- Email: [email protected]
CMF revisited in the 21st century
reviews
Annals of Oncology
Annals of Oncology 23: 305–311, 2012 doi:10.1093/annonc/mdr309 Published online 29 June 2011
CMF revisited in the 21st century E. Munzone1*, G. Curigliano1, H. J. Burstein2, E. P. Winer2 & A. Goldhirsch1 1
Division of Medical Oncology, European Institute of Oncology, Milan, Italy; 2Department of Medical Oncology, Breast Oncology Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
Received 4 May 2011; accepted 6 May 2011
‘‘Don’t bury me ’cause I’m not dead yet.’’ Elvis Costello
introduction A pioneer in the field of medical oncology, classical CMF (combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil) is facing hard times as most medical oncologists prefer the so-called ‘third-generation regimens’ with anthracyclines and taxanes as adjuvant treatment for women with operated breast cancer. Because our field of medical oncology is only a few decades old, CMF has been one of our leaders for much of our history, leaving an indelible mark on our specialty. Since 3 July 1973, when the first patient was enrolled in the first adjuvant Milan trial [1], CMF has certainly been a milestone in the adjuvant treatment of women with breast cancer. The success of CMF remained unchallenged until the mid80s when anthracyclines appeared on the scene. Subsequently, the stature of CMF was further threatened in the nineties when the taxanes made a dramatic entrance on the scene of chemotherapy worldwide. *Correspondence to: Dr E. Munzone, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489405; Fax: +39-02-57489457; E-mail: [email protected]
In this brief review, we would like to pay a tribute to CMF, highlighting the great contribution that it made to oncology and particularly to the treatment of women with breast cancer. As clinically oriented medical oncologists, we would like to investigate whether, after observing the classical CMF being overtaken by more modern regimens, it should continue to have a place in the care of at least a subgroup of patients.
portrait of CMF: deeds and misdeeds We can set the birth of the classical CMF in Milan (Italy) in the early seventies, although few years before Paul P. Carbone reported initial National Cancer Institute data on a quadruple drug regimen containing cyclophosphamide, methotrexate, fluorouracil and prednisone for advanced breast cancer patients [2]. CMF was originally designed to resemble the MOPP (combination chemotherapy with mechlorethamine, vincristine, procarbazine and prednisone) scheme used successfully in the treatment of Hodgkin’s disease, which includes 2 weeks of cytotoxic treatment and 2 weeks interval without treatment for recovery [3]. In 1976, CMF efficacy as adjuvant treatment for node-positive breast cancer patients was firstly reported by Bonadonna et al. [1]. These results, along with those reported in a similar population of patients by the National Surgical Adjuvant Breast and Bowel Project (NSABP), raised hopes that chemotherapy could have a more central role in the primary management of breast cancer [4].
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
Over the last 35 years, classical CMF (combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil) has been a milestone in the adjuvant treatment of women with breast cancer. However, after an early burst of success lasted just over 10 years, classical CMF has been supplanted by ‘third-generation’ regimens containing taxanes and anthracyclines. Questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients and particularly, recent retrospective data support the fact that the CMF might have a role in the treatment of patients with triple-negative breast cancer. One possible justification for supporting this role of CMF may be sought in the mechanism of action of drugs used in the regimen, as triple-negative cells may be sensitive to alkylating agents that cause double-strand breaks in DNA. The lesson learned from the CMF could lead us to identify new combinations of drugs that could include the optimal chemotherapy backbone for triplenegative breast cancer such as platinum compounds or alkylating agents or Poly (ADP-ribose) polymerase inhibitors. In conclusion, although we have learned a lot from the use of CMF, many questions are still open and hopefully stimulate our thinking, as clinicians, leading us to find new and more effective ways to treat breast cancer. Key words: adjuvant chemotherapy, alkylating agents, breast cancer, classical CMF, triple-negative, tumor heterogeneity
reviews
Annals of Oncology
CMF-like regimens and the classical CMF During the following years, all regimens containing the three ingredients—cyclophosphamide, methotrexate and fluorouracil—have become collectively known as CMF, despite
significant differences in schedule, dosage and route of administration compared with the ‘classical regimen’ initially tested in Bonadonna’s studies. These modified schedules have been widely used without the support of a direct comparison between the classical CMF regimen and the variants [8]. Indeed, over the years, many oncologists have changed the classical CMF schedule by switching cyclophosphamide administration from oral to i.v., based on the empirical assumption that compliance would have been better. However, no randomized trial has directly compared CMF regimens in which all three drugs were given i.v. on days 1 and 8 with those using 14 days of oral cyclophosphamide and MF i.v. on days 1 and 8, either in the adjuvant or advanced disease (Table 1). Only two studies compared classical CMF with i.v. CMF (schedule 1, 21) in metastatic breast cancer patients [12, 13]. The results of the European Organisation for Research and Treatment of Cancer trial showed a better response rate and time to progression for the classical CMF, and further emphasized the importance of cyclophosphamide dose intensity delivered orally as compared with i.v. [13]. However, there is currently no evidence that oral cyclophosphamide is either more toxic or more or less effective than an equivalent dose of i.v. cyclophosphamide [14]. Moreover, during the first 10 years, adjuvant classical CMF survived many other schemes including combination with other drugs, as leukeran, nitrogen mustard, and vincristine,
Table 1. CMF-like and cCMF trials: doses, duration, and schedule Trial DOSES
EORTC
Toronto, Canada
No. of patients 452
133
Setting
Trial design
Doses and schedule (mg/m2)
Duration
Outcome
Ref.
Adj
LD CMF versus no treatment i.v. CMF versus halfdose CMF i.v. CMF versus no treatment i.v. CMF versus cCMF
C 50 os, days 1–14, 28; M 15 i.v., days 1, 8–28; F 350 i.v., days 1, 8–28 C 600/300 i.v., 1–21; M 40/20 i.v., 1–21; F 600/300 i.v., 1–21 C 600 i.v., 1–21; M 40 i.v., 1–21; F 600 i.v., 1–21 C 600 i.v., 1–21 or 100 os, 1–14, 28; M 40 i.v., 1–21 or 1, 8–28; F 600 i.v., 1–21 or 1, 8–28 C 600 i.v., 1–21 or 100 os, 1–14, 28; M 40 i.v., 1–21 or 1, 8–28; F 600 i.v., 1–21 or 1, 8–28 C 100 os, days 1–14, 28; M 40 i.v., days 1, 8–28; F 600 i.v., days 1, 8–28 C 400 i.v., days 1–8; M 40 i.v.; F 600 i.v.; L 15 i.v. C 100 os, days 1–14, 28; M 40 i.v., days 1, 8–28; F 600 i.v., days 1, 8–28
24
CMF better
[5]
NA
i.v. CMF better
[6]
12 cycles
CMF better
[7]
NA
No difference
[8]
NA
cCMF better
[9]
6 or 12 cycles
No difference
[10]
1 or 6 cycles
cCMF ·6 better
[11]
3 or 6 cycles
cCMF ·6 better (cCMF ·3 = cCMF ·6 >40 years and ER+)
[12]
Met
INT, Milan
90
Adj (N2, ER2)
Italian trial
68
Met
254
Met
i.v. CMF versus cCMF
DURATION Tancini
466
Adj
cCMF ·6 versus ·12
Ludwig
1275
Adj
IBCSG-VI; GBCSG
735; 289
Adj
PeriopCMF versus cCMF cCMF ·3 versus ·6
SCHEDULE
EORTC Trial 10808
months
C, cyclophosphamide; M, methotrexate; F, fluorouracil; c, classical; EORTC, European Organisation for Research and Treatment of Cancer; LD, low dose; INT, Istituto Nazionale Tumori; ER, estrogen receptor; Adj, adjuvant; Met, metastatic; os, oral; NA, not assessed; N, node; Periop, perioperative; L, leucovorin; GBCSG, German Breast Cancer Study Group; IBCSG, International Breast Cancer Study Group.
306 | Munzone et al.
