While neoadjuvant systemic therapy downstages tumors and improves the chance for breast conservation, disease-free and overall survival appears to be comparable with postoperative therapy. The next generation of studies is evaluating a variety of strategies such as taxanes, dose intensive chemotherapy, new systemic agents and predictors of tumor response, including DNA microarray analysis

NEOADJUVANT CHEMOTHERAPY

I view induction chemotherapy as a positive trend, because you do not lose anything, and there is a higher likelihood of being able to do a lumpectomy with a much better cosmetic result. It also provides an in vivo chemosensitivity assay. This trend will also allow us to start looking at minimally invasive surgery to the primary tumor.

— Eva Singletary, MD

EFFECT ON PRIMARY TUMOR RESPONSE FROM THE ADDITION OF SEQUENTIAL DOCETAXEL TO AC

In NSABP B-18, survival was equal for preoperative and postoperative adjuvant chemotherapy, thus allowing preoperative therapy to be used safely to make breast conservation treatment feasible. In addition, the breast tumor response was a powerful predictor of both disease-free and overall survival. Based on these results and the very promising data coming out showing the high response rate with taxanes in women with anthracycline-resistant metastatic breast cancer, we embarked on protocol B-27. B-27 showed that the addition of docetaxel to four cycles of preoperative AC did add toxicity, but it significantly increased response rates. The clinical complete response rate was increased by 60%, pathologic complete response rate increased by 87%, and the pathologically negative nodes were increased by 15%. The questions that remain are whether or not this effect on response will translate into an advantage in terms of overall and disease-free survival and whether or not postoperative docetaxel will similarly increase overall and disease-free survival.

— Harry D Bear, MD, PhD Presentation, 2001 San Antonio
Breast Cancer Symposium

NEOADJUVANT TRASTUZUMAB

A neoadjuvant randomized trial of trastuzumab-based therapy would be very interesting. One interpretation of the pivotal study in the metastatic setting of trastuzumab-based treatment is that earlier trastuzumab exposure is better than later trastuzumab exposure. Chemotherapy plus trastuzumab up front was superior to chemotherapy alone, even though two-thirds of the women who got chemotherapy in the metastatic setting without trastuzumab subsequently did receive trastuzumab therapy as part of their treatment.

— Harold J Burstein, MD, PhD

NSABP B-27 TRIAL: PHASE III RANDOMIZED STUDY OF PREOPERATIVE DOXORUBICIN AND CYCLOPHOSPHAMIDE (AC) VERSUS PREOPERATIVE AC FOLLOWED BY DOCETAXEL VERSUS PREOPERATIVE AC AND POSTOPERATIVE DOCETAXEL IN WOMEN WITH OPERABLE CARCINOMA OF THE BREAST CLOSED PROTOCOL   AC=doxorubicin/cyclophosphamide; T=docetaxel; TAM=tamoxifen po x 5 years * Patients undergoing breast-conserving surgery receive radiotherapy.   PRELIMINARY RESULTS OF NSABP B-27: PREOPERATIVE AC DOCETAXEL THE ADDITION OF DOCETAXEL TO AC ON PRIMARY TUMOR RESPONSE RESULTED IN: Equivalent rates of breast conserving surgery and mastectomy Significantly increased clinical (65% to 40%) and pathological (25.6% to 13.7%) complete response rates A higher percentage of patients with histological negative axillary nodes (59.5% to 51.5%) Additional toxicity (grade 4: 24% to 10%) Note : 2,411 patients randomized , with an average time on study of approximately 40 months   Derived from NSABP Presentation, 2001 San Antonio Breast Cancer Symposium; Abstract PHASE II STUDY OF PREOPER ATIVE TRASTUZUMAB (HERCEPTIN) AND PACLITAXEL (TAXOL) IN STAGE II/III HER2 OVEREXPRESSING (IHC 2+/3+) BREAST CANCER PROTOCOL: H + T -> DEFINITIVE SURGERY -> AC Objective Response (CR + PR) 29/40 (73%) Pathological Complete Response 7/40 (18%) H = t rastuzumab; T = paclitaxel Derived from Burstein HJ et al. Breast Cancer Res Treat 2001; Abstract 507.     ONCOLOGISTS What would be your usual preoperative systemic therapy for a 43-year-old woman with the following breast tumors? TUMOR SIZE/STATUS ACT FAC AC FEC PACLITAXEL NONE UNDECIDED 10% 5% 40% 5% 5% 30% 5% 2.8 cm ER+ HER2 -neg TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 25% 15% 5% 5% 50%   TUMOR SIZE/STATUS ACT FAC AC FEC PACLITAXEL NONE 15% 5% 35% 10% 5% 30% 2.2 cm ER-neg HER2+ (IHC 3+) TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 10% 0% 10% 5% 75% TRASTUZUMAB NONE 35% 65% What would be your usual preoperative systemic therapy if she were 43 years old with a 6.5 cm tumor? STATUS ACT FAC AC DOXORUBICIN PACLITAXEL GEMCITABINE 35% 15% 35% 5% 5% 50% ER-neg, HER2+ (IHC 3+) TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE 10% 0% 10% 5% 75% TRASTUZUMAB NONE 60% 40% What would be your usual preoperative systemic therapy if she were 43 years old with inflammatory breast cancer? STATUS ACT FAC AC PACLITAXEL GEMCITABINE 35% 15% 25% 20% 5% ER-neg, HER2+ (IHC 3+) TAMOXIFEN LETROZOLE OVARIAN ABLATION NONE 10% 10% 5% 75% TRASTUZUMAB NONE 65% 35%

Colleoni M et al. Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node-negative breast cancer. J Clin Oncol 2001;19:4141-9. Abstract

El-Didi MH et al. Pathological assessment of the response of locally advanced breast cancer to neoadjuvant chemotherapy and its implications for surgical management. Surg Today 2000;30:249-54. Abstract

Mamounas EP, Fisher B. Preoperative (neoadjuvant) chemotherapy in patients with breast cancer. Semin Oncol 2001;28:389-99. Abstract

NSABP. The effect of primary tumor response of adding sequential Taxotere to Adriamycin and cyclophosphamide: Preliminary results from NSABP Protocol B-27. Breast Cancer Res Treat 2001;Abstract 5.

Singletary SE. Neoadjuvant chemotherapy in the treatment of stage II and III breast cancer. Am J Surg 2001;182:341-6. Abstract

van der Hage JA et al. Improved survival after one course of perioperative chemotherapy in early breast cancer patients. Long-term results from the European Organization for Research and Treatment of Cancer (EORTC) Trial 10854. Eur J Cancer 2001;37:2184-93. Abstract

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