This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gralow, J. R. Articles by Winer, E. Search for Related Content PubMed PubMed Citation Articles by Gralow, J. R. Articles by Winer, E.

Preoperative Therapy in Invasive Breast Cancer: Reviewing the State of the Science and Exploring New Research Directions

Department of Medicine/Oncology, University of Washington and Fred Hutchinson Cancer Research Institute, Seattle, WA

Jo Anne Zujewski

Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Bethesda, MD

Eric Winer

Department of Medicine, Dana-Farber Cancer Institute, Boston, MA

In March 2007, the National Cancer Institute (NCI) sponsored a State of the Science Conference on Preoperative Therapy in Invasive Breast Cancer. The major goals of the conference were to review current clinical standards and to identify opportunities for future research. The conference did not seek to develop a consensus statement or a clinical guideline, but it did attempt to characterize appropriate clinical care. Importantly, an additional conference objective was to explore how research in the preoperative setting could be used to accelerate progress in the development of new and more effective treatments for individuals with breast cancer.

In patients with operable breast cancer, randomized trials have demonstrated that preoperative and postoperative chemotherapy (using the identical agents and treatment schedules) result in the same disease-free and overall survival.¹ Because preoperative chemotherapy leads to tumor shrinkage, it can increase the proportion of women who may be eligible for breast-conserving surgery.² For this reason, it is an appealing treatment option for those women who are believed, on the basis of tumor size, not to be optimal candidates for breast conservation, but want to avoid mastectomy. However, caution must be taken not to overstate the probability of avoiding a mastectomy in this setting.^2,3 A multidisciplinary treatment team is critical for optimal outcomes from preoperative systemic therapy. Preoperative treatment, specifically chemotherapy, is contraindicated if it is unclear whether the patient would be a candidate for postoperative chemotherapy (eg, small receptor-positive tumor with clinically negative lymph nodes), if the patient is not committed to the approach, or if a multidisciplinary team is not available. Accurate pathologic assessment is critical both before beginning preoperative therapy and at the time of definitive surgery.

Many of the unresolved clinical controversies surrounding the use of preoperative therapy in patients with operable disease relate to the optimal use of locoregional therapy. The role of sentinel biopsy techniques, the timing of nodal evaluation, and the indications for postmastectomy and/or third-field radiation are not well defined. For that matter, it is unclear if resection margins should be evaluated differently after preoperative therapy than in the standard setting, where upfront surgical resection is used. The conference participants concluded that a local therapy panel should be convened to discuss unresolved local therapy questions with the goal of developing clinical trials.

Preoperative systemic therapy is the standard of care in locally advanced and inflammatory breast cancer. In this setting, the intent of preoperative systemic therapy is to render inoperable disease amendable to surgery. By definition, initial surgery is not possible in this setting. Systemic therapy is also administered with the clear goal of improving disease-free and overall survival. Although often grouped together, locally advanced and inflammatory breast cancer have different biologic features. The management of these patients necessitates involvement of a multidisciplinary team from the onset. In appropriately selected patients with locally advanced breast cancer, but not inflammatory disease, conservative surgery may be applicable, but this option must be considered early in treatment planning. There are a variety of unique research opportunities in the setting of locally advanced breast cancer, and there is great need for better treatment approaches.

Whether preoperative systemic therapy is used in the operable or locally advanced setting, it is clear that there are many unanswered questions and that evidence-based treatment guidelines should be followed when available, and established where lacking. The preoperative setting provides an excellent opportunity to study the impact of systemic therapies on breast cancer biology. Using pathologic complete response and other biologic measures as study end points,⁴ new drugs and regimens can be tested in rapid sequence, providing an early indication of drug activity and the ability to identify novel prognostic and predictive factors. Although short-term end points such as pathologic complete response are not sufficiently robust to change clinical practice or lead to drug approval, these studies can generate important preliminary data that can inform the design of larger, definitive trials. Ultimately, it is hoped that this approach will lead to greater individualization of breast cancer treatment.

As clinicians and researchers, we need to be watchful of the needs of patients participating in preoperative trials. Many trials, particularly those with biologic end points, may result in an increased burden on patients. Women with breast cancer need to be full partners in the process. Although the preoperative setting provides unique opportunities for translational research, the conference participants emphasized the expense associated with this research and the need for enhanced funding. Financial partnerships involving the federal government, foundations, academic institutions, and the pharmaceutical industry will be needed.

The conference led to the development of five articles that highlight particular aspects of the 2-day meeting. These articles are published together in this issue of the Journal of Clinical Oncology. The articles are not intended to provide a systematic review nor meant to be clinical practice guidelines, but, like the conference, are intended to highlight the state of the science. Two of the articles (Buchholz et al⁵ and Gralow et al⁶) highlight locoregional treatment and systemic therapy. A third article by Chia et al⁷ addresses the unique attributes of locally advanced and inflammatory breast cancer. In a fourth article, Wolff et al⁸ discuss the opportunities for research in the preoperative setting. Finally, because of the unparalleled contribution of the National Surgical Adjuvant Breast and Bowel Project (NSABP) to the area of preoperative therapy, we have asked the NSABP investigators to provide an update of their two large, randomized trials preoperative trials, NSABP B-18 and B-27.⁹ We are grateful the authors for devoting considerable time in the development of these manuscripts. We hope that you will find these manuscripts to be both educational and thought provoking.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Manuscript writing: Julie Gralow, Jo Zujewski, Eric Winer

REFERENCES

1. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract]

2. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15:2483-2493, 1997[Abstract/Free Full Text]

3. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 22:4165-4174, 2003

4. Mohsin SK, Weiss HL, Gutierrez MC, et al: Neoadjuvant trastuzumab induces apoptsosis in primary breast cancers. J Clin Oncol 23:2460-2468, 2005[Abstract/Free Full Text]

5. Buchholz TA, Lehman CD, Harris JR, et al: Statement of the science concerning locoregional treatments after preoperative chemotherapy for breast cancer: A National Cancer Institute Conference. J Clin Oncol 26:791-797, 2008[Abstract/Free Full Text]

6. Gralow JR, Burstein HJ, Wood W, et al: Preoperative therapy in invasive breast cancer: Pathologic assessment and systemic therapy issues in operable disease. J Clin Oncol 26:814-819, 2008[Abstract/Free Full Text]

7. Chia S, Swain SM, Byrd DR, et al: Locally advanced and inflammatory breast cancer. J Clin Oncol 26:786-790, 2008[Free Full Text]

8. Wolff AC, Berry D, Carey L, et al: Research issues affecting preoperative systemic therapy for operable breast cancer. J Clin Oncol 26:806-813, 2008[Abstract/Free Full Text]

9. Rastogi P, Anderson S, Bear HD, et al: Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26:778-785, 2008[Abstract/Free Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gralow, J. R. Articles by Winer, E. Search for Related Content PubMed PubMed Citation Articles by Gralow, J. R. Articles by Winer, E.