Volume 23 | No. 2 | February 2012
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
The original CMF regimen consisted of cyclophosphamide (100 mg/m2 orally from day 1 to 14), methotrexate (40 mg/m2 i.v. on days 1 and 8), and fluorouracil (600 mg/m2 i.v. on days 1 and 8), repeated every 4 weeks. In 1989, during the Karnofsky lecture at the American Society of Clinical Oncology, Bonadonna [5], based on the studies of the Istituto Nazionale Tumori started in 1973, 1975 and 1985, concluded that in premenopausal women with primary node-positive disease, classical CMF for six cycles could be considered a standard. The role of tamoxifen in premenopausal women was not yet understood and part of the benefit in younger women was also attributed to the effect on the endocrine ovarian suppression exerted by the CMF. In postmenopausal women with estrogen receptor (ER)positive tumors, tamoxifen was recommended, while women with ER-negative tumors had an advantage from the classical CMF. In women with node-negative and ER-positive tumors, tamoxifen was recommended, while in the ER-negative tumors, classical CMF for six cycles offered a significant advantage both on relapse-free survival (RFS) and overall survival (OS) [6, 7].
reviews
Annals of Oncology
showing its superiority in terms of disease-free survival (DFS) and OS [15–18]. In 2005, Bonadonna et al. [19] further emphasized that CMF after 30 years is still an effective regimen with long-lasting benefit maintained in patients with both favorable and unfavorable prognostic indicators, at the cost of minimal long-term sequelae.
Table 2. Anthracyline-based trials compared with classical CMF Trial
No. of patients
Nodes
Anthracycline regimen (dose mg/m2)
Outcome
Ref.
Onco-Francea Sweden NSABP B-15 GUN3-Italy Belgium NCI-C MA.5 SWOG8897 NSABP B-23
249 43 2194 220 777 710 2691 2008
Positive Positive Positive Positive Positive Positive Negative Negative
A30VCF ·12 A40C ·6 A60C ·4 6 CMF i.v. CMF/E75Vc ·6 E60C 1–3/E100C ·8 CE60F 1–8 ·6 FA30C 1–8 ·6 A60C ·4
AVCF better (OS/DFS) No difference No difference No difference No difference CEF better (OS/DFS) FAC better (OS/DFS) No difference
[21] [22] [23] [14] [15] [16] [17] [18]
a
Classical CMF ·12 cycles. C, cyclophosphamide; M, methotrexate; F, fluorouracil; A, doxorubicin; V, vinca alkaloid; OS, overall survival; DFS, disease-free survival; NSABP, National Surgical Adjuvant Breast and Bowel Project; E, epirubicin; Vc, vincristine.
Volume 23 | No. 2 | February 2012
doi:10.1093/annonc/mdr309 | 307
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
the decline of CMF and the rise of anthracyclines and taxanes Although after 30 years of follow-up CMF continues to show a significant benefit for RFS and OS compared with no chemotherapy [20], classical CMF was used as a comparator only in few clinical trials. In the direct comparison, a total of eight trials of anthracyclines versus classical CMF have been identified and summarized in Table 2 [20, 24–30]. Three of them showed a better OS/DFS for the anthracycline-containing arm [20, 28, 30] and the remaining trials showed no difference. In the Early Breast Cancer Trialists’ Collaborative Group overview, among 11 studies of anthracycline-based regimens compared with CMF (total N = 5942 patients), only one study found a lower recurrence rate for CMF treatment, but this trial compared only one cycle of an anthracycline-containing regimen with six cycles of low-dose i.v. CMF [31]. The meta-analysis showed that compared with CMF (any schedule), anthracyclinebased regimens produced a 12% proportional reduction in recurrence (P = 0.006; absolute benefit 3.2%) and an 11% proportional reduction in mortality (P = 0.02; absolute benefit 2.7%) [32]. However, the patient population in this meta-analysis included both pre- and postmenopausal women (70% of the women in this analysis were aged <50 years) with both hormone receptor-positive and hormone receptor-negative disease. Specifically in the subset of women aged <50 years, there was a 13% reduction in risk of recurrence (P = 0.01) and a nonsignificant (P = 0.09) reduction in mortality with anthracycline-based regimens compared with CMF [33]. In advanced breast cancer, the taxanes, docetaxel and paclitaxel, are among the most active chemotherapeutic agents currently in use. However, in the adjuvant setting, trials of taxanes have not been conclusive in showing an advantage over CMF mainly because no direct comparison has been done [34–37].
Two trials, Cancer and Leukaemia Group B (CALGB) 9344 and NSABP B-28, compared anthracycline–taxane experimental regimens with the standard doxorubicin and cyclophosphamide regimen (AC) and, thus, were indirectly comparable with classical CMF, based on the results of the NSABP B-15 trial [25]. CALGB 9344 trial [36] compared four cycles of 60–90 mg/m2 doxorubicin and cyclophosphamide followed by 175 mg/m2 paclitaxel infused over 3 h with four cycles of 60–90 mg/m2 doxorubicin and cyclophosphamide alone. The resulting proportional reduction in mortality was 13%. Results showed that 60 mg/m2 doxorubicin followed by 175 mg/m2 paclitaxel is favored clinically. Unfortunately, the study did not report on activity outcome for the three doxorubicin groups separately, which would have provided a more accurate measure of activity for the 60 mg/m2 doxorubicin followed by 175 mg/m2 paclitaxel regimen. The second anthracycline–taxane trial, the NSABP B-28 [38], compared an almost identical anthracycline–taxane regimen (four cycles of AC60) with that in the CALGB 9344 and showed no significant survival benefit. Although longer treatment can improve outcome, the addition of four cycles of paclitaxel to four cycles of AC did not improve OS consistently compared with AC alone. Of the 19 trials assessing the role of taxanes in the adjuvant treatment of breast cancer, there are four trials comparing the taxane-containing regimen with an anthracycline-based treatment known to be more active than classical CMF as summarized in Table 3 [39–42]. Interestingly, among these trials, only two have anthracycline-based regimens, which have previously shown superiority over classical CMF [28, 43], as a control arm. Nevertheless, the other two trials have a sequential anthracycline–CMF treatment as a control arm, which is very similar to the sequential epirubicin–CMF regimen proven to be more effective than CMF in the UK trial [43]. In these trials, RFS was significantly better for the taxane arm in three of them and data about OS are not yet conclusive. However, there are some limitations in interpreting these results from recently reported taxane-based adjuvant trials that consist in the use of an anthracycline-based control arm that is
reviews
Annals of Oncology
Table 3. Taxane trials with an anthracycline-containing regimen as control arm with proven superiority to cCMF Trial
No. of patients
Nodes
Design
Control arm
Outcome
Ref.
BIG 02-98
2890
Positive
1355
Any
A75 ·4 / cCMF ·3; A60C ·4 / cCMF ·3 A75 ·4 / CMF 1–8 i.v. ·4
Better DFS for T arms; OS NA Better RFS for P arms; OS NA
[28]
ECTO MA.21
1500
Any
CEF ·6a
TACT
4162
Any
A / CMF; AC / CMF; A/ T / CMF; AT / CMF S / A / CMF; S / AP / CMF; AP / CMF / S CEF; CEF 2 weeks / P; AC /P E / CMF or FEC; FEC / T
Better RFS for CEF or CEF 2 weeks / P No difference
E100 ·4 / cCMF ·4a
[29] [30] [31]
a
Superior over cCMF. c, classical; C, cyclophosphamide; M, methotrexate; F, fluorouracil; A, doxorubicin; DFS, disease-free survival; OS, overall survival; S, surgery; P, paclitaxel; E, epirubicin; T, taxotere; RFS, relapse-free surviva; ECTO, European cooperative trial in operable breast cancer; TACT, Taxotere as Adjuvant Chemotherapy Trial; NA, not assessed.
breast cancer is heterogeneous: is there a role for classical CMF in triplenegative disease? Questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients. Early studies suggested that Human Epidermal growth factor Receptor 2 (HER-2/neu)-positive tumors do not benefit from CMF-based chemotherapy that, by contrast, has a considerable effect in tumors with no or minimal expression of this oncogene. The notion that breast cancer is a heterogeneous disease has been around for many years, but in the past years, few investigators have had the perseverance to analyze the effects of adjuvant chemotherapy in clinically relevant subgroups (e.g. ER-negative or low-ER, intermediate-ER and ER-rich disease). More recently, intrinsically different subtypes of breast cancer based on genetic profile and Immunohistochemistry (IHC) determination of selected targets have been identified [44, 45]. Perou et al. [44] demonstrated that the phenotypic diversity of breast tumors was associated with corresponding gene expression diversity. Using this subset, the authors were able to identify four different molecular subtypes of breast cancer: ER-positive/luminal-like, basal-like, HER-2/neu-positive, and normal breast. Subsequent data expanded the classification to distinguish between luminal A and luminal B [45]. The recognition of a specific target or a feature within a homogeneous subgroup of patients results in the identification of specific and biologically targeted adjuvant treatments. NSABP B-13 and B-19 [46] randomized clinical trials carried out to evaluate the use of adjuvant chemotherapy for the treatment of patients with node-negative ER-negative tumors showed that both MF and CMF are effective therapies for patients with ER-negative tumors and negative axillary nodes. In patients aged £49 years, CMF results in a clearly better DFS and survival than does MF, whereas in patients ‡50 years of age,
308 | Munzone et al.
