Treatment of triple-negative breast cancer, so named because it lacks estrogen receptors, progesterone receptors, and HER2 overexpression, is one of the most challenging areas of breast oncology. Not only do patients with this aggressive cancer have some of the shortest absolute survival times, but they also are the only group for whom we still have no targeted therap
It is becoming increasingly clear that effectively treating triple-negative disease will require recognition of its diversity. Viewing it as a single entity is inherently flawed, an oversimplified way of referring to a disease that’s incredibly heterogeneous and complicated. And that’s probably been our biggest challenge in the design of clinical trials for this cancer.
By Dr. Hope S. Rugo
Gene expression profiling is helping to tease apart molecular subtypes of triple-negative breast