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© 2003 American Society for Clinical Oncology
International Expert Panel on the Use of Primary (Preoperative) Systemic Treatment of Operable Breast Cancer: Review and Recommendations
From the Department of Gynecology and Obstetrics, Goethe University, Frankfurt am Main; Red Cross Gynecological Hospital; University Großhadern, Munich; Charité Hospital, Berlin; University of Heidelberg, Heidelberg; General Hospital, Hagen; General Hospital, Bayreuth; University Hospital, Ulm; Germany; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; The University of Texas M.D. Anderson Cancer Center, Houston, TX; National Cancer Institute, Milan, Italy; Christie Hospital NHS Trust, Manchester, United Kingdom; Institute Curie, Paris, France; and Center for Tumor Prevention, St Gallen, Switzerland. Address reprint requests to Manfred Kaufmann, MD, Klinik für Gynäkologie und Geburtshilfe, J.W. Goethe-Universität Frankfurt am Main, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany; email: M.Kaufmann{at}em.uni-frankfurt.de.
Primary systemic therapy (PST) represents the standard of care in patients with locally advanced breast cancer. In addition, there is increasing information on PST in operable breast disease that supports the use of PST in routine practice. However, current regimens and techniques vary. To address this concern, a group of representatives from breast cancer clinical research groups in France, Germany, Italy, the United Kingdom, and the United States reviewed all available data on prospective randomized trials in this setting. Recommendations are made regarding terminology, indications, regimen, diagnosis before treatment, monitoring of efficacy, tumor localization, surgery, pathologic evaluation, and postoperative treatment.
REVISED GUIDELINES for the treatment of breast cancer outside clinical trials have been published by the National Institutes of Health in the United States and by the St Gallen Consensus Panel (St. Gallen, Switzerland) on the Treatment of Primary Breast Cancer.1,2 These recommendations, however, apply to patients with early stages of breast cancer. Approximately 10% to 30% of all primary breast cancers are diagnosed as locally advanced (eg, inflammatory cancer or cancer with skin, chest wall, or extensive regional lymph node involvement) or are carcinomas with an unfavorable breast-to-tumor size ratio. A large portion of these patient cases are excluded from prospective randomized systemic therapy trials and therefore are not included in the meta-analyses conducted periodically by the Early Breast Cancer Trialists’ Collaborative Group,3–5 on which many clinicians base their recommendations for the treatment of patients with breast cancer. These patients require different treatment strategies, and more appropriately, should receive systemic therapy before surgery. In addition to the fact that the existing recommendations do not take all breast cancers into account, indications for primary systemic therapy (PST) have changed over time. Although patients with inoperable, locally advanced breast cancer represent the majority of those treated with PST in routine practice, there is an increasing tendency also to treat operable breast cancer with PST. However, the type of systemic treatment as well as the methods used for diagnosis, monitoring, and surgery currently vary. Because several large randomized trials in operable disease now provide a much larger pool of evidence-based data than exists for locally advanced disease, it seems reasonable to summarize the available experience and to formulate recommendations for the use of PST in operable and (in part) for locally advanced disease.
On the basis of the hypothesis of primary systemic disease and experiences in various animal models,6–10 PST was first introduced into clinical practice in the 1970s (Table 1  ). Tumor cells assumed to have disseminated before the diagnosis and independent of mechanical manipulations of the tumor by the surgeon were considered to be more sensitive to PST than to adjuvant systemic therapy (AST). High tumor regression rates of approximately 70% established PST as a standard treatment option for patients with inoperable locally advanced or inflammatory breast cancer.11 In the late 1980s, the use of PST was shown to improve the breast-conserving surgery rate in up to 98% of patients with large operable breast tumors.12–19 During the same period, Forrest et al20 demonstrated that PST allows the primary tumor response to serve as an in vivo21 chemosensitivity test: A reduction in the primary tumor volume can be used to predict a reduction in micrometastatic tumor volume as well as clinical benefit.