a benefit from both regimens is apparent, although it is less clear which regimen is more effective. Long-term findings of the NSABP B-20 trial [47] show that the benefit from adding CMF to tamoxifen is inversely related to the quantitative concentration of tumor ERs. A previous study by Rakha et al. [48] has suggested that the negative prognosis of the triple-negative phenotype may be alleviated by adjuvant chemotherapy. In that study, patients with triple-negative breast cancer who received adjuvant chemotherapy following primary surgery were uniformly treated with CMF. This raises the intriguing possibility that regimens including antimetabolites and high cumulative doses of alkylating agents such as cyclophosphamide may be more effective than anthracycline-based chemotherapeutic regimens in triple-negative tumors. A recent study in the preoperative setting further supports this hypothesis by clearly identifying p53mutant ER-negative tumors as those most sensitive to high-dose alkylating agents and allowing very high levels of pathological Complete Response in triple-negative tumors treated with doseintense cyclophosphamide [49]. In this context, CMF chemotherapy, being not inferior to anthracycline-containing therapy in patients with tumors lacking overexpression of topoisomerase II [50] or with HER-2/neu-negative breast cancer [51], may have a role as adjuvant therapy in patients with triplenegative tumors, particularly those patients with relatively small node-negative tumors. Falo et al. [52] recently published a trial in a series of operable breast cancer patients treated with primary CMF chemotherapy. In this series, 300 patients with operable breast cancer were treated with primary CMF1-8 i.v. HER-2/neu overexpression or amplification was found in 23.66% cases. Univariate analysis showed that response was similar in HER-2/neu-positive and -negative tumors (51.38% versus 47.36%, P = 0.6). Triplenegative tumors presented the highest response rate (64.9%). Patients with the combination of response to CMF and HER-2/ neu-negative tumors presented the best outcome. On the other hand, the association of no response to CMF and positive HER2/neu score was statistically related to poor DFS and OS. Furthermore, tissue blocks from patients of MA5 trial were recently analyzed for ER, progesterone receptor, HER2, Ki67, CK5/6 and epidermal growth factor receptor and for tissue microarray to determine the biological subtype [53]. The results showed that in the CEF (cyclophosphamide, epirubicin,
Volume 23 | No. 2 | February 2012
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
no more effective than classical CMF, the interference of the endocrine effects of chemotherapy in premenopausal patients with hormone receptor-positive tumors and, finally, the lack of subgroup analysis that differentiates node-positive from nodenegative patients.
reviews
Annals of Oncology
conclusions what we have learned from CMF? After an early burst of success lasted just over 10 years, classical CMF has been supplanted by more toxic and more expensive regimens, so-called third-generation regimens, containing taxanes and anthracyclines. However, while the CMF regimen is old and is a very ‘firstgeneration’ regimen, it certainly has at least three points in its favor. First, CMF has a safe and very well-known toxicity profile based on data now older than 35 years and well consolidated. Secondly, recent retrospective data support the fact that the CMF might have a role in the treatment of patients with triple-negative breast cancer. The last point—not to be underestimated—is certainly an economic point, CMF being a not-expensive scheme. Willing to look forward, we should ask how to take advantage of the positive points that we learned from the CMF, and especially how to use these strengths to improve our skills to treat breast cancer patients. One of the main limitations that we stressed throughout this review derives from the interference due to populations with hormone receptor-positive disease included in studies, which may benefit from chemotherapy. Furthermore, the data published so far, in most cases, were interpreted on heterogeneous populations including patients with either positive or negative axillary lymph nodes and with hormone receptors or HER-2/neu positive or negative. But when analyzed by subgroups, the proper niche of patients for each treatment may be identified. This point may serve as an opportunity for opening a discussion in favor of the use of
Volume 23 | No. 2 | February 2012
classical CMF chemotherapy, which might still have role, for instance, as effective adjuvant systemic therapy for triplenegative node-negative population [55]. One possible justification for supporting this role of CMF may be sought in the mechanism of action of drugs used in the CMF regimen. In vitro chemosensitivity studies have found that human cells lacking BRCA1, and to some extent other triplenegative cells, may be sensitive to drugs that cause doublestrand breaks in DNA, such as alkylating agents, [50] and less sensitive to doxorubicin, as well as to paclitaxel [56]. Moreover, methotrexate and 5-fluorouracil used in CMF regimens are both antimetabolites, which are more suitable for the higher proliferative index of triple-negative breast cancers [55]. To further support the notion of breast cancer heterogeneity, it has been recently reported that the category of triple-negative tumors can be additionally divided into subtypes [57]. In consequence, the response to various agents may differ depending on the intrinsic molecular subtypes. For example, as previously reported, the subgroup of p53-mutant ER-negative tumors has proved to be more sensitive to high-dose alkylating agents [49]. Another possible limitation is that over the years CMF has not been directly compared with a taxane-containing regimen, and this information is lacking especially within the triplenegative subgroup. For this purpose, it would be interesting to explore the combination of taxanes with alkylating agents or platinum compounds, which are the backbone of regimens for triplenegative breast cancers, compared with classical CMF. Finally, recent results from preclinical and clinical studies have highlighted poly (ADP-ribose) polymerase (PARP) inhibitors as one of the most promising ‘targeted therapies’ for metastatic triple-negative breast cancer, DNA repair being the intended ‘target’ [58, 59]. Looking at the future development of these agents, one challenging task might consist in further defining triplenegative patients most likely to respond to PARP inhibitors and determining the optimal chemotherapy backbone to combine with them. This direction is particularly important as these drugs move to the adjuvant setting because long-term toxic effects to normal tissues as a result of prolonged suppression of DNA repair have yet to be defined. In conclusion, although we have learned a lot from the use of CMF, many questions are still open and hopefully stimulate our thinking, as clinicians, leading us to find new and more effective ways to treat breast cancer.
disclosure The authors declare no conflict of interest.
references 1. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976; 294: 405–410. 2. Canellos GP, De Vita VT, Gold GL et al. Cyclical combination chemotherapy for advanced breast carcinoma. Br \Med J 1974; 1: 218–220. 3. Moore MR, Jones SE, Bull JM et al. MOPP chemotherapy for advanced Hodgkin’s disease. Prognostic factors in 81 patients. Cancer 1973; 32(1): 52–60.
doi:10.1093/annonc/mdr309 | 309
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
and fluorouracil) arm, patients with core basal tumors had a hazard ratio (HR) of 1.8 (log-rank P = 0.02) for OS relative to the other biological subtypes. In the CMF arm, there was no significant difference (HR 0.9, P = 0.7). The interaction between core basal status and treatment was borderline significant (P = 0.06). RFS differences did not reach significance. Authors concluded that data from this randomized trial support the hypothesis that anthracycline-containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal-like breast cancer. These results further support previous reports in which early breast cancer patients with negative hormone receptors have less or even no survival advantage with anthracycline-based adjuvant chemotherapy compared with non-anthracycline regimens [51, 54]. Recently, a retrospective study by Colleoni et al. highlights a larger magnitude of benefit of classical CMF in patients with triple-negative node-negative breast cancer after a median followup of 11 years. In this report, authors explored patterns of recurrence according to treatment received in a group of patients (n = 2257) enrolled in International Breast Cancer Study Group trials VII–IX with node-negative breast cancer, randomly assigned to receive classical CMF for three or six cycles with or without endocrine therapy versus endocrine therapy alone. Patients with triple-negative tumors were 303 (15%) and chemotherapy significantly improved 10-year DFS in this subtype group (73% versus 57%, P = 0.007) [55].
reviews
310 | Munzone et al.
26.
27.
28.
29.
30.
31.
32.
33. 34.
35.
36.
37. 38.
