Annals of Oncology Advance Access originally published online on June 20, 2008
Annals of Oncology 2008 19(11):1847-1852; doi:10.1093/annonc/mdn395
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breast cancer |
Platinum-based chemotherapy in triple-negative breast cancer
Breast Unit, Royal Marsden NHS Foundation Trust, London
* Correspondence to: Prof. I. E. Smith, Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK. Tel: +44-20-7808-2751; Fax: +44-20-7352-5441; E-mail: ian.smith{at}rmh.nhs.uk
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Abstract |
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Background: Experimental data suggest that triple-negative (TN) breast cancer may have increased sensitivity to platinum-based chemotherapy but clinical data are limited. We present our long-term results with platinum-based chemotherapy for TN breast cancer.
Patients and methods: In all, 94 (17 TN), 79 (11 TN) and 155 (34 TN) patients receiving platinum-based chemotherapy in neo-adjuvant/adjuvant and advanced setting were included. Response rates and outcome were compared for TN tumours versus others.
Results: Neo-adjuvant complete response rates were significantly higher for TN tumours (88%) than others (51%; P = 0.005). The 5-year overall survival (OS) for TN tumours following adjuvant/neo-adjuvant chemotherapy was 64% [95% confidence interval (CI) 44% to 79%] compared with 85% (95% CI 79% to 90%) for others. Five-year disease-free survival for TN tumours was 57% (95% CI 37% to 73%) compared with 72% (95% CI 64% to 78%) for others. For patients with advanced breast cancer, overall response rates were 41% for TN tumours and 31% for others (P = 0.3). Patients with TN tumours had a significantly prolonged progression-free survival of 6 months compared with 4 months for others (P = 0.05), though the OS was not significantly different between the two groups (11 versus 7 months).
Conclusion: Platinum-based chemotherapy achieves increased response rates for TN tumours, with a trend towards worse survival in early breast cancer through an improved survival in advanced disease. Prospective randomised trials are warranted.
Key words: breast cancer, early and advanced, platinum chemotherapy, triple-negative
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introduction |
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In recent years, the term ‘triple-negative’ (TN) breast cancer has emerged to describe those cancers which do not express oestrogen receptor (ER), progesterone receptor (PgR) or overexpress human epidermal growth factor receptor 2 (Her2) [1]. Around 12%–20% of breast cancers are TN [1–3]. Treatment options for TN breast cancers are limited because of lack of targeted treatments. It has been postulated that their phenotypic and molecular similarity to BRCA1-associated breast cancers might prove useful in terms of treatment [4]. There is increasing evidence that the DNA repair defects characteristic of BRCA1-related cancers, especially defective homologous recombination, confer sensitivity to certain systemic agents, which could be relevant by extrapolation to the treatment of TN breast cancers [5, 6]. In vitro studies of BRCA1-associated breast cancers have shown increased sensitivity to agents that bring about interstrand cross-links, such as the bifunctional alkylating agent, mitomycin C and platinum drugs [5, 6]. So far, there are no major clinical studies to substantiate this although trials are under way or planned [7, 8]. In a phase II study, Garber et al. [9] have shown a pathological complete remission rate of 21% with neo-adjuvant cisplatin.
For other reasons, we have considerable clinical experience with the use of platinum agents in patients with breast cancer in neo-adjuvant, adjuvant and metastatic settings [10–18]. In view of renewed interest in the use of platinum salts in patients with TN tumours, we have retrospectively reviewed patients within our database to assess outcome in those treated with platinum-based chemotherapy.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
From the Royal Marsden prospectively maintained breast unit database, 541 patients who had received platinum-based chemotherapy in neo-adjuvant, adjuvant or metastatic setting were identified. Triple receptor data for ER, PgR and Her2 receptor were not available for the patients treated in early 1990s; hence, the paraffin blocks for patients with ER-negative disease were identified and tested for PgR and Her2. These paraffin blocks were stored at room temperature in a standard way and there was minimal loss of antigens due to storage of the blocks. For patients with ER-positive disease at diagnosis, PgR and Her2 testing was not done.
treatment, response assessments and follow-up
Details of the regimens used here and their outcomes are described in detail elsewhere [10, 11, 13].
adjuvant and neo-adjuvant.
