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Preoperative weekly cisplatin–epirubicin–paclitaxel with G-CSF support in triple-negative large operable breast cancer
original article
Annals of Oncology 20: 1185–1192, 2009 doi:10.1093/annonc/mdn748 Published online 13 February 2009
Preoperative weekly cisplatin–epirubicin–paclitaxel with G-CSF support in triple-negative large operable breast cancer G. Frasci1*, P. Comella2, M. Rinaldo1, G. Iodice2, M. Di Bonito3, M. D’Aiuto1, A. Petrillo4, S. Lastoria4, C. Siani5, G. Comella2 & G. D’Aiuto1 Departments of 1Senology; 2Medical Oncology; 3Pathology and 4Radiology, National Cancer Institute of Naples, Naples and 5Department of Surgery, Faculty of Medicine, University of ‘‘Magna Grecia’’, Catanzaro, Italy
Received 3 November 2008; accepted 18 November 2008
(pCR) rate in patients with triple-negative large operable breast cancer after the administration of eight cisplatin– epirubicin–paclitaxel (PET) weekly cycles. The safety and efficacy data of the initial population were updated, with inclusion of additional experience with the same therapy. Methods: Patients with triple-negative large operable breast cancer (T2–T3 N0–1; T > 3 cm) received eight preoperative weekly cycles of cisplatin 30 mg/m2, epirubicin 50 mg/m2, paclitaxel (Taxol) 120 mg/m2, with granulocyte colony-stimulating factor (5 lg/kg days 3–5) support. Results: Overall 74 consecutive patients (T2/T3 = 35/39; N0/N+ = 26/48) were treated, from May 1999 to May 2008. At pathological assessment, 46 women (62%; 95% confidence interval 50–73) showed pCR in both breast and axilla. At a 41-month median follow-up (range 3–119), 13 events (nine distant metastases) had occurred, 5-year projected disease-free survival (DFS) and distant disease-free survival being 76% and 84%, respectively. Five-year DFS was 90% and 56% in pCRs and non-pCRs, respectively. Severe neutropenia and anemia occurred in 23 (31%) and eight (10.8%) patients, respectively. Severe non-hematological toxicity was recorded in <20% of patients. Peripheral neuropathy was quite frequent but never severe. Conclusions: Eight weekly PET cycles are a highly effective primary treatment in women with triple-negative large operable breast cancer. This approach results in a very promising long-term DFS in this poor prognosis population. This triplet regimen is worthy of evaluation in phase III trials. Key words: cisplatin, epirubicin, operable breast cancer, paclitaxel, triple negative, weekly administration
introduction There is an increasing enthusiasm among medical oncologists about the role of targeted therapy in the treatment of breast cancer patients. Hormonal manipulation represents the oldest, and maybe most effective, targeted treatment for breast cancer expressing hormone receptors. Recently, trastuzumab has shown to improve prognosis in women with human epidermal growth factor receptor 2 (HER-2) overexpressing breast cancer [1]. For the time being, chemotherapy is the only effective treatment for breast tumors not expressing hormone receptors and not overexpressing HER-2. Primary chemotherapy is becoming a very common treatment in women with large operable breast cancer because it allows to increase the rate of breast-conserving surgery. The *Correspondence to: Dr G. Frasci, Department of Senology, Unit of Preoperative Treatments, National Cancer Institute, via Mariano Semmola 80131, Naples, Italy. Tel: +39-081-5903347; Fax: +39-81-5903802; E-mail: [email protected]
large majority of women with large operable breast cancer who achieve the complete eradication of the invasive tumor in both breast and axilla [pathologic complete remission (pCR)] with primary chemotherapy show long-term disease-free survival (DFS) [2]. Most investigators have identified negative hormone receptor status and HER-2 overexpression as strong predictive factors of response to neo-adjuvant chemotherapy [3–7]. The impact of neo-adjuvant chemotherapy in patients with triple-negative breast cancer has been clearly analyzed by Liedtke et al. [8]. The pCR rate was double in triple-negative patients as compared with non-triple negative, although 3-year DFS was worse in the former group. Interestingly, the longterm DFS of patients achieving pCR was similar in the two groups, while the rate of early relapse in patients with residual tumor was dramatically higher in triple-negative patients as compared with the others. Since the achievement of pCR with primary chemotherapy is of crucial importance in triple-negative breast cancer patients,
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: Findings from our previously published phase II study showed a high pathologic complete remission
original article a maximal effort should be made in selecting for these patients the best possible drugs, doses, and administration timing. Anthracycline- and taxane-based regimens are the first-choice primary treatment. Weekly paclitaxel is much more effective than q3-week paclitaxel and at least as effective than every 3-week docetaxel [9]. Preoperative weekly paclitaxel followed by fluorouracil-adriamycin-cyclophosphamide (FAC) yielded a 28.8% pCR rate in patients with large operable disease, as compared with a 13.6% pCR rate obtained with the tri-weekly paclitaxel followed by FAC [10]. On the whole, shortening the interval administration from 3 to 2 weeks could substantially improve efficacy, at least in triple-negative patients [11]. In the last few years, there has been a renewed interest about the role of platinum compounds in the treatment of breast cancer patients. Platin- and taxane-based primary chemotherapy has proven to be highly effective in patients with either large operable or locally advanced disease [12–15]. Experimental data indicate that triple-negative tumors maybe highly sensitive to platinum-based chemotherapy [16, 17]. In the mid-1990s, we started the evaluation of a weekly triplet regimen including cisplatin, epirubicin, and paclitaxel (PET regimen) in breast cancer patients. Cumulative doses of 90 mg/m2 for cisplatin, 150 mg/m2 for epirubicin, and 360 mg/m2 for paclitaxel were given over 3 weeks with the utilization of granulocyte colony-stimulating factor (G-CSF) support. This weekly approach was evaluated in phase II and III trials, including women with either locally advanced breast cancer or large operable disease [18–21]. In a previous paper [20], we reported the results of a phase II study, which tested the PET regimen in 63 women with large operable breast cancer. The pCR rate was particularly impressive in estrogen (ER)-negative and HER-2-positive patients (>60%). In view of that, we expanded the accrual into the study of women with ER-negative or HER-2-positive operable breast cancer. The present paper reports the safety and efficacy data of patients with triple-negative large operable breast cancer receiving preoperative PET from 1999 to 2008. Patients with ER-negative and HER-2-positive tumor have been excluded from the present analysis because the administration of trastuzumab after surgery could lead to an overestimation of the effect of chemotherapy on long-term DFS.
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functions. Previous or concurrent malignancy was also considered as exclusion criteria, except for inactive nonmelanoma skin cancer and in situ carcinoma of the cervix. All patients gave their written informed consent, and the trial was approved by the Independent Ethical Committee of the National Tumor Institute of Naples.
pretreatment evaluation Pretreatment evaluation included a complete history and physical examination, electrocardiogram and bi-dimensional echocardiography, mammography, chest X-ray, liver ultrasonography, radionuclide scan of the bone (with X-ray evaluation of the suspicious bone segments), and computed tomography or magnetic resonance imaging of the brain in case of suspicion of brain involvement. A core biopsy of the tumor in the breast was also carried out with the immunohistochemical assessment of the main prognostic variables (steroid hormone receptors, Ki-67, HER-2/neu). The HER-2/neu was measured by using the mAbs mAb 1 and CB11 on 3-lm sections of paraffin-embedded tumor samples.
