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ASCO 2009 Report: Breast Cancer

New trials in triple-negative and HER2-negative disease

PARP INHIBITORS FOR TRIPLE-NEGATIVE BREAST CANCER

Triple-negative breast cancer (TNBC) — i.e., estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative disease — accounts for about 15% of all breast cancers, is more common in younger patients and blacks, and is associated with aggressive clinical behavior, poor response to therapy, and short progression-free survival (PFS).

Data from a randomized phase II clinical trial suggest an approach to treating TNBC patients with agents that prevent the enzyme poly (ADP-ribose) polymerase (PARP) from repairing DNA damage (including that caused by chemotherapeutic agents). Mutations in the BRCA1 and BRCA2 genes can impair this function, leaving cells unable to repair their own DNA. TNBC might have a relative loss of this repair function. The underlying rationale for using PARP inhibitors in patients with TNBC — as well as those with BRCA1/2-associated breast cancers — is that PARP inhibition has the potential to overwhelm cancer cells that have lethal DNA damage by exploiting the impaired DNA repair function inherent in BRCA-associated cancers and the relative lack of repair function in TNBCs.

The trial involved 116 women with metastatic TNBC who received conventional chemotherapy with gemcitabine and carboplatin with or without the PARP inhibitor BSI-201. Patients who received BSI-201 achieved higher overall response rates (48% vs. 16%; P=0.002), longer median PFS (6.9 months vs. 3.3 months; P<0.0001), and longer median overall survival (9.2 months vs. 5.7 months; P=0.0005). Of note, BSI-201 was not associated with greater toxicity than was chemotherapy alone.

A British trial of the oral PARP inhibitor olaparib involved 54 patients with BRCA1/2-deficient, chemotherapy-refractory advanced breast cancer. Patients who received a high dose (400 mg twice daily) of olaparib achieved a higher overall response rate than those who received a low dose (100 mg twice daily; 41% vs. 22%). Olaparib was well tolerated; the most common adverse effects were low-grade nausea and fatigue. These exciting results will lead to rapid development of more-definitive, phase III clinical trials to evaluate the role of PARP inhibitors in TNBC and BRCA-mutated breast cancer.

BEVACIZUMAB FOR HER2-NEGATIVE DISEASE

The RIBBON 1 trial was designed to evaluate the clinical activity and toxicity of bevacizumab (Avastin) plus chemotherapy agents other than paclitaxel versus the same chemotherapy alone in the first-line treatment of HER2-negative locally recurrent or metastatic breast cancer. A total of 1237 patients were randomized 2:1 to receive capecitabine (Xeloda), taxane-based chemotherapy (nab-paclitaxel or docetaxel), or anthracycline-based chemotherapy concurrently with bevacizumab (15 mg/kg every 3 weeks) or placebo.

At median follow-up of 15.6 months, patients who received bevacizumab plus capecitabine achieved longer median PFS (the primary outcome) than those who received capecitabine alone (8.6 months vs. 5.7 months; P=0.0002). At median follow-up of 19.2 months, patients who received bevacizumab plus either taxane-based or anthracycline-based chemotherapy achieved longer median PFS than those who received either chemotherapy regimen alone (9.2 months vs. 8.0 months; P<0.0001).

These data indicate that the benefits of bevacizumab as treatment for metastatic disease are not restricted to combination with taxane-based therapy as previously reported (JW Oncol Hematol Jan 15 2008), but also can be achieved when the drug is partnered with other commonly used agents. Excess toxicity associated with bevacizumab — including a small increase in risk for hypertension, proteinuria, neutropenia, and bleeding episodes — was predictable from past experience. The ongoing RIBBON 2 trial will address questions about the use of bevacizumab with second-line chemotherapy for metastatic breast cancer, and the pending RIBBON 3 trial is planned to examine the potential benefits of continuing bevacizumab beyond disease progression.

— William J. Gradishar, MD

Published in Journal Watch Oncology and Hematology June 16, 2009