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A nonreplicating adenoviral vector that contains the wild‐type p53 transgene combined with chemotherapy for primary breast cancer
Author(s) -
Cristofanilli Massimo,
Krishnamurthy Savitri,
Guerra Laura,
Broglio Kristine,
Arun Banu,
Booser Daniel J.,
Menander Kerstin,
Van Wart Hood Jill,
Valero Vicente,
Hortobagyi Gabriel N.
Publication year - 2006
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.22080
Subject(s) - medicine , chemotherapy , docetaxel , breast cancer , doxorubicin , cancer , phases of clinical research , cyclophosphamide , surgery , oncology
Abstract BACKGROUND. Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild‐type p53 , AdCMV‐ p53 , combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response. METHODS. In a prospective, open‐label, Phase II trial, 13 patients with LABC were treated with 6 3‐week cycles of PST, which consisted of intratumoral injections of Ad5CMV‐ p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods. RESULTS. The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39–71 years), and the median tumor size was 8 cm (range, 5–11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21 WAF1/Cip1 mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor‐infiltrate leukocytes (predominantly T‐lymphocytes). At a median follow‐up of 37 months (range, 30–41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer‐specific survival rate at 3 years was 84% (95% confidence interval, 65.7–100%). There was no increase in systemic toxicity. CONCLUSIONS. Ad5CMV‐ p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies. Cancer 2006. © 2006 American Cancer Society.