The role of taxanes as a component of neoadjuvant chemotherapy for breast cancer

H. Gogas1,+ and G. Fountzilas2

1 First Department of Medicine, Laiko Hospital, University of Athens, Athens; 2 AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

Received 7 August 2002; revised 24 December 2002; accepted 31 January 2003

Introduction

Neoadjuvant therapy for breast cancer generally refers to the administration of chemotherapy prior to local treatment with surgery and/or radiation. The biological rationale for neoadjuvant therapy of breast cancer is based on the observation of accelerated metastatic growth following tumor resection in animal models. It is suspected that in addition to decreasing the spread of metastatic disease, neoadjuvant chemotherapy can also minimize the emergence of chemoresistant clones. Additional rationale for the use of neoadjuvant chemotherapy is based on its potential clinical benefits, such as increasing tumor resectability by reducing the size of an unresectable tumor, improving local control and improving cosmesis by allowing breast-conserving treatment. It also offers an important test bed for novel therapies including new drugs and new combinations of drugs.

Paclitaxel was the first taxane to show activity in breast cancer. The introduction of paclitaxel into metastatic breast cancer (MBC) treatment has yielded encouraging results. It has a unique cytotoxic mechanism of promoting assembly and preventing disassembly of microtubules [1]. Disruption of microtubule dynamics arrests and subsequently kills cells in the G2 and M phases of the cell cycle. It has also been shown to have anti-angiogenic activity in a highly vascularized transgenic mouse model of breast cancer [2]. Results from many phase II trials have demonstrated that paclitaxel is effective against MBC as single agent, and in combination regimens yielding clinical response rates (cRR) between 56% and 62% [3, 4]. Importantly, it has been shown to be partially non-cross resistant with many other agents and is active in heavily pre-treated patients, including those who have received prior treatment with anthracyclines [5, 6].

Docetaxel was subsequently developed, which binds to the ß-tubulin subunit [7], and several phase II and III trials reported a high activity in first- and second-line therapy of MBC, as well as in patients previously exposed or resistant to anthracycline [8, 9]. When docetaxel was compared with doxorubicin, it produced statistically superior response rates (RR) compared with doxorubicin (48% versus 33%, P = 0.008) and longer time to treatment failure [8]. It has also been studied in patients who have progressed on anthracycline-containing chemotherapy and differences in progression-free survival have been found [9]. Taken together, these study results indicate that the taxanes, as single agents, are among the most active chemotherapeutic agents for the treatment of MBC.

This paper presents results from phase II and randomized studies of single-agent taxanes and of their combination with anthracyclines as neoadjuvant chemotherapy in patients with breast cancer.

Search for studies

The objective of the literature search was to identify all studies reporting the results of neoadjuvant chemotherapy incorporating a taxane-based regimen. The selection process first involved two steps: (i) Medline was searched for potentially relevant articles published from 1966 to December 2001; and (ii) relevant abstracts were selected from proceedings of the American Society of Clinical Oncology and Breast Cancer Research in Treatment Supplements. All retrieved articles and abstracts were reviewed by H.G. and G.F.

Phase II studies with docetaxel

An increasing number of trials using docetaxel as a single agent or in combination with anthracyclines have been reported recently.

Preliminary results from a phase II [10] study including 33 patients with locally advanced breast cancer treated with four cycles of docetaxel 100 mg/m2 administered as a 1-h infusion once every 3 weeks showed that a clinical partial response (cPR) was achieved in 22 patients (67%) with six patients (18%) experiencing a clinical complete response (cCR). Disease was stable in four patients (12%) and progressed in one (3%). One patient with a cCR was confirmed to have a complete pathological response (pCR) at the time of surgery. Febrile neutropenia was noted in eight patients (24%) and in eight of the 120 treatment cycles (7%) administered.

In another phase II study [11], 42 patients with histologically confirmed primary breast cancer tumors of at least 2 cm in diameter received doxorubicin 50 mg/m2 over 15 min and docetaxel 75 mg/m2 over 1 h every 2 weeks (24 patients) or every 3 weeks (18 patients) for four cycles. The overall response rate (ORR), as assessed by physical examination, was 93%, and cCR of the primary tumor occurred in 33% of patients. The remission rate as assessed by sonographic measurement was 67%. Of note, two patients (5%) had histologically confirmed complete responses. No grade 4 toxicity was noted, while frequently seen grade 3 toxicities included lethargy, loss of appetite, stomatitis, leucopenia, skin desquamation and infection; alopecia was less frequent. The 3-week schedule was associated with less toxicity than the 2-week schedule.

