Cole BF, Viale G, Regan MM, Price KN, Maiorano E, Mastropasqua MG, Crivellari D, Gelber RD, Goldhirsch A, et al. Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Clin Oncol. 2010;28(18):2966–73.

    CAS  Article  Google Scholar 

  8. 8.

    Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164–72.

    Article  Google Scholar 

  9. 9.

    Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275–81.

    Article  Google Scholar 

  10. 10.

    von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014;15(7):747–56.

    Article  Google Scholar 

  11. 11.

    Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015;33(1):13–21.

    CAS  Article  Google Scholar 

  12. 12.

    Lehmann BD, Pietenpol JA. Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol. 2014;232(2):142–50.

    Article  Google Scholar 

  13. 13.

    Collignon J, Lousberg L, Schroeder H, Jerusalem G. Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer (Dove Med Press). 2016;8:93–107.

    CAS  Google Scholar 

  14. 14.

    Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

    Article  Google Scholar 

  15. 15.

    Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, Hortobagyi GN, Arun BK. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26(26):4282–8.

    Article  Google Scholar 

  16. 16.

    Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, Ramus SJ, Spurdle A, Robson M, Sherman M, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev. 2012;21(1):134–47.

    CAS  Article  Google Scholar 

  17. 17.

    Hartman AR, Kaldate RR, Sailer LM, Painter L, Grier CE, Endsley RR, Griffin M, Hamilton SA, Frye CA, Silberman MA, et al. Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer. 2012;118(11):2787–95.

    CAS  Article  Google Scholar 

  18. 18.

    Sharma P, Klemp JR, Kimler BF, Mahnken JD, Geier LJ, Khan QJ, Elia M, Connor CS, McGinness MK, Mammen JM, et al. Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Res Treat. 2014;145(3):707–14.

    CAS  Article  Google Scholar 

  19. 19.

    Greenup R, Buchanan A, Lorizio W, Rhoads K, Chan S, Leedom T, King R, McLennan J, Crawford B, Kelly Marcom P, et al. Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort. Ann Surg Oncol. 2013;20(10):3254–8.

    Article  Google Scholar 

  20. 20.

    Stoppa-Lyonnet D. The biological effects and clinical implications of BRCA mutations: where do we go from here? Eur J Hum Genet. 2016;24(Suppl 1):S3–9.

    CAS  Article  Google Scholar 

  21. 21.

    Hahnen E, Lederer B, Hauke J, Loibl S, Krober S, Schneeweiss A, Denkert C, Fasching PA, Blohmer JU, Jackisch C, et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol. 2017;3(10):1378–85.

    Article  Google Scholar 

  22. 22.

    Bartsch R, Bergen E. ASCO 2017: highlights in breast cancer. Memo. 2017;10(4):228–32.

    Article  Google Scholar 

  23. 23.

    Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rutgers E, Zackrisson S, Cardoso F, Committee EG. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v8–30.

    Article  Google Scholar 

  24. 24.

    Paluch-Shimon S, Pagani O, Partridge AH, Abulkhair O, Cardoso MJ, Dent RA, Gelmon K, Gentilini O, Harbeck N, Margulies A, et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3). Breast. 2017;35:203–17.

    Article  Google Scholar 

  25. 25.

    Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, Colleoni M, Regan MM, Piccart-Gebhart M, Senn HJ, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international expert consensus conference on the primary therapy of early breast cancer 2017. Ann Oncol. 2017;28(8):1700–12.

    CAS  Article  Google Scholar 

  26. 26.

    Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, Group P-P. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1.

    Article  Google Scholar 

  27. 27.

    Kolacinska A, Chalubinska J, Blasinska-Morawiec M, Dowgier-Witczak I, Fendler W, Kordek R, Morawiec Z. Pathological complete response in younger and older breast cancer patients. Arch Med Sci. 2012;8(2):310–5.

    Article  Google Scholar 

  28. 28.

    Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018;19(4):497–509.

    CAS  Article  Google Scholar 

  29. 29.

    Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rucker G, Harbord RM, Schmid CH, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.

    Article  Google Scholar 

  30. 30.

    Byrski T, Huzarski T, Dent R, Marczyk E, Jasiowka M, Gronwald J, Jakubowicz J, Cybulski C, Wisniowski R, Godlewski D, et al. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat. 2014;147(2):401–5.

    CAS  Article  Google Scholar 

  31. 31.

    Clifton K, Gutierrez-Barrera A, Ma J, Bassett R Jr, Litton J, Kuerer H, Moulder S, Albarracin C, Hortobagyi G, Arun B. Adjuvant versus neoadjuvant chemotherapy in triple-negative breast cancer patients with BRCA mutations. Breast Cancer Res Treat. 2018;170:101.

    CAS  Article  Google Scholar 

  32. 32.

    Guan X, Ma F, Fan Y, Zhu W, Hong R, Xu B. Platinum-based chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis of randomized-controlled trials. Anti-Cancer Drugs. 2015;26(8):894–901.

    CAS  Article  Google Scholar 

  33. 33.

    Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, Barni S. The value of platinum agents as neoadjuvant chemotherapy in triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res Treat. 2014;144(2):223–32.

    CAS  Article  Google Scholar 

  34. 34.

    Gluz O, Nitz U, Liedtke C, Christgen M, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, et al. Comparison of neoadjuvant nab-paclitaxel+carboplatin vs nab-paclitaxel+gemcitabine in triple-negative breast cancer: randomized WSG-ADAPT-TN trial results. J Natl Cancer Inst. 2017;110:628.