Patients received postoperative or neo-adjuvant infusional 5-fluorouracil 200 mg/m2 by daily 24-h continuous infusion via a Hickman line for 18 weeks with epirubicin 60 mg/m2 i.v. and cisplatin 60 mg/m2 i.v. both repeating three weekly (infusional ECisF) for six courses as part of the adjuvant TRAFIC trial [13] or neo-adjuvant TOPIC trial [11]. Carboplatin was substituted for cisplatin in the event of renal toxicity, peripheral neuropathy or persistent emesis. The carboplatin dose was calculated according to renal function with an area under curve (AUC) = 5.
assessment of neo-adjuvant response.
Primary tumours were assessed at each 3-week visit for chemotherapy and again 3 weeks after the last course. Response was assessed according to standard World Health Organisation (WHO) criteria [19] as follows: complete response (CR) was defined as the clinical disappearance of palpable disease in the breast for 
4 weeks; partial response (PR) was defined as 50% decrease in the product of the tumour’s two longest perpendicular diameters for a duration of 4 weeks; progressive disease (PD) was defined as a 25% increase in the product of one or more of the measurable lesions of the appearance of a new lesions. Patients were assessed both by physical examination before each chemotherapy cycle and an ultrasound was carried out after every two cycles to assess response. Following completion of chemotherapy and local treatment, patients were assessed three monthly for 2 years, six monthly until 5 years after randomisation and annually thereafter.
Some patients who attained a clinical and radiological CR did not undergo surgery and received radical radiotherapy only [16, 20].
metastatic or advanced disease.
Patients with metastatic or advanced disease received treatment with MVP: mitomycin C 6 or 8 mg/m2 i.v. (only given during courses 1, 2, 4 and 6, if patients received 8 mg/m2, maximum dose 14 mg), vinblastine 6 mg/m2 i.v. (maximum dose 10 mg) and cisplatin 50 mg/m2 i.v. on day 1 [10]. Carboplatin was substituted for cisplatin in the event of renal toxicity, peripheral neuropathy or persistent emesis. The carboplatin dose was calculated according to renal function with an AUC = 5.
Clinical assessment of tumour response as well as clinical examination and full blood count test was carried out before each cycle. Formal radiological assessment of response by computed tomography or X-ray was undertaken before start of first cycle, after three cycles and after six cycles or at the end of treatment if earlier. Standard WHO criteria were used to define response before 2002 [19]. Response evaluation criteria in solid tumors were used to assess response thereafter [21].
assessment of TN status
Tumours from all patients were assessed or reassessed (if initial results already available) for ER, PgR and Her2 status in a central reference laboratory in the Royal Marsden Hospital. ER and PgR were determined by immuno-histochemistry (IHC) and graded from 0 to 8 (Allred score). Scoring >2 was considered as positive. Her2 was determined initially by IHC (HercepTest DAKO) and graded from 0 to 3+. Patients were defined as having TN breast cancer if ER, PgR and Her2 were all negative. If any of the three receptors was positive, patients were categorised as ‘others’ and this group was compared with the TN patients.
statistical considerations
The patient characteristics of the two treatment arms (TN versus others) were compared by means of the chi-squared test with Yates correction for categorical data or the Mann–Whitney test for quantitative or ordinal data. Survival curves were constructed by the Kaplan–Meier method and compared by means of the log-rank test. All P values were two sided. Disease-free survival (DFS) and overall survival (OS) were measured from the date of the platinum-based chemotherapy until recurrence in any site or death from any cause (DFS) or until death from any cause (OS). For metastatic patients, progression-free survival (PFS) was measured from the date of platinum-based chemotherapy until a progression in any site or death from any cause. Response to treatment (CR/PR/stable disease(SD)/PD) was compared by the Mann–Whitney test. Overall response rates were compared by Fisher's exact test.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
Patient flow chart is shown in Figure 1. Of the 541 patients, 328 (61%) patients had available receptor data. Of these, 62 (19%) patients had TN breast cancer.
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neo-adjuvant/adjuvant.
Ninety-four patients for whom tumour blocks were available (time period of treatment June 1991 to April 1998) received platinum-based neo-adjuvant chemotherapy, and of these, 17 (18%) patients had TN tumours. The median age of patients with TN tumours was 50 years (range 33–58) compared with 46 years (range 26–61) for others (P = 0.4). Patients with TN tumours were significantly more likely to have grade 3 disease (12 of 17) compared with those without (29 of 77; P = 0.01); the pathology was comparable in the two groups, 16 of 17 (94%) had invasive ductal cancers in TN group compared with 59 of 77 (77%) in the other group (P = 0.2). Of the 17 patients in the TN group, seven (42%) patients had T2 disease, five (29%) patients had T3 and five (29%) patients had T4 disease; of the 77 patients in the other group, 30 (39%) patients had T2 disease, 34 (44%) had T3 and 13 (17%) patients had T4 disease. Nodal status was not available in all patients. Of the 17 patients in the TN group, 11 (65%) patients did not undergo surgery compared with the 23 of 77 (30%) patients from the other group (P = 0.007).