39.
40.
41.
42.
43.
patients with tamoxifen-nonresponsive tumours: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8: 1483–1496. De Placido S, Perrone F, Carlomango C et al. CMF vs alternating CMF/EV in the adjuvant treatment of operable breast cancer: a single centre randomised clinical trial (Naples GUN-3 study). Br J Cancer 1995; 71: 1283–1287. Piccart M, Di Leo A, Beauduin M et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate and fluorouracil in node-positive breast cancer. J Clin Oncol 2001; 19: 3103–3110. Levine MN, Pritchard KI, Bramwell VH et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 2005; 23: 5166–5170. Hutchins LF, Green SJ, Ravdin PM et al. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, nodenegative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 2005; 23(33): 8313–8321. Fisher B, Anderson S, Tan-Chiu E et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001; 19(4): 931–942. Ploner F, Jakesz R, Hausmaninger H et al. Randomized trial: one cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients. Onkologie 2003; 26(2): 115–119. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–1467. Buzdar AU, Singletary SE, Valero V et al. Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer: preliminary data of a prospective randomized trial. Clin Cancer Res 2002; 8: 1073–1079. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21: 1431–1439. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003; 21: 976–983. Piccart MJ, Lohrisch C, Duchateau L et al. Taxanes in the adjuvant treatment of breast cancer: why not yet? J Natl Inst Monogr 2001; 30: 88–95. Mamounas EP, Bryant J, Lembersky B et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005; 23: 3686–3696. Francis P, Crown J, Di Leo A et al. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 Randomized Trial. J Natl Cancer Inst 2008; 100: 121–133. Gianni L, Baselga J, Eiermann W et al. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol 2009; 27: 2474–2481. Burnell M, Levine M, Chapman J. A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21). J Clin Oncol 2007; 25 (Suppl): (Abstr 550). Ellis P, Barrett-Lee P, Bloomfield D et al. Preliminary results of the UK Taxotere as Adjuvant Chemotherapy (TACT) Trial. UK-CRUK trial. In 30th San Antonio Breast Cancer Symposium 2007 (Abstr 78). San Antonio, TX. 2007. Poole CJ, Earl HM, Hiller L et al. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 2006; 355(18): 1851–1862.
Volume 23 | No. 2 | February 2012
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
4. Fisher B, Carbone P, Economou SG et al. 1-phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med 1975; 292: 117–122. 5. Bonadonna G. Conceptual and practical advances in the management of breast cancer. J Clin Oncol 1989; 7(10): 1380–1397. 6. Fisher B, Redmond C, Dimitrov NV et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with nodenegative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 1989; 320: 473–478. 7. Mansour EG, Gray R, Shatila AH et al. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer. An intergroup study. N Engl J Med 1989; 320: 485–490. 8. Goldhirsch A, Colleoni M, Coates AS et al. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? Ann Oncol 1998; 9: 489–493. 9. Clahsen PC, Van de Velde CJH, Welvaart K. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organization for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. Cooperating Investigators. J Clin Oncol 1995; 13: 33–41. 10. Tannock IF, Boyd NF, DeBoer G et al. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 1988; 6: 1399–1487. 11. Zambetti M, Valagussa P, Bonadonna G. Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Updated results. Ann Oncol 1996; 7: 481–485. 12. Brandi M, De Nitrio A, Ditonno P et al. Oral versus intravenous CMF in metastatic breast cancer: a randomized trial. Int J Oncol 1994; 4: 559–565. 13. Engelsman E, Klijn JC, Rubens RD et al. ‘Classical’ CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC Breast Cancer Co-operative Group Phase III trial (10808). Eur J Cancer 1991; 27: 966–970. 14. O’Shaughnessy JA. Oral alkylating agents for breast cancer therapy. Drugs 1999; 58 (Suppl 3): 1–9. 15. Senn HJ, Jungi WF, Amgwerd R et al. Results of adjuvant LMF/BCG in N2 and N+ breast cancer. In Jones SE, Salmon SE (eds): Adjuvant Therapy of Cancer IV. Orlando, FL: Grune & Stratton 1984; 261–270. 16. Rivkin SE, Glucksberg H, Foulkes M. Adjuvant chemotherapy for operable breast cancer with positive axillary nodes. In Jones SE, Salmon SE (eds): Adjuvant Therapy of Cancer IV. Orlando, FL: Grune & Stratton 1984; 209–215. 17. Davis HL, Metter GE, Ramirez G et al. An adjuvant trial of L-phenylalanine mustard (L-PAM) vs cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F) and vincristine (V)—CMFV following mastectomy for operable breast cancer. Proc Am Soc Clin Oncol 1981; 22: (Abstr 246). 18. Howell A, Rubens RD, Bush H et al. A controlled trial of adjuvant chemotherapy with melphalan versus cyclophosphamide, methotrexate, and fluorouracil in breast cancer. Recent Results Cancer Res 1984; 96: 74–79. 19. Bonadonna G, Moliterni A, Zambetti M et al. 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ 2005; 330(7485): 217. 20. Misset JL, di Palma M, Delgado M et al. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil and vincristine versus cyclophosphamide, methotrexate and fluorouracil: final report after a 16year median follow-up duration. J Clin Oncol 1996; 14: 1136–1145. 21. Tancini G, Bonadonna G, Valagussa P et al. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983; 1: 2–10. 22. Ludwig Breast Cancer Study Group. Combination adjuvant chemotherapy for node-positive breast cancer: inadequacy of a single peri-operative cycle. N Engl J Med 1988; 319: 677–683. 23. Colleoni M, Litman HJ, Castiglione-Gertsch M et al. Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomized trials investigating three versus six courses of CMF. Br J Cancer 2002; 86: 1705–1714. 24. Hrafnkesson J, Nilsson K, Soderberg M. Tolerance of radiotherapy combined with adjuvant chemotherapy in breast cancer. Acta Oncol 1987; 26: 269–272. 25. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate and fluorouracil in positive-node breast cancer
Annals of Oncology
Annals of Oncology
52. Falo C, Moreno A, Varela M et al. HER-2/neu status and response to CMF: retrospective study in a series of operable breast cancer treated with primary CMF chemotherapy. J Cancer Res Clin Oncol 2007; 133(7): 423–429. 53. Cheang M, Chia SK, Tu D et al. Anthracyclines in basal breast cancer: the NCICCTG trial MA5 comparing adjuvant CMF to CEF. J Clin Oncol 2009; 27 (Suppl): 15s (Abstr 519). 54. Tan DS, Marchio´ C, Jones RL et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat 2008; 111: 27–44. 55. Colleoni M, Cole BF, Viale G et al. Classical CMF chemotherapy is more effective in selected breast cancer subtypes: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Clin Oncol 2010; 28(18): 2966–2973. 56. Tassone P, Tagliaferri P, Perricelli A et al. BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 2003; 88: 1285–1291. 57. Carey LA. Directed therapy of subtypes of triple-negative breast cancer. Oncologist 2010; 15 (Suppl 5): 49–56. 58. Bryant HE, Schultz N, Thomas H et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434: 913–917. 59. O’Shaughnessy J, Osborne C, Pippen JE et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011; 364(3): 205–214.
