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.

Inclusion Criteria:

- Patients must be women with a histologically confirmed diagnosis of breast cancer that
is more than 2 cm and/or lymph node positive. Histologic confirmation shall be by
either core needle biopsy or incisional biopsy. Punch biopsy is allowed if invasive
breast cancer is documented.

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

1. 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.

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

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

- All patients must have a multiple gated acquisition (MUGA) scan or echocardiogram scan
performed within 90 days prior to registration and left ventricular ejection fraction
(LVEF) percentage must be greater than the institutional lower limit of normal.

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

- 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.

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

- In calculating days of tests and measurements, the day a test or measurement is done
is considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks
later would be considered Day 28. This allows for efficient patient scheduling without
exceeding the guidelines. If Day 28 or 42 falls on a weekend or holiday, the limit may
be extended to the next working day.

- 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.

Exclusion Criteria:

- Patients with the clinical diagnosis of congestive heart failure or angina pectoris
are NOT eligible.

- 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.