Neoadjuvant Biweekly Treatment Followed by Weekly Treatment of Breast Cancer

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 (1,2). 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(3,4,5,6,7,8,9). Two of the smaller trials suggested a
survival advantage for patients treated with neoadjuvant chemotherapy (5,6). Other studies,
including the largest trial (1523 patients) run by the NSABP, found no differences in
disease-free and overall survival (4,6,9).

Induction of a 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 (10).

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 use of G-CSF
(11). There is as yet no standard best neoadjuvant treatment. Generally patients receive AC
(NSABP 14) on 3-weekly regimens in neoadjuvant setting. In addition, incorporation of taxanes
on a 3 weekly schedule has resulted in statistically higher pathological CR (12,13). 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 (14). Moreover, the combination of carboplatin and
paclitaxel has been found to be synergistic both in three-weekly regimens and weekly
regimens. In fact, combination of carboplatin, paclitaxel and trastuzumab has demonstrated a
survival advantage over paclitaxel and trastuzumab alone. The Phase III study, the
preliminary results of which 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 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
(15). Therefore, we propose to use 4 cycles of AC q 2 weeks, as used in the dose dense
adjuvant study with GM-CSF support on days 5-14 of the cycle. After the completion of AC we
plan to administer taxol and carboplatin weekly for a total of 9 doses with 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 as the combination has been found to be synergistic in advanced
breast cancer with improved clinical outcome.

In a separate trial, GMCSF was used in breast cancer patients treated with adriamycin based
chemotherapy as the preferred growth factor in a neoadjuvant setting (16). The initial
results are suggestive of improved survival of breast cancer patients given 6 versus 5 versus
4 cycles of chemotherapy with GMCSF support. Higher dendritic cell (DC) trafficking showed a
trend toward improved survival. Moreover, intrapatient 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.

Eligibility Criteria:

1. Patients must be women with a histologically confirmed diagnosis of locally advanced
or inflammatory breast carcinoma. Histologic confirmation shall be by either core
needle biopsy or incisional biopsy. Punch biopsy is allowed if invasive breast cancer
is documented.

2. Patients must meet one of the criteria defined below (indicate one):

a .Selected Stage IIB (T3, N0, M0) or IIIA (T3, N1-2, M0) disease judged primarily
unresectable by an experienced breast surgeon; or otherwise deemed appropriate
candidates for neoadjuvant treatment.

b. Stage IIIB (T4, Any N, M0) or (Any T, N3, M0) disease.

3. Physical examination, chest x-ray and any x-rays or scans needed for tumor assessment
must be performed within 90 days prior to registration.

4. Patients with the clinical diagnosis of congestive heart failure or angina pectoris
are NOT eligible. Patients with hypertension or age > 60 years must have a Multiple
Gated Acquisition (MUGA) or echocardiogram scan performed within 90 days prior to
registration (indicate not applicable (NA) if no MUGA required) and Left Ventricular
Ejection Fraction (LVEF) % must be greater than the institutional lower limit of
normal.

5. Patients must have a serum creatinine and bilirubin ≤ the institutional upper limit of
normal, and an Serum glutamic oxaloacetic transaminase (SGOT) or Serum glutamic
pyruvic transaminase (SGPT) ≤ 2x the institutional upper limit of normal. These tests
must have been performed within 90 days prior to registration.

6. Patients must have an Absolute neutrophil count (ANC) of ≥ 1,500/μl and a platelet
count of ≥ 100,000/μl. These tests must have been performed within 90 days prior to
registration.

7. Patients must have a performance status of 0-2 by Zubrod criteria

8. Pregnant or nursing women may not participate due to the possibility of fetal harm or
of harm to nursing infants from this treatment regimen. Women of reproductive
potential may not participate unless they have agreed to use an effective
contraceptive method. A urine pregnancy test is required for women of childbearing
potential.

9. All patients must be informed of the investigational nature of this study and must
sign and give written informed consent in accordance with institutional and federal
guidelines.