Preoperative chemotherapy treatment of breast cancer—A review
Despite proven benefits of neoadjuvant chemotherapy in patients with locally advanced, invasive breast cancer, no regimen is recommended as the treatment of choice. Neoadjuvant chemotherapy regimens encompass single-agent and combination therapy and sequential treatment. For this report, the author reviewed the literature to determine which regimen, if any, was most beneficial. The results indicated that studies have yielded a wide range of response rates, but no single regimen has emerged as a clear leader. The literature is compounded further by lack of standardized criteria to determine pathologic complete response (which is predictive of survival benefits) and between-study variation in the stringency by which this endpoint is defined. Given the lack of a preferred treatment regimen in the neoadjuvant setting, identifying patients who are likely to respond to specific agents could inform treatment decisions, improve treatment outcomes, and aid in avoiding unnecessary exposure to potential toxicities. The development of novel agents for use alone or in combination with existing agents may improve response rates further in the neoadjuvant setting, especially because a significant proportion of breast tumors can be resistant to many current antineoplastic agents. Particularly noteworthy are the epothilones and their analogs because of their low susceptibility to common tumor-resistance mechanisms. Initial data have indicated that ixabepilone, which is an epothilone analog, has activity in the neoadjuvant setting, and predictive factors for response have been identified. The future of neoadjuvant therapy lies in tailoring treatment to individual patients by identifying response predictors and developing novel agents. This ultimately may lead to improved outcomes for women with breast cancer. Cancer 2007. © 2007 American Cancer Society.
Neoadjuvant chemotherapy is currently the standard of care for the management of locally advanced, stage III invasive breast cancer (BC) and for some stage IIA and IIB breast tumors. Ultimately, the goal of therapy is to extend survival and improve quality of life. Neoadjuvant chemotherapy plays an important role in achieving this goal, although uncertainty remains about the impact timing of chemotherapy (neoadjuvant vs adjuvant) on survival outcome. Neoadjuvant chemotherapy is included in treatment guidelines for patients with locally advanced, invasive BC.1 However, a recent update of the B-18 trial provided suggestive evidence that preoperative systemic therapy may be superior to postoperative adjuvant therapy. (Norman Wolmark, MD, presented “Preoperative Therapy in Invasive Breast Cancer: Reviewing the State of the Science and Exploring New Research Directions” at the National Cancer Institute meeting, Batcher Conference Center, Bethesda, Maryland, March 26–27, 2007.)
Neoadjuvant chemotherapy was sued first in 1973 in patients with inoperable, locally advanced disease to afford tumor shrinkage and to render these tumors treatable by radical mastectomy or radiotherapy.2, 3 Neoadjuvant chemotherapy has evolved since to use in operable breast tumors with the objective of down staging the tumor so that breast-conserving surgery (BCS) could become a viable alternative to radical mastectomy.3 Several studies have attempted to assess whether, in the clinical setting, neoadjuvant chemotherapy can impair metastatic growth and provide the survival benefits that are concomitant with the eradication of metastases, including metastases that are occult at the time of surgery. Those studies included the use of a variety of classes of chemotherapeutic agents as monotherapy, combination regimens, or sequential/alternating therapies.
This article is a review of clinical experience with the different neoadjuvant chemotherapy regimens that provides insight into treatment decisions and highlights data from some of the newer classes of agents in the neoadjuvant setting. Before reviewing these studies, however, it is important to outline the most meaningful markers of response, ie, those that are most predictive of survival when using neoadjuvant therapy for the treatment of BC.
PATHOLOGIC COMPLETE RESPONSE—A MEANINGFUL MARKER OF RESPONSE IN NEOADJUVANT CHEMOTHERAPY
A variety of endpoints can be used to measure outcomes of neoadjuvant chemotherapy for BC other than directly measuring survival (both disease-free survival [DFS] and overall survival [OS]), which, of course, requires long-term follow-up. These include overall response, clinical response (determined by physical examination), radiologic response (determined by mammography, ultrasonography, or magnetic resonance imaging [MRI]), pathologic response (determined by histologic examination), and the rate of BCS. The results from several clinical trials have indicated that, of these outcome measures, pathologic complete response (pCR) is most predictive of survival.4–8
Despite the proven predictive value of pCR in this context, there is no consensus on the measurement of this important endpoint. Three of the most commonly used criteria in the literature are those of Sataloff et al.,7 Chevallier et al.,9 and Feldman et al.4 These 3 sets of criteria have some overlap (particularly Chevallier et al. and Feldman et al., because the criteria described by Chevallier et al. are a modified version of those described by Feldman et al.) but, for the most part, differ from each other (Table 1). Sataloff et al. provided specific criteria for both the primary tumor and the axillary lymph nodes. To add to the complexity, the M. D. Anderson Cancer Center uses pCR criteria that are distinct from other pCR methodologies; these criteria also are stringent and are defined by no evidence of clinically invasive cancer in either the breast or the axilla.10, 11
Table 1. Summary of Commonly Used Pathologic Complete Response Criteria
|Feldman et al., 19864||Samples from each quadrant, the nipple-areolar complex, areas of suspicious or prior tumor involvement, and axillary content||pCR defined as the absence of any macroscopic evidence of tumor upon gross inspection of the mastectomy specimen and axillary contents, regardless of subsequent findings on microscopy|
|Chevallier et al., 19939||≥6 Sections per mastectomy (≥1 each from nipple, areolar, and retroareolar regions); whole axillary specimen (for lymph node involvement)||Grade 1, disappearance of all tumor either on macroscopic or microscopic assessment; grade 2, presence of in situ carcinoma in the breast, no invasive tumor and no tumor found in the lymph nodes; grade 3, presence of invasive carcinoma with stromal alteration (eg, sclerosis or fibrosis); grade 4, no or few modifications of the tumor appearance|
|Sataloff et al., 19957||Multiple sections from biopsy site; random sections of nipple and subareolar area and the 4 quadrants||Primary site: T-A, total or near therapeutic effect; T-B, subjectively >50% therapeutic effect, but < total/near total; T-C, <50% therapeutic effect, but effect evident; T-D, no therapeutic effect; axillary lymph nodes: N-A, evidence of therapeutic effect, no metastatic disease; N-B, no lymph node metastasis, or therapeutic effect; N-C, evidence of therapeutic effect, but lymph node metastasis still present; N-D, viable metastatic disease, no therapeutic effect|
|M. D. Anderson Cancer Center (Sahin, 200510; Schnitt and Connolly, 199211)||No. of sections taken from each quadrant based on gross inspection, radiographic features, and size of resection specimen; for nonpalpable cases, >10–15 blocks were examined, and 1 or 2 representative histologic sections were evaluated for lymph nodes that contained identifiable metastatic carcinoma||pCR defined as no evidence of clinical invasive cancer in either the breast or axilla|
Differences in pCR evaluation criteria are compounded further by the different sites from which tissue can be sampled for pathologic evaluation and by the various number of samples that may be collected for evaluation. These discrepancies are highlighted in the studies discussed here, in which an enormous amount of variation was observed in the criteria used for the measurement of pCR. Standardization of pCR evaluation is needed before between-study comparisons of pCR rates can be possible.