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
44. Perou CM, Sørlie T, Eisen MB et al. Molecular portraits of human breast tumours. Nature 2000; 406(6797): 747–752. 45. Andre F, Pusztai L. Molecular classification of breast cancer: implications for selection of adjuvant chemotherapy. Nat Clin Pract Oncol 2006; 3(11): 621–632 Review. 46. Fisher B, Dignam J, Mamounas EP et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptornegative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996; 14: 1982–1992. 47. Fisher B, Jeong J-H, Bryant J et al. Treatment of lymph-node-negative, estrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet 2004; 364: 858–868. 48. Rakha EA, El-Sayed ME, Green AR et al. Prognostic markers in triple-negative breast cancer. Cancer 2007; 109: 25–32. 49. Lehmann-Che J, Andre´ F, Desmedt C et al. Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers. Oncologist 2010; 15(3): 246–252. 50. O’malley FP, Chia S, Tu D et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 2009; 101: 644–650. 51. Gennari A, Sormani MP, Pronzato P et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008; 100: 14–20.
reviews
Annals of Oncology
Annals of Oncology 23: 305–311, 2012 doi:10.1093/annonc/mdr309 Published online 29 June 2011
CMF revisited in the 21st century E. Munzone1*, G. Curigliano1, H. J. Burstein2, E. P. Winer2 & A. Goldhirsch1 1
Division of Medical Oncology, European Institute of Oncology, Milan, Italy; 2Department of Medical Oncology, Breast Oncology Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
Received 4 May 2011; accepted 6 May 2011
‘‘Don’t bury me ’cause I’m not dead yet.’’ Elvis Costello
introduction A pioneer in the field of medical oncology, classical CMF (combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil) is facing hard times as most medical oncologists prefer the so-called ‘third-generation regimens’ with anthracyclines and taxanes as adjuvant treatment for women with operated breast cancer. Because our field of medical oncology is only a few decades old, CMF has been one of our leaders for much of our history, leaving an indelible mark on our specialty. Since 3 July 1973, when the first patient was enrolled in the first adjuvant Milan trial [1], CMF has certainly been a milestone in the adjuvant treatment of women with breast cancer. The success of CMF remained unchallenged until the mid80s when anthracyclines appeared on the scene. Subsequently, the stature of CMF was further threatened in the nineties when the taxanes made a dramatic entrance on the scene of chemotherapy worldwide. *Correspondence to: Dr E. Munzone, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39-02-57489405; Fax: +39-02-57489457; E-mail: [email protected]
In this brief review, we would like to pay a tribute to CMF, highlighting the great contribution that it made to oncology and particularly to the treatment of women with breast cancer. As clinically oriented medical oncologists, we would like to investigate whether, after observing the classical CMF being overtaken by more modern regimens, it should continue to have a place in the care of at least a subgroup of patients.
portrait of CMF: deeds and misdeeds We can set the birth of the classical CMF in Milan (Italy) in the early seventies, although few years before Paul P. Carbone reported initial National Cancer Institute data on a quadruple drug regimen containing cyclophosphamide, methotrexate, fluorouracil and prednisone for advanced breast cancer patients [2]. CMF was originally designed to resemble the MOPP (combination chemotherapy with mechlorethamine, vincristine, procarbazine and prednisone) scheme used successfully in the treatment of Hodgkin’s disease, which includes 2 weeks of cytotoxic treatment and 2 weeks interval without treatment for recovery [3]. In 1976, CMF efficacy as adjuvant treatment for node-positive breast cancer patients was firstly reported by Bonadonna et al. [1]. These results, along with those reported in a similar population of patients by the National Surgical Adjuvant Breast and Bowel Project (NSABP), raised hopes that chemotherapy could have a more central role in the primary management of breast cancer [4].
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
Over the last 35 years, classical CMF (combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil) has been a milestone in the adjuvant treatment of women with breast cancer. However, after an early burst of success lasted just over 10 years, classical CMF has been supplanted by ‘third-generation’ regimens containing taxanes and anthracyclines. Questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients and particularly, recent retrospective data support the fact that the CMF might have a role in the treatment of patients with triple-negative breast cancer. One possible justification for supporting this role of CMF may be sought in the mechanism of action of drugs used in the regimen, as triple-negative cells may be sensitive to alkylating agents that cause double-strand breaks in DNA. The lesson learned from the CMF could lead us to identify new combinations of drugs that could include the optimal chemotherapy backbone for triplenegative breast cancer such as platinum compounds or alkylating agents or Poly (ADP-ribose) polymerase inhibitors. In conclusion, although we have learned a lot from the use of CMF, many questions are still open and hopefully stimulate our thinking, as clinicians, leading us to find new and more effective ways to treat breast cancer. Key words: adjuvant chemotherapy, alkylating agents, breast cancer, classical CMF, triple-negative, tumor heterogeneity
reviews
Annals of Oncology
CMF-like regimens and the classical CMF During the following years, all regimens containing the three ingredients—cyclophosphamide, methotrexate and fluorouracil—have become collectively known as CMF, despite
significant differences in schedule, dosage and route of administration compared with the ‘classical regimen’ initially tested in Bonadonna’s studies. These modified schedules have been widely used without the support of a direct comparison between the classical CMF regimen and the variants [8]. Indeed, over the years, many oncologists have changed the classical CMF schedule by switching cyclophosphamide administration from oral to i.v., based on the empirical assumption that compliance would have been better. However, no randomized trial has directly compared CMF regimens in which all three drugs were given i.v. on days 1 and 8 with those using 14 days of oral cyclophosphamide and MF i.v. on days 1 and 8, either in the adjuvant or advanced disease (Table 1). Only two studies compared classical CMF with i.v. CMF (schedule 1, 21) in metastatic breast cancer patients [12, 13]. The results of the European Organisation for Research and Treatment of Cancer trial showed a better response rate and time to progression for the classical CMF, and further emphasized the importance of cyclophosphamide dose intensity delivered orally as compared with i.v. [13]. However, there is currently no evidence that oral cyclophosphamide is either more toxic or more or less effective than an equivalent dose of i.v. cyclophosphamide [14]. Moreover, during the first 10 years, adjuvant classical CMF survived many other schemes including combination with other drugs, as leukeran, nitrogen mustard, and vincristine,
Table 1. CMF-like and cCMF trials: doses, duration, and schedule Trial DOSES
EORTC
Toronto, Canada
No. of patients 452
133
Setting
Trial design
Doses and schedule (mg/m2)
Duration
Outcome
Ref.
Adj
LD CMF versus no treatment i.v. CMF versus halfdose CMF i.v. CMF versus no treatment i.v. CMF versus cCMF
C 50 os, days 1–14, 28; M 15 i.v., days 1, 8–28; F 350 i.v., days 1, 8–28 C 600/300 i.v., 1–21; M 40/20 i.v., 1–21; F 600/300 i.v., 1–21 C 600 i.v., 1–21; M 40 i.v., 1–21; F 600 i.v., 1–21 C 600 i.v., 1–21 or 100 os, 1–14, 28; M 40 i.v., 1–21 or 1, 8–28; F 600 i.v., 1–21 or 1, 8–28 C 600 i.v., 1–21 or 100 os, 1–14, 28; M 40 i.v., 1–21 or 1, 8–28; F 600 i.v., 1–21 or 1, 8–28 C 100 os, days 1–14, 28; M 40 i.v., days 1, 8–28; F 600 i.v., days 1, 8–28 C 400 i.v., days 1–8; M 40 i.v.; F 600 i.v.; L 15 i.v. C 100 os, days 1–14, 28; M 40 i.v., days 1, 8–28; F 600 i.v., days 1, 8–28
24
CMF better
[5]
NA
i.v. CMF better
[6]
12 cycles
CMF better
[7]
NA
No difference
[8]
NA
cCMF better
[9]
6 or 12 cycles
No difference
[10]
1 or 6 cycles
cCMF ·6 better
[11]
3 or 6 cycles
cCMF ·6 better (cCMF ·3 = cCMF ·6 >40 years and ER+)
[12]
Met
INT, Milan
90
Adj (N2, ER2)
Italian trial
68
Met
254
Met
i.v. CMF versus cCMF
DURATION Tancini
466
Adj
cCMF ·6 versus ·12
Ludwig
1275
Adj
IBCSG-VI; GBCSG
735; 289
Adj
PeriopCMF versus cCMF cCMF ·3 versus ·6
SCHEDULE
EORTC Trial 10808
months
C, cyclophosphamide; M, methotrexate; F, fluorouracil; c, classical; EORTC, European Organisation for Research and Treatment of Cancer; LD, low dose; INT, Istituto Nazionale Tumori; ER, estrogen receptor; Adj, adjuvant; Met, metastatic; os, oral; NA, not assessed; N, node; Periop, perioperative; L, leucovorin; GBCSG, German Breast Cancer Study Group; IBCSG, International Breast Cancer Study Group.
306 | Munzone et al.
