Outcomes of systemic therapy for advanced triple-negative breast cancer: A single centre experience

The Breast 40 (2018) 60e66

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Original article

Outcomes of systemic therapy for advanced triple-negative breast cancer: A single centre experience  Matteo Luca Battisti a, *, David Okonji a, Thubeena Manickavasagar a, Nicolo Kabir Mohammed b, Mark Allen a, Alistair Ring a a b

Department of Medicine e Breast Unit, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom Research and Development Department, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 January 2018 Received in revised form 17 March 2018 Accepted 16 April 2018

Background: Prognosis is worse for advanced triple-negative breast cancer (aTNBC) compared to other disease subtypes. Trials describe treatment outcomes in single specified lines of therapy; but few data describe treatment outcomes across the whole treatment pathway, which is critical in determining when patients should be referred for trials and to inform discussion. We evaluated treatment outcomes for aTNBC (overall response rate [ORR], median progression-free survival [mPFS] and median overall survival [mOS]) in patients treated largely outside of clinical trials. Methods: We retrospectively identified 268 patients diagnosed with aTNBC from 01/12/2011 to 30/11/ 2016 from our electronic records and recorded patients' and tumour characteristics and treatment outcomes. Chi-squared/Fishers exact test and Kaplan-Meier statistical methods were utilised. Results: 186 patients treated with
1 line of systemic treatment were eligible and had median age of 55 (range 26e91). 53.8% had ECOG Performance Status 0 and 69.9% visceral involvement. 38.6% had diseasefree interval (DFI)12 months following surgery or adjuvant chemotherapy completion and 14.0% had de-novo advanced disease. 11.4% carried a BRCA mutation. 64.5% received two lines of therapy, 37.6% three and 21.5% four. ORR and mPFS were 43.9% and 3.7 months for first-line therapy, 40.2% and 3.5 months for second-line, 28.8% and 2.5 months for third-line and 25.0% and 2.1 months for fourth-line. In first line, DFI>12 months was associated with higher ORR and longer PFS compared DFI 12 months. Conclusions: The observed response rates are consistent with literature. However, PFS is short, and early consideration of clinical trials can be justified in these patients. © 2018 Elsevier Ltd. All rights reserved.

Keywords: Breast cancer Triple-negative Advanced stage Chemotherapy Systemic therapy

Introduction Triple-negative breast cancer (TNBC) lacks expression of the oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) [1,2]. It accounts for up to 20% of all breast cancer prevalence, with an annual incidence of 200,000 new patient diagnoses worldwide [3]. Compared to other disease subtypes, TNBC has an inherently aggressive behaviour and a poorer prognosis with higher rates of recurrence and shorter progression-free survival (PFS) and overall survival (OS) [4]. Therapeutic decisions are based on individual

patient and disease characteristics and previous treatments. However, TNBC is a highly diverse group of cancers with six molecular subtypes identified based on gene expression [5]. Despite extensive ongoing research for biomarkers and new drugs, only two potential molecular targets have been identified in TNBC. First, targeting the androgen receptor with anti-androgen receptor or anti-androgen synthesis drugs has demonstrated anti-tumour efficacy in advanced disease in three prospective trials [6e8]. Second, targeting homologous recombination deficiency in patients with BRCA1 or 2 mutations with inhibitors of the enzyme poly ADP ribose polymerase (PARP) has also shown promising clinical

* Corresponding author. Department of Medicine e Breast Unit, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. E-mail addresses: [email protected], [email protected] (N.M.L. Battisti), [email protected] (D. Okonji), [email protected] (T. Manickavasagar), [email protected] (K. Mohammed), [email protected] (M. Allen), [email protected] (A. Ring). https://doi.org/10.1016/j.breast.2018.04.014 0960-9776/© 2018 Elsevier Ltd. All rights reserved.

