What is the role of neoadjuvant chemotherapy in the treatment of breast cancer?

Updated: May 21, 2019
  • Author: Erin V Newton, MD; Chief Editor: Neetu Radhakrishnan, MD  more...
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Answer

Most programs of neoadjuvant therapy used in the United States have been anthracycline-based, with FAC (doxorubicin [Adriamycin] in combination with fluorouracil and cyclophosphamide) as the best historical reference. In inflammatory breast cancer (IBC), the early program of 4 cycles of FAC, then surgery followed by an additional 4 cycles of FAC, then irradiation, led to a median survival of about 2 years and 5-year survival of about 30% of patients, which are dramatic improvements over historical outcome with local therapy alone (5-year survival of < 5%).

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 trial proved that preoperative chemotherapy with 4 cycles of standard-dose AC was equivalent to 4 cycles of postoperative standard-dose AC. This trial also found that pathologically complete response (pCR) in the primary tumor predicts excellent overall survival and is an excellent surrogate for long-term disease-free survival and overall survival. [54]

In the NSABP B-27 trial, the addition of 4 cycles of docetaxel to standard AC increased pCR from 14% to 26%; in addition, sandwiching surgery in between the chemotherapy regimens was less effective than administering all chemotherapy up front. This trial consisted of 3 arms: 4 cycles of standard-dose AC; 4 cycles of standard-dose AC combined with non–cross-resistant docetaxel at 100 mg/m2; and primary surgery sandwiched between the neoadjuvant 4 cycles of AC and the adjuvant 4 cycles of docetaxel. [54]

About 15% of initially node-positive patients who achieve pCR in the breast have residual disease in the axilla. Patients who have no residual disease in both the primary site (pCR) and lymph nodes (N0) have the best overall prognosis, with a markedly prolonged disease-free survival.

To date, no cooperative group trial has attempted to improve upon the results of neoadjuvant chemotherapy, given as induction, with administration of alternative treatment after surgery when the surgical result was suboptimal. A final important observation made by the MD Anderson group, from a randomized design, was that 12 cycles of weekly docetaxel followed by FAC was superior to paclitaxel given every 3 weeks for 4 cycles, followed by the same FAC program, resulting in a doubling of the pCR rate for locally advanced breast cancer from 14% to 28%.

The pCR in this trial was defined as disappearance of microscopic evidence of all invasive disease at both the primary site and the axilla, whereas much of the other literature (including trials done by the NSABP) reports on pCR at the primary site only. About 15% of initially node-positive patients who achieve pCR in the breast have residual disease in the axilla. Both criteria, however, predict for markedly superior long-term disease-free survival, with the pCR N0 criterion having the best outcome.

The Southwest Oncology Group (SWOG) confirmed the results of several other neoadjuvant trials in that ER-negative tumors have a higher pCR compared with ER-positive tumors and that infiltrating ductal histologies have a higher pCR rate compared with infiltrating lobular histologies. The investigators reported the preliminary results of their prospective, randomized trial in which "standard" AC, given every 3 weeks at standard doses, was compared with a schedule of continuous chemotherapy with the same agents (weekly Adriamycin [A], daily oral cyclophosphamide [C] [Cytoxan]) in patients with locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC).

The continuous or "metronomic" schedule required administration of granulocyte colony-stimulating factor (GCSF) as growth factor support. All patients on the trial, after completing AC, went on to receive weekly paclitaxel. The pCR rate was higher on the "continuous" arm, and this effect was most marked in patients with IBC, as well as triple negative (ER-negative, PR-negative, HER2-negative) patients with LABC.


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