Seventy-nine patients for whom blocks were available (time period December 1993 to January 2001) received adjuvant chemotherapy with platinum-based chemotherapy and of these, 11 (14%) patients had TN tumours (median age 46 years; range 33–61) compared with 68 patients labelled as others (median age 48.5 years; range 26–64; P = 0.4). Patients with TN tumours were significantly more likely to have grade 3 disease (9 of 11) compared with those without (30 of 68; P = 0.01); the pathology was comparable in the two groups, 10 of 11 (91%) had invasive ductal cancers in TN group compared with 51 of 68 (75%) in the other group (P = 0.5).
On combining the data for adjuvant and neo-adjuvant groups, 28 (16%) patients had TN tumours compared with 145 without TN phenotype. The median age for those with TN tumours was 48.5 years (range 26–64) compared with 46 years (range 33–61) for others (P = 0.6); patients with TN tumours were significantly more likely to have grade 3 disease [21 of 28 (75%)] compared with others [59 of 145 (41%)] and pathology was comparable between the two groups; 26 of 28 (93%) patients with TN tumours had invasive ductal carcinoma compared with 110 of 145 (76%) others.
metastatic/locally recurrent.
In all, 155 patients for whom blocks were available were treated for locally recurrent or metastatic disease (time period August 1991 to June 2006) with platinum-based chemotherapy, and of these, 34 (22%) patients had TN tumours. Demography of these patients is shown in Table 1. Patients in the TN group had a significantly shorter time to commence platinum-based treatment from the time of being diagnosed with metastatic disease (7 versus 17 months; P = 0.03). As shown, a total of 120 of 155 (77%) had previously been treated with anthracyclines and 125 of 155 (81%) with taxanes. All patients had received at least one prior chemotherapy regimen either as adjuvant therapy or for advanced disease.
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response rates and survival
neo-adjuvant.
Table 2 shows the response rates, the pattern of recurrence and survival in the two groups. Fifteen patients with TN tumours achieved CR (88%) compared with 39 (51%) others (P = 0.005); the overall response rate (CR and PR) was 100% in TN tumours and 72 of 77 (94%) in others (P = 0.6).
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Pathological CR rates could not be compared since 65% (11 of 17) of patients within the TN group and 30% (23 of 77) in the other group did not undergo surgery because of CR, according to the unit policy at the time [20]. One out of six (17%) patients with TN tumours who underwent surgery had a pathological CR compared with 5 of 54 (9%) patients in the other group (P = 0.5).
The DFS and OS in the two groups was not significantly different although there was a DFS trend against the TN group with a median of 68 months (range 4–122) compared with 90 months (range 56–123) for others. The median OS has not been reached in either group. The 5/10-year OS in patients with TN tumours was 65%/53% compared with 80%/65% for others.
combined neo-adjuvant and adjuvant.
On combining the data for patients who received adjuvant and neo-adjuvant chemotherapy, as shown in Figure 2A and B, the DFS and OS of the two groups were not significantly different. The median DFS was 79 months for patients with TN tumours versus 109 months for others. The 5/10-year DFS in patients with TN tumours versus others was 64%/53% versus 85%/69%, respectively. The median OS for patients with TN tumours was 125 versus 169 months for others. The 5-/10-year OS in patients with TN tumours versus others was 57%/46% versus 72%/48%, respectively.
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metastatic/locally recurrent.
Table 3 shows the response rate and survival for patients who received platinum-based chemotherapy for locally recurrent or metastatic cancer. There was no significant difference in the response rate between the two groups. Of the 34 patients with TN tumours, one (3%) patient attained CR and 13 (38%) PR; of the 121 patients in the other group, two (1%) attained CR and 36 (30%) PR (P = 0.3). The overall response rate (CR + PR) for patients with TN tumours was 41% [14 of 34; 95% confidence interval (CI) 25% to 58%] compared with 31% (38 of 121; 95% CI 23% to 40%) for others (P = 0.3).
