Neoadjuvant Treatment of Breast Cancer
Neoadjuvant Treatment of Breast Cancer
Study Aims

 1. To measure the clinic response rates in patients with breast cancer more than 2 cm
 and/or lymph node positive breast cancer treated with 2-4 cycles of biweekly
 doxorubicin, cyclophosphamide with Granulocyte-macrophage colony-stimulating factor
 (GM-CSF) (days 4-13) followed by weekly carboplatin/nab-paclitaxel given for 3 weeks,
 followed by 1 week of rest, for a total of 9-12 doses. (Her-2 positive patients, in
 addition, will receive Trastuzumab weekly (12-16 doses) and Her-2 negative patients will
 receive Bevacizumab (6-8 doses) q 2 weeks).

 2. To measure the microscopic pathological response rate of this regimen.

 3. To measure toxicity and the delivered dose intensity of this regimen.

 4. To assess the association between microscopic pathologic complete response and clinical
 complete response at the primary tumor site in these patients.

 5. To determine whether the GM-CSF increases the post treatment dendritic cells (S100+)
 percentage in the tumor draining lymph node as compared to pretreatment S100+ cells.

 6. To determine whether the patients with a higher percent S100+ have a better clinical,
 pathological response, Disease Free Survival (DFS), and overall Survival (OS).

 7. To determine whether flow cytometry of dendritic cells performed post-treatment in blood
 sample shows an increase in dendritic cell population compared to pretreatment levels.
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.