Several other phase II trials have been reported in abstract form that have adopted the combination of docetaxel with doxorubicin [12, 13] or epirubicin [1416], three-drug combinations [17, 18], or the weekly administration of docetaxel [19, 20]. cRRs varied from 72% [13, 20] to 100% [17, 18], and pCR rates from 13.5% [12] to 28% [17]. A grade 3 decrease in left ventricular ejection fraction (LVEF; congestive heart failure responsive to treatment) was noted in 10% of patients when combining docetaxel with cisplatin and trastuzumab [18]. Moreover, heart failure developed in 10.5% of patients receiving the combination of doxorubicin with docetaxel [12]. These results are summarized in Table 1.


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Table 1. Selected phase II studies of neoadjuvant docetaxel-containing regimens
 
Randomized studies with docetaxel

So far, there have been only a few randomized studies incorporating docetaxel in neoadjuvant chemotherapy of breast cancer.

The optimal sequence of administration of docetaxel and doxorubicin was addressed in a pilot randomized study conducted by the Hoosier Oncology Group [21]. Forty patients with newly diagnosed stage II or non-inflammatory stage III breast cancer were randomly assigned to receive different sequences with the same cumulative doses of doxorubicin and docetaxel over a 12-week period before definitive surgery. Patients in arm A received sequential therapy with doxorubicin 75 mg/m2 every 2 weeks for three cycles followed by docetaxel 100 mg/m2 every 2 weeks also for three cycles. Patients in arm B received combination therapy with doxorubicin 56 mg/m2 plus docetaxel 75 mg/m2 every 3 weeks for four cycles. The cumulative dose of doxorubicin and docetaxel was almost identical in both groups, as initially planned, but the dose intensity (DI) of both drugs was 50% less in the combination as compared with the sequential schedule. Clinical responses were similar in both groups, with an ORR of 87%, including 20% cCR. pCR or residual in situ disease only was confirmed in five patients (13%). Patients who received sequential therapy had fewer positive lymph nodes (mean 2.17 versus 4.81; P < 0.037) at the time of definitive surgery. Myelosuppression was severe in both groups; nevertheless, >80% of the planned DI was delivered. Hand-foot syndrome was more common after sequential therapy. This pilot trial is the first reported randomized study to test directly Norton and Simon’s dose-dense hypothesis. Doses were calculated to deliver the same total amount of both drugs over a 12-week period to limit any confounding effect of differing dose between the treatment groups. However, the results of this study should be interpreted cautiously due to the small number of patients.

The results of several randomized trials that compared docetaxel-based regimens with non-docetaxel-containing combinations as neoadjuvant treatment have recently been reported.

In one such study, conducted by the Aberdeen Breast Group, patients with large or locally advanced breast cancer were initially treated with four cycles of CVAP (cyclophosphamide, vincristine, doxorubicin, prednisolone) chemotherapy. Those with a cCR or cPR were randomized to receive either four further cycles of CVAP or four further cycles of docetaxel (100 mg/m2). All non-responders received four additional cycles of docetaxel. The primary aim of this study was to compare the efficacy of docetaxel with an anthracycline-based neoadjuvant chemotherapy regimen. The secondary aim was to determine the efficacy of neoadjuvant docetaxel in patients with breast cancers that initially failed to respond to anthracycline-based neoadjuvant chemotherapy.

A total of 162 patients entered onto the study and 145 completed eight cycles of neoadjuvant chemotherapy. The cRR of the primary tumor in 162 evaluable patients after four initial cycles of CVAP was 66%. A total of 145 patients completed eight cycles of chemotherapy and subsequently were reassessed for clinical response. Based on an intention-to-treat analysis, the final clinical CR or PR status was 64% in the CVAP group and 85% in the docetaxel group (P = 0.03), while the pCR rate was 15% and 31% in the two groups, respectively (P = 0.06). Non-randomized patients had a final cRR of 55%. Additionally, in patients randomized to receive further CVAP, 3-year survival was 84%, while in those randomized to receive docetaxel, 3-year survival was 97% (P = 0.02, log-rank test). In patients randomized to receive further CVAP, the 3-year disease-free interval was 77%, while in those randomized to receive docetaxel it was 90% (P = 0.03; log-rank test) [22]. In this study the sequential use of neoadjuvant docetaxel after initial CVAP chemotherapy in patients with anthracycline c-refractory cancers resulted in enhanced clinical response. Furthermore, for the treatment of patients with anthracycline-sensitive cancers, the sequential administration of neoadjuvant docetaxel after anthracycline-based therapy resulted in a significantly greater complete pRR than that achieved by further administration of anthracycline-based treatment.