CLINICAL EXPERIENCE WITH NEOADJUVANT CHEMOTHERAPY—COMPARING THE EVIDENCE
Although few would question the value of neoadjuvant chemotherapy in the management of both operable and inoperable BC, currently, there is no consensus about which chemotherapy regimen is the best. To evaluate this further, a systematic review of the literature was conducted using the Medline and EMBASE databases. The search terms used were “neoadjuvant” or “preoperative,” and “breast cancer.” The search was open to all languages but was restricted to clinical trials only and to dates between 1993 and September 2006. Abstract databases for recent key congresses (American Society of Clinical Oncology, 2002–2006; San Antonio Breast Cancer Symposium, 2002–2005) also were searched. Because between-study comparisons are limited by differences in study design, patient types, and criteria used to measure response, only randomized clinical trials were included in the literature analysis, thus allowing direct comparison between chemotherapy regimens within a robust study design.
Randomized clinical trial publications that were identified from this search encompassed studies of patients with inoperable and operable BC. To evaluate only the most clinically meaningful data, studies with <30 patients were excluded from the analysis, which left a total of 49 publications.
Single-agent versus combination neoadjuvant chemotherapy
In the context of single-agent neoadjuvant chemotherapy, the taxanes compared favorably with combination therapies or anthracycline monotherapy in terms of clinical responses and, to a lesser extent, with pCR (Table 2). It is important to note that studies may differ in terms of the criteria used to determine pCR; thus, direct comparison of pCR rates across trials should be made with caution. In an M. D. Anderson Cancer Center study comparing paclitaxel monotherapy with combined fluorouracil (5-FU)/doxorubicin/cyclophosphamide (FAC) before local therapy, the clinical complete response (cCR) rates were 27% and 24%, respectively; however, the pCR rate (pCR criteria from the M. D. Anderson Cancer Center) was lower with paclitaxel than with FAC neoadjuvant therapy (8% vs 17%; P value nonsignificant [NS]).12 Another study compared neoadjuvant doxorubicin/cyclophosphamide (AC) followed by adjuvant docetaxel with neoadjuvant docetaxel followed by adjuvant AC.13 Although the overall response rate (ORR) was similar between the 2 regimens, neoadjuvant docetaxel alone afforded greater therapeutic benefit with respect to pCR (pCR criteria not specified) and BCS rates, with the largest between-treatment difference observed with respect to the pCR rate (12.5% vs 4.8%; P = .2). However, in a study comparing neoadjuvant docetaxel with neoadjuvant AC, similar ORR rates (65% and 57%, respectively) and pCR rates (9.4% vs 7.7%; pCR criteria not specified) were observed in the docetaxel and AC groups (no P values were provided).14
Table 2. Neoadjuvant Chemotherapy: Randomized Trials of Single Chemotherapeutic Agents
|Buzdar et al., 199912||87; 87||T1-T3, N0-N1, M0||Pac × 4, then LT followed by FAC × 4; or FAC × 4, then LT followed by FAC × 4||80; 79||27; 24||8; 17||38; 27 (SAD)||94; 89 (est 2 y)||—|
|Overmoyer et al., 200417; Lyons et al., 200618||24; 25||Locally unresectable, with or without metastasis||Bev-Doc × 6; or Doc × 6||79.6||14.3||—||—||—||—|
|Makris et al., 200513||45; 46||—||Doc × 4; or Dox-Cyc × 4||62; 59||—||12.5; 4.8||48; 34||—||—|
|Chang et al., 200514||57; 56||—||Doc × 4; Dox × 4 (+Cyc)||65; 57||—||9.4; 7.7||—||—||—|
|Formenti et al., 200115; Formenti et al., 200316||42; 44||IIB/III||Pac × 4; Pac × 8, RT||67.5; 86||12.5; 9||5; 16||—||—||—|
Increased responses to single-agent neoadjuvant chemotherapy have been demonstrated after the addition of radiation treatment. For example, the addition of radiation to paclitaxel neoadjuvant chemotherapy slightly improved the ORR (68% vs 86%; P value NS) and, it is worth noting, substantially increased the pCR rate (defined as clearance of invasive cancer in the breast and axilla) from 5% to 16% (no P value was provided). However, limited data support the concomitant use of irradiation and taxanes, and further safety evaluations will be necessary before such treatments become part of regular clinical practice15, 16 (Table 212–18).
