Future Prospects Gabriel N. Hortobagyi,* and Gordon F. Schwartz† The development of neoadjuvant chemotherapy paralleled that of postoperative adjuvant chemotherapy programs. Initially based-on single-arm studies, evidence in support of neoadjuvant chemotherapy emerged recently from large, prospective randomized trials demonstrating the equivalence of preoperative and postoperative chemotherapy with the same regimen, although preoperative chemotherapy increases the frequency of breast conserving surgery and provides the opportunity for early assessment of response to therapy. Multiple questions remain about the optimal utilization of neoadjuvant chemotherapy. Novel technologies will lead to better selection of patients, more accurate prediction of response and individualized treatment approaches. Semin Breast Dis 7:135–137 © 2004 Elsevier Inc. All rights reserved.
djuvant chemotherapy has been traditionally administered exclusively in the postoperative setting.1 However, over the past three decades, numerous studies have evaluated its use preoperatively.2 This approach has been variously denominated neoadjuvant chemotherapy (NACT), primary chemotherapy, preoperative chemotherapy, up-front chemotherapy, and proto-adjuvant chemotherapy. As described in the contributions to this issue of the Seminars, the potential benefits to neoadjuvant chemotherapy include downstaging the primary tumor to allow breast-conserving surgery and assessment of a tumor’s in vivo sensitivity to individual chemotherapeutic regimens.2-4 The largest study that compared the value of neoadjuvant chemotherapy with that of postoperative adjuvant chemotherapy was NSABP B-18.5 In this study, 1523 women were randomized to receive four cycles of doxorubicin and cyclophosphamide either before or after surgical resection. The timing of chemotherapy did not affect the disease-free or overall survival for the entire cohort, although more patients who received preoperative therapy were able to undergo breast conservation rather than mastectomy compared with those treated postoperatively. An important finding in this study was the clear correlation of pathological complete response (pCR) in the breast (absence of invasive cancer cells) with survival.5 This finding confirmed several pioneering observations from single-arm studies performed a decade earlier.4,6 In the B-18 study, using a single chemotherapy regimen, the pCR rate was 13%. The
*Department of Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX. †Jefferson Medical College, Philadelphia, PA. Address reprint requests to Gabriel N. Hortobagyi, Breast Medical Oncology, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0424, Houston, TX 77030. E-mail: [email protected]
1092-4450/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.sembd.2005.01.012
definition of pCR, however, did not include absence of lymph node involvement, which is potentially the most important component of pCR. The pCR rate has become one of the most important intermediate trial endpoints in assessing the efficacy of new adjuvant chemotherapy regimens.6,7 A second large randomized clinical trial had an identical design and was implemented by the European Organization for Research and Treatment of Cancer.8 This study, although half the size of NSABP B-18, confirmed the findings of B-18, with equivalent survival rates and an increased rate of breast-conserving therapy after NACT. The preliminary results of a third important prospective randomized trial, demonstrating equivalent effects of preoperative and postoperative chemotherapy, was recently reported by the European Cooperative Trial in operable breast cancer investigators.9 In this study, the addition of paclitaxel to a doxorubicin plus cyclophosphamide, methotrexate, fluorouracil (CMF)-containing regimen resulted in a doubling of the pCR rate. A similar association between pathologic response and survival was shown when axillary lymph nodes were cleared after neoadjuvant fluorouracil, doxorubucin (Adriamycin), cyclophosphamide (FAC) chemotherapy at the M.D. Anderson Cancer Center.7 Published studies of anthracyclinebased preoperative chemotherapy demonstrated pCR rates as high as 17%.6-10 Several recently reported studies including the sequential use of anthracycline-based regimens and taxanes have achieved significantly higher pathologic responses, ranging from 25% to 34%.11-15 For instance, NSABP B-27 compared NACT with four cycles of doxorubicin and cyclophosphamide (AC) with the same followed by four cycles of docetaxel (AC ⫹ T). pCR rates were twice as high in the AC ⫹ T arm as in the AC arm.12 Another, smaller study by Smith et al, using an AC-like regimen followed by docetaxel sug135
G.N. Hortobagyi and G.F. Schwartz