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activity in metastatic disease [9,10]. However, cytotoxic chemotherapy still remains the standard of care in the management of early- and advanced-stage disease [11]. In the metastatic disease setting, systemic treatment options aim at extending survival and palliating symptoms [12]. Response duration to chemotherapy is usually short-lived [13] and, depending on different therapeutic regimens, overall response rates (ORR) range from 10% to 35% with a median PFS of approximately 3 months [14e16]. There are a large number of clinical trials in patients with metastatic TNBC. However, the outcomes in clinical trial populations do not necessarily reflect those in day-to-day clinical practice. Furthermore, clinical trials focus on a single line of therapy (usually first line for TNBC) and do not examine outcomes across the whole treatment pathway involving subsequent lines of therapy [17e19]. Discussing prognosis and potential treatment outcomes is an essential part of shared decision-making [20,21] and helps contextualize therapeutic goals. This retrospective analysis aims to provide better insight into the efficacy of different lines of systemic

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therapy for advanced TNBC in terms of ORR, median PFS and median OS to better inform discussion with patients, clinical decisionmaking and referral for clinical trials. Materials and methods We retrospectively identified and reviewed the medical records of 268 patients diagnosed with advanced TNBC and treated with any line of systemic therapy from 01/12/2011 to 30/11/2016 at The Royal Marsden NHS Foundation Trust. These time limits were chosen to ensure adequate data quality and potential follow-up. Patients' and tumour characteristics (including age, performance status, BRCA mutational status, stage and grade at diagnosis, sites of metastatic involvement, early and advanced stage treatment history, and enrolment within clinical trials) were extracted from our electronic medical records, along with systemic treatment outcomes. TNBC was defined as ER-negative (Allred score  2), PR-negative (Allred score  2) and HER2-not amplified (score  1 on

Fig. 1. CONSORT diagram.

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immunohistochemistry or single-probe average HER2 copy number < 4.0 signals/cell or dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell on in situ hybridization) according to the current international guidelines [1,2]. Patients were regarded as affected by advanced TNBC if they had relapsed with radiological features of metastatic disease following a previous diagnosis of early TNBC or presented with de novo stage IV disease. If a metastatic biopsy had been performed, we excluded patients who were not confirmed as TNBC on their first metastatic biopsy. We also excluded patients who had not been treated with palliative intent (such as those with disease amenable to radical therapy), those who were diagnosed with concomitant malignancies or who received treatment in other institutions. To be eligible for this analysis, patients had to have received at least one line of systemic therapy in the advanced setting. According to the Food and Drug Administration definitions [22], ORR was calculated as the proportion of patients achieving partial response (PR) or complete response (CR) on systemic therapy. The disease-free interval (DFI) was calculated as the time from surgery or completion of adjuvant chemotherapy until disease recurrence; for patients who received neoadjuvant treatment, DFI was calculated from the date of surgery. PFS was defined as time from commencement of any line of systemic therapy until disease progression or death. Non-responding patients were counted as PFS event on the response assessment date. Progression-free patients were censored at the last follow-up date. OS was calculated as time from commencement of first-line systemic therapy until death from any cause. Surviving patients were censored at the last followup date. This analysis was approved as a service evaluation by The Royal Marsden Hospital/Institute of Cancer Research Committee for Clinical Research. Descriptive analysis method was used to summarise the data using counts and percentages for categorical variables and for the continuous non-normal variables using median and range or interquartile range. Proportion of patients responding after each chemo cycle was calculated with 95% confidence interval. Chisquared and Fishers exact test used as appropriate to compare the response rates in the patient groups. Kaplan Meier method was utilised for the calculation of overall survival time from date of advanced disease diagnosis to death or last follow-up date. Kaplan Meier method was also used for the calculation of progression free survival from day 1 of the first cycle of each chemotherapy line to disease progression or death; progression-free and lost to followup patients are censored at last follow-up date. Median time to event reported with 95% confidence interval and compare patient groups using Log-rank test. Results As shown in the CONSORT diagram reported in Fig. 1, of 286 patients diagnosed with advanced TNBC and assessed for eligibility, 186 patients were included in the analysis. Out of 82 excluded patients, 25 patients did not have a diagnosis of TNBC on first metastatic biopsy, 12 patients had not received any palliative therapy for advanced stage disease, 2 patients had concomitant malignancies, 41 patients had received systemic treatment in other institutions (and records regarded as incomplete) and 2 patients had operable disease. The median age of these patients at metastatic diagnosis was 55 years old (range 26e91). As shown in Table 1, at metastatic diagnosis, 62.9% of patients were younger than 60 years (n ¼ 117). 53.8% (n ¼ 100) had an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, whereas 40.3% (n ¼ 75) had an ECOG PS of 1 and 5.9% (n ¼ 11) had an ECOG PS of 2.69.9% (n ¼ 130) of our patients had metastatic visceral involvement, while 30.1% (n ¼ 56) had non-