Much of the evidence comparing PST with AST is from randomized controlled clinical trials in patients with operable (stage T1C-3, N0, M0 or T1–3, N1, M0) breast cancer. These studies have shown that primary (preoperative) systemic therapy with cyclophosphamide, methotrexate, and fluorouracil22; doxorubicin and cyclophosphamide (AC)23; fluorouracil, doxorubicin, and cyclophosphamide24; or fluorouracil, epirubicin, and cyclophosphamide25 offers the same disease-free survival and overall survival benefits as does AST with the same drug combinations (Table 2 ). In addition, PST results in an increase in the proportion of patients who are subsequently shown to have axillary lymph nodes free of metastatic involvement or who become candidates for breast-conserving surgery.
Several clinical trials in operable breast cancer have compared different PST regimens in patients with breast tumor sizes as small as 1 to 2 cm (Table 3 ). Complete pathologic remission (pCR) of these tumors correlates strongly with both prolonged disease-free survival and overall survival26–29 (even though tumor progression during PST is rare [approximately 3%], its occurrence predicts a poor prognosis).14,25,26 The absence of identifiable tumor cells in the removed breast tissue has been reported in 6% to 19% of patients who have received PST (Table 3).30–36 In most of the large clinical trials that compare PST with AST, the primary chemotherapy regimens that result in higher pCR rates are also associated with a higher rate of successful breast conservation and a higher proportion of patients subsequently found to have axillary lymph nodes free of metastatic involvement. None of the larger trials has detected a disease-free survival or overall survival advantage in favor of PST. One small clinical trial showed a potential advantage with the use of preoperative chemotherapy because clinical response to the first regimen was used as a guide in selecting additional therapy.29 At present, this approach has not been confirmed in a more appropriate trials setting and was not compared with conventional postoperative chemotherapy.
In October 2001, representatives of a number of breast cancer clinical research groups from France, Germany, Italy, the United Kingdom, and the United States (see Appendix) were invited to join the panel. All representatives have been chairpersons of trials exploring PST or members of the corresponding trials’ steering committees, or are reference experts for pathology, radiodiagnostics, or radiotherapy. Available data from all prospective randomized clinical trials on PST in operable breast cancer including at least 100 patients were critically reviewed with a goal of formulating a set of recommendations for the use of PST in operable breast cancer, both inside and outside clinical trials. Through a series of questions about terminology, indications, diagnosis, regimen, surgery, and radiotherapy, specialists representing biologic, pathologic, radiodiagnostic, surgical, and radiotherapeutic points of view arrived at a consensus and prepared the recommendations that follow. During the review process of the article, new trial results presented at the San Antonio Breast Cancer Conference in December 2001 and at the Annual Meeting of the American Society of Clinical Oncology at Orlando in May 2002 were included. Because the available amount of evidence-based data in the literature is limited, some answers contain review components that express educated opinions of the authors.
The following sections describe the recommendations of the panel.
Recommended Terminology
For Whom Is PST the Standard of Care?
For Whom Can PST Be Recommended as an Alternative to AST?
Numerous investigators have found that the rate of successful breast-conservation surgery is statistically significantly increased, as well as clinically relevant, in patients who receive PST compared with those who receive AST. Reported absolute differences in the rate of successful breast-conservation surgery between patients who receive PST and those who receive AST range from 5% to 36% (Table 2 In addition to the type of primary systemic chemotherapy, the rate of successful breast-conservation surgery also correlates with clinical response and the size of the primary tumor. Patients who experience a clinical complete response may have a successful breast-conservation rate of 90% and more.30,34 Patients who receive PST can increase their chance for breast conservation by 12.5% if the tumor size is 2 to 5 cm, and by 17.5% if the tumor size is more than 5 cm.23 In the largest trial reported to date, in which patients had a median follow-up time of 8 years, no statistically significant difference was found in local recurrence-free survival between patients treated with PST (four cycles of AC) and those treated with AST (four cycles of AC).37 The local recurrence rate among those who achieved complete clinical response was as low as 5.6%, and among those who did not achieve complete clinical response, the local recurrence rate was 9.7%. The local recurrence rate did not correlate with size of the primary tumor before treatment. However, among a small cohort of 69 patients who were considered candidates for mastectomy before receiving PST, a local recurrence rate of 14.5% was reported. This