treatment All eligible patients received epirubicin 50 mg/m2 as an i.v. bolus, followed by paclitaxel (Taxol, Bristol Myers Squibb, Rome, Italy) 120 mg/m2 as a 1-h infusion and cisplatin 30 mg/m2 as a 30-min infusion, weekly for 8 weeks. Recombinant human G-CSF 300 lg/day was also given s.c. on days 3–5 of each week. A short-term forced hyperhydration (1 l of saline over 2 h) and antiemetic prophylaxis (HT3 receptor antagonists) were also carried out. Prophylaxis for hypersensibility reactions consisted of dexamethasone 8 mg i.v. and promethazine 50 mg i.m. plus ranitidine 50 mg i.v. 30 min before paclitaxel administration. Chemotherapy was delivered at full doses if ANC >1.5 · 109/l and platelets >100 · 109/l. For ANC 1–1.499 · 109/l and/or platelets 75– 99.99 · 109/l, chemotherapy was administered at doses reduced to 50%. In presence of lower ANC or platelet values, treatment was always omitted. Within 3 weeks from the end of chemotherapy, patients underwent surgery. Breast-sparing surgery was carried out when feasible. It consisted of quadrantectomy together with standard level I and II axillary lymph node dissection. Four cycle of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil were delivered after surgery in patients showing less than four axillary nodes involved at pathologic assessment. An additional four cycles of fluorouracil-epirubicin-cyclophosphamide (FEC) (epirubicin instead of methotrexate) cycles were administered in those women showing four or more axillary nodes involved. On completion of postoperative chemotherapy, radiotherapy was carried out in those patients who underwent conservative surgery, as well as in those submitted to mastectomy who had shown more than three axillary nodes involved, skin and/or nipple involvement, or had T3 or G3 tumor at diagnosis.
eligibility criteria Patients with histological confirmation of ER-negative, progesterone receptor (PgR)-negative, HER-2-negative large operable breast cancer (T2–3, T size > 3 cm and N0–1) with no prior chemotherapy or hormone treatment were included in the present analysis. Other eligibility requirements were as follows: age £ 70, Eastern Cooperative Oncology Group performance status of less than two, adequate bone marrow [absolute neutrophil count (ANC) ‡ 2 · 109/l, platelet count ‡ 100 · 109/l, and hemoglobin level ‡ 100 g/l], liver [bilirubin level < 1.5· the upper limit of normal, aspartate aminotransferase (AST), and/or alanine aminotransferase (ALT) < 3· the upper limit of normal, prothrombin time < 1.5 · control], renal (creatinine clearance ‡ 60 ml/ min), and cardiac [left ventricular ejection fraction (LVEF) > 50%, absence of severe cardiac arrhythmia or heart failure, second- or third-degree heart block, or acute myocardial infarction within 4 months before study entry]
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toxicity and response evaluation criteria Toxicity was assessed at the weekly visits and recorded according to the National Cancer Institute—Common Toxicity Criteria version 3. Complete blood cell count and chemistry were carried out once a week in all patients and every other day in cases of grade 4 hematological toxicity. Bidimensional echocardiography was carried out on completion of treatment and every 4 months thereafter for 3 years. Clinical tumor response was assessed within 2 weeks from the end of chemotherapy and classified according to standard World Health Organization criteria [22]. Clinical examination, mammography, and breast ultrasonography were carried out to assess the regression of the tumor in both breast and axilla. For the pathologic analysis of response, the amount of residual epithelial neoplastic cells in the tumor mass, the mitotic index in malignant epithelial cells, and the location of malignant
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component (invasive versus intraductal) were taken into account [23]. Response in the breast was scored as follows: class I (absence of residual malignant epithelial cells), class II (persistence of only in situ residual malignant component), class III (only focal invasive tumor residuals, with substantial histological modifications of the tumor tissue related to chemotherapy), and class IV (no substantial modifications in the tumor mass related to chemotherapy). Patients showing a class I or II response in the breast, together with absence of axillary involvement, were considered as pathological complete responders.
statistical analyses The pCR was the main end point of the present study. We aimed to evaluate whether this short-term dose-dense approach could produce at least a 55% pCR rate (p1), setting 40% as the lowest pCR rate of interest (p0). With an alpha error of 5% and a power of 80%, at least 70 patients were required, according to the Simon’s two-stage minimax design [24]. This approach would have been considered unworthy of further evaluation if <35 pCRs were observed in the 70 enrolled patients. Fisher’s exact test and logistic regression were used to determine factors predictive of pCR. Parameters assessed were tumor size, grading, proliferation score (Ki-67), and clinical nodal status. DFS, distant disease-free survival (DDFS), and overall survival (OS) were also analyzed. DFS was considered as the interval between surgery and documentation of a relapse (ipsilateral, locoregional, or distant) or new contralateral breast cancer or new other cancer or death by any cause. DDFS was considered as the interval between surgery and documentation of distant metastasis or death by any cause. OS was considered as the interval between diagnosis and death by any cause. All time-dependent curves were estimated by the Kaplan–Meier method, and log-rank test was used for comparisons [25, 26]. All patients were included in the analysis of response and survival on an intention-to-treat basis.
Table 1. Patient characteristics (n = 74) Characteristic
Patients (%)
Age (years) Median Tumor grade 1–2 3 T status 2 3 N status 0 1 2 Ki-67 <20% ‡20% Largest tumor diameter, mm Mean Range
48 (range 26–69) 25 (33.8) 49 (66.2) 35 (47.3) 39 (52.7) 26 (35.1) 44 (59.4) 4 (5.5) 18 (24.3) 56 (75.3) 63 34–110
results demographics From May 1999 to June 2008, 74 consecutive women with triple-negative large operable breast cancer received preoperative PET. Table 1 outlines the main patient characteristics. Thirty-five patients showed T2 and 39 T3 disease. Clinical N0 and N+ were 26 and 48 (4 N2), respectively. The mean T size at diagnosis was 6.3 cm. Tumor grade was low-intermediate or high in 25 and 49 patients, respectively. Ki67 was ‡20% in 56 of 74 (75.8%) patients. compliance All but one women received the planned 8-weekly treatment cycles. An at least 1 week delay due to hematological toxicity (ANC < 1 · 109/l, platelets < 75 · 109/l, or hemoglobin < 8 g/ l), or persistence of grade >1 non-hematological toxicity on day of recycling, occurred in 16 patients. A dose reduction was carried out in 29 patients for overall 67 cycles. Sixty-three of 74 (85.1%) patients actually received ‡80% of the planned dose intensity (Figure 1).
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Figure 1. Relative dose intensity.
response All the 74 enrolled patients underwent surgery. Thus, they were evaluated for both clinical and pathologically documented response (pathological response). Table 2 summarizes clinical response data. Fifty-two women (70%) showed absence of residual tumor in the breast and axilla at clinical restaging. T stage was at diagnosis T2 in 30 and T3 in 22 patients, mean diameter initially being 4.6 cm. An additional 21 women (28.3%) obtained a partial regression of the tumor, giving a 98.3% overall response rate [95% confidence interval (CI) 91% to 100%]. The remaining patient achieved only a minor regression of the tumor, but nevertheless underwent surgery. Overall, 50 of 74 (67.5%) patients underwent breast-sparing surgery. A modified radical mastectomy had been considered in 31 of them at diagnosis.
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Table 2. Clinical response (74 patients assessable)
CR (%) PR (%) Minor response (%) PD (%) ORR
52 21 1 0 73
(70%) (28.3%) (1.7%)
N0
Class I–II + N0, n (%)
Total
3 7
26 24
35 39
3 13
1 9
24 26
11 37
10 6
4 6
12 38
Ki67 < 20 Ki67 ‡ 20
8 40
7 9
3 7
8 42
Total
48
16
10
50
26 (74.3) 20 (51.3) P = 0.03 22 (84.6) 24 (50) P = 0.003 10 (40) 36 (73.5) P = 0.005 7 (38.9) 39 (69.6) P = 0.02 46 (62)
Class I–II
Class III
T2 T3
27 21
5 11
N0 N+
22 26
G1–2 G3
Class IV
[98.3% (95% CI 92–100)]
CR, complete response; PR, partial response; CI, confidence interval.