Comparison of combination neoadjuvant chemotherapy
The 23 publications that described clinical studies comparing combination chemotherapy (summarized in Table 3) fell broadly into 2 groups: those that compared regimens with 2 agents and those that compared regimens with ≥3 agents.
Table 3. Neoadjuvant Chemotherapy: Randomized Trials of Combination Chemotherapeutic Agents
| Wolmark et al., 20018||763; 760||T1-T3, N0-N1, M0, operable||S, then AC; or AC then S||—||36||13||—||55; 53 (9 y)||70; 69 (9 y)|
| Dieras et al., 200420||133; 67||T2-T3, N0-N1, M0, not accessible for BCS||Dox-Pac × 4; or AC × 4||89; 70||15; 7||16/8; 10/6 (Inv/Ind)||58; 45||70; 70 (31 mo)||—|
| Evans et al., 200521||180; 183||T ≥ 3 cm, operable||AC; or Dox-Doc||61; 70||17; 20||24; 21||20; 20||69.4; 75.4 (32 mo)||84; 86 (32 mo)|
| Chua et al., 200519||240; 211||Operable EBC, ≥3 cm||Vinorel-Epi × 6; or AC × 6||74; 73||24; 20||12; 12||—||—||—|
| Fenton et al., 200522||35; 18||IIA-IIIA and IIIB-IIIC, 78% resectable||Carb-Pac (HER2-negatiave); or Pac-Trast (HER2-positive)||—||—||29; 78||—||—||—|
| Romieu et al., 200224||232||T2-T3, N0-N1, M0, noncandidates for BCS||Dox-Pac × 4; or Dox-Pac × 6||—||20; 32||17/11; 24/16 (Sat/Chev)||61; 64||—||—|
| Steger et al., 200425||288||T1-T4a-c, N+/−, M0, operable||Epi-Doc × 3; Epi-Doc × 6||—||—||7.7; 18.6||66.9; 75.9||—||—|
| Tong et al., 200426||39; 36||IIB, IIIA, IIIB||Epi-Pac × 2; Epi-Pac × 4||74; 94||3; 58||0; 25||33||—||—|
| Reitsamer et al., 200523||20; 25||II/III||Epi-Doc × 3; or Epi-doc × 6||90; 64||—||10; 36||70; 76||—||—|
| Euler et al., 200227||76; 75||T2-T4, N0-N2, M0, primarily not suitable for BCS||EC × 3 DTI; or EC × 3 DI||79; 83||—||4; 10||81.5; 80||—||—|
|Three or more agents|
| Scholl et al., 199428||200; 190||IIB/IIIA, T2-T3, N0-N1, M0, operable||Neoadj: FAC × 4, then RT/S; or Adj: RT/S, then FAC × 4||82||30; 41 (4 mo)||—||31; 32||59; 55||86; 78 (5 y)|
| Powles et al., 199529||101; 99||T1-T2, N0-N1, operable||3M × 4, then Tam, RT, 3M × 4, Tam; or RT, 3M × 8, Tam||85||18.8||10; 0||—||—||—|
| Smith et al., 200430||211; 215||T ≥3 cm, operable||Fluor-Epi-Cis × 6; or AC × 6||77; 75||34; 31||16; 16||—||62; 63||82; 74 (5 y)|
| Pierga et al., 200031||120; 123||T2-T3, N0-N1, M0, operable||FAC × 4; or Thio-Cyc-Fluor × 4||75; 59||—||—||77; 71||58; 66 (5 y)||78; 86 (5 y)|
| Yang et al., 200232||24; 24||II; III||FEC × 2; Epi-Pac × 2||50; 79.2||4; 4||0; 0||—||—||—|
| Vallejo et al., 200333||57; 54||LABC||FAC × 3; or CMF × 3||67; 67||—||—||—||—||—|
| Therasse et al., 200334||224; 224||T4, any N, M0 or any T, N2-N3, M0 or IBC||FEC × 6; or Epi-Cyc × 6 DI||—||31.3; 26.5||14; 10||—||—||53; 51 (5 y)|
| Dhingra et al., 199936||102; 100||LABC IIB-IV||FAC 1000, 50, 500 mg/m2 × 8; or FAC 1200, 60, 1000 mg/m2 × 8||76; 90||—||9; 13||24; 28||53 (5 y); 65||57 (5 y); 66|
| Pelissier et al., 200235||84||T2-T3, N0-N1, operable||High-dose FEC × 4; or lower dose FEC × 4||38; 36||—||5; 5||67; 57||62; 72||75; 77|
| Boddie et al., 199637||31; 6||IIB; IIIA,B||FAC 6 mo; or CMF 6 mo||77; 50||32; 0||—||49 (All)||65 (All)||86 (All)|
| Moliterni et al., 199738||32; 41||LABC or T2-T3||Dox-Pac × 4, then: S (+RT) with or without CMF||—||31; 20||9; 5||19; 78||71 (17 mo); 100 (10 mo)||74 (17 mo); 100 (10 mo)|
| Pierga et al., 199739||69||T2-T3, ≥3 cm, operable||FEC × 4 or FAC × 4||59 (All)||11.6 (All)||—||—||—||—|
| Adkins et al., 199940||33||Stage IIIB, IBC||AC with or without Fluor; or Dox-Fluor-Meth; or Dox alone||82 (All)||27 (All)||3 (All)||—||—||—|
| Chang et al., 200641||45||Stage III, T3/T4, any N, M0||Doc-Carb + Trast or Doc-Carb||—||49||30||—||—||—|
Two-agent neoadjuvant chemotherapy regimens
Ten randomized studies of 2-agent neoadjuvant clinical trials were identified (Table 3), and 4 of those studies compared different 2-agent regimens,19–22 5 which compared differing numbers of cycles of the same regimen23–27 and 1 of which compared the same regimen presurgery and postsurgery.8 The latter study was one of the first studies to directly compare neoadjuvant AC and adjuvant AC.8 At 9-years of follow-up, the DFS and OS rates were similar in both groups.