A large multi-national randomized trial, including 407 patients with stage IIIA or IIIB breast cancer, compared the efficacy of docetaxel and doxorubicin (adriamycin) (AT) versus 5-fluorouracil, doxorubicin and cyclophosphamide (FAC). An interim analysis, presented at the 2001 American Society of Clinical Oncology (ASCO) meeting [23], showed that the ORR was 72% in the AT group compared with 63% in the FAC group (P = 0.0056). There was a trend towards increased pathological response in the AT group compared with the FAC group (16% versus 11%, respectively). Median overall survival (OS) was 26 months in the AT group and 21 months in the FAC group. The difference between the arms is not significant so far. Main grade 3/4 treatment-related toxicities seen respectively in AT and FAC groups were: neutropenia (72% versus 23%), febrile neutropenia (13% versus 0%), nausea (5% versus 5%), vomiting (5% versus 7%), diarrhea (6% versus 2%), fatigue (3% versus 1%) and stomatitis (1% versus 0%). These interim results suggest that a docetaxel–doxorubicin combination may improve prognosis and surgical options for patients with unresectable locally advanced breast cancer. Additional patient follow-up will evaluate the impact of docetaxel neoadjuvant therapy of OS.

In another randomized phase II study coordinated by the GIREC group [24], 90 patients with unilateral, non-inflammatory, operable T2, T3 or T4 tumours were randomized to receive six cycles of the combination of fluorouracil (600 mg/m2), epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) (FEC100) or the combination of epirubicin (100 mg/m2) and docetaxel (75 mg/m2) (ED). The primary endpoint of the study was to compare the efficacy of the two regimens. The objective cRR was 72% with FEC100 and 84% with ED. After six cycles, the pCR rate was 24% in both arms.

Several large studies of docetaxel-containing neoadjuvant regimens are currently in progress. One study, NSABP B-27, has recently closed to accrual, with 2411 patients enrolled. In this study, patients were randomized to receive either four cycles of adriamycin and cyclophosphamide (AC) followed by surgery, or four cycles of AC followed by four cycles of docetaxel, and then followed by surgery or four cycles of AC, followed by surgery and four cycles of docetaxel postoperatively. Tamoxifen was given to all patients for 5 years. Preliminary results of this study were presented at the 24th Annual San Antonio Breast Cancer Symposium [25]. The addition of preoperative docetaxel increased the number of clinical responders from 85% to 91%, and the number of pCRs from 14% to >25%.

Another study conducted by the Anglo-Celtic Cooperative Oncology Group (ACCOG) has also completed accrual. The interim analysis was presented at the ASCO Annual Meeting in 2002. The objectives were to compare the RRs (clinical and pathological), the relapse-free survival (RFS) after subsequent surgery and the OS of patients treated with AC and adriamycin and docetaxel (AD) as primary medical therapy. Eligible patients were those with operable disease >=3 cm in diameter, locally advanced disease (T4 included) and inflammatory breast cancer. Three hundred and sixty-three patients were randomized to adriamycin 50 mg/m2 and docetaxel 75 mg/m2 (183 patients), or adriamycin 60 mg/m2 and cyclophosphamide 600 mg/m2 (180 patients) once every 3 weeks for a maximum of six courses. Clinical response rates (cCR and cPR) were 78% and 88% for AC and AD, respectively (P = 0.11). Pathological involvement of axillary lymph nodes at surgery was present in 63% treated with AC and 64% treated with AD.

pCR rates for AC and AD were 12% and 8%, respectively. Median RFS for AC and AD are 63 and 55 months, respectively, with median OS of 64 and 63 months, respectively (median follow-up 18 months) [26]. It is noteworthy that the doses of adriamycin were lower in the arm containing taxane. Again, further follow-up is needed.

Phase II studies with paclitaxel

A considerable number of phase II studies evaluating the efficacy of paclitaxel as neoadjuvant treatment has been reported.