Table 1 Patient characteristics at advanced stage diagnosis. [1: regardless of non-visceral involvement; 2: radiological diagnosis of advanced disease; 3: 157 (84.4%) patients included in the DFI analysis; 4: either BRCA1 or BRCA2.]. Median age

55 (range: 26e91)

Age group N (%)

<60 years
60 years 0 1 2 Visceral1 Non-visceral only Invasive ductal Invasive lobular Mixed Metaplastic Other Not available2 26 (14.0%) 1 2 3 4 5 6 7 12 months >12 months Wild-type Mutated4 Unknown First line Second line Third line Fourth line

ECOG Performance Status N (%)

Disease sites N (%) Advanced disease histology N (%)

De novo advanced disease N (%) No. of lines of systemic therapy received N (%)

DFI3 BRCA

Patients enrolled in therapeutic trials N (%)

117 (62.9) 69 (37.1) 100 (53.8) 75 (40.3) 11 (5.9) 130 (69.9) 56 (30.1) 112 (60.2) 7 (3.8) 2 (1.1) 3 (1.6) 2 (1.1) 60 (32.3) 186 (100) 120 (64.5) 70 (37.6) 40 (21.5) 20 (10.7) 5 (2.7) 1 (0.5) 61 (38.6) 96 (61.4) 66 (35.7) 21 (11.4) 98 (53.0) 19 (10.2) 12 (10.0) 6 (12.9) 3 (7.5)

visceral only disease. Other population characteristics are shown in Table 1. All 186 eligible patients received at least one line of palliative systemic treatment. 64.5% of them (n ¼ 120) were given at least two lines, 37.6% (n ¼ 70) at least three and 21.5% (n ¼ 40) at least four. After surgery or completion of adjuvant treatment, 38.6% (n ¼ 61) relapsed within 12 months, whereas 61.4% (n ¼ 96) had a DFI longer than one year. Patients enrolled within clinical trials represented 10.2% (n ¼ 19) of those treated in first line, 10.0% (n ¼ 12) of them in second line, 12.9% (n ¼ 6) in third line and 7.5% (n ¼ 3) in fourth line. We classified treatment regimens in seven categories based on their mechanism of action and class of drugs: 1) fluoropyrimidines (e.g., capecitabine); 2) platinum compounds and their combinations (including carboplatin, carboplatin/gemcitabine with or without bevacizumab, carboplatin/paclitaxel with or without bevacizumab and cisplatin or carboplatin/mitomycin-C/vinblastine); 3) taxanes and their combinations (including paclitaxel with or without bevacizumab and docetaxel); 4) anthracyclines and their combinations (including epirubicin/cyclophosphamide, doxorubicin/cyclophosphamide, epirubicin alone and 5-fluorouracil/epirubicin/cyclophosphamide); 5) vinca alkaloids (e.g., vinorelbine); 6) eribulin with or without bevacizumab; 7) other options including experimental options (mostly targeted treatments and immunotherapy). The proportion of patients treated with different agents are shown in Fig. 2. As documented in Table 2 and Fig. 3, the ORR decreased from 43.9% (95% CI 36.5e51.5) in first line, to 40.2% (95% CI 31.2e49.6) in second line, 28.8% (95% CI 18.3e41.3) in third line and 25.0% (95% CI 12.7e41.2) in fourth line. Likewise, the median PFS decreased from 3.7 months (95% CI 2.9e5.1), to 3.5 months (95% CI 2.6e4.1) in second line, 2.5 months (95% CI 2.0e3.0) in third line and 2.1 months (95% CI 1.6e2.8) in fourth line. In the first-line setting,

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Fig. 2. Distribution of patients treated with different drugs and combinations across the first four lines of therapy.