Thirty-four patients (46%) showed absence of residual malignant epithelial cells, either invasive or intraductal, in the breast specimen (class I). An additional 14 (18.9%) women had only in situ residual tumor cells (class II). Therefore, 48 of 74 (64.9%) women obtained a pCR of the tumor in the breast. Forty-six of 48 patients with pCR of the tumor in the breast showed negative axilla too, giving a 62% (95% CI 50% to 73%) pCR rate in both breast and axilla. A pathological partial response in the breast (class III, only focal invasive tumor residuals in the removed breast tissue) was recorded in 16 patients. In the remaining 10 women, no substantial modifications in the tumor mass were observed (class IV). Overall, 52 women (70%) showed negative axilla. Six of 52 axillary negative patients showed residual in the breast (five class III and one class IV). Among the 22 patients with persistence of tumor in the axilla, 15 had one to three lymph nodes involved and 7 four or more. A pCR occurred in 26 of 35 (74.3%) T2 as compared with 20 of 39 (51.3%) T3 patients (P = 0.03) and in 22 of 26 (84.6%) N0 versus 24 of 48 (50%) N+ (P = 0.003). Thirty-six of 49 (73.5%) patients with high-grade tumor achieved a pCR as compared with 10 of 25 (40%) patients with low-intermediate grade tumor (P = 0.005). Seven of 18 (38.9%) patients with baseline Ki-67 <20% achieved a pCR, as compared with 39 of 56 (69.6%) women with Ki-67 ‡20% (P = 0.02). At logistic analysis, T2 (P = 0.04), N0 (P = 0.02), and G3 (P = 0.003) were independently predictive of higher pCR rate (Table 3). Table 4 summarizes the postchemotherapy patterns of the 28 patients who did not achieve a pCR. Two patients had class II response in the breast and positive axilla (one to three nodes), 16 patients had class III response (five with negative axilla, nine with one to three, two with more than three positive nodes), and 10 patients class IV response (one negative, four with one to three, five with more than three positive nodes). Twelve of 26 patients with residual tumor in the breast, showed a Ki-67 score ‡20% and 15 of 26 were G3. At a 41-month median follow-up (range 3–119), with 42 of 74 patients having a >3-year time from surgery, three locoregional relapses, nine distant relapses, one contralateral breast cancer and six deaths had occurred, the 3-year DFS, DDFS, and OS being 83%, 84%, and 96%, respectively. Fiveyear DFS, DDFS, and OS were 76%, 84%, and 89%, respectively (Figure 2). One locoregional, two distant relapses (one liver and one lung), and two deaths had occurred in the 46 patients who achieved a pCR, 3- and 5-year DFS being 97% and 90%, respectively. With 16 patients having a ‡5-year follow-up, no events occurred after 5 years in this group (Figure 3). The
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Table 3. Pathological assessment (74 patients submitted to surgery)
26 48 25 49 18 56 74
Table 4. Postchemotherapy patterns of 28 non-pCR patients Class
G 1–2 G 3 Ki67 < 20 Ki67 ‡ 20 N0 N1–3 N > 3 Total
I–II – III 9 IV 2 Total 11
– 7 8 15
– 12 2 14
– 4 8 12
0 5 1 6
2 9 4 15
0 2 5 7
2 16 10 28
pCR, pathologic complete remission.
Figure 2. Disease-free and overall survival.
baseline characteristics of the three pCR relapsed patients were as follows: T > 5 cm three of three, G3 three of three, Ki67 ‡ 20% two of three, N+ three of three, and N2 two of three. In patients showing residual disease after primary chemotherapy, a total of 10 events (two locoregional, seven distant relapses, one contralateral breast cancer) occurred, 3- and 5-year DFS being 61% and 56%, respectively. Three relapses (one locoregional and two distant) occurred in the 16 patients who had achieved a pathological partial
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Table 5. Toxicity
Figure 3. Disease-free survival (DFS) according to pathological response.
response (class III), all of them had shown high proliferation rate in the residual tumor and more than three axillary nodes involved. Six relapses (one locoregional and five distant) occurred in the 10 patients with absence of a pathological response (class IV).
toxicity Table 5 summarizes the toxicity data observed in the 74 patients enrolled and 589 cycles delivered. No treatment-related deaths or life-threatening events occurred. Twenty-three (31%) patients showed grade 3–4 neutropenia. Neutrophils fell below 0.5 · 109/l in five patients, with only one episode of febrile neutropenia. Four patients showed grade 3 thrombocytopenia, but no episodes of severe thrombocytopenia occurred. Eight patients (10.8%) required red blood cell transfusions due to hemoglobin level falling <8 g/ l. Alopecia was almost universal. Among the other nonhematological side-effects, emesis, fatigue, loss of appetite, and mucositis were the most common. In particular, 80% of patients complained of nausea/vomiting, but only in 10 (13.5%) cases was it severe. Eight (10.8%) patients suffered from severe diarrhea. A 25% dose reduction was carried out in all cases, and chemotherapy could be completed without occurrence of other episodes of severe diarrhea. Severe stomatitis was observed in nine (12.2%) patients, and severe palmar–plantar erythrodysesthesia occurred in three (4.1%) cases. No episodes of grade 3 peripheral neuropathy were recorded. Overall 26 (35.1%) patients complained of mild or moderate paresthesias in the hands and feet. A complete recovery from neurotoxicity occurred within 3 months in all but two women. Musculoskeletal symptoms like transient arthralgias and myalgias occurred in a total of 36 (48.6%) patients, but they were severe in only two cases, and generally responded well to anti-inflammatory drugs. In the majority of cases, these symptoms were related to G-CSF administration. Cardiac toxicity was almost absent. Only two patients developed a decline in LVEF by >15%, but a decrease of LVEF to a value <50% never occurred.
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Neutropenia Thrombocytopenia Anemia Emesis Loss of appetite Diarrhea Mucositis Neurotoxicity Skin toxicity Fatigue Liver Cardiac toxicity ‡ 15% Y LVEF < 50% LVEF Congestive failure
WHO grade 1–2, No. of patients (%)
WHO grade 3–4, No. of patients (%)
41 18 60 49 41 27 21 26 11 31 6
23 4 8 10 7 8 9 0 3 6
(55.4) (24.3) (81) (66.2) (55.5) (36.4) (28.3) (35.1) (15.1) (41.9) (8.1)
(31) (5.4) (10.8) (13.5) (9.5) (10.8) (12.2) (4.1) (8.1)
2 (2.7) 0 0
LVEF, left ventricular ejection fraction.
Finally, six episodes of transient increase of the AST/ALT serum levels were observed, without any clinical sign of liver dysfunction.