Combination therapy of doxorubicin with either paclitaxel (AP) or cyclophosphamide (AC) also has been assessed.20 ORR and cCR rates were higher with the AP regimen than with the AC regimen (ORR, 89% vs 70%; cCR, 15% vs 7%; no P values were provided) (Table 3). The pCR rate (Chevallier et al. criteria; the Sataloff et al. criteria also were used to grade pathologic response by an independent pathologist) also was higher with the AP regimen (no P values were provided), with a range similar to that reported in the single-agent studies (8–16% for the AP arm and 6–10% for the AC arm as assessed by investigators and independent review). DFS rates were high in both treatment arms (70% at 31-month follow-up). In addition, BCS was more frequent in the AP arm (58%) compared with the AC arm (45%; no P value was provided). In an Anglo-Celtic Cooperative Oncology Group study comparing doxorubicin in combination with either docetaxel or cyclophosphamide, a similar pattern was observed with respect to ORR and cCR rates (both of which were slightly higher in the taxane-containing arm; P value NS), but the pCR rate (with pCR defined as the absence of invasive cancer in the breast) was slightly, but not significantly, lower in the taxane-containing arm.21 The rates of BCS in both arms were identical (20%), and the OS and DFS rates were slightly higher (P value NS) with the taxane-containing regimen.
The efficacy of vinorelbine/epirubicin (VE) as neoadjuvant therapy in early BC was compared with that of the standard neoadjuvant AC (the Trial of Preoperative Infusional Chemotherapy [TOPIC] 2 trial). ORR and cCR rates were similar, and pCR rates were identical (pCR criteria not specified) for the 2 arms.19 Therefore, VE was as effective as AC as neoadjuvant treatment; it is noteworthy, however, that the toxicity profile of VE generally was better than that of AC.
In studies that compared the same 2-agent neoadjuvant therapy regimen with differing numbers of treatment cycles, increasing the number of cycles of chemotherapy generally increased the cCR and pCR rates.23–27 In 3 instances, the difference in pCR rates was statistically significant (P = .045,23P = .0045,25 and P = .04).27
Neoadjuvant chemotherapy regimens with ≥3 agents
Fourteen randomized studies provided head-to-head comparisons of combination neoadjuvant regimens that involved ≥3 agents (Table 3). Two of those studies compared the effect of a regimen as neoadjuvant versus adjuvant chemotherapy.28, 29 The studies generally supported the use of neoadjuvant therapy in the management of BC but did not provide insight into the optimal combination of neoadjuvant chemotherapeutic agents.
Among the studies that compared multiple-drug combinations, the TOPIC trial compared the efficacy of continuous infusional 5-FU (5-FU)-based chemotherapy (plus epirubicin and cisplatin) with conventional bolus AC chemotherapy. 5-FU–based chemotherapy was no more active than the conventional treatment, and no trend was observed toward a significant effect on survival. The pCR rate (pCR criteria not specified) in both arms was 16%.30
Several studies have investigated the value of anthracyclines in combination chemotherapy regimens. Some improvement in ORR with the inclusion of doxorubicin was observed in women who were randomized to receive either 4 cycles of neoadjuvant AC plus 5-FU or 4 cycles of the alkylating agent thiotepa plus cyclophosphamide and 5-FU (ORR, 75% vs 59%, respectively; P = .01).31 The 5-year OS and DFS rates, however, were slightly higher in the thiotepa arm (P value NS), and rates of BCS were similar between the 2 cohorts (Table 3). Combinations of another anthracycline (epirubicin) with a taxane (paclitaxel) or with cyclophosphamide and 5-FU as neoadjuvant therapy both were effective regimens.32 ORRs were higher in the double-agent arm (79.2%) compared with the triple-agent arm (50%; no P value was provided), although cCR rates were low in both groups (4%), and no patients achieved a pCR (pCR criteria not specified).
Direct comparison of anthracycline-containing FAC with the combined cyclophosphamide, methotrexate, and 5-FU (CMF) regimen was made in patients with locally advanced BC.33 ORRs were identical (67%) in both groups.
Dose intensification has been used as an approach to increasing the efficacy of anthracycline-based neoadjuvant chemotherapy in 3 studies, all of which reported no benefit with this approach. In a European Organization for Research and Treatment of Cancer-National Cancer Institute of Canada-Swiss Study Group for Clinical Cancer Research study, patients with locally advanced BC were randomized to receive either a standard (cyclophosphamide 75mg/m2, epirubicin 60 mg/m2, and 5-FU 500 mg/m2 for 6 cycles every 28 days) or a dose-intensified (cyclophosphamide 830 mg/m2 and epirubicin 120 mg/m2 for 6 cycles every 14 days) anthracycline-based regimen.34 No measurable therapeutic benefit for dose intensification was observed. Similar results were observed in a study of anthracycline dose intensification in patients with operable BC that compared 4 cycles of high-dose neoadjuvant cyclophosphamide/epirubicin (100 mg/m2)/5-FU with standard-dose cyclophosphamide/epirubicin (60 mg/m2)/5-FU.35 An M. D. Anderson Cancer Center study investigated dose-intensified FAC administered at doses of 1200 mg/m2, 60 mg/m2, 1000 mg/m2 and compared with standard FAC (1000 mg/m2, 50 mg/m2, and 500 mg/m2). Although the ORR was significantly higher on the dose-intensified arm (76% vs 90%; P = .01), neither the pCR and BCS rates nor the 5-year DFS and OS rates differed significantly between the 2 treatment arms. Moreover, there was substantially greater toxicity on the dose-intensified standard regimen, precluding further development of this schedule36 (Table 38, 19–41).