Table 2 ORR and PFS to first, second, third and fourth line systemic treatment.

No. of patients ORR (95% CI), % PFS (95% CI), months

First line

Second line

Third line

4th line

186 43.9% (36.5e51.5) 3.7 (2.9e5.1)

120 40.2% (31.2e49.6) 3.5 (2.6e4.1)

70 28.8% (18.3e41.3) 2.5 (2.0e3.0)

40 25.0% (12.7e41.2) 2.1 (1.6e2.8)

patients with a DFI longer than 12 months had an ORR of 40.4% (95% CI 34.2e50.4) compared to 34.5% (95% CI 22.5e48.1) for those with a DFI shorter than 12 months (p 0.176) (Table 3). Median PFS was respectively 5.6 months (95% CI 3.7e6.9) compared to 2.7 (95% CI 2.1e3.6) (p 0.002) (Table 3). The median OS for the overall population was 14.3 months (95% CI 11.7e17.5); however, patients with a DFI longer than 12 months had a median OS of 21.3 months (95% CI 14.2e22.9) while those with a shorter DFI had a median OS of 8.3 months (7.2e11.5) (p < 0.001) (Fig. 4). In the multivariate analysis, only ECOG PS and DFI were associated with a statistically significant difference in PFS and in OS. Regarding PFS, the hazard ratio (HR) was 0.62 (0.44e0.87) for patients with a DFI longer than 12 months compared to those with a shorter DFI (p 0.006). HR was 1.60 (1.13e2.27) for patients with an ECOG PS 1 and 2.53 (1.92e8.82) for ECOG PS 2 compared to those with ECOG PS 0 (p < 0.001). Regarding OS, HR was 0.45 (0.31e0.65) for patients with a DFI longer than 12 months compared to those

with a shorter DFI (p < 0.001). HR was 1.85 (1.28e2.67) for patients with an ECOG PS 1 and 3.53 (1.49e8.35) for ECOG PS 2 compared to those with ECOG PS 0 (p < 0.001). Discussion A number of chemotherapy agents are active in metastatic triple-negative breast cancer. However, the outcomes of palliative systemic therapy across a number of lines of treatment still remain poorly described, as clinical trials examine outcomes in a single line of therapy in a selected population. There is therefore limited data to guide day to day decision-making. In this analysis, the proportion of patients on systemic treatment declined significantly in later lines, in keeping with a previous analysis conducted by Seah et al., outcomes were examined in 199 patients commencing first line chemotherapy for advanced breast cancer [23]. Data were available on 44 patients with TNBC

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Fig. 3. Decline of patients on treatment (%, left), PFS (months, centre) and ORR (%, right) across the first four lines of therapy.

Table 3 Impact of DFI on ORR and PFS after initiation of first line systemic treatment. ORR (95% CI), %

p-value

DFI  12 months (N ¼ 61) DFI >12 months (N ¼ 96)

34.5 (22.5e48.1) 40.4 (34.2e50.4)

0.176

Median PFS (95% CI), months

p-value

DFI  12 months (N ¼ 61) DFI >12 months (N ¼ 96)

2.7 (2.1e3.6) 5.6 (3.7e6.9)

0.002

Fig. 4. Overall survival Kaplan-Meier plot by DFI.

commencing first line chemotherapy, of whom 84% went on to receive second-line and 59% third-line treatment. Overall response rate and PFS also decreased with later lines of