discussion The data reported herein confirm our preliminary findings that preoperative administration of weekly PET results into a very high pCR rate in women with triple-negative large operable breast cancer. The sample size (74 patients) of the present study is large enough to state that there is a 95% chance to yield a pCR ‡50% in triple-negative patients with this approach. This range of activity appears better than that reported by other authors in similar populations with much longer treatments. In the M.D. Anderson Cancer Center (MDACC) retrospective analysis [8], 35 of 112 (28%) triple-negative patients achieved a pCR with paclitaxel / FAC/FEC 24-week treatment. Gianni et al. [3] reported a 42% pCR rate in the breast in ER-negative patients after a 24-week preoperative treatment. The pCR rate reported by Colleoni et al. [4] in patients with ER-negative large operable tumor was 33.3%. In the Arbeitsgemeinschaft Gynacologische Onkologie (AGO) trial [6], a 12-week epirubicin–paclitaxel dose-dense sequential treatment yielded a 28% pCR in ER-negative patients; however, a substantial proportion of patients were T4 in that study. In the NSABPB27 trial [27], the AC / docetaxel treatment yielded a 22.8% pCR rate in ER-negative patients, although the ER status was unknown in a relevant proportion of the patients enrolled. Baseline patients’ characteristics were not at all favorable in the present study. Only tumors >3 cm were included, more than half of patients had T3 disease and almost 65% had clinically positive axilla. If we compare these figures with those of the European Cooperative Trial in Operable Breast Cancer trial, we notice that the cutoff was 2 cm in that trial, with 80% of patients having <4 cm tumor and 53% negative axilla. Speculations about the effect of our approach on long-term survival should be made with caution. The accrual time goes
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original article through 9 years, and only 42 of 74 patients had a ‡3-year follow-up. However, the risk of short-term relapse is much higher in triple-negative as compared with other patients, thus 3- and 5-year DFS are more predictive of long-term DFS in these patients than in the others. The 83% 3-year and 76% 5-year DFS we observed in this poor prognosis population appear quite promising. The 3-year freedom from progression was 63% in the MDACC reported series. It is also interesting to remark that the DDFS in the present study was 84% at both 3 and 5 years. The achievement of pCR in a very high proportion of patients can explain the encouraging DFS figure we observed. Indeed, our data confirm that the complete eradication of the tumor in breast and axilla is a reliable predictor of long-term DFS. Three- and 5-year DFS were 96% and 90% in patients achieving pCR, and no failures were observed in the 16 patients at risk after 5 years. The presence of some unfavorable baseline characteristics could, however, result into a not negligible risk of relapse even if pCR has been obtained. The three pCR patients who showed a relapse had very large tumor, clinical axillary involvement (massive in two of three), and high nuclear grade. The importance of pretreatment staging variables in determining the outcome of patients treated with neo-adjuvant chemotherapy has been clearly remarked by Jeruss et al. [28]. The authors developed a scoring system which took into account the clinical stage, the pathologic stage, and biological parameters like ER and grading. A woman with stage IIB, ER-negative G3 tumor before chemotherapy who achieves a pCR (clinical pathologic staging + estrogen receptor and grading score 3) would have a 5-year distant metastasis-free survival of 79% as compared with 98% of a woman having I–IIA, ER-positive G 1–2 tumor at diagnosis. Our results also confirm that the lack of pCR achievement predicts a poorer outcome in triple-negative as compared with ER-positive patients. Ten of 28 non-pCR patients relapsed, the DFS being 61% and 56% at 3 and 5 years, respectively. However, patients who achieved a pathological partial response in the breast had a much better survival outcome than those without pathological response (3 of 16 versus 7 of 10). The small number of patients and events does not permit us to determine other parameters able to better define the risk in noncomplete responder patients. However, we must point out that the three patients with class III response, who relapsed, had ki-67 >20% and more than three axillary nodes involved. It has been reported that the clearance of axilla after chemotherapy per se correlates with better survival. Therefore, the persistence of a relevant tumor residual in the axillary nodes can be associated to a substantial risk of relapse, whatever is the response in the breast. The correlation between postchemotherapy Ki-67 and survival was analyzed in a cohort of 284 patients at the Royal Marsden Hospital. The authors concluded that Ki-67 score of the residual tumor is a strong predictor of outcome for patients not achieving a pathological complete response [29]. Three aspects make our approach substantially different from the other neo-adjuvant treatments, namely the administration of cisplatin, the weekly schedule adopted, and the high-dose intensity of epirubicin. Breast cancers lacking ER and PgR and HER-2 amplification often exibit DeltaNp63 isoforms. The DeltaNp63alpha isoform
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promotes survival of breast cancer cells by binding Tap73 and thereby inhibiting its proapoptotic activity. Cisplatin treatment induces Tap73 c-Abl-dependent phosphorilation, which promotes dissociation of DeltaNp63alpha–Tap73 protein complex, Tap73-dependent transcription of proapoptotic Bcl-2 family, and apoptosis [16]. Rottenberg et al. [30] studied in vivo responses of ‘spontaneous’ Brca1- and p53-deficient mammary tumors arising in conditional mouse mutants to treatment with doxorubicin, docetaxel, or cisplatin. All the tumors became resistant to doxorubicin or docetaxel, but did not become resistant to cisplatin, even after multiple treatments. Thirty large operable patients received four epirubicin– cisplastin–fluorouracil (continuous infusion) cycles followed by four cycles of weekly paclitaxel. A pCR was obtained in 12 patients (40, 95% CI 22.7% to 59.4%), and negative axillary nodes were found in 80% of patients at surgery. The weekly schedule can represent the best way to administer paclitaxel, in view of the peculiar pharmacokinetics of this drug. The administration of 80–150 mg/m2 of paclitaxel each week produces tumoricidal, but not myelotoxic serum concentration [32]. Paclitaxel given on a frequent basis also potentially exhibits antiangiogenic and proapoptotic effects, thereby enhancing the efficacy of this schedule [33–37]. Symmans et al. [37] found that the apoptotic response to paclitaxel was almost complete within 4 days, suggesting that more frequent dosing (such as the weekly dose) of paclitaxel might be beneficial to maintain continued apoptotic response. We think that also the high-dose intensity of epirubin has a substantial relevance in our approach. In the AGO study [6], three q2-week cycles of high-dose epirubicin (150 mg/m2) followed by three q2-week cycles of paclitaxel (250 mg/m2) yielded a double pCR rate as compared with four q3-week cycles of a combination of both drugs (epirubicin 90 mg/m2 and paclitaxel 175 mg/m2). It could be hypothesized that a longer duration of our treatment could result into a further increase of pCR rate, perhaps shifting to pCR a proportion of patients with minimal residual in the breast and/or axilla after eight cycles. However, in our previous experience with LABC patients, 12-weekly cycles of our regimen resulted in a substantially impaired patient’s compliance. Therefore, we think that another way to overcome complete or partial tumor resistance should be pursued. Recent advances in functional tumor imaging (fluorodeoxyglucose positron emission tomography, dynamic magnetic resonance imaging) allow us to early select patients who are not going to achieve a pCR [38–41]. These patients should be early shifted (after 3–4 weeks) to another treatment. In moderately responding patients, a biological agent targeting vascular endothelial growth factor [42, 43] or the tyrosine kinase pathway [44] could be combined with PET in order to potentiate its antitumor activity. An alternative chemotherapy regimen, a biological agent, or both should be delivered in nonresponding patients. In conclusion, a 2-month preoperative treatment with PET plus G-CSF support yields a pathological complete response in 60% of women with triple-negative large operable breast cancer, with a 3-year DFS exceeding 80%. This result is
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obtained without any risk of life-threatening hematologic toxicity and at a price of a moderate non-hematologic toxicity in the large majority of patients. A longer follow-up is needed to better evaluate the impact of this new approach on survival outcome. The combination of this regimen with biological agents should be tested in the attempt of further improving both pCR rate and long-term DFS. A large randomized trial comparing the PET regimen with a standard anthracycline–taxane combination should be carried out in women with triple-negative large operable breast cancer.
