Randomized phase II trial of the anti-angiogenic potential of doxorubicin and docetaxel; primary chemotherapy as Biomarker Discovery Laboratory.
OBJECTIVE
Primary chemotherapy provides an ideal opportunity to correlate potential non-invasive surrogate markers of angiogenesis with tumor microvessel density (MVD) and response.


METHODS
Patients with newly diagnosed stages II or III breast cancer were treated with sequential doxorubicin 75 mg/M2 q2 wks x 3 and docetaxel 40 mg/M2 weekly x 6; treatment order was randomly assigned. Potential serologic and imaging markers of angiogenesis were obtained pre-treatment, at crossover and completion of chemotherapy. Non-invasive biomarkers were correlated with MVD and pathologic response.


RESULTS
From June 1999 to October 2002, 70 patients were entered. Median pretreatment tumor diameter was 6.0 cm with clinically involved axillary nodes in 33 (47%) patients; 20% had inflammatory disease. Clinical response rate was 91%, including 46% clinical complete responses. Pathologic complete response (pCR) was confirmed in 9 (12.8%) patients. Baseline MVD did not correlate with clinical or pathologic response. Serologic markers were obtained in all patients; basic fibroblast growth factor (bFGF) was lower at baseline and increased during treatment in patients with a pCR but did not correlate with MVD. Color Doppler ultrasound (CDUS) was completed in 47 patients; no parameter reliably correlated with MVD or response. Positron emission tomography (PET) with [F-18]-fluoro-deoxyglucose, [O-15]-water and [C-11]-carbon monoxide were completed in 19 patients; uptake of all tracers decreased during treatment in virtually all patients.


CONCLUSIONS
Sequential doxorubicin and docetaxel is generally well tolerated and highly active. Serum angiogenic factors and imaging parameters frequently varied throughout treatment but did not correlate with MVD or consistently predict response.
Miller
Kathy D
KD
Division of Hematology and Oncology, Indiana University, Indianapolis, IN, USA. kathmill@iupui.edu
Soule
Sharon E
SE
Calley
Cynthia
C
Emerson
Robert E
RE
Hutchins
Gary D
GD
Kopecky
Kenyon
K
Badve
Sunil
S
Storniolo
AnnaMaria
A
Goulet
Robert
R
Sledge
George W
GW
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D004334:Drug Administration Schedule; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008833:Microcirculation; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D016896:Treatment Outcome; D018615:Ultrasonography, Doppler, Color
D014408:Biomarkers, Tumor; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D016222:Fibroblast Growth Factor 2