therapy, consistent with expectations. These data are important in informing discussions with patients regarding the likelihood of clinical benefit and its duration. Furthermore, it is important that we can make realistic estimates of benefit from standard therapies when considering when to refer for clinical trials of novel agents. These data also emphasise the clinicopathological heterogeneity of metastatic TNBC, with 39% of patients over 60 years of age, 13% of patients presenting with de novo disease, and 29% presenting with non-visceral disease. These characteristics, along with the different patterns of metastatic spread, suggests that molecular subtypes by gene expression (basal-like categories BL1 and BL2, immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen classes) [5,24,25]. may be associated with different outcomes in aTNBC. This inter-patient heterogeneity is reflected in the different treatment regimens used. For example, capecitabine is frequently used in first line and was shown to be beneficial in two multicentre single-arm phase II studies demonstrating a median time to progression (TTP) of 4e5 months and an ORR of 28e30% irrespective of the hormone-receptor status [26,27]. Capecitabine has also been shown to be efficacious in a retrospective series of TNBC patients [28]. Likewise, the use of taxanes is common in early lines and is supported by single-arm trials [29], studies comparing different schedules [30,31] and agents [32e34] and experiences translated from the adjuvant setting [35] showing mixed outcomes and regardless of receptor status. The role of anthracyclines is often limited by their use for early-stage breast cancer but has been tested in randomized trials versus different regimens confirming heterogeneous ORR of 10%e50% [36e42]. In combination with other agents they are associated with even higher ORR up to 60% [43e45]. Eribulin improved OS up to 13.1 months in a randomized phase III study of all-comers who had received two to five previous therapeutic lines compared to treatment of physician's choice, with 19% of them having a triple-negative histology [17]; the benefit in

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OS was maintained in aTNBC patients in a subsequent pooled analysis of two trials [46]. Interestingly, no prospective trials demonstrate a survival advantage for the use of platinum compounds compared to other regimens [47] in the unselected TNBC population. However, platinum is recognised to be particularly effective in patients with altered DNA repair pathways (e.g., BRCA germline mutation carriers) [48,49]: for example, in the TNT trial patients with TNBC were randomized to receive either Docetaxel or Carboplatin and in the subset of BRCA1 or BRCA2 germline mutation carriers the use of platinum led to improved PFS compared to the taxane [49]. In a further phase II study, single-agent Cisplatin produced an 80% response rate in BRCA1 mutation-associated metastatic disease [50]. Based on available trials, there is no clear evidence that nonBRCA-mutant metastatic TNBC patients benefit specifically from platinums as compared to other agents, although several studies are ongoing to evaluate their clinical activity. For example, a study is currently testing Cisplatin with or without Veliparib in advanced TNBC or BRCA mutation-associated breast cancer patients (NCT02595905). Vinorelbine has been investigated in different lines and with ORR ranging from 25 to 45% also in heavily pretreated subjects [51e54], whereas single-agent gemcitabine proved to be active and safe but only in small experiences [55,56] and certainly less effective compared to anthracyclines [57]. Our study has several limitations. First, the analysis is retrospective and has been conducted in a single centre on a small number of patients that may not reflect the outcomes in the general cohort. Also, a significantly higher number of subjects are referred to our Institution for consideration of clinical trials and in our study a proportion ranging between 7.5 and 12.9% were treated with investigational approaches across the first four lines of therapy. 2e3% of breast cancer patients have been previously found to enrol in clinical trials [58]. Thus, our caseload may not reflect the general population of advanced TNBC patients. Moreover, the ORR analysis has been conducted on a definition of treatment failure based on clinical, radiological and biochemical findings at different time intervals, which may not adhere to RECIST requirements [59]. An individualized approach is required to prolong survival and improve quality of life in patient with metastatic TNBC. Clinicians should take into account several factors in the decision-making, including patient preferences, general health status, tumour burden and previous treatment and related toxicities. It is important to recognise the attrition rate with each subsequent lines of therapy: relatively low numbers of patients with aTNBC go on to receive later lines of therapy. Our study also highlights the relevance of the DFI as predictor of response to first-line treatment. Nevertheless, even for patients who experienced a longer DFI, PFS remains short and ORR low. In summary, enrolment within clinical trials investigating novel agents should be considered in patients with aTNBC at an early stage in their treatment pathway and particularly in those with a short DFI. Conflicts of interest The authors have no conflict of interest to declare. Funding source The authors wish to acknowledge the support of the Royal Marsden NIHR Biomedical Research Centre for Cancer. Ethical approval This research project has been reviewed and approved by The Committee for Clinical Review of The Royal Marsden NHS

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