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original article 17. Rocca A, Viale G, Gelber RD et al. Pathologic complete remission rate after cisplatin-based primary chemotherapy in breast cancer: correlation with p63 expression. Cancer Chemother Pharmacol 2007; 61: 965–971. 18. Frasci G, D’Aiuto G, Comella P et al. Cisplatin-epirubicin-paclitaxel weekly administration in advanced breast cancer: a phase I study of the Southern Italy Cooperative Oncology Group. Breast Cancer Res Treat 1999; 56: 239–252. 19. Frasci G, D’Aiuto G, Comella P et al. Cisplatin-epirubicin-paclitaxel weekly administration with G-CSF support in advanced breast cancer. A Southern Italy Cooperative Oncology Group phase II study. Breast Cancer Res Treat 2000; 62: 87–97. 20. Frasci G, D’Aiuto G, Comella P et al. A 2-month cisplatin-epirubicin-paclitaxel (PET) weekly combination as primary systemic therapy for large operable breast cancer: a phase II study. Ann Oncol 2005; 16: 1268–1275. 21. Frasci G, D’Aiuto G, Comella P et al. Southern Italy Cooperative Oncology Group (SICOG). Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colonystimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br. J. Cancer 2006; 95: 1005–1012. 22. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214. 23. Chevallier B, Roche H, Olivier JP et al. Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 1993; 16: 223–228. 24. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10. 25. Kaplan ES, Meier P. Non parametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 557–580. 26. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective analysis of disease. J Natl Cancer Inst 1959; 22: 719–748. 27. Bear HD, Anderson S, Brown A et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from the National Surgical Adjuvant Breast and Bowel Project protocol B-27. J Clin Oncol 2003; 21: 4165–4174. 28. Jeruss JS, Mittendorf EA, Tucker SR et al. Combined use of clinical and pathologic staging variables to define outcomes for breast cancer patients treated with neoadjuvant therapy. J Clin Oncol 2008; 26: 246–252. 29. Jones RL, Salter J, A’hern R et al. The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat 2008; in press. 30. Rottenberg S, Nygren AO, Pajic M et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci U S A 2007; 104(29): 12117–12122. 31. Torrisi R, Balduzzi A, Ghisini R et al. Tailored preoperative treatment of locally advanced triple negative (hormone receptor negative and HER2 negative) breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel. Cancer Chemother Pharmacol 2008; 62(4): 667–672. 32. Seidman AD, Hudis CA, Albanell J et al. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 1998; 16: 3353–3361. 33. Wang J, Lou P, Lesniewski R et al. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. Anticancer Drugs 2003; 14(1): 13–19. 34. Belotti D, Vergani V, Drudis T et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 1996; 2(11): 1843–1849. 35. Lau D, Guo L, Gandara D et al. Is inhibition of cancer angiogenesis and growth by paclitaxel schedule dependent? Anticancer Drugs 2004; 15(9): 871–875. 36. Taghian AG, Abi-Raad R, Assaad SI et al. Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications. J Clin Oncol 2005; 23(9): 1951–1961. 37. Symmans WF, Volm MD, Shapiro RL et al. Paclitaxel-induced apoptosis and mitotic arrest assessed by serial fine-needle aspiration: implications for early prediction of breast cancer response to neoadjuvant treatment. Clin Cancer Res 2000; 6(12): 4610–4617. 38. Rousseau C, Devillers A, Sagan C et al. Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by
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Annals of Oncology 20: 1185–1192, 2009 doi:10.1093/annonc/mdn748 Published online 13 February 2009
Preoperative weekly cisplatin–epirubicin–paclitaxel with G-CSF support in triple-negative large operable breast cancer G. Frasci1*, P. Comella2, M. Rinaldo1, G. Iodice2, M. Di Bonito3, M. D’Aiuto1, A. Petrillo4, S. Lastoria4, C. Siani5, G. Comella2 & G. D’Aiuto1 Departments of 1Senology; 2Medical Oncology; 3Pathology and 4Radiology, National Cancer Institute of Naples, Naples and 5Department of Surgery, Faculty of Medicine, University of ‘‘Magna Grecia’’, Catanzaro, Italy
Received 3 November 2008; accepted 18 November 2008
(pCR) rate in patients with triple-negative large operable breast cancer after the administration of eight cisplatin– epirubicin–paclitaxel (PET) weekly cycles. The safety and efficacy data of the initial population were updated, with inclusion of additional experience with the same therapy. Methods: Patients with triple-negative large operable breast cancer (T2–T3 N0–1; T > 3 cm) received eight preoperative weekly cycles of cisplatin 30 mg/m2, epirubicin 50 mg/m2, paclitaxel (Taxol) 120 mg/m2, with granulocyte colony-stimulating factor (5 lg/kg days 3–5) support. Results: Overall 74 consecutive patients (T2/T3 = 35/39; N0/N+ = 26/48) were treated, from May 1999 to May 2008. At pathological assessment, 46 women (62%; 95% confidence interval 50–73) showed pCR in both breast and axilla. At a 41-month median follow-up (range 3–119), 13 events (nine distant metastases) had occurred, 5-year projected disease-free survival (DFS) and distant disease-free survival being 76% and 84%, respectively. Five-year DFS was 90% and 56% in pCRs and non-pCRs, respectively. Severe neutropenia and anemia occurred in 23 (31%) and eight (10.8%) patients, respectively. Severe non-hematological toxicity was recorded in <20% of patients. Peripheral neuropathy was quite frequent but never severe. Conclusions: Eight weekly PET cycles are a highly effective primary treatment in women with triple-negative large operable breast cancer. This approach results in a very promising long-term DFS in this poor prognosis population. This triplet regimen is worthy of evaluation in phase III trials. Key words: cisplatin, epirubicin, operable breast cancer, paclitaxel, triple negative, weekly administration
introduction There is an increasing enthusiasm among medical oncologists about the role of targeted therapy in the treatment of breast cancer patients. Hormonal manipulation represents the oldest, and maybe most effective, targeted treatment for breast cancer expressing hormone receptors. Recently, trastuzumab has shown to improve prognosis in women with human epidermal growth factor receptor 2 (HER-2) overexpressing breast cancer [1]. For the time being, chemotherapy is the only effective treatment for breast tumors not expressing hormone receptors and not overexpressing HER-2. Primary chemotherapy is becoming a very common treatment in women with large operable breast cancer because it allows to increase the rate of breast-conserving surgery. The *Correspondence to: Dr G. Frasci, Department of Senology, Unit of Preoperative Treatments, National Cancer Institute, via Mariano Semmola 80131, Naples, Italy. Tel: +39-081-5903347; Fax: +39-81-5903802; E-mail: [email protected]
large majority of women with large operable breast cancer who achieve the complete eradication of the invasive tumor in both breast and axilla [pathologic complete remission (pCR)] with primary chemotherapy show long-term disease-free survival (DFS) [2]. Most investigators have identified negative hormone receptor status and HER-2 overexpression as strong predictive factors of response to neo-adjuvant chemotherapy [3–7]. The impact of neo-adjuvant chemotherapy in patients with triple-negative breast cancer has been clearly analyzed by Liedtke et al. [8]. The pCR rate was double in triple-negative patients as compared with non-triple negative, although 3-year DFS was worse in the former group. Interestingly, the longterm DFS of patients achieving pCR was similar in the two groups, while the rate of early relapse in patients with residual tumor was dramatically higher in triple-negative patients as compared with the others. Since the achievement of pCR with primary chemotherapy is of crucial importance in triple-negative breast cancer patients,
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Background: Findings from our previously published phase II study showed a high pathologic complete remission
original article a maximal effort should be made in selecting for these patients the best possible drugs, doses, and administration timing. Anthracycline- and taxane-based regimens are the first-choice primary treatment. Weekly paclitaxel is much more effective than q3-week paclitaxel and at least as effective than every 3-week docetaxel [9]. Preoperative weekly paclitaxel followed by fluorouracil-adriamycin-cyclophosphamide (FAC) yielded a 28.8% pCR rate in patients with large operable disease, as compared with a 13.6% pCR rate obtained with the tri-weekly paclitaxel followed by FAC [10]. On the whole, shortening the interval administration from 3 to 2 weeks could substantially improve efficacy, at least in triple-negative patients [11]. In the last few years, there has been a renewed interest about the role of platinum compounds in the treatment of breast cancer patients. Platin- and taxane-based primary chemotherapy has proven to be highly effective in patients with either large operable or locally advanced disease [12–15]. Experimental data indicate that triple-negative tumors maybe highly sensitive to platinum-based chemotherapy [16, 17]. In the mid-1990s, we started the evaluation of a weekly triplet regimen including cisplatin, epirubicin, and paclitaxel (PET regimen) in breast cancer patients. Cumulative doses of 90 mg/m2 for cisplatin, 150 mg/m2 for epirubicin, and 360 mg/m2 for paclitaxel were given over 3 weeks with the utilization of granulocyte colony-stimulating factor (G-CSF) support. This weekly approach was evaluated in phase II and III trials, including women with either locally advanced breast cancer or large operable disease [18–21]. In a previous paper [20], we reported the results of a phase II study, which tested the PET regimen in 63 women with large operable breast cancer. The pCR rate was particularly impressive in estrogen (ER)-negative and HER-2-positive patients (>60%). In view of that, we expanded the accrual into the study of women with ER-negative or HER-2-positive operable breast cancer. The present paper reports the safety and efficacy data of patients with triple-negative large operable breast cancer receiving preoperative PET from 1999 to 2008. Patients with ER-negative and HER-2-positive tumor have been excluded from the present analysis because the administration of trastuzumab after surgery could lead to an overestimation of the effect of chemotherapy on long-term DFS.