Volume 23 | No. 2 | February 2012
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
The original CMF regimen consisted of cyclophosphamide (100 mg/m2 orally from day 1 to 14), methotrexate (40 mg/m2 i.v. on days 1 and 8), and fluorouracil (600 mg/m2 i.v. on days 1 and 8), repeated every 4 weeks. In 1989, during the Karnofsky lecture at the American Society of Clinical Oncology, Bonadonna [5], based on the studies of the Istituto Nazionale Tumori started in 1973, 1975 and 1985, concluded that in premenopausal women with primary node-positive disease, classical CMF for six cycles could be considered a standard. The role of tamoxifen in premenopausal women was not yet understood and part of the benefit in younger women was also attributed to the effect on the endocrine ovarian suppression exerted by the CMF. In postmenopausal women with estrogen receptor (ER)positive tumors, tamoxifen was recommended, while women with ER-negative tumors had an advantage from the classical CMF. In women with node-negative and ER-positive tumors, tamoxifen was recommended, while in the ER-negative tumors, classical CMF for six cycles offered a significant advantage both on relapse-free survival (RFS) and overall survival (OS) [6, 7].
reviews
Annals of Oncology
showing its superiority in terms of disease-free survival (DFS) and OS [15–18]. In 2005, Bonadonna et al. [19] further emphasized that CMF after 30 years is still an effective regimen with long-lasting benefit maintained in patients with both favorable and unfavorable prognostic indicators, at the cost of minimal long-term sequelae.
Table 2. Anthracyline-based trials compared with classical CMF Trial
No. of patients
Nodes
Anthracycline regimen (dose mg/m2)
Outcome
Ref.
Onco-Francea Sweden NSABP B-15 GUN3-Italy Belgium NCI-C MA.5 SWOG8897 NSABP B-23
249 43 2194 220 777 710 2691 2008
Positive Positive Positive Positive Positive Positive Negative Negative
A30VCF ·12 A40C ·6 A60C ·4 6 CMF i.v. CMF/E75Vc ·6 E60C 1–3/E100C ·8 CE60F 1–8 ·6 FA30C 1–8 ·6 A60C ·4
AVCF better (OS/DFS) No difference No difference No difference No difference CEF better (OS/DFS) FAC better (OS/DFS) No difference
[21] [22] [23] [14] [15] [16] [17] [18]
a
Classical CMF ·12 cycles. C, cyclophosphamide; M, methotrexate; F, fluorouracil; A, doxorubicin; V, vinca alkaloid; OS, overall survival; DFS, disease-free survival; NSABP, National Surgical Adjuvant Breast and Bowel Project; E, epirubicin; Vc, vincristine.
Volume 23 | No. 2 | February 2012
doi:10.1093/annonc/mdr309 | 307
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
the decline of CMF and the rise of anthracyclines and taxanes Although after 30 years of follow-up CMF continues to show a significant benefit for RFS and OS compared with no chemotherapy [20], classical CMF was used as a comparator only in few clinical trials. In the direct comparison, a total of eight trials of anthracyclines versus classical CMF have been identified and summarized in Table 2 [20, 24–30]. Three of them showed a better OS/DFS for the anthracycline-containing arm [20, 28, 30] and the remaining trials showed no difference. In the Early Breast Cancer Trialists’ Collaborative Group overview, among 11 studies of anthracycline-based regimens compared with CMF (total N = 5942 patients), only one study found a lower recurrence rate for CMF treatment, but this trial compared only one cycle of an anthracycline-containing regimen with six cycles of low-dose i.v. CMF [31]. The meta-analysis showed that compared with CMF (any schedule), anthracyclinebased regimens produced a 12% proportional reduction in recurrence (P = 0.006; absolute benefit 3.2%) and an 11% proportional reduction in mortality (P = 0.02; absolute benefit 2.7%) [32]. However, the patient population in this meta-analysis included both pre- and postmenopausal women (70% of the women in this analysis were aged <50 years) with both hormone receptor-positive and hormone receptor-negative disease. Specifically in the subset of women aged <50 years, there was a 13% reduction in risk of recurrence (P = 0.01) and a nonsignificant (P = 0.09) reduction in mortality with anthracycline-based regimens compared with CMF [33]. In advanced breast cancer, the taxanes, docetaxel and paclitaxel, are among the most active chemotherapeutic agents currently in use. However, in the adjuvant setting, trials of taxanes have not been conclusive in showing an advantage over CMF mainly because no direct comparison has been done [34–37].
Two trials, Cancer and Leukaemia Group B (CALGB) 9344 and NSABP B-28, compared anthracycline–taxane experimental regimens with the standard doxorubicin and cyclophosphamide regimen (AC) and, thus, were indirectly comparable with classical CMF, based on the results of the NSABP B-15 trial [25]. CALGB 9344 trial [36] compared four cycles of 60–90 mg/m2 doxorubicin and cyclophosphamide followed by 175 mg/m2 paclitaxel infused over 3 h with four cycles of 60–90 mg/m2 doxorubicin and cyclophosphamide alone. The resulting proportional reduction in mortality was 13%. Results showed that 60 mg/m2 doxorubicin followed by 175 mg/m2 paclitaxel is favored clinically. Unfortunately, the study did not report on activity outcome for the three doxorubicin groups separately, which would have provided a more accurate measure of activity for the 60 mg/m2 doxorubicin followed by 175 mg/m2 paclitaxel regimen. The second anthracycline–taxane trial, the NSABP B-28 [38], compared an almost identical anthracycline–taxane regimen (four cycles of AC60) with that in the CALGB 9344 and showed no significant survival benefit. Although longer treatment can improve outcome, the addition of four cycles of paclitaxel to four cycles of AC did not improve OS consistently compared with AC alone. Of the 19 trials assessing the role of taxanes in the adjuvant treatment of breast cancer, there are four trials comparing the taxane-containing regimen with an anthracycline-based treatment known to be more active than classical CMF as summarized in Table 3 [39–42]. Interestingly, among these trials, only two have anthracycline-based regimens, which have previously shown superiority over classical CMF [28, 43], as a control arm. Nevertheless, the other two trials have a sequential anthracycline–CMF treatment as a control arm, which is very similar to the sequential epirubicin–CMF regimen proven to be more effective than CMF in the UK trial [43]. In these trials, RFS was significantly better for the taxane arm in three of them and data about OS are not yet conclusive. However, there are some limitations in interpreting these results from recently reported taxane-based adjuvant trials that consist in the use of an anthracycline-based control arm that is
reviews
Annals of Oncology
Table 3. Taxane trials with an anthracycline-containing regimen as control arm with proven superiority to cCMF Trial
No. of patients
Nodes
Design
Control arm
Outcome
Ref.
BIG 02-98
2890
Positive
1355
Any
A75 ·4 / cCMF ·3; A60C ·4 / cCMF ·3 A75 ·4 / CMF 1–8 i.v. ·4
Better DFS for T arms; OS NA Better RFS for P arms; OS NA
[28]
ECTO MA.21
1500
Any
CEF ·6a
TACT
4162
Any
A / CMF; AC / CMF; A/ T / CMF; AT / CMF S / A / CMF; S / AP / CMF; AP / CMF / S CEF; CEF 2 weeks / P; AC /P E / CMF or FEC; FEC / T
Better RFS for CEF or CEF 2 weeks / P No difference
E100 ·4 / cCMF ·4a
[29] [30] [31]
a
Superior over cCMF. c, classical; C, cyclophosphamide; M, methotrexate; F, fluorouracil; A, doxorubicin; DFS, disease-free survival; OS, overall survival; S, surgery; P, paclitaxel; E, epirubicin; T, taxotere; RFS, relapse-free surviva; ECTO, European cooperative trial in operable breast cancer; TACT, Taxotere as Adjuvant Chemotherapy Trial; NA, not assessed.
breast cancer is heterogeneous: is there a role for classical CMF in triplenegative disease? Questions have been raised in the past years concerning the true effectiveness of adjuvant CMF for specific subgroups of patients. Early studies suggested that Human Epidermal growth factor Receptor 2 (HER-2/neu)-positive tumors do not benefit from CMF-based chemotherapy that, by contrast, has a considerable effect in tumors with no or minimal expression of this oncogene. The notion that breast cancer is a heterogeneous disease has been around for many years, but in the past years, few investigators have had the perseverance to analyze the effects of adjuvant chemotherapy in clinically relevant subgroups (e.g. ER-negative or low-ER, intermediate-ER and ER-rich disease). More recently, intrinsically different subtypes of breast cancer based on genetic profile and Immunohistochemistry (IHC) determination of selected targets have been identified [44, 45]. Perou et al. [44] demonstrated that the phenotypic diversity of breast tumors was associated with corresponding gene expression diversity. Using this subset, the authors were able to identify four different molecular subtypes of breast cancer: ER-positive/luminal-like, basal-like, HER-2/neu-positive, and normal breast. Subsequent data expanded the classification to distinguish between luminal A and luminal B [45]. The recognition of a specific target or a feature within a homogeneous subgroup of patients results in the identification of specific and biologically targeted adjuvant treatments. NSABP B-13 and B-19 [46] randomized clinical trials carried out to evaluate the use of adjuvant chemotherapy for the treatment of patients with node-negative ER-negative tumors showed that both MF and CMF are effective therapies for patients with ER-negative tumors and negative axillary nodes. In patients aged £49 years, CMF results in a clearly better DFS and survival than does MF, whereas in patients ‡50 years of age,
308 | Munzone et al.