is in contrast to the 6.9% local failure rate seen among patients initially thought to be candidates for breast-conservation surgery who received PST.28 In another small trial,22 patients who did not respond to PST had a significantly increased risk of recurrence compared with those who did respond to PST. These results are consistent with the hypothesis that a poor response to PST is a predictor of poor prognosis and a high risk of recurrence, irrespective of the type of surgery performed. The results may also indicate that patients who convert to breast-conserving surgery as a result of PST also have a higher risk of experiencing local treatment failure. Because at present there is no evidence that PST offers a disease-free survival or overall survival benefit over AST, knowledgeable patients may choose to receive systemic therapy before surgical resection to take advantage of the response-assessment of the primary tumor before it is removed. A demonstrable response to PST may have a positive effect on the patient’s compliance with additional treatment and on the patient’s willingness to accept some adverse events. When the primary tumor increases in size during PST, immediate surgical intervention should be considered, with the aim of avoiding additional adverse effects of ineffective systemic treatment. PST may also be advisable for certain patients who have medical contraindications to surgery or simply wish to delay surgery. For example, PST can be used in the second or third trimester in pregnant patients diagnosed with breast cancer; this is followed by surgery and radiotherapy after delivery.38
PST offers an optimal test situation for the evaluation of new compounds and the detection of new biologic or molecular discriminants of either response or resistance. pCR may be used as a surrogate end point to substitute for survival and potentially provides a possibility of avoiding the arduous process of large randomized trials. In addition, tissue banking before, during, and after PST may permit the identification of undiscovered patterns of presentation of biologic or molecular discriminants that could help exclude ineffective treatments and optimize systemic regimens (Fig 1
How Should a Diagnosis of Invasive Breast Cancer Be Confirmed Before PST? Core biopsy and histologic examination are considered the most appropriate techniques for the detection of both invasive and noninvasive breast carcinomas. The highest diagnostic accuracy for confirming malignant disease can be reached by obtaining at least three core biopsies from various locations within the primary tumor using, at minimum, a 14-gauge needle.39 In contrast to the relatively small cytologic sample obtained by fine-needle aspiration biopsy, the three ≥ 14-gauge cores obtained by core biopsy should provide enough tissue to permit the performance of complex biologic studies on the tissue samples at a later time. In patients with a pCR, the initial core biopsy will be the only source of available tumor tissue; for this reason, these samples should be stored in a tumor bank for at least 10 years.
Are There Markers That Should Be Assessed Before PST?
Which Regimen Is Recommended for PST? Trastuzumab and other new targeted therapies are still under investigation and should not be used outside clinical trials.
Is There a Role for Endocrine PST Alone? Nevertheless, endocrine therapy remains attractive for patients for whom it is desirable to avoid certain chemotherapy-related adverse events. Clinical trials that evaluate endocrine PST or short-course presurgical endocrine PST in patients with hormone receptor–positive tumors may help answer questions about the endocrine-induced modulation of biologic markers. Endocrine therapy may be considered a second choice for selected patients; for example, for elderly women with impaired organ function, for patients who are unwilling to accept the adverse events associated with chemotherapy, for those with a low performance status, or for those who are at increased surgical risk. A positive ER or PgR status (or both) is a prerequisite for this treatment approach because hormone receptor content is predictive of the efficacy of endocrine compounds. According to prospective data from one randomized PST trial40 and several sequential phase II studies,42 aromatase inhibitors are more active and better tolerated than tamoxifen and thus are preferred in postmenopausal patients. At present, there are no data available about the efficacy of endocrine PST in premenopausal patients.
How Should Chemotherapy and Endocrine Treatment Combinations Be Administered?
How, When, and How Often Should the Effect of PST Be Monitored?
Possible definitions used to report tumor response to primary systemic treatment are given in Table 4
How Should Tumor Location Be Documented? PST requires collaboration among the medical oncologist, cancer surgeon, and diagnostic radiologist. All three disciplines should be involved in treatment decision making and in patient follow-up during PST. Cooperation is particularly important if the patient’s tumor does not respond to PST and immediate surgery is required. Close interdisciplinary patient follow-up is also required should the tumor shrink rapidly and presurgical tumor localization become difficult.