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functions. Previous or concurrent malignancy was also considered as exclusion criteria, except for inactive nonmelanoma skin cancer and in situ carcinoma of the cervix. All patients gave their written informed consent, and the trial was approved by the Independent Ethical Committee of the National Tumor Institute of Naples.
pretreatment evaluation Pretreatment evaluation included a complete history and physical examination, electrocardiogram and bi-dimensional echocardiography, mammography, chest X-ray, liver ultrasonography, radionuclide scan of the bone (with X-ray evaluation of the suspicious bone segments), and computed tomography or magnetic resonance imaging of the brain in case of suspicion of brain involvement. A core biopsy of the tumor in the breast was also carried out with the immunohistochemical assessment of the main prognostic variables (steroid hormone receptors, Ki-67, HER-2/neu). The HER-2/neu was measured by using the mAbs mAb 1 and CB11 on 3-lm sections of paraffin-embedded tumor samples.
treatment All eligible patients received epirubicin 50 mg/m2 as an i.v. bolus, followed by paclitaxel (Taxol, Bristol Myers Squibb, Rome, Italy) 120 mg/m2 as a 1-h infusion and cisplatin 30 mg/m2 as a 30-min infusion, weekly for 8 weeks. Recombinant human G-CSF 300 lg/day was also given s.c. on days 3–5 of each week. A short-term forced hyperhydration (1 l of saline over 2 h) and antiemetic prophylaxis (HT3 receptor antagonists) were also carried out. Prophylaxis for hypersensibility reactions consisted of dexamethasone 8 mg i.v. and promethazine 50 mg i.m. plus ranitidine 50 mg i.v. 30 min before paclitaxel administration. Chemotherapy was delivered at full doses if ANC >1.5 · 109/l and platelets >100 · 109/l. For ANC 1–1.499 · 109/l and/or platelets 75– 99.99 · 109/l, chemotherapy was administered at doses reduced to 50%. In presence of lower ANC or platelet values, treatment was always omitted. Within 3 weeks from the end of chemotherapy, patients underwent surgery. Breast-sparing surgery was carried out when feasible. It consisted of quadrantectomy together with standard level I and II axillary lymph node dissection. Four cycle of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil were delivered after surgery in patients showing less than four axillary nodes involved at pathologic assessment. An additional four cycles of fluorouracil-epirubicin-cyclophosphamide (FEC) (epirubicin instead of methotrexate) cycles were administered in those women showing four or more axillary nodes involved. On completion of postoperative chemotherapy, radiotherapy was carried out in those patients who underwent conservative surgery, as well as in those submitted to mastectomy who had shown more than three axillary nodes involved, skin and/or nipple involvement, or had T3 or G3 tumor at diagnosis.
eligibility criteria Patients with histological confirmation of ER-negative, progesterone receptor (PgR)-negative, HER-2-negative large operable breast cancer (T2–3, T size > 3 cm and N0–1) with no prior chemotherapy or hormone treatment were included in the present analysis. Other eligibility requirements were as follows: age £ 70, Eastern Cooperative Oncology Group performance status of less than two, adequate bone marrow [absolute neutrophil count (ANC) ‡ 2 · 109/l, platelet count ‡ 100 · 109/l, and hemoglobin level ‡ 100 g/l], liver [bilirubin level < 1.5· the upper limit of normal, aspartate aminotransferase (AST), and/or alanine aminotransferase (ALT) < 3· the upper limit of normal, prothrombin time < 1.5 · control], renal (creatinine clearance ‡ 60 ml/ min), and cardiac [left ventricular ejection fraction (LVEF) > 50%, absence of severe cardiac arrhythmia or heart failure, second- or third-degree heart block, or acute myocardial infarction within 4 months before study entry]
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toxicity and response evaluation criteria Toxicity was assessed at the weekly visits and recorded according to the National Cancer Institute—Common Toxicity Criteria version 3. Complete blood cell count and chemistry were carried out once a week in all patients and every other day in cases of grade 4 hematological toxicity. Bidimensional echocardiography was carried out on completion of treatment and every 4 months thereafter for 3 years. Clinical tumor response was assessed within 2 weeks from the end of chemotherapy and classified according to standard World Health Organization criteria [22]. Clinical examination, mammography, and breast ultrasonography were carried out to assess the regression of the tumor in both breast and axilla. For the pathologic analysis of response, the amount of residual epithelial neoplastic cells in the tumor mass, the mitotic index in malignant epithelial cells, and the location of malignant
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component (invasive versus intraductal) were taken into account [23]. Response in the breast was scored as follows: class I (absence of residual malignant epithelial cells), class II (persistence of only in situ residual malignant component), class III (only focal invasive tumor residuals, with substantial histological modifications of the tumor tissue related to chemotherapy), and class IV (no substantial modifications in the tumor mass related to chemotherapy). Patients showing a class I or II response in the breast, together with absence of axillary involvement, were considered as pathological complete responders.
statistical analyses The pCR was the main end point of the present study. We aimed to evaluate whether this short-term dose-dense approach could produce at least a 55% pCR rate (p1), setting 40% as the lowest pCR rate of interest (p0). With an alpha error of 5% and a power of 80%, at least 70 patients were required, according to the Simon’s two-stage minimax design [24]. This approach would have been considered unworthy of further evaluation if <35 pCRs were observed in the 70 enrolled patients. Fisher’s exact test and logistic regression were used to determine factors predictive of pCR. Parameters assessed were tumor size, grading, proliferation score (Ki-67), and clinical nodal status. DFS, distant disease-free survival (DDFS), and overall survival (OS) were also analyzed. DFS was considered as the interval between surgery and documentation of a relapse (ipsilateral, locoregional, or distant) or new contralateral breast cancer or new other cancer or death by any cause. DDFS was considered as the interval between surgery and documentation of distant metastasis or death by any cause. OS was considered as the interval between diagnosis and death by any cause. All time-dependent curves were estimated by the Kaplan–Meier method, and log-rank test was used for comparisons [25, 26]. All patients were included in the analysis of response and survival on an intention-to-treat basis.
Table 1. Patient characteristics (n = 74) Characteristic
Patients (%)
Age (years) Median Tumor grade 1–2 3 T status 2 3 N status 0 1 2 Ki-67 <20% ‡20% Largest tumor diameter, mm Mean Range
48 (range 26–69) 25 (33.8) 49 (66.2) 35 (47.3) 39 (52.7) 26 (35.1) 44 (59.4) 4 (5.5) 18 (24.3) 56 (75.3) 63 34–110
results demographics From May 1999 to June 2008, 74 consecutive women with triple-negative large operable breast cancer received preoperative PET. Table 1 outlines the main patient characteristics. Thirty-five patients showed T2 and 39 T3 disease. Clinical N0 and N+ were 26 and 48 (4 N2), respectively. The mean T size at diagnosis was 6.3 cm. Tumor grade was low-intermediate or high in 25 and 49 patients, respectively. Ki67 was ‡20% in 56 of 74 (75.8%) patients. compliance All but one women received the planned 8-weekly treatment cycles. An at least 1 week delay due to hematological toxicity (ANC < 1 · 109/l, platelets < 75 · 109/l, or hemoglobin < 8 g/ l), or persistence of grade >1 non-hematological toxicity on day of recycling, occurred in 16 patients. A dose reduction was carried out in 29 patients for overall 67 cycles. Sixty-three of 74 (85.1%) patients actually received ‡80% of the planned dose intensity (Figure 1).
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Figure 1. Relative dose intensity.
response All the 74 enrolled patients underwent surgery. Thus, they were evaluated for both clinical and pathologically documented response (pathological response). Table 2 summarizes clinical response data. Fifty-two women (70%) showed absence of residual tumor in the breast and axilla at clinical restaging. T stage was at diagnosis T2 in 30 and T3 in 22 patients, mean diameter initially being 4.6 cm. An additional 21 women (28.3%) obtained a partial regression of the tumor, giving a 98.3% overall response rate [95% confidence interval (CI) 91% to 100%]. The remaining patient achieved only a minor regression of the tumor, but nevertheless underwent surgery. Overall, 50 of 74 (67.5%) patients underwent breast-sparing surgery. A modified radical mastectomy had been considered in 31 of them at diagnosis.