a benefit from both regimens is apparent, although it is less clear which regimen is more effective. Long-term findings of the NSABP B-20 trial [47] show that the benefit from adding CMF to tamoxifen is inversely related to the quantitative concentration of tumor ERs. A previous study by Rakha et al. [48] has suggested that the negative prognosis of the triple-negative phenotype may be alleviated by adjuvant chemotherapy. In that study, patients with triple-negative breast cancer who received adjuvant chemotherapy following primary surgery were uniformly treated with CMF. This raises the intriguing possibility that regimens including antimetabolites and high cumulative doses of alkylating agents such as cyclophosphamide may be more effective than anthracycline-based chemotherapeutic regimens in triple-negative tumors. A recent study in the preoperative setting further supports this hypothesis by clearly identifying p53mutant ER-negative tumors as those most sensitive to high-dose alkylating agents and allowing very high levels of pathological Complete Response in triple-negative tumors treated with doseintense cyclophosphamide [49]. In this context, CMF chemotherapy, being not inferior to anthracycline-containing therapy in patients with tumors lacking overexpression of topoisomerase II [50] or with HER-2/neu-negative breast cancer [51], may have a role as adjuvant therapy in patients with triplenegative tumors, particularly those patients with relatively small node-negative tumors. Falo et al. [52] recently published a trial in a series of operable breast cancer patients treated with primary CMF chemotherapy. In this series, 300 patients with operable breast cancer were treated with primary CMF1-8 i.v. HER-2/neu overexpression or amplification was found in 23.66% cases. Univariate analysis showed that response was similar in HER-2/neu-positive and -negative tumors (51.38% versus 47.36%, P = 0.6). Triplenegative tumors presented the highest response rate (64.9%). Patients with the combination of response to CMF and HER-2/ neu-negative tumors presented the best outcome. On the other hand, the association of no response to CMF and positive HER2/neu score was statistically related to poor DFS and OS. Furthermore, tissue blocks from patients of MA5 trial were recently analyzed for ER, progesterone receptor, HER2, Ki67, CK5/6 and epidermal growth factor receptor and for tissue microarray to determine the biological subtype [53]. The results showed that in the CEF (cyclophosphamide, epirubicin,
Volume 23 | No. 2 | February 2012
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
no more effective than classical CMF, the interference of the endocrine effects of chemotherapy in premenopausal patients with hormone receptor-positive tumors and, finally, the lack of subgroup analysis that differentiates node-positive from nodenegative patients.
reviews
Annals of Oncology
conclusions what we have learned from CMF? After an early burst of success lasted just over 10 years, classical CMF has been supplanted by more toxic and more expensive regimens, so-called third-generation regimens, containing taxanes and anthracyclines. However, while the CMF regimen is old and is a very ‘firstgeneration’ regimen, it certainly has at least three points in its favor. First, CMF has a safe and very well-known toxicity profile based on data now older than 35 years and well consolidated. Secondly, recent retrospective data support the fact that the CMF might have a role in the treatment of patients with triple-negative breast cancer. The last point—not to be underestimated—is certainly an economic point, CMF being a not-expensive scheme. Willing to look forward, we should ask how to take advantage of the positive points that we learned from the CMF, and especially how to use these strengths to improve our skills to treat breast cancer patients. One of the main limitations that we stressed throughout this review derives from the interference due to populations with hormone receptor-positive disease included in studies, which may benefit from chemotherapy. Furthermore, the data published so far, in most cases, were interpreted on heterogeneous populations including patients with either positive or negative axillary lymph nodes and with hormone receptors or HER-2/neu positive or negative. But when analyzed by subgroups, the proper niche of patients for each treatment may be identified. This point may serve as an opportunity for opening a discussion in favor of the use of
Volume 23 | No. 2 | February 2012
classical CMF chemotherapy, which might still have role, for instance, as effective adjuvant systemic therapy for triplenegative node-negative population [55]. One possible justification for supporting this role of CMF may be sought in the mechanism of action of drugs used in the CMF regimen. In vitro chemosensitivity studies have found that human cells lacking BRCA1, and to some extent other triplenegative cells, may be sensitive to drugs that cause doublestrand breaks in DNA, such as alkylating agents, [50] and less sensitive to doxorubicin, as well as to paclitaxel [56]. Moreover, methotrexate and 5-fluorouracil used in CMF regimens are both antimetabolites, which are more suitable for the higher proliferative index of triple-negative breast cancers [55]. To further support the notion of breast cancer heterogeneity, it has been recently reported that the category of triple-negative tumors can be additionally divided into subtypes [57]. In consequence, the response to various agents may differ depending on the intrinsic molecular subtypes. For example, as previously reported, the subgroup of p53-mutant ER-negative tumors has proved to be more sensitive to high-dose alkylating agents [49]. Another possible limitation is that over the years CMF has not been directly compared with a taxane-containing regimen, and this information is lacking especially within the triplenegative subgroup. For this purpose, it would be interesting to explore the combination of taxanes with alkylating agents or platinum compounds, which are the backbone of regimens for triplenegative breast cancers, compared with classical CMF. Finally, recent results from preclinical and clinical studies have highlighted poly (ADP-ribose) polymerase (PARP) inhibitors as one of the most promising ‘targeted therapies’ for metastatic triple-negative breast cancer, DNA repair being the intended ‘target’ [58, 59]. Looking at the future development of these agents, one challenging task might consist in further defining triplenegative patients most likely to respond to PARP inhibitors and determining the optimal chemotherapy backbone to combine with them. This direction is particularly important as these drugs move to the adjuvant setting because long-term toxic effects to normal tissues as a result of prolonged suppression of DNA repair have yet to be defined. In conclusion, although we have learned a lot from the use of CMF, many questions are still open and hopefully stimulate our thinking, as clinicians, leading us to find new and more effective ways to treat breast cancer.
disclosure The authors declare no conflict of interest.
references 1. Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976; 294: 405–410. 2. Canellos GP, De Vita VT, Gold GL et al. Cyclical combination chemotherapy for advanced breast carcinoma. Br \Med J 1974; 1: 218–220. 3. Moore MR, Jones SE, Bull JM et al. MOPP chemotherapy for advanced Hodgkin’s disease. Prognostic factors in 81 patients. Cancer 1973; 32(1): 52–60.
doi:10.1093/annonc/mdr309 | 309
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
and fluorouracil) arm, patients with core basal tumors had a hazard ratio (HR) of 1.8 (log-rank P = 0.02) for OS relative to the other biological subtypes. In the CMF arm, there was no significant difference (HR 0.9, P = 0.7). The interaction between core basal status and treatment was borderline significant (P = 0.06). RFS differences did not reach significance. Authors concluded that data from this randomized trial support the hypothesis that anthracycline-containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal-like breast cancer. These results further support previous reports in which early breast cancer patients with negative hormone receptors have less or even no survival advantage with anthracycline-based adjuvant chemotherapy compared with non-anthracycline regimens [51, 54]. Recently, a retrospective study by Colleoni et al. highlights a larger magnitude of benefit of classical CMF in patients with triple-negative node-negative breast cancer after a median followup of 11 years. In this report, authors explored patterns of recurrence according to treatment received in a group of patients (n = 2257) enrolled in International Breast Cancer Study Group trials VII–IX with node-negative breast cancer, randomly assigned to receive classical CMF for three or six cycles with or without endocrine therapy versus endocrine therapy alone. Patients with triple-negative tumors were 303 (15%) and chemotherapy significantly improved 10-year DFS in this subtype group (73% versus 57%, P = 0.007) [55].
reviews
310 | Munzone et al.
26.
27.
28.
29.
30.
31.
32.
33. 34.
35.
36.
37. 38.
39.
40.
41.
42.
