Abstract P3-10-09: A Phase II trial of doxil, carboplatin and bevacizumab in metastatic triple negative breast cancer and molecular correlates of response
Authors: Hirshfield Kim M , Lu Shou-En , Wong Serena , Tan Antoinette , Kirstein Laurie , Kearney Thomas , Shih Weichung , Ganesan Shridar , Toppmeyer Deborah L 
Published: May 2015

Background. Despite improved outcomes for other breast cancer subtypes, triple negative breast cancer continues to display the worst prognosis with conventional, standard of care chemotherapy. A growing body of evidence suggests that platinating agents may offer superior outcomes in a subset of triple negative breast cancers and that genomic alterations may identify those tumors most likely to respond.

Patients and Methods. Eligibility included previously untreated, stage IV ER, PgR, and Her2neu negative breast cancer with measurable disease. Thirty-one patients with ECOG PS≤2 and adequate bone marrow, renal and hepatic function were enrolled to receive doxil (30 mg/m2), carboplatin (AUC 5) and bevacizumab (15 mg/m2) every 4 weeks in an open-label, multicenter, investigator-initiated Phase II trial from 2008-2012. The primary endpoint was median progression free survival (PFS). Secondary endpoints were response rate based on RECIST criteria, survival time, and toxicity profile.

Results. Thirty-one patients received a median of 5.6 cycles (range 1-13). Prior adjuvant or neoadjuvant anthracycline or taxane was given in 38.7% or 41.9%, respectively. Clinical benefit rate (CBR= CR+PR+SD ≥ 6months) was 38.7% where 9/18 (50%) with CBR&lt;6 months and 4/13 (30.7%) with CBR&gt;6 months had prior taxane. Median progression free survival (PFS) was 5.6 months, 95% CI [4.4-6.9] and 6-month PFS rate was 41.9%, 95% CI [24.6-59.3]. Median overall survival was 11.9 months, 95% CI [8.8-21.8] and 1-year survival rate was 47.3%, 95% CI [29.5-65.1]. Thirteen patients were alive at 10 months or longer. Grade 3 non-hematologic and hematologic toxicities included fatigue (n=1), hand-foot skin reaction (n=1), and neutropenia (n=1). Grade 4 hematologic toxicity included thrombocytopenia (n=1). Grade 4 hypertension (n=2) and thrombosis (n=1) were attributable to bevacizumab and this drug was discontinued from the protocol. Neither significant change in cardiac function nor alopecia were observed. Next-generation sequencing from tumors revealed p53 alterations as the most common alteration. For three patients with serial pre- and post-platinum specimens, gain of genomic alterations were observed at time of progression of disease occurring at 5 months, 8 months, and 20 months (eight months of these were off study but receiving doxil and carboplatin).

Conclusions. Results demonstrate that the combination of doxil, carboplatin, and bevacizumab is an active and well-tolerated regimen in previously untreated, metastatic, triple negative breast cancer. We anticipated presentation of additional genomic tumor profiling results that may yield insights into markers of sensitivity and mechanism of resistance to anthracycline and/or platinum.

Citation Format: Kim M Hirshfield, Shou-En Lu, Serena Wong, Antoinette Tan, Laurie Kirstein, Thomas Kearney, Weichung Shih, Shridar Ganesan, Deborah L Toppmeyer. A Phase II trial of doxil, carboplatin and bevacizumab in metastatic triple negative breast cancer and molecular correlates of response [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-09.