A pilot study with four cycles of neoadjuvant chemotherapy with bolus doxorubicin (60 mg/m2) plus paclitaxel (200 mg/m2) infused over 3 h was performed in 38 women with locally advanced breast cancer and in 41 with stage II/III breast cancer. Major clinical response was observed in 88% of patients. On pathological examination of the surgical specimens, 40% were pT1, 15% had no macroscopic tumor and 7% had complete disappearance of invasive neoplastic cells. The combination was well tolerated. Primary toxicity consisted of grade 1 or 2 reversible peripheral neuropathy and grade 3 alopecia. After a median follow-up of 13 months, none of the patients has developed cardiac toxicity or any significant alteration of LVEF, which was measured before each cycle of chemotherapy and every 3 months thereafter [27].

In a multicenter phase II study conducted by our group (35 patients), the combination of paclitaxel at a dose of 175 mg/m2 and pegylated liposomal doxorubicin 35 mg/m2 were administered every 3 weeks for a maximum of six cycles. Twenty-five patients (71%) responded. Six (17%) had a CR, 19 (54%) had a PR, four remained stable, two progressed and four patients were not evaluated for response due to discontinuation of chemotherapy because of skin toxicity. Three patients had a pCR. The primary toxicity was skin toxicity. Grade 3 skin toxicity was noted in four patients (11%). Palmar–Plantar erythrodysesthesis grade 3 was experienced in three patients (9%). With a median follow-up of 16 months there have been eight recurrences and three deaths. The median time to progression has not yet been reached [28].

Preliminary results of phase II studies with weekly paclitaxel or with two-drug or three-drug combinations of paclitaxel, epirubicin and cyclophosphamide have been reported, and suggest that high cRR (82% to 84%) and pCR (21% to 52%) can be achieved with these combinations [2932]. Furthermore, high rates of pCR were also observed with the combination of trastuzumab and paclitaxel in patients with HER-2/neu-overexpressing tumors [33].

It should be noted that all of these trials have been reported in abstract form and detailed data on survival are lacking (Table 2).


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Table 2. Selected phase II studies with neoadjuvant paclitaxel-containing regimens
 
Randomized trials with paclitaxel

Only six randomized trials of paclitaxel-containing neoadjuvant chemotherapy, so far, have been completed. As most of them have only been presented in abstract form, a complete analysis of the data is not possible.

One such trial, conducted at the MD Anderson Cancer Center randomized 174 patients with T1–3 N0–1 M0 breast cancer to receive preoperatively either paclitaxel (250 mg/m2) as 24-h infusion or FAC with doxorubicin given as a 72-h continuous infusion through a central venous catheter, at 3-week intervals. Each patient was treated with four cycles of neoadjuvant chemotherapy. The cCR plus cPR rate was 79% (21 cCRs and 48 cPRs among 87 patients) after FAC therapy and 80% (23 CRs and 46 cPRs among 86 patients) after paclitaxel therapy. Among 85 patients treated with FAC who underwent surgery, 14 (16%) achieved a pCR or had only in situ disease on examination of histological specimens; the corresponding results for paclitaxel-treated patients were seven pCR among 86 surgical cases (8%). Distribution of nodal disease detected at the time of surgery were similar between the treatment groups. A somewhat higher percentage of patients had breast preservation in the paclitaxel arm of the study. Three patients on the FAC arm and one patient on the paclitaxel arm had progressive disease during the induction phase. The difference in response rates of 0.9% (paclitaxel minus FAC) had a 95% confidence interval ranging from –11.1% to 13%. Results were thus consistent, with a possible difference in cRR of ~12% in favor of either regimen. A higher fraction of patients in the paclitaxel arm had neutropenic fever (53% versus 21%) and there were no episodes of clinical cardiac dysfunction in either treatment arm [34].

In a multicenter randomized trial, conducted in France, 247 patients with T2–3 N0–1 M0 previously untreated breast cancer were randomized to receive neoadjuvant chemotherapy either with doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) or the same dose of doxorubicin (adriamycin) and paclitaxel (Taxol®) 200 mg/m2 in 3-h infusion (AT). The primary endpoint of that study was to compare the pCR rate in the two groups; secondary endpoints were to compare ORR, progression-free survival and OS. In March of 1998, an independent panel of experts performed a planned interim analysis of the first 120 evaluable patients (40 in the AC group and 80 in the AT group). Early stopping rules dictated that if <=3 pCRs (<=7.5%) in the AC group and <=7 (<=9%) in the AT group were observed, then accrual would be halted. At that point, two pCRs were seen in the AC group and 11 in the AT patients. Thus, accrual to the AC arm was stopped, but was continued in the AT arm. A total of 247 patients were enrolled in the study; 67 were randomized to receive AC and 180 AT. Patients were well matched in terms of age, extent of disease and menopausal status. pCR was observed in 10% of patients in the AC group compared with 16% in the AT group. Overall response was 66% for AC and 83% for AT, with cCR rates of 9% and 14%, respectively. Most importantly, neoadjuvant chemotherapy enabled breast conserving surgery to be performed in 45% of patients treated with AC compared with 56% of those in the AT group. These results were statistically significant. Cardiac toxicity was monitored carefully. Abnormal values of LVEF were noted in 5% and 8% in the AC and AT group, respectively. One patient in the AC arm developed congestive heart failure [35]. These results indicated the need for further investigation of this combination regimen in the neoadjuvant setting, and the investigators concluded that the AT would be the standard arm in their future trial.