The radiation oncologist will play an important role in deciding if postoperative radiation therapy is indicated and in its planning. Preoperative external beam and brachytherapy are not established as modes of treatment in conjunction with PST. For this reason, precise documentation of the tumor location with a sketch (Fig 2
How Should the Tumor Be Treated Surgically? The aim of surgery with or without PST is to obtain clear margins of at least 1 mm at pathology examination; tumor-free margins after the use of PST should be ≥ 1 mm. It is assumed that defined tumor-free margins will result in a higher breast conservation rate. No compromise should be made in surgical margins to obtain a better cosmetic result. Again, no significant difference has been found between PST and AST in 8-year local recurrence rates of breast cancer (randomized trials).37 Patients diagnosed before the age of 40 years and those with larger tumors, high rates of tumor proliferation, or close or involved surgical margins are at higher risk for ipsilateral tumor recurrence after breast-conserving surgery.44 This may be due to the aggressive characteristics of the primary tumor, to suboptimal surgery, or to the increased difficulty a surgeon may have when estimating tumor area after multifocal tumor shrinkage induced by PST occurs.30 For these women, an increased rate of second surgical procedures has been reported.35 Patients should be informed about this possible disadvantage before deciding for or against the use of PST.
How Should Tumor Tissue Be Examined by the Pathologist?
We advise that the summary report should include a reference to one of the recognized grading systems for tumor regression.45–47 The presence or absence of invasive or noninvasive tumor components should be clearly stated (Table 4
What Is the Role of Postoperative Chemotherapy After PST? Conclusive data on this point may become available in the near future from the National Surgical Adjuvant Breast and Bowel Project Trial B-27 or from the European Cooperative Trial in Operable Breast Cancer.33,35
When and Where Should Postoperative Radiotherapy Be Administered?
What Issues Remain to Be Resolved? New compounds directed against specific molecular targets associated with the tumor should be explored in the primary therapy setting. The use of such compounds for PST may demonstrate their effect and proof of concept that the target may serve as a surrogate marker for either clinical benefit or disadvantage, which could lead to the development of new drugs that have demonstrated activity against breast cancer. PST is considered the standard of care for nonoperable, locally advanced breast cancer. For operable breast cancer, PST provides additional opportunity for breast-conserving surgery. Current data indicate that pCR may be used as a surrogate indicator for the beneficial effect of PST on both disease-free and overall survival. On the basis of the biologic characteristics of a tumor and differences in the response to systemic treatment, PST should be regarded as a tool that can be used to individualize systemic therapy for patients with breast cancer.
The following were contributors to the International Consensus Statement: Philippe Beuzeboc, Institut Curie, Paris, France; Jens Uwe Blohmer, Department of Gynecology, Charité Hospital, Berlin; Serban D. Costa, Manfred Kaufmann, and Gunter von Minckwitz, Department of Gynecology and Obstetrics, University Hospital, Frankfurt; Wolfgang Eiermann, Red Cross Hospital; Rolf Sittek, Department of Radiology and Michael Untch, Department of Gynecology, University Hospital, Grosshadern, Munich; Hans-Peter Sinn, University of Heidelberg, Heidelberg; Rainer Souchon, General Hospital, Hagen; Augustinos H. Tulusan, General Hospital, Bayreuth; Tanja Volm, Department of Gynecology, University Hospital, Ulm, Germany; Lucca Gianni, Istituto Tumori, Milan, Italy; Anthony Howell, Manchester, United Kingdom; Hans-Jörg Senn, Center for Tumor Prevention, St Gallen, Switzerland; Roy Smith, National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; and Vicente Valero, M.D. Anderson Cancer Center, University of Texas, Houston, TX.
This manuscript is written in memory of Helen Louise Smith. The authors thank Barbara C. Good, PhD, for editorial assistance, and Theodor Weigel, BANSS-Foundation, for financial support.
This consensus symposium received financial support from the BANSS Foundation, a nonprofit body based in Biedenkopf an der Lahn, Germany. The founder of the BANSS Foundation, who died from breast cancer, wished to help extend the information resources available to clinicians and investigators in the field of oncology. Both the symposium and the preparation of this manuscript were conducted in an independent and unbiased fashion.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