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Table 2. Clinical response (74 patients assessable)
CR (%) PR (%) Minor response (%) PD (%) ORR
52 21 1 0 73
(70%) (28.3%) (1.7%)
N0
Class I–II + N0, n (%)
Total
3 7
26 24
35 39
3 13
1 9
24 26
11 37
10 6
4 6
12 38
Ki67 < 20 Ki67 ‡ 20
8 40
7 9
3 7
8 42
Total
48
16
10
50
26 (74.3) 20 (51.3) P = 0.03 22 (84.6) 24 (50) P = 0.003 10 (40) 36 (73.5) P = 0.005 7 (38.9) 39 (69.6) P = 0.02 46 (62)
Class I–II
Class III
T2 T3
27 21
5 11
N0 N+
22 26
G1–2 G3
Class IV
[98.3% (95% CI 92–100)]
CR, complete response; PR, partial response; CI, confidence interval.
Thirty-four patients (46%) showed absence of residual malignant epithelial cells, either invasive or intraductal, in the breast specimen (class I). An additional 14 (18.9%) women had only in situ residual tumor cells (class II). Therefore, 48 of 74 (64.9%) women obtained a pCR of the tumor in the breast. Forty-six of 48 patients with pCR of the tumor in the breast showed negative axilla too, giving a 62% (95% CI 50% to 73%) pCR rate in both breast and axilla. A pathological partial response in the breast (class III, only focal invasive tumor residuals in the removed breast tissue) was recorded in 16 patients. In the remaining 10 women, no substantial modifications in the tumor mass were observed (class IV). Overall, 52 women (70%) showed negative axilla. Six of 52 axillary negative patients showed residual in the breast (five class III and one class IV). Among the 22 patients with persistence of tumor in the axilla, 15 had one to three lymph nodes involved and 7 four or more. A pCR occurred in 26 of 35 (74.3%) T2 as compared with 20 of 39 (51.3%) T3 patients (P = 0.03) and in 22 of 26 (84.6%) N0 versus 24 of 48 (50%) N+ (P = 0.003). Thirty-six of 49 (73.5%) patients with high-grade tumor achieved a pCR as compared with 10 of 25 (40%) patients with low-intermediate grade tumor (P = 0.005). Seven of 18 (38.9%) patients with baseline Ki-67 <20% achieved a pCR, as compared with 39 of 56 (69.6%) women with Ki-67 ‡20% (P = 0.02). At logistic analysis, T2 (P = 0.04), N0 (P = 0.02), and G3 (P = 0.003) were independently predictive of higher pCR rate (Table 3). Table 4 summarizes the postchemotherapy patterns of the 28 patients who did not achieve a pCR. Two patients had class II response in the breast and positive axilla (one to three nodes), 16 patients had class III response (five with negative axilla, nine with one to three, two with more than three positive nodes), and 10 patients class IV response (one negative, four with one to three, five with more than three positive nodes). Twelve of 26 patients with residual tumor in the breast, showed a Ki-67 score ‡20% and 15 of 26 were G3. At a 41-month median follow-up (range 3–119), with 42 of 74 patients having a >3-year time from surgery, three locoregional relapses, nine distant relapses, one contralateral breast cancer and six deaths had occurred, the 3-year DFS, DDFS, and OS being 83%, 84%, and 96%, respectively. Fiveyear DFS, DDFS, and OS were 76%, 84%, and 89%, respectively (Figure 2). One locoregional, two distant relapses (one liver and one lung), and two deaths had occurred in the 46 patients who achieved a pCR, 3- and 5-year DFS being 97% and 90%, respectively. With 16 patients having a ‡5-year follow-up, no events occurred after 5 years in this group (Figure 3). The
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Table 3. Pathological assessment (74 patients submitted to surgery)
26 48 25 49 18 56 74
Table 4. Postchemotherapy patterns of 28 non-pCR patients Class
G 1–2 G 3 Ki67 < 20 Ki67 ‡ 20 N0 N1–3 N > 3 Total
I–II – III 9 IV 2 Total 11
– 7 8 15
– 12 2 14
– 4 8 12
0 5 1 6
2 9 4 15
0 2 5 7
2 16 10 28
pCR, pathologic complete remission.
Figure 2. Disease-free and overall survival.
baseline characteristics of the three pCR relapsed patients were as follows: T > 5 cm three of three, G3 three of three, Ki67 ‡ 20% two of three, N+ three of three, and N2 two of three. In patients showing residual disease after primary chemotherapy, a total of 10 events (two locoregional, seven distant relapses, one contralateral breast cancer) occurred, 3- and 5-year DFS being 61% and 56%, respectively. Three relapses (one locoregional and two distant) occurred in the 16 patients who had achieved a pathological partial
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Table 5. Toxicity
Figure 3. Disease-free survival (DFS) according to pathological response.
response (class III), all of them had shown high proliferation rate in the residual tumor and more than three axillary nodes involved. Six relapses (one locoregional and five distant) occurred in the 10 patients with absence of a pathological response (class IV).
toxicity Table 5 summarizes the toxicity data observed in the 74 patients enrolled and 589 cycles delivered. No treatment-related deaths or life-threatening events occurred. Twenty-three (31%) patients showed grade 3–4 neutropenia. Neutrophils fell below 0.5 · 109/l in five patients, with only one episode of febrile neutropenia. Four patients showed grade 3 thrombocytopenia, but no episodes of severe thrombocytopenia occurred. Eight patients (10.8%) required red blood cell transfusions due to hemoglobin level falling <8 g/ l. Alopecia was almost universal. Among the other nonhematological side-effects, emesis, fatigue, loss of appetite, and mucositis were the most common. In particular, 80% of patients complained of nausea/vomiting, but only in 10 (13.5%) cases was it severe. Eight (10.8%) patients suffered from severe diarrhea. A 25% dose reduction was carried out in all cases, and chemotherapy could be completed without occurrence of other episodes of severe diarrhea. Severe stomatitis was observed in nine (12.2%) patients, and severe palmar–plantar erythrodysesthesia occurred in three (4.1%) cases. No episodes of grade 3 peripheral neuropathy were recorded. Overall 26 (35.1%) patients complained of mild or moderate paresthesias in the hands and feet. A complete recovery from neurotoxicity occurred within 3 months in all but two women. Musculoskeletal symptoms like transient arthralgias and myalgias occurred in a total of 36 (48.6%) patients, but they were severe in only two cases, and generally responded well to anti-inflammatory drugs. In the majority of cases, these symptoms were related to G-CSF administration. Cardiac toxicity was almost absent. Only two patients developed a decline in LVEF by >15%, but a decrease of LVEF to a value <50% never occurred.
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Neutropenia Thrombocytopenia Anemia Emesis Loss of appetite Diarrhea Mucositis Neurotoxicity Skin toxicity Fatigue Liver Cardiac toxicity ‡ 15% Y LVEF < 50% LVEF Congestive failure
WHO grade 1–2, No. of patients (%)
WHO grade 3–4, No. of patients (%)
41 18 60 49 41 27 21 26 11 31 6
23 4 8 10 7 8 9 0 3 6
(55.4) (24.3) (81) (66.2) (55.5) (36.4) (28.3) (35.1) (15.1) (41.9) (8.1)
(31) (5.4) (10.8) (13.5) (9.5) (10.8) (12.2) (4.1) (8.1)
2 (2.7) 0 0
LVEF, left ventricular ejection fraction.
