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A Randomized Multicenter Trial of Neoadjuvant Taxotere and Adriamycin/Cytoxan(AC): A Biologic Correlative Study

Phase 2
18 Years
Not Enrolling
Breast Cancer

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Trial Information

A Randomized Multicenter Trial of Neoadjuvant Taxotere and Adriamycin/Cytoxan(AC): A Biologic Correlative Study

Breast cancer and systemic chemotherapy: Systemic chemotherapy for operable breast cancer
significantly decreases the risk of relapse and death. However, it is not possible to
identify those patients at the outset who are likely to respond to adjuvant treatment and
which type of treatment should be used. Adjuvant treatment given before surgery (neoadjuvant
therapy) has a number of advantages in breast cancer, including a reduction in the
requirement for mastectomy. Access to the primary tumor during early treatment allows for in
vivo testing for predictive markers obtained by core biopsies that occur with successful

Predictive markers in breast cancer: Prognostic factors like tumor size and nodal
involvement are important indicators for breast cancer survival but have not been shown to
be predictive of sensitivity to chemotherapy. With endocrine therapy, the prime example of a
predictive marker is estrogen receptor (ER) expression, which predicts for response to
tamoxifen and other endocrine treatments. However, predictive markers for chemotherapy are
not established. Overexpression of c-erbB-2 might be associated with decreased response to
CMF and increased response to anthracycline-based treatment, but these observations are
still contentious. Expression of topoisomerase II may also reflect responsiveness to
anthracycline chemotherapy. Recently, some emerging data also suggest that c-erbB2 may be a
marker of taxane sensitivity. As such, we lack predictive biomarkers that could give early
information on how effective chemotherapy is and whether additional treatment might be
beneficial. A test for chemotherapy sensitivity, equivalent to ER in predicting response to
endocrine therapy, would greatly facilitate treatment decisions so that in an ideal
scenario, the treatment of each individual patient could be based on specific features of
her disease.

Neoadjuvant chemotherapy: Preoperative chemotherapy for large tumors (>3cm) or inoperable
breast cancer is well established and is the standard of care for locally advanced breast
cancer. Data from large series of patients have demonstrated that preoperative (neoadjuvant)
chemotherapy leads to significant reduction of tumor size (downstaging) and improves both
the rate and the cosmetic results of breast-conserving surgery. A recent large randomized
trial involving 1,523 patients compared preoperative and postoperative chemotherapy (NSABP
B-18). Although results of this study have shown no difference in disease-free survival and
survival in women on preoperative or postoperative doxorubicin and cyclophosphamide
chemotherapy, significant downstaging of tumors was achieved so that more patients who
received preoperative therapy were able to undergo breast-conserving surgery. The rate of
breast conservation in NSABP B-18 was 85% in patients with tumors greater than 3 cm, with
less than 5% of patients reported to have progressive disease while receiving neoadjuvant

cDNA arrays: High-Throughput Quantitative Profiling of Gene Expression: With the advent of
high-throughput quantitation of gene expression and cDNA technology, it is now possible to
study expression of many genes simultaneously to characterize expression patterns in
different breast cancers that may distinguish molecular phenotypes associated with clinical
response to a treatment. In a recent report, a molecular classification of leukemia was
demonstrated. Bone marrow aspirates taken from 38 patients with acute leukemia were
evaluated for expression of 6,817 human genes. The 50 best discriminating genes were used to
create a predictive index that was then applied to new samples and was found to accurately
assign them as AML or ALL.

Preliminary data for differential patterns of gene expression in responders vs
non-responders of Taxotere chemotherapy: We conducted a pilot study to investigate gene
expression patterns on core biopsies of human breast cancers in responders and
non-responders to Taxotere chemotherapy.

RNA was isolated from core biopsies of primary breast cancers taken from women before
initiation of Taxotere chemotherapy. Clinical response was assessed after 12 weeks of
treatment. We compared patterns of gene expression statistically in order to identify genes
differentially expressed between responders and non-responders to this single
chemotherapeutic agent.

Overall, these genes efficiently cluster tumors into 3 groups: CR, PR, and NR. We have
selected 2337 genes from these data for further analysis. As expected, the majority of these
genes show heterogeneous expression patterns independent of treatment response, but six
large gene clusters (approximately 180 genes) appear to predict likelihood of response to
Taxotere therapy. Consistent with an apoptosis-induction mode of action for taxanes,
responsive tumors appear to have higher expression of stress-related proteins, such as
mitochondrial proteins involved in apoptosis (cytochromes, proteasome subunits), and higher
levels of motility-related microfilament proteins (actin, myosin, and tropomyosin).
Non-responders patterns are more complex but show elevated levels of some microtubule
proteins presumed to be targets of Taxotere therapy (tubulins, tubulin-interacting proteins)
and elevated levels of inflammatory-response genes. Surprisingly, non-responders also showed
elevated proliferation (KI67) and oncogene (ABL1, MYC and JUNB) expression levels. This
molecular portrait of Taxotere resistance differs from the expected profiles of general
chemoresistance. Quantitative RT-PCR and immunohistochemistry studies to confirm these
differential gene patterns of expression are in progress for all 40 patients.

Inclusion Criteria:

1. All patients must be female.

2. Signed informed consent.

3. Primary breast cancers must be of clinical and/or radiologic size >3 cm, and deemed
surgically operable.

4. Negative serum pregnancy test (bHCG) within 7 days of starting study, if of
child-bearing potential.

5. Adequate bone marrow function: Hematocrit of greater than 30%, total neutrophil count
must be >1.5 x 109/L and platelets of > 100 x 109/L prior to the start of any cycle.

6. Renal function tests: creatinine within 1.5 times of the institution's upper limit of
normal (ULN).

7. Liver function tests: Total serum bilirubin within ULN, and liver transaminases
within 2.5 times ULN, and alkaline phosphatase within 5 times ULN.

8. Electrocardiogram showing no acute ischemic changes.

9. Performance status (WHO scale) <2.

10. Age > 18 years.

11. Patients older than 70 years of age should have left ventricular ejection fraction
within ULN by MUGA or 2D Echocardiogram.

Exclusion Criteria:

1. Patients with metastatic breast cancer.

2. Pregnancy or unwillingness to use a reliable contraceptive method in women of
child-bearing potential.

3. Women who are lactating or breastfeeding.

4. Severe underlying chronic illness or disease.

5. Peripheral neuropathy - grade 2 or greater.

6. Patients on other investigational drugs while on study will be excluded.

7. Severe or uncontrolled hypertension, history of congestive heart failure, acute
myocardial infarction, or severe coronary arterial disease.

8. Prior taxane or anthracycline chemotherapy for malignancy.

9. Patients with a history of severe hypersensitivity reaction to Taxotere or other
drugs formulated with polysorbate 80.

10. No previous or current malignancies at other sites within the last 5 years, with
exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri
and basal or squamous cell carcinoma of the skin.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary objective this extension study is to obtain enough additional cases evaluable for microarray analyses to complete our studies to identify profiles of a small number of genes that are predictive of response.

Outcome Time Frame:

10 years

Safety Issue:


Principal Investigator

Mothaffar C Rimawi, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor Breast Center


United States: Institutional Review Board

Study ID:




Start Date:

April 2002

Completion Date:

January 2012

Related Keywords:

  • Breast Cancer
  • neoadjuvant
  • chemosensitivity
  • chemotherapy
  • breast cancer
  • tumor
  • taxotere
  • AC
  • Breast Neoplasms



Baylor Breast CenterHouston, Texas  77030