Neoadjuvant chemotherapy regimens with sequential or alternating regimens
Since the first suggestion that sequential chemotherapy potentially was superior,42 many studies have investigated this approach. Sequential chemotherapy can mean either the administration of multiple drugs in a preplanned sequence with no breaks or the administration of each new drug after disease progression on the prior drug. Either way, its use often results in survival rates comparable to those achieved with combination regimens and allows each drug to be administered to its maximum tolerated dose while minimizing cross-toxicity risk.43 It is noteworthy that several trials have demonstrated that sequential chemotherapy is an effective means of increasing the pCR rate.
The National and Surgical Adjuvant Breast and Bowel Project (NSABP)-27 trial evaluated the use of 1) sequential docetaxel after neoadjuvant AC, 2) neoadjuvant AC alone, and 3) neoadjuvant AC followed by adjuvant docetaxel44 (Table 4). Preoperative response results for Groups 1 and 3 (neoadjuvant AC alone) were pooled and compared with those for Group 1 (neoadjuvant AC + docetaxel). The addition of docetaxel to the neoadjuvant AC regimen resulted in significantly increased pCR rates (with pCR defined as the absence of invasive cancer in the breast), from 12.9% to 26.1% (P < .001), and cCR rates increased from 40.1% to 63.6% (P < .001). There was no significant difference in the rate of BCS between patients who received neoadjuvant docetaxel compared with those who did not, which the authors noted was not surprising, because the addition of docetaxel resulted only in a 6% increase in the number of patients who had an objective clinical response (Table 4). Full results of this study indicated that neoadjuvant docetaxel, but not adjuvant docetaxel, significantly improved DFS in patients who achieved a pCR after AC and that pCR was a significant predictor of OS regardless of treatment (P < .0001).6
Table 4. Neoadjuvant Chemotherapy: Randomized Trials of Sequential Chemotherapy Agents
|Bear et al., 200344; Bear et al., 20066||Group I, 804; Group II, 805; Group III, 802||T1-T3, N0-N1, operable||Group I, AC × 4 then S; or Group II, AC then Doc × 4 then S; or Group III AC × 4 then S and Doc × 4 (Group III)||Group I, 85.7; Group II, 90.7; Group III, 85.4||Group I, 40.2; Group II, 63.6; Group III, 40||Group I, 12.9; Group II, 26.1; Group III, 14.5||61.6 (Groups I and III) vs 63.7 (Group II)||Group I, 67.7 (5 yr); Group II, 71.1; Group III, 70||—|
|von Minckwitz et al., 200545||451; 453||T2-T3, N0-N2, M0, operable||Dox-Doc × 4; or AC × 4 and Doc × 4||75.2; 85||31.2; 55.7||7; 14.3||58.1; 63.4||—||—|
|Heys et al., 200246; Smith et al., 200247||162; 52; 52; 55||T3, T4, Tx/N2||All, CVAP × 4; responders, CVAP × 4; or Doc × 4; nonresponders, Doc × 4||66; 64; 85; 47||14; 33; 56; 11||15.4; 30.8; 1.8||—||—||—|
|Toi et al., 200448||Group 1, 14; Group 2, 58; Group 3, 20||T2-T4, N0-N1, M0, operable||Group 1, AC/EC; or Group 2, FAC/FEC; or Group 3, FEC followed by Doc||50; 41.4; 70|| ||14.3; 12.1; 6.7||—||—||—|
|Limentani et al., 200549||51; 55||II/III||AC × 4; or Doc × 6 then AC × 4||93; 85||58; 53||27; 33||—||—||—|
|Miller et al., 199950||19; 21||T ≥ 2 cm, TII, or TIII/N1||Dox × 3 then Doc × 3; or Dox + Doc × 4||89; 81||32; 10||16; 5||37; 19||—||—|
|Untch et al., 200251||242; 233||IBC, T > 3 cm||Epi × 3 then Pac × 3; or Epi + Pac × 4||—||—||18; 10||66; 55||—||—|
|Gianni et al., 200552||444; 432; 448||T > 2 cm, T2-T3, N0-N1, M0, operable||S, then Dox × 4, then CMF × 4; or S, then Dox-Pac × 4, then CMF × 4; or Dox-Pac × 4, then CMF × 4, then S||—||49||20||34 (Arms A and B); 65||—||—|
|Buzdar et al., 200557||19; 23||HER2-positive, II-IIIA, operable||Pac × 4 then FEC × 4; or Pac × 4 then FEC × 4 + Trast||95; 96||47.4; 86.9||26.3; 65.2||52.6; 56.5||1 y, 94.7; 3 y, 85.3; 1 and 3 y, 100||—|
|Buzdar et al., 200758||22|| ||Pac × 4 then FEC × 4 + Trast||—||—||54.5||—||—||—|
|von Minckwitz et al., 200553*; von Minckwitz et al., 200654||284; 208; 40; 32 (306; 294)||T > 2 cm||All, TAC × 2; responders, TAC × 4; if no response, then TAC × 4 or Vinorel-Cap × 4 (responders to TAC × 2 then received TAC × 4; or TAC × 6)||73||8.4; 50.5; 22.5; 21.9||22.9; 7.3; 3.1; 17 (Overall)||86.3; 66 (All nonresponders)||—||—|
|Green et al., 200556||131; 127||T1-T3, N0-N1, M0, operable||Pac weekly then FAC; or Pac once every 3 wks then FAC||85; 86||56; 39||30.5; 21.3||47; 38||—||—|
|Mauriac et al., 199159†; Mauriac et al., 199960||134; 138||T2 > 3 cm or T3, N0-N1, M0, operable||Epi-Vinc-Meth × 3, then Mitomyc-Thio-Vind, then RT/S; or S, then Epi-Vinc-Meth × 3, then Mitomyc-Thio-Vind||—||32†; 30†||—||63.1||50†; 50†||73†; 72†|
|Shenkier et al., 200361||47; 44||T0-T4, any N||Dox-Pac, then Pac-Cyc; or Pac-Cyc then Dox-Pac||84 (All)||42 (All)||19 Overall (no difference between groups)||—||—||79 (Overall)|
|Rajan et al., 200462||120; 120||T0-T3||Pac then FAC; or primary S alone||—||29||—||—||—||—|
|Thomas et al., 200455||193; 51; 55||T3/T4, N1-N3, and M1||VACP × 3, then S, and either VACP × 5 or VbMF × 5||—||—||—||—||46; 26; 46; (10 y)||48; 37; 45 (10 y)|
The German Preoperation Adriamycin Docetaxel Trial (Gepar-DUO) study from the German Breast Group45 compared responses between 4 cycles of doxorubicin and docetaxel (ADOC) with 4 cycles of AC followed sequentially by 4 cycles of docetaxel (AC-DOC). Like in the NSABP-27 trial, sequential use of docetaxel resulted in a higher pCR rate (14.3%; pCR defined as the absence of invasive cancer in the breast and axilla) compared with combination use (7%; P < .001). Moreover, the increased rate of BCS with AC-DOC was of borderline significance (AC-DOC, 63.4%; ADOC, 58.1%; P = .05).