43.
patients with tamoxifen-nonresponsive tumours: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8: 1483–1496. De Placido S, Perrone F, Carlomango C et al. CMF vs alternating CMF/EV in the adjuvant treatment of operable breast cancer: a single centre randomised clinical trial (Naples GUN-3 study). Br J Cancer 1995; 71: 1283–1287. Piccart M, Di Leo A, Beauduin M et al. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate and fluorouracil in node-positive breast cancer. J Clin Oncol 2001; 19: 3103–3110. Levine MN, Pritchard KI, Bramwell VH et al. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol 2005; 23: 5166–5170. Hutchins LF, Green SJ, Ravdin PM et al. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, nodenegative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol 2005; 23(33): 8313–8321. Fisher B, Anderson S, Tan-Chiu E et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001; 19(4): 931–942. Ploner F, Jakesz R, Hausmaninger H et al. Randomized trial: one cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients. Onkologie 2003; 26(2): 115–119. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930–942. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–1467. Buzdar AU, Singletary SE, Valero V et al. Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer: preliminary data of a prospective randomized trial. Clin Cancer Res 2002; 8: 1073–1079. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21: 1431–1439. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003; 21: 976–983. Piccart MJ, Lohrisch C, Duchateau L et al. Taxanes in the adjuvant treatment of breast cancer: why not yet? J Natl Inst Monogr 2001; 30: 88–95. Mamounas EP, Bryant J, Lembersky B et al. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 2005; 23: 3686–3696. Francis P, Crown J, Di Leo A et al. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 Randomized Trial. J Natl Cancer Inst 2008; 100: 121–133. Gianni L, Baselga J, Eiermann W et al. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol 2009; 27: 2474–2481. Burnell M, Levine M, Chapman J. A phase III adjuvant trial of sequenced EC + filgrastim + epoetin-alpha followed by paclitaxel compared to sequenced AC followed by paclitaxel compared to CEF in women with node-positive or high-risk node-negative breast cancer (NCIC CTG MA.21). J Clin Oncol 2007; 25 (Suppl): (Abstr 550). Ellis P, Barrett-Lee P, Bloomfield D et al. Preliminary results of the UK Taxotere as Adjuvant Chemotherapy (TACT) Trial. UK-CRUK trial. In 30th San Antonio Breast Cancer Symposium 2007 (Abstr 78). San Antonio, TX. 2007. Poole CJ, Earl HM, Hiller L et al. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 2006; 355(18): 1851–1862.
Volume 23 | No. 2 | February 2012
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
4. Fisher B, Carbone P, Economou SG et al. 1-phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med 1975; 292: 117–122. 5. Bonadonna G. Conceptual and practical advances in the management of breast cancer. J Clin Oncol 1989; 7(10): 1380–1397. 6. Fisher B, Redmond C, Dimitrov NV et al. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with nodenegative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med 1989; 320: 473–478. 7. Mansour EG, Gray R, Shatila AH et al. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer. An intergroup study. N Engl J Med 1989; 320: 485–490. 8. Goldhirsch A, Colleoni M, Coates AS et al. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? Ann Oncol 1998; 9: 489–493. 9. Clahsen PC, Van de Velde CJH, Welvaart K. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organization for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. Cooperating Investigators. J Clin Oncol 1995; 13: 33–41. 10. Tannock IF, Boyd NF, DeBoer G et al. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 1988; 6: 1399–1487. 11. Zambetti M, Valagussa P, Bonadonna G. Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer. Updated results. Ann Oncol 1996; 7: 481–485. 12. Brandi M, De Nitrio A, Ditonno P et al. Oral versus intravenous CMF in metastatic breast cancer: a randomized trial. Int J Oncol 1994; 4: 559–565. 13. Engelsman E, Klijn JC, Rubens RD et al. ‘Classical’ CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC Breast Cancer Co-operative Group Phase III trial (10808). Eur J Cancer 1991; 27: 966–970. 14. O’Shaughnessy JA. Oral alkylating agents for breast cancer therapy. Drugs 1999; 58 (Suppl 3): 1–9. 15. Senn HJ, Jungi WF, Amgwerd R et al. Results of adjuvant LMF/BCG in N2 and N+ breast cancer. In Jones SE, Salmon SE (eds): Adjuvant Therapy of Cancer IV. Orlando, FL: Grune & Stratton 1984; 261–270. 16. Rivkin SE, Glucksberg H, Foulkes M. Adjuvant chemotherapy for operable breast cancer with positive axillary nodes. In Jones SE, Salmon SE (eds): Adjuvant Therapy of Cancer IV. Orlando, FL: Grune & Stratton 1984; 209–215. 17. Davis HL, Metter GE, Ramirez G et al. An adjuvant trial of L-phenylalanine mustard (L-PAM) vs cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F) and vincristine (V)—CMFV following mastectomy for operable breast cancer. Proc Am Soc Clin Oncol 1981; 22: (Abstr 246). 18. Howell A, Rubens RD, Bush H et al. A controlled trial of adjuvant chemotherapy with melphalan versus cyclophosphamide, methotrexate, and fluorouracil in breast cancer. Recent Results Cancer Res 1984; 96: 74–79. 19. Bonadonna G, Moliterni A, Zambetti M et al. 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ 2005; 330(7485): 217. 20. Misset JL, di Palma M, Delgado M et al. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil and vincristine versus cyclophosphamide, methotrexate and fluorouracil: final report after a 16year median follow-up duration. J Clin Oncol 1996; 14: 1136–1145. 21. Tancini G, Bonadonna G, Valagussa P et al. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983; 1: 2–10. 22. Ludwig Breast Cancer Study Group. Combination adjuvant chemotherapy for node-positive breast cancer: inadequacy of a single peri-operative cycle. N Engl J Med 1988; 319: 677–683. 23. Colleoni M, Litman HJ, Castiglione-Gertsch M et al. Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomized trials investigating three versus six courses of CMF. Br J Cancer 2002; 86: 1705–1714. 24. Hrafnkesson J, Nilsson K, Soderberg M. Tolerance of radiotherapy combined with adjuvant chemotherapy in breast cancer. Acta Oncol 1987; 26: 269–272. 25. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate and fluorouracil in positive-node breast cancer
Annals of Oncology
Annals of Oncology
52. Falo C, Moreno A, Varela M et al. HER-2/neu status and response to CMF: retrospective study in a series of operable breast cancer treated with primary CMF chemotherapy. J Cancer Res Clin Oncol 2007; 133(7): 423–429. 53. Cheang M, Chia SK, Tu D et al. Anthracyclines in basal breast cancer: the NCICCTG trial MA5 comparing adjuvant CMF to CEF. J Clin Oncol 2009; 27 (Suppl): 15s (Abstr 519). 54. Tan DS, Marchio´ C, Jones RL et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat 2008; 111: 27–44. 55. Colleoni M, Cole BF, Viale G et al. Classical CMF chemotherapy is more effective in selected breast cancer subtypes: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Clin Oncol 2010; 28(18): 2966–2973. 56. Tassone P, Tagliaferri P, Perricelli A et al. BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 2003; 88: 1285–1291. 57. Carey LA. Directed therapy of subtypes of triple-negative breast cancer. Oncologist 2010; 15 (Suppl 5): 49–56. 58. Bryant HE, Schultz N, Thomas H et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434: 913–917. 59. O’Shaughnessy J, Osborne C, Pippen JE et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 2011; 364(3): 205–214.
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 25, 2015
44. Perou CM, Sørlie T, Eisen MB et al. Molecular portraits of human breast tumours. Nature 2000; 406(6797): 747–752. 45. Andre F, Pusztai L. Molecular classification of breast cancer: implications for selection of adjuvant chemotherapy. Nat Clin Pract Oncol 2006; 3(11): 621–632 Review. 46. Fisher B, Dignam J, Mamounas EP et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptornegative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996; 14: 1982–1992. 47. Fisher B, Jeong J-H, Bryant J et al. Treatment of lymph-node-negative, estrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet 2004; 364: 858–868. 48. Rakha EA, El-Sayed ME, Green AR et al. Prognostic markers in triple-negative breast cancer. Cancer 2007; 109: 25–32. 49. Lehmann-Che J, Andre´ F, Desmedt C et al. Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers. Oncologist 2010; 15(3): 246–252. 50. O’malley FP, Chia S, Tu D et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 2009; 101: 644–650. 51. Gennari A, Sormani MP, Pronzato P et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008; 100: 14–20.
reviews