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The median PFS for patients with TN tumours was significantly longer at 6 months compared with 4 months for others (P = 0.05) though the OS (11 and 7 months, respectively) was not significantly different (P = 0.1) Figures 3A and B.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Triple-negative breast cancer is a high-risk breast cancer in view of younger age, poorly differentiated tumours and shortened survival [1, 2, 22, 23] that lacks the benefit of targeted therapies. Bauer et al [2] have shown in population-based study comprising 51074 patients with breast cancer that patients with TN phenotype were significantly more likely to be under age 40, had more advanced stage at diagnosis, were more likely to have a poorly differentiated histology and regardless of stage at diagnosis, women with TN breast cancers had poorer survival than those with other breast cancers. No specific systemic regimen is currently recommended for the treatment of these patients because of the lack of data on which to base treatment selection. There is therefore current interest in the observation that cell lines of the BRCA1 phenotype and by extrapolation TN cancer cell lines in general appear to be highly sensitive to platinum salts [1, 5, 24].
The clinical activity of cisplatin and carboplatin against unselected breast cancer was found many years ago to be modest with an overall response rate of 32%–54% [18, 25, 26] and clinical experience with them is therefore limited. For reasons described elsewhere [10, 17, 18], we started investigating cisplatin/carboplatin combinations over 10 years ago both as adjuvant/neo-adjuvant therapy and in advanced disease. This retrospective analysis of these data provides some clinical support for the experimental data. The limitations of the data must be acknowledged. The neo-adjuvant experience was assessed by achievement of clinical response only and not pathologic response because 36% patients did not go to surgery. Also, the combination regimens in neo-adjuvant/adjuvant setting included anthracycline, another active agent; hence, it is difficult to know whether the response was to the anthracycline or the platinum salt or both, though we felt that these data would add to the debate of using platinum combinations in patients with TN breast cancer.
Response rates with neo-adjuvant therapy were significantly higher for TN tumours than the rest, and there was a nonsignificant trend for this in patients with metastatic disease. On the other hand, others have reported similar findings with noncisplatin regimens. Carey et al. [27] showed that the clinical response to doxorubicin and cyclophosphamide was markedly higher among patients with TN tumours than among those with non-TN tumours. Pathologic complete response to neo-adjuvant chemotherapy was higher in patients with TN tumours [27]. Rouzier et al. [28] showed that the TN and Her2-positive subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative chemotherapy than the luminal and normal-like cancers.
Despite this initial sensitivity to chemotherapy, several studies have shown that the TN subtype carries a poor prognosis [2, 29–31]. We have shown in a group of 245 breast cancer patients uniformly treated with adjuvant anthracycline-based chemotherapy that TN phenotype was significantly associated with shorter metastases-free survival and breast cancer-specific survival [31]. Bauer et al. [2] confirmed the same.
Our results for early breast cancer show no significant difference in DFS or OS between TN cancers and the rest with adjuvant or neo-adjuvant platinum-containing chemotherapy though it must be emphasised that the dataset is significantly underpowered to show a true ‘noninferiority’ in outcome. Nevertheless, there was a trend towards a worse prognosis for TN tumours that might have reached significance with larger numbers.
Our data in metastatic disease was more supportive of the hypothesis, in that patients with TN tumours had a significantly longer PFS than the rest and an associated trend towards improved OS. This was despite the fact that the patients with TN disease were younger (median 47 versus 53 years), had a shorter time to development of metastases (28 versus 36 months) and had a shorter DFS on anthracyclines (12 versus 15 months) and similar disease-free interval on taxanes (5 months). It is worth noting that the metastatic cohort patients also received mitomycin C along with the platinums which could have added to the better outcome.
In conclusion, our results suggest that there may indeed be some clinical gain with platinum salt chemotherapy for TN tumours but if so it is likely to be modest. Prospective randomised trials are now indicated. One such is the UK phase III Triple Negative Trial in which patients with advanced TN breast cancer are randomised to first-line carboplatin or docetaxel, with cross-over on progression [7]. A nonrandomised phase II cisplatin study is also under way in the United States [32].
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Acknowledgements |
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We would like to thank Jessica Stuart-Harris and Amaka Ejibe for taking out the blocks and the Cridlan fund for sponsoring Dr Arnedos's research.
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Footnotes |
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Current address: Oncology Centre, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK 
Received for publication January 8, 2008. Accepted for publication May 21, 2008.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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