Neoadjuvant Treatment of Breast Cancer

Background

Neoadjuvant chemotherapy, also termed primary, induction, or preoperative chemotherapy, is defined as chemotherapy administered before locoregional treatment. It was first used in locally advanced breast cancer 30 years ago. Classically, these tumors were treated with radical surgery and/or radiotherapy. However, despite this aggressive local therapy, most patients relapsed with distant metastases and eventually died. The aim of neoadjuvant therapy is to reduce the tumor volume in patients before surgical resection, thus increasing the likelihood of breast conservation. More recently, neoadjuvant therapy has been studied as a way of testing the relevance of biological markers in predicting disease outcome.

At least six randomized trials have compared survival in patients managed with either the neoadjuvant or adjuvant approaches. Two of the smaller trials suggested a survival advantage for patients treated with neoadjuvant chemotherapy. Other studies, including the largest trial (1,523 patients) run by the National Surgical Adjuvant Breast and Bowel Project (NSABP), found no differences in disease-free and overall survival.

Induction of a Polymerase chain reaction (pCR) should be one of the primary goals of neoadjuvant therapy because patients with no evidence of tumor cells in breast and lymph nodes after treatment may have a longer disease-free and overall survival.

Biweekly and weekly regimens may enhance dose intensity by minimizing re-growth of cells between cycles of treatment. In fact, dose dense regimens have even shown a survival benefit in an adjuvant setting in lymph node positive breast cancer, made possible with the use of G-CSF. There is no best standard neoadjuvant treatment yet. Generally patients receive AC (NSABP 14) on 3-weekly regimens in the neoadjuvant setting. In addition, incorporation of taxanes on a 3 weekly schedule has resulted in statistically higher pathological CR. More recently, weekly paclitaxel regimens have reported increased pathological responses compared to 3 weekly taxane regimens. Carboplatin has also emerged as an effective agent in the treatment of metastatic breast cancer. Moreover, the combination of carboplatin and paclitaxel has been found to be synergistic both in three-weekly regimens and weekly regimens. In fact, the combination of carboplatin, paclitaxel and trastuzumab has demonstrated a survival advantage over paclitaxel and trastuzumab alone. The Phase III study, which the preliminary results were presented at the San Antonio Breast Cancer Symposium, show that the addition of carboplatin to trastuzumab and paclitaxel resulted in a six-month improvement in the time it took for the disease to progress, compared to the standard trastuzumab and paclitaxel regimen. The study found the median survival in the trastuzumab and paclitaxel arm was 33.5 months, while the group receiving the tripartite therapy had yet to reach that point after 36 months of follow-up. Furthermore, the weekly regimens of these drugs have been found to have significantly improved tolerability over three weekly regimens. Therefore, we propose to use 2-4 cycles of AC q 2 weeks, as used in the dose dense adjuvant study with GM-CSF support on days 4-13 of the cycle. After the completion of AC we plan to administer taxol and carboplatin weekly for a total of 9-12 doses with a one-week rest after every 3 weeks of treatment over 12 weeks.

Patients who are her-2 overexpressors by FISH will also receive trastuzumab with weekly carboplatin and paclitaxel since this combination has been found to be synergistic in advanced breast cancer with improved clinical outcome. In a small study, higher pathological response rates were achieved in patients who received trastuzumab with chemotherapy compared to chemotherapy alone in the neoadjuvant. This study had a total of 34 patients who completed therapy. One arm received neoadjuvant chemotherapy with four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide. In the second arm, the patients received the same chemotherapy regimen with the addition of trastuzumab on a weekly schedule for twenty-four weeks. A pCR was achieved at 65.2% in the trastuzumab plus chemotherapy compared to 25% in the chemotherapy alone arm.

In metastatic breast cancer, the administration of bevacizumab to capecitabine has shown in a significant increase in response rates. The combination arm of bevacizumab plus capecitabine demonstrated a response rate of 19.8% compared to 9.1% in the capecitabine arm alone. However, the prolonged free survival or overall survival were comparable in both treatment arms. In a separate trial, the addition of bevacizumab to standard chemotherapy regimen (carboplatin and paclitaxel) in patients with advanced or relapsed non-small cell lung cancer demonstrate improved overall response and time to progression. In the bevacizumab plus standard chemotherapy, higher response rates (31.5% vs. 18.8%), longer median time to progression (7.4 vs. 4.2 months), and a modest increase in survival (17.7 vs. 14.9 months were found).

In a press release, South San Francisco, California, and Basil, Switzerland on March 14, 2005, an interim analysis of a Phase III trial showed bevacizumab plus paclitaxel and carboplatin improved overall survival compared to chemotherapy alone as a first-line therapy for non-squamous, non-small cell lung cancer. These results were presented at the American Society of Clinical Oncology (ASCO) meeting, May 13-17, 2005. This was a randomized, controlled, multicenter trial that enrolled 878 patients who had not received previous chemotherapy for non-small cell lung cancer, and compared standard chemotherapy with paclitaxel and carboplatin with or without bevacizumab. The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, under a Cooperative Research and Development Agreement between NCI and Genentech, Inc., and conducted by the Eastern Cooperative Oncology Group (ECOG).

At the San Antonio Breast Cancer Conference on December 8, 2004, Dr. Mehta et al. presented the sequential use of doxorubicin and cyclophosphamide (AC) followed by paclitaxel, carboplatin, and trastuzumab (TCH) in patient with Her-2 positive breast cancer. A pathological complete remission (pCR) was seen in 7 of 8 patients. All patients received 2-4 cycles of AC followed by 4 cycles of 3 weekly TCH regimens. Only 1 of 8 patients had a 3mm residual invasive carcinoma in the biopsy scan. Moreover, 7 of 7 patients with palpable lymph nodes demonstrated no residual cancer after this neoadjuvant regimen.

On April 18, 2005, an interim analysis of the first Phase III randomized study confirmed a significant benefit in the use of bevacizumab as first-line treatment for metastatic breast cancer. This multi-center study enrolled 722 women with previously untreated metastatic breast cancer and randomized the patients to receive adjuvant paclitaxel with or without bevacizumab. The trial excluded women who had her-2/neu positive breast cancer unless they received trastuzumab previously or were unable to receive this medication. The interim analysis showed a progression-free survival and early indication of survival benefit with the addition of bevacizumab to chemotherapy compared to chemotherapy alone. These findings were presented at ASCO this year.

In a separate trial, GM-CSF was used in breast cancer patients treated with adriamycin based chemotherapy as the preferred growth factor in a neoadjuvant setting. The initial results are suggestive of improved survival of breast cancer patients given 6 versus 5 versus 4 cycles of chemotherapy with GM-CSF support. Higher dendritic cell (DC) trafficking showed a trend toward improved survival. Moreover, patient comparison before and after treatment showed that the percentage of S100+ DC significantly increased over the course of GM-CSF treatment. The results form the basis of current hypothesis that the primary tumor may be an in vivo antigenic stimulus for dendritic cell trafficking, and that the combination of prolonged neoadjuvant chemotherapy with GM-CSF induced immune enhancement may contribute to better tumor control and better survival.