    Article  Google Scholar 

  35. 35.

    Poggio F, Bruzzone M, Ceppi M, Ponde NF, La Valle G, Del Mastro L, de Azambuja E, Lambertini M. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann Oncol. 2018;29:1497.

    CAS  PubMed  Google Scholar 

  36. 36.

    Fontaine C, Cappoen N, Renard V, Van Den Bulk H, Vuylsteke P, Glorieux P, De Grève J, Decoster L, Vanhoeij M, Awada A, et al. Updated results of the breast cancer task force phase II study of neoadjuvant weekly carboplatin (Cp) added to paclitaxel (P) followed by epirubicin (E) and cyclophosphamide (C) in triple negative breast cancer (TNBC) patients (pts). Ann Oncol. 2017;28(suppl_5):168P.

    Article  Google Scholar 

  37. 37.

    Kim GM, Jeung H-C, Jung KH, Kim SH, Kim HJ, Lee KH, Park KH, Lee JE, Ahn MS, Kohn S, et al. PEARLY: A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo)adjuvant therapy in patients with early triple-negative breast cancer. J Clin Oncol. 2017;35(15_suppl):TPS587.

    Article  Google Scholar 

  38. 38.

    Pohl E, Schneeweiss A, Hauke J, Rhiem K, Weber-Lassalle N, Schmutzler RK, Untch M, Luebbe K, Jackisch C, Moebus V, et al. Germline mutation status and therapy response in patients with triple-negative breast cancer (TNBC): Results of the GeparOcto study. Ann Oncol. 2018;29(suppl_8):243P.

    Article  Google Scholar 

  39. 39.

    Earl HM, Vallier A-L, Qian W, Grybowicz L, Thomas S, Mahmud S, Harvey C, McAdam K, Hughes-Davies L, Roylance R, et al. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. J Clin Oncol. 2017;35(15_suppl):TPS591.

    Article  Google Scholar 

  40. 40.

    Frolova M, Ignatova E, Stenina MB, Petrovsky A, Tjulandin S. Role of different germline BRCA mutations in response to platinum-based chemotherapy in patients (pts) with triple-negative breast cancer (TNBC). J Clin Oncol. 2016;34(15_suppl):e13008.

    Article  Google Scholar 

  41. 41.

    Kaklamani VG, Jeruss JS, Hughes E, Siziopikou K, Timms KM, Gutin A, Abkevich V, Sangale Z, Solimeno C, Brown KL, et al. Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). Breast Cancer Res Treat. 2015;151(3):629–38.

    CAS  Article  Google Scholar 

  42. 42.

    Telli ML, Jensen KC, Vinayak S, Kurian AW, Lipson JA, Flaherty PJ, Timms K, Abkevich V, Schackmann EA, Wapnir IL, et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol. 2015;33(17):1895–901.

    CAS  Article  Google Scholar 

  43. 43.

    Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, Owen J, Abraham J, Barrett S, Barrett-Lee P, et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial. Nat Med. 2018;24(5):628–37.

    CAS  Article  Google Scholar 

  44. 44.

    Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A, Fatima A, Gelman RS, Ryan PD, Tung NM, De Nicolo A, Ganesan S, Miron A, Colin C, Sgroi DC, Ellisen LW, Winer EP, Garber JE (2010) Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28:1145-1153. doi: 10.1200/JCO.2009.22.4725.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Sharma P, Lopez-Tarruella S, Garcia-Saenz JA, Ward C, Connor CS, Gomez HL, Prat A, Moreno F, Jerez-. Gilarranz Y, Barnadas A, Picornell AC, Del Monte-Millan M, Gonzalez-Rivera M, Massarrah T. Pelaez.Lorenzo B, Palomero MI, Gonzalez Del Val R, Cortes J, Fuentes Rivera H, Bretel Morales D. Marquez-Rodas I, Perou CM, Wagner JL, Mammen JM, McGuiness MK, Klemp JR, Amin AL, Fabian CJ. Heldstab J, Godwin AK, Jensen RA, Kimler BF, Jhan QJ, Martin M (2017) Efficacy of Neoadjuvant. Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohort. Clin. Cancer Res 23:649–657.

  46. 46.

    Sella T, Gal Yam EN, Levanon K, Rotenberg TS, Gadot M, Kuchuk I, Molho RB, Itai A, Modiano TM, Gold R, Kaufman B, Shimon SP (2018) Evaluation of tolerability and efficacy of incorporating carboplatin in neoadjuvant anthracycline and taxane based therapy in a BRCA1 enriched triple-negative breast cancer cohort. Breast 40:141-146.

    Article  PubMed  Google Scholar 

Download references


The authors would like to thank to Catarina Miranda for the careful review of the manuscript.


This work received no funding.

Availability of data and materials

Data sharing not applicable to this article, as no datasets were generated or analysed during the current study.

Author information




OC conceived the literature review and the design of the review. OC and CS undertook all the literature searches and data extraction. OC, CS and FC assumed the statistical analysis. OC, CS and FC drafted the manuscript and all authors read, edited and approved the final manuscript.

Corresponding author

Correspondence to Olga Caramelo.

Ethics declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Caramelo, O., Silva, C., Caramelo, F. et al. The effect of neoadjuvant platinum-based chemotherapy in BRCA mutated triple negative breast cancers -systematic review and meta-analysis. Hered Cancer Clin Pract 17, 11 (2019).

Download citation


  • Triple negative breast cancer
  • BRCA
  • Neoadjuvant chemotherapy
  • Cisplatin
  • Carboplatin