A third randomized study (ETNA trial) of 191 patients with T2,3–N0,1–M0 breast cancer was conducted by the same group. Patient recruitment ended in January 2001. The primary objective of the study was to compare the rate of pCR after four or six cycles of the AT combination. Secondary objectives were to compare ORR, progression-free survival and OS between the two groups. In a preliminary analysis, reported as an abstract [36], the rate of pCR was 5% and 17% in the two groups, respectively. cCR rates were 20% and 32% and ORR were 82% and 86%, respectively. These results suggest that six cycles of neoadjuvant treatment might be the standard of care. Even though no cases with congestive heart failure were reported, a >20% decline of LVEF was seen in 19% and 22% of patients, respectively.

Finally, in an ongoing randomized trial at the MD Anderson Cancer Center, patients were randomized to receive paclitaxel preoperatively either weekly for 12 weeks, or four cycles every 3 weeks. The primary aim of this study was to determine whether different schedules or DIs improve pCR rates. The dose of weekly paclitaxel was planned by patient pretreatment nodal status. Node-negative (N0) patients received 80 mg/m2/week for 12 weeks. Node-positive (N+) patients received 150 mg/m2/week for 3 weeks followed by a 1-week break (one cycle) for four cycles. Standard paclitaxel was given to N0 and N+ patients as a 24 h continuous infusion (225/mg/m2) every 3 weeks for four cycles. All patients received four cycles of FAC after paclitaxel. A preliminary analysis of the initial 127 patients who have completed all therapy on this ongoing study showed that pCRs were seen in 31% of patients in the weekly arm and 18.5% in the 3-weekly arm [37].

During the 38th Annual Meeting of ASCO (2002) the preliminary results of the AGO study were also presented. This study was designed to compare the frequency of breast conserving surgery, the response rates and the safety between two epirubicin (E) and paclitaxel (T) containing regimens given either as dose-dense sequential chemotherapy (arm A) or in a standard dose (arm B), both as preoperative therapy for primary breast cancer. Patients with large primary tumours (T >3 cm) or inflammatory disease were randomly assigned to receive either three cycles of epirubicin 150 mg/m2 followed by three cycles of paclitaxel 250 mg/m2 every 2 weeks with granulocyte colony-stimulating factor support or four cycles of combination epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 every 3 weeks as preoperative therapy. A total of 631 patients were enrolled. Preliminary data from 475 patients demonstrated a significantly higher frequency of breast conserving surgery (66% versus 55%, P = 0.016), pCR (18% versus 10%, P = 0.03) and negative axillary lymph nodes at surgery (51% versus 42%, P = 0.098) with the 2-weekly regimen [38].

In the same meeting, the first report of the European Cooperative Trial in operable breast cancer (ECTO) was also presented. In the ECTO study women with operable breast cancer (T >2 cm) were randomized to adjuvant doxorubicin (A 75 mg/m2 every 21 days) for four cycles followed by CMF (cyclophosphamide, methotrexate and 5-fluorouracil), or adjuvant doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2 over 3 h every 21 days) for four cycles followed by CMF (AT-CMF) or AT-CMF as primary systemic therapy (PST). The aim was assess whether paclitaxel and PST improve disease-free survival and OS. PST produced cCR in 52% of patients (27% after AT and 25% more after CMF). pCR was documented in 23% of specimens and was associated with negative axillary nodes in 87%. Conservative surgery was more frequent after PST (71% versus 35% before adjuvant therapy, P <0.00001) regardless of tumor size at diagnosis. The frequency of pathologically negative nodes was also significantly higher in PST (61% versus 38%) [39] (Table 3).


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Table 3. Randomized phase III studies
 
Following the incorporation of herceptin in phase II trials, the role of this agent will be further evaluated by cooperative groups in large randomized trials. The CALGB is proposing a trial (CALGB 9808) in patients with HER-2/neu overexpressing, stage III breast cancer. All patients will be treated with four cycles of AC chemotherapy every 3 weeks with or without the cardioprotector dexrazoxane, and will then be randomized to weekly paclitaxel (90 mg/m2 as 1 h infusion) for 12 weeks with or without trastuzumab. Following surgery, there will be a second randomization to further treatment of trastuzumab for 40 weeks or no treatment; all patients will receive adjuvant radiation and tamoxifen for 5 years if they are hormone receptor positive.

Future prospectives

There is a substantial body of evidence from randomized studies suggesting that the incorporation of taxanes into anthracycline-based neoadjuvant chemotherapy increases the pCR rate. This is an important achievement, since it is well established that patients with the greatest survival advantage following neoadjuvant chemotherapy are those who demonstrate a pathological complete disappearance of the tumor. However, there is much work to be done before the use of taxanes can be introduced in to daily clinical practice. Response rates for the group of patients with locally advanced and/or unresectable breast cancer exceed those usually associated with neoadjuvant chemotherapy and can be considered a valuable treatment option in standard practice. At present, there are certain limitations with randomized trials evaluating the role of taxanes in conjunction to anthracyclines as part of neoadjuvant chemotherapy, especially of operable breast cancer. Most of them were relatively small in size and thus not of sufficient statistical power to detect small but meaningfully differences in survival. Furthermore, most of them have so far been published only in abstract form, which precludes a thorough analysis of results. Also, detailed information on radiotherapy is not provided in most of these studies, even though survival is also dependent in optimal local control. There is no doubt that as these studies mature over time, they will provide us with valuable information regarding the impact of the combinations of anthracyclines and taxanes on the survival of patients with breast cancer. Additionally, the optimal dose, the schedule (i.e. weekly, dose-dense, sequential) versus combination, and which taxane should be employed, have to be explored.

As neoadjuvant chemotherapy also offers the important possibility of performing biological studies on the primary tumor and thus increasing our understanding of mechanisms of response and chemoresistance, several groups are currently conducting translational research studies in order to identify useful predictive and prognostic factors. In such a trial (EORTC 10994), the potential predictive value of p53 is assessed in patients with locally advanced, inflammatory or large operable breast cancer randomized to a taxane-containing versus a non-taxane-containing regimen. Additionally, two ancillary studies to the NSABP-27 trial are attempting to evaluate serum and tumor biomarkers as they relate to outcome and response to preoperative AC and/or docetaxel chemotherapy. The first trial (B-27.1) has been designed to evaluate the value of soluble HER-2/neu extracellular domain and anti-HER-2/neu antibodies in predicting response to neoadjuvant chemotherapy and long-term outcome in patients randomized to B-27 trial. In addition, obtaining the serum samples at pre-specified times (i.e. before administration and after completion of neoajuvant chemotherapy, after surgery, 1 year after randomization, and at the time of tumor recurrence) will enable investigators to evaluate whether changes in the levels of HER-2/neu extracellular domain and anti-HER-2/neu antibodies are induced by chemotherapy or are associated with tumor recurrence. The second trial (B-27.2) has been designed to evaluate whether tumor biomarkers obtained by fine needle aspiration or core biopsy can be used to predict response to preoperative chemotherapy and long-term outcome in patients entered in the B-27 trial. Another aim of the B-27.2 study is to determine whether neoadjuvant chemotherapy results in changes in tumor biomarker expression and whether these changes can be correlated with tumor response and long-term outcome. Some of the biomarkers being evaluated include nuclear grade, estrogen and progesterone receptors, proliferation markers, p53, bcl-2, HER-2/neu oncoprotein, P-glycoprotein, and biomarkers related to angiogenesis.

In conclusion, the addition of taxanes to anthracycline-containing neoadjuvant chemotherapy has resulted in high cRRs and has provided intriguing data on pCR rate and progression-free survival. However, mature results on its impact on survival are awaited in order to establish their definite role in the management of patients with breast cancer.

Footnotes

+ Correspondence to: Dr H. Gogas, First Department of Medicine, University of Athens, PO Box 14120, Athens 115 10, Greece. Tel: +30-6944-681159; Fax: +30-210-7781517; E-mail: hgogas{at}hol.gr Back

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