136 gested that both responders and nonresponders to the ACtype regimen benefited from crossover to the taxane, in terms of higher response rates and longer time to progression and survival.13 The recent presentation of preliminary results of NSABP B-27 demonstrated that the increase in pCR rate associated with the addition of docetaxel to four cycles of AC led to a significant increase in relapse-free survival, although event-free and overall survival rates were unaffected at the time of the analysis, with a median follow-up of 68 months. Longer follow-up is necessary to determine whether these high pathologic response rates seen from the sequential use of the taxanes in the preoperative setting will translate into a favorable impact on survival. However, should pCR be validated by additional trial results as an accurate surrogate marker of long-term outcome and, even more importantly, if improvement of pCR rates can be shown to have a commensurate effect on long-term survival, we could short-cut the process of evaluation of adjuvant systemic therapies and accelerate the assessment of new systemic interventions by converting to the systematic use of NACT. There are multiple remaining questions related to the use of this strategy, however. Some relate to optimal local-regional therapies, eg, when should axillary assessment be performed in relation to NACT, what should be the criteria for administration of postmastectomy radiation therapy following NACT, and how to optimally perform breast-conserving surgery following NACT.16-19 The role and relative timing of neoadjuvant hormone therapy is also under intensive evaluation at this time. This is solely relevant to the group of patients with hormone receptor–positive tumors, but it has potential impact on the type and sequence of local, regional, and systemic therapies. There is much interest in emerging technology based on gene and protein expression profiles. Gene profiling with either cDNA or oligonucleotide arrays has shown promise in molecular classification of breast cancer, prediction of prognosis, and prediction of response to chemotherapy.20-22 More recently, determination of prognosis has been proposed on a reverse transcriptase polymerase chain reaction– based 21-gene profile.23 This profile, which incorporates estrogen receptor and estrogen receptor–modulated genes, human epidermal growth factor receptor 2 (HER-2), cell cycle, and proliferation-related genes among others, has been shown to predict good and bad prognosis in several cohorts of lymph node–negative breast cancers. In addition, preliminary reports suggest that the same profile can predict response to tamoxifen and response to chemotherapy in tamoxifen-treated patients.24 There is much interest also in the preliminary results of studies with protein-expression profiles based on surface enhanced laser/desorption ionization (SELDI) or matrix assisted laser desorption ionisation (MALDI) technologies.25,26 Early analyses suggest that these profiles can differentiate invasive from noninvasive cancers. It is plausible, therefore, that these techniques might contribute to the molecular classification, prognostication, and prediction of treatment response.
Determination of efficacy and utility of systemic treatment in the management of primary breast cancer with traditional approaches require enormous patient resources as well as protracted observation periods measured in years and sometimes decades. The promise of a reliable surrogate marker of long-term survival such as pCR would make this process much more efficient. Thus, while we assess the optimal methods to sequence various local, regional, and systemic therapies, we must also develop innovative clinical trial methodology, introduce new molecular technology to optimize selection of patients, and accelerate progress in breast cancer treatment and research.
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137 22. Ayers M, Symmans WF, Stec J, et al: Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22:2284-2293, 2004 23. Paik S, Shak S, Tang G, et al: Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients - NSABP studies B-20 and B-14. Breast Cancer Res Treat 82(suppl 1):S10-S11, 2003 (abstr 16) 24. Paik S, Shak S, Tang G, et al: Risk classification of breast cancer patients by the Recurrence Score: comparison to guidelines based on patient age, tumor size, and tumor grade. Breast Cancer Res Treat 88(suppl 1): S21, 2004 (abstr 104) 25. Mundhenke C, Meinhold-Heerlein I, van Bergen M, et al: Detection of DCIS and invasive ductal carcinoma in human serum by protein profiling (SELDI). Breast Cancer Res Treat 88(suppl 1):S9, 2004 (abstr 8) 26. Sanders ME, Xu BJ, Shaktour B, et al: Protein profiling by MALDI-MS classifies breast tumors with high accuracy and distinguishes ductal carcinoma in situ from invasive mammary carcinoma. Breast Cancer Res Treat 88(suppl 1):S9, 2004 (abstr 7)