Finally, six episodes of transient increase of the AST/ALT serum levels were observed, without any clinical sign of liver dysfunction.
discussion The data reported herein confirm our preliminary findings that preoperative administration of weekly PET results into a very high pCR rate in women with triple-negative large operable breast cancer. The sample size (74 patients) of the present study is large enough to state that there is a 95% chance to yield a pCR ‡50% in triple-negative patients with this approach. This range of activity appears better than that reported by other authors in similar populations with much longer treatments. In the M.D. Anderson Cancer Center (MDACC) retrospective analysis [8], 35 of 112 (28%) triple-negative patients achieved a pCR with paclitaxel / FAC/FEC 24-week treatment. Gianni et al. [3] reported a 42% pCR rate in the breast in ER-negative patients after a 24-week preoperative treatment. The pCR rate reported by Colleoni et al. [4] in patients with ER-negative large operable tumor was 33.3%. In the Arbeitsgemeinschaft Gynacologische Onkologie (AGO) trial [6], a 12-week epirubicin–paclitaxel dose-dense sequential treatment yielded a 28% pCR in ER-negative patients; however, a substantial proportion of patients were T4 in that study. In the NSABPB27 trial [27], the AC / docetaxel treatment yielded a 22.8% pCR rate in ER-negative patients, although the ER status was unknown in a relevant proportion of the patients enrolled. Baseline patients’ characteristics were not at all favorable in the present study. Only tumors >3 cm were included, more than half of patients had T3 disease and almost 65% had clinically positive axilla. If we compare these figures with those of the European Cooperative Trial in Operable Breast Cancer trial, we notice that the cutoff was 2 cm in that trial, with 80% of patients having <4 cm tumor and 53% negative axilla. Speculations about the effect of our approach on long-term survival should be made with caution. The accrual time goes
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original article through 9 years, and only 42 of 74 patients had a ‡3-year follow-up. However, the risk of short-term relapse is much higher in triple-negative as compared with other patients, thus 3- and 5-year DFS are more predictive of long-term DFS in these patients than in the others. The 83% 3-year and 76% 5-year DFS we observed in this poor prognosis population appear quite promising. The 3-year freedom from progression was 63% in the MDACC reported series. It is also interesting to remark that the DDFS in the present study was 84% at both 3 and 5 years. The achievement of pCR in a very high proportion of patients can explain the encouraging DFS figure we observed. Indeed, our data confirm that the complete eradication of the tumor in breast and axilla is a reliable predictor of long-term DFS. Three- and 5-year DFS were 96% and 90% in patients achieving pCR, and no failures were observed in the 16 patients at risk after 5 years. The presence of some unfavorable baseline characteristics could, however, result into a not negligible risk of relapse even if pCR has been obtained. The three pCR patients who showed a relapse had very large tumor, clinical axillary involvement (massive in two of three), and high nuclear grade. The importance of pretreatment staging variables in determining the outcome of patients treated with neo-adjuvant chemotherapy has been clearly remarked by Jeruss et al. [28]. The authors developed a scoring system which took into account the clinical stage, the pathologic stage, and biological parameters like ER and grading. A woman with stage IIB, ER-negative G3 tumor before chemotherapy who achieves a pCR (clinical pathologic staging + estrogen receptor and grading score 3) would have a 5-year distant metastasis-free survival of 79% as compared with 98% of a woman having I–IIA, ER-positive G 1–2 tumor at diagnosis. Our results also confirm that the lack of pCR achievement predicts a poorer outcome in triple-negative as compared with ER-positive patients. Ten of 28 non-pCR patients relapsed, the DFS being 61% and 56% at 3 and 5 years, respectively. However, patients who achieved a pathological partial response in the breast had a much better survival outcome than those without pathological response (3 of 16 versus 7 of 10). The small number of patients and events does not permit us to determine other parameters able to better define the risk in noncomplete responder patients. However, we must point out that the three patients with class III response, who relapsed, had ki-67 >20% and more than three axillary nodes involved. It has been reported that the clearance of axilla after chemotherapy per se correlates with better survival. Therefore, the persistence of a relevant tumor residual in the axillary nodes can be associated to a substantial risk of relapse, whatever is the response in the breast. The correlation between postchemotherapy Ki-67 and survival was analyzed in a cohort of 284 patients at the Royal Marsden Hospital. The authors concluded that Ki-67 score of the residual tumor is a strong predictor of outcome for patients not achieving a pathological complete response [29]. Three aspects make our approach substantially different from the other neo-adjuvant treatments, namely the administration of cisplatin, the weekly schedule adopted, and the high-dose intensity of epirubicin. Breast cancers lacking ER and PgR and HER-2 amplification often exibit DeltaNp63 isoforms. The DeltaNp63alpha isoform
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promotes survival of breast cancer cells by binding Tap73 and thereby inhibiting its proapoptotic activity. Cisplatin treatment induces Tap73 c-Abl-dependent phosphorilation, which promotes dissociation of DeltaNp63alpha–Tap73 protein complex, Tap73-dependent transcription of proapoptotic Bcl-2 family, and apoptosis [16]. Rottenberg et al. [30] studied in vivo responses of ‘spontaneous’ Brca1- and p53-deficient mammary tumors arising in conditional mouse mutants to treatment with doxorubicin, docetaxel, or cisplatin. All the tumors became resistant to doxorubicin or docetaxel, but did not become resistant to cisplatin, even after multiple treatments. Thirty large operable patients received four epirubicin– cisplastin–fluorouracil (continuous infusion) cycles followed by four cycles of weekly paclitaxel. A pCR was obtained in 12 patients (40, 95% CI 22.7% to 59.4%), and negative axillary nodes were found in 80% of patients at surgery. The weekly schedule can represent the best way to administer paclitaxel, in view of the peculiar pharmacokinetics of this drug. The administration of 80–150 mg/m2 of paclitaxel each week produces tumoricidal, but not myelotoxic serum concentration [32]. Paclitaxel given on a frequent basis also potentially exhibits antiangiogenic and proapoptotic effects, thereby enhancing the efficacy of this schedule [33–37]. Symmans et al. [37] found that the apoptotic response to paclitaxel was almost complete within 4 days, suggesting that more frequent dosing (such as the weekly dose) of paclitaxel might be beneficial to maintain continued apoptotic response. We think that also the high-dose intensity of epirubin has a substantial relevance in our approach. In the AGO study [6], three q2-week cycles of high-dose epirubicin (150 mg/m2) followed by three q2-week cycles of paclitaxel (250 mg/m2) yielded a double pCR rate as compared with four q3-week cycles of a combination of both drugs (epirubicin 90 mg/m2 and paclitaxel 175 mg/m2). It could be hypothesized that a longer duration of our treatment could result into a further increase of pCR rate, perhaps shifting to pCR a proportion of patients with minimal residual in the breast and/or axilla after eight cycles. However, in our previous experience with LABC patients, 12-weekly cycles of our regimen resulted in a substantially impaired patient’s compliance. Therefore, we think that another way to overcome complete or partial tumor resistance should be pursued. Recent advances in functional tumor imaging (fluorodeoxyglucose positron emission tomography, dynamic magnetic resonance imaging) allow us to early select patients who are not going to achieve a pCR [38–41]. These patients should be early shifted (after 3–4 weeks) to another treatment. In moderately responding patients, a biological agent targeting vascular endothelial growth factor [42, 43] or the tyrosine kinase pathway [44] could be combined with PET in order to potentiate its antitumor activity. An alternative chemotherapy regimen, a biological agent, or both should be delivered in nonresponding patients. In conclusion, a 2-month preoperative treatment with PET plus G-CSF support yields a pathological complete response in 60% of women with triple-negative large operable breast cancer, with a 3-year DFS exceeding 80%. This result is
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obtained without any risk of life-threatening hematologic toxicity and at a price of a moderate non-hematologic toxicity in the large majority of patients. A longer follow-up is needed to better evaluate the impact of this new approach on survival outcome. The combination of this regimen with biological agents should be tested in the attempt of further improving both pCR rate and long-term DFS. A large randomized trial comparing the PET regimen with a standard anthracycline–taxane combination should be carried out in women with triple-negative large operable breast cancer.
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