Another clinical benefit of adding sequential docetaxel, this time after combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CVAP) neoadjuvant chemotherapy, was demonstrated in the Aberdeen trial.46, 47 Responders to 4 cycles of CVAP were randomized to receive either 4 additional cycles of CVAP or 4 cycles of docetaxel. Responses were higher in the docetaxel group, with a cCR rate of 56% versus 33% in the CVAP-only group (no P value was provided). Moreover, the pCR rate in the docetaxel group (30.8%) was higher than in the CVAP-only group (15.4%; P = .04). OS and DFS rates also were increased in the docetaxel group along with the rate of BCS (data not supplied). The authors noted that, in 2002, the pCR rate (pCR defined as absence of invasive cancer in the breast) of 19% among all patients (both initially responsive and nonresponsive to CVAP) who were treated with neoadjuvant docetaxel was one of the highest reported among such patients.
An advantage of adding sequential docetaxel also was observed in a study of patients who were randomized to receive 5-FU, doxorubicin or epirubicin, and cyclophosphamide (FAC and FEC, respectively), or FEC followed by docetaxel.48 ORRs with docetaxel were 70% versus 41.4% (no P value was provided) in the FAC/FEC only group. In contrast, however, pCR rates (based on Japanese Breast Cancer Society criteria) with sequential docetaxel were approximately half those reported in the FAC/FEC group (no P value was provided) (Table 4). In a separate study, no increases in ORR or cCR were observed on treatment with docetaxel before doxorubicin and AC versus AC alone; pCR rates (pCR criteria not specified) also were comparable between the 2 treatment arms.49 Similar results were reported in a Hoosier Oncology Group trial that involved patients with newly diagnosed stage II or noninflammatory stage II BC.50 The clinical response rates were similar in both treatment arms (sequential doxorubicin × 3 followed by docetaxel × 3 or both drugs in combination × 4) (Table 4); however, pCR rates (pCR defined as the absence of invasive cancer in the breast and axilla) were slightly higher among patients in the sequential group, who also had fewer positive lymph nodes than patients in the combination group (mean, 2.17 vs 4.81 positive lymph nodes; P = .037) and were more likely to undergo BCS (37% vs 19%, respectively; no P value was provided). It is noteworthy that there was an unexpected incidence of grade 3 of 4 hand-foot syndrome in the sequential group, suggesting that sequential chemotherapy does not improve toxicity in all instances.
A German Gynecologic Oncology Breast Cancer Study Group trial compared 2 epirubicin- and paclitaxel-containing regimens given either as dose-dense sequential chemotherapy or in a standard dose as neoadjuvant therapy for primary BC.51 Both the pCR rate (defined as the absence of invasive tumor in the breast) and the BCS rate were significantly higher in patients who received the sequential regimens (P = .030 and P = .016, respectively), although the finding that dosing levels and frequencies varied between the 2 treatment arms makes a direct between-treatment comparison difficult. An increased rate of BCS also was reported after the large European Cooperative Trial in Operable Breast Cancer trial, in which women were to either 1) undergo surgery followed by 4 cycles each of doxorubicin then CMF; or 2) undergo surgery followed by 4 cycles each of doxorubicin-paclitaxel (AT) then CMF; or 3) receive 4 cycles each of AT then CMF followed by surgery.52 The rate of BCS in the adjuvant groups (Groups 1 and 2) was significantly lower at 34% than in the neoadjuvant group (Group 3; 65%; P < .001).
A different study, Gepar-TRIO, failed to demonstrate a difference in response in patients who had not responded to treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) and subsequently were treated with either further TAC or sequential vinorelbine and capecitabine.53 The cCR rates in the 2 arms were 22.5% and 21.9%, respectively, whereas the pCR rates were 7.3% and 3.1%, respectively (no P values were provided). Further accrual into the Phase III study should allow a more thorough analysis. Patients with an early response to TAC × 2 were randomized to receive either 4 or 6 additional cycles of TAC. The overall pCR was 17%, and there was a moderate increase in toxicity in the patients who received 8 cycles.54
The potential benefits of noncross-resistance in sequential doxorubicin-based chemotherapy were suggested in an M. D. Anderson Cancer Center study. Patients were treated with 3 cycles of neoadjuvant vincristine, doxorubicin, cyclophosphamide, and prednisone (VACP) followed by surgery.55 The ORR was 83.4% and the pCR rate was 12.2%; both types of responses were predictive of improved survival. Poor responders to this neoadjuvant regimen were randomized after surgery to receive either 5 more cycles of VACP or 5 cycles of noncross-resistant treatment: vinblastine, methotrexate with calcium leukovorin rescue and 5-FU (VbMF). Recurrence-free survival and OS were higher in patients who received VbMF compared with patients who received further VACP, although the difference did not reach statistical significance. It is possible that alternative postsurgery regimens, based on this principle of noncross-resistance, may prove more successful.
Another study from the M. D. Anderson Cancer Center and the Brown University Oncology Group has demonstrated that increasing the dosing frequency of a single component of a sequential chemotherapy regimen can afford multiple efficacy benefits. Patients were randomized to receive weekly paclitaxel (at a dose dependent on lymph node status) followed with FAC versus paclitaxel given every 3 weeks followed by the same FAC regimen.56 Although the weekly and every-3-week schedules resulted in similar rates of cCR (34% vs 24%, respectively; P value NS) and pCR (defined as the absence of invasive tumor in the breast; 30.5% vs 21.3%, respectively; P = .2), the schedule that contained weekly paclitaxel resulted in significantly higher pCR (defined as absence of invasive tumor in the breast and axilla; 28.2% vs 15.7%; P = .02) and BCS (47% vs 38%; P = .05) (Table 4).6, 44–62
THE FUTURE OF NEOADJUVANT THERAPY IN BREAST CANCER
The results from the literature review described in this report illustrate 2 key points. First, no clear patterns emerged that may identify the optimal neoadjuvant treatment regimen for all patients. Anthracycline-based regimens are used frequently because they have demonstrated activity as adjuvant therapy. When taxanes are used, it appears that paclitaxel is administered weekly more often and, if it is included in a sequence, as the first agent in the series. Docetaxel, in contrast, has been administered more frequently every 3 weeks and after other chemotherapy when it is used sequentially. Second, in those studies in which pCR rates were reported, there was enormous variation in the criteria used for the measurement of pCR. This highlights the need for standardization of pCR evaluation, which would facilitate simpler between-study comparisons. It is noteworthy that a new continuous measure of pathologic response, residual cancer burden (RCB), has been proposed.63 This is calculated as an index combining pathologic measurements of primary tumor (size and cellularity) and lymph node metastases (number and size). It has been demonstrated that RCB is predictive of distant recurrence-free survival, and RCB identified a larger group of high-risk patients compared with post-treatment revised American Joint Committee on Cancer staging. Such a measure may prove to be more predictive of survival and better able to define chemotherapy resistance in future trials than current pCR assessments.
The apparent lack of a trend toward a particular regimen as the optimal neoadjuvant treatment in this literature summary underscores the finding that it is highly unlikely that a single neoadjuvant regimen will become the “magic bullet” in all types of patients. Therefore, identifying which patients are most likely to respond to a specific regimen could significantly improve neoadjuvant treatment outcomes. The use of individualized neoadjuvant chemotherapy regimens opens the door to potential improvements in prognosis without increasing the potential for unwanted side effects that are experienced needlessly by patients who are resistant to specific types of chemotherapy.
Identifying new agents for neoadjuvant therapy in breast cancer
The use of novel agents, either alone or in combination with existing agents, potentially could improve response rates to neoadjuvant regimens in patients with both operable and inoperable BC. New agents currently are under evaluation in this setting in both Europe and the United States, because information on efficacy and safety can be obtained easily with neoadjuvant treatment. The combination of a chemotherapeutic agent with nonchemotherapeutic agents, such as monoclonal antibodies, is clearly an avenue for further studies. One study has compared neoadjuvant docetaxel monotherapy with docetaxel plus the antiangiogenic agent bevacizumab. Although data were presented for the 2 groups combined with no between-treatment comparisons, clinical response was favorable, with an ORR of 79.6% and a cCR rate of 14.3%.17, 18 The addition of the monoclonal antibody trastuzumab to paclitaxel was assessed by comparing 2 different 2-agent neoadjuvant chemotherapy regimens: paclitaxel/carboplatin in patients with HER2-negative BC compared with paclitaxel/trastuzumab in patients with HER2-positive BC. The latter regimen was associated with a pCR rate (pCR criteria not specified) almost 3 times as high as that in the HER2-negative patients (78% vs 29%; Table 3).22 It also has been demonstrated that the addition of trastuzumab to docetaxel and carboplatin generates a much higher pCR rate than the chemotherapeutic agents alone (36.4% vs 9%), reaffirming the benefit of trastuzumab as an addition to combination chemotherapy.41
The therapeutic benefit of adding trastuzumab to sequential chemotherapy (4 cycles of paclitaxel followed by 4 cycles of 5-FU, epirubicin, and cyclophosphamide) in HER2-positive patients also has been demonstrated.57 The addition of trastuzumab improved cCR rates from 47.4% to 86.9% and improved pCR rates (defined as the absence of invasive cancer in the breast and axilla) from 26.3% to 65.2% (P = .016). The original protocol was modified to include 22 additional patients in the trastuzumab arm.58 In these additional patients, the pCR rate was 54.5%, and the pCR rate among all patients on chemotherapy plus trastuzumab was 60%. It is worth noting that a follow-up analysis has indicated no recurrences in patients who were randomized to receive chemotherapy plus trastuzumab, and the estimated DFS at both 1 years and 3 years was 100%.
Despite the push to identify new agents, neoadjuvant trials that currently are recruiting (see www.clinicaltrials.gov) mainly involve familiar classes of agent, including various combinations of chemotherapy agents (eg, taxanes and anthracyclines), hormone therapies (eg, letrozole, triptorelin, and exemestane), or kinase inhibitors (eg, lapatinib, gefitinib, and AZD2171). One novel agent, the mammalian target of rapamycin inhibitor and immunosuppressant everolimus, is being studied in combination with letrozole in women with newly diagnosed estrogen-receptor (ER)-positive BC.
Of the novel chemotherapeutic agents, the epothilone analog class may be of particular interest. Epothilones and their analogs are a novel class of antineoplastic agents that promote tumor cell death by stabilizing microtubules and inducing apoptosis.64, 65 Derived from the myxobacterium Sorangium cellulosum, epothilones and their analogs are 16-membered macrolides with unique antibiotic and antifungal properties.66, 67 Natural epothilones A and B are of greatest interest from a therapeutic perspective, because they inhibit the growth of human cancer cells in vitro at nanomolar or even subnanomolar concentrations. Since 1996, several synthetic and semisynthetic analogs have been synthesized from epothilone B (EPO-906, patupilone).68 Of these, ixabepilone (BMS247550) is the furthest along in terms of clinical development and has shown promising efficacy and a manageable safety profile in a range of tumor types, including multiresistant BC.69–75 EPO-906 also has shown promising activity in a Phase II trial of gastric cancer,76 and patients currently are being recruited for a Phase III trial in ovarian cancer (see www.clinicaltrials.gov; NCT00262990). In addition, epothilone D (KOS-862) is undergoing Phase II clinical evaluation in BC and lung cancer.77, 78
The development of this novel class of antineoplastic agents is particularly relevant given the high rate of resistance developed by breast tumors to many current antineoplastic agents, including the anthracyclines and taxanes. A major cause of both intrinsic and acquired tumor resistance is overexpression of multidrug resistance 1 (MDR1) and multidrug-resistance–associated protein (MRP) genes, resulting in the removal of drugs from tumor cells by the protein efflux pump P-glycoprotein (P-gp) and MRP. Ixabepilone does not induce tumor cells to overexpress MDR1 or MRP, and it has low susceptibility to the encoded efflux pumps.79 Similarly, it has been demonstrated that EPO-906 possesses anticancer activity in in vitro and in vivo preclinical studies, including paclitaxel-resistant models in which cancer cells overexpress P-gp.80 Additional mechanisms through which tumor cells derive resistance to antimicrotubule agents, such as paclitaxel, is through point mutations in β-tubulin or preferential overexpression of the βIII-tubulin isotype, which is not targeted by paclitaxel. Because the tubulin-binding mode of ixabepilone affects the microtubule dynamics of multiple β-tubulin isoforms, including βIII-tubulin, the drug still was active in a paclitaxel-resistant tumor cell model in which βIII-tubulin was overexpressed.81 Currently, these preclinical observations are translating into clinical effects: Adjuvant ixabepilone has demonstrated antitumor activity in taxane-refractory patients in Phase I and II studies.69, 82 Tumor response to EPO-906 also has been demonstrated in Phase I trials in patients with several cancers, including BC, and Phase II studies are in progress.
The full results are eagerly awaited from a clinical trial evaluating ixabepilone in the neoadjuvant setting, specifically in treatment-naive patients with locally advanced BC (stage IIA-IIIB). Early analyses (to date, presented only in abstract form) are promising, with an acceptable safety profile and pCR rate in the breast of 18%.83, 84 To put this into context, recently published studies of single-agent taxane neoadjuvant therapy with docetaxel achieved a pCR rate in the range from 9% to 12.5% (Table 2).13, 14 Moreover, ixabepilone maintained activity in ER- negative, progesterone receptor (PR)-negative, and HER2-negative (triple-negative) patients, with a pCR in breast of 26% and a pCR in breast and lymph nodes of 19%.85 It is worth noting that the pCR rate was evaluated in the ixabepilone study using the criteria of Sataloff et al.,7 which, as highlighted above in this review, are stringent pCR criteria.
Identifying pharmacogenomic predictors of response to neoadjuvant therapy
Clinical trials of neoadjuvant therapy provide an ideal scenario for determining prognostic and predictive factors of response to specific regimens, because biopsies can be taken before chemotherapy and compared with tumors after surgical removal. HER2 status, ER/PR status, and p53 and Ki67 levels are just some of the pharmacogenomic markers that already have been correlated with response to chemotherapy using this approach.84, 86–88
With respect to the epothilone analogs, the trial mentioned above in which ixabepilone is being evaluated in the neoadjuvant setting is assessing gene expression for the prediction of pCR to ixabepilone as the primary endpoint. The ER and several genes that are part of the ER pathway appear to be predictive of response to ixabepilone.84 Such a predictive model could be used in future trials with the objective of selecting those patients who are likely to benefit from ixabepilone.
For years, neoadjuvant chemotherapy has been the cornerstone of BC treatment in both inoperable and operable tumors. To date, research has provided many answers with regard to neoadjuvant therapy for BC but also has raised numerous questions. The answers include patient selection (patients with stage IIA, IIB, and III disease are considered for neoadjuvant chemotherapy, including patients with operable disease and those with inoperable disease) and the use of pCR as a reasonable surrogate endpoint for survival. The unanswered questions include the following: What should be the standardized method for determining pCR (primary tumor or primary tumor and lymph node assessment)? Which drug or drug combinations are preferred based on efficacy and toxicity? And which regimens (drugs, dosing, intervals, sequencing, and number of cycles) are recommended? Currently, there is no “gold standard” neoadjuvant regimen, and no single regimen has emerged to date as a clear leader in terms of treatment outcomes. What is clear, however, is that pCR is highly predictive of survival benefits and that standardization of this measure is needed.
The future of neoadjuvant chemotherapy lies in the ability to predict response to specific chemotherapeutic agents, including newer agents in development, such as the epothilone analogs. By combining these avenues of research, treatment could be tailored to be of greatest benefit to the individual patient and ultimately should improve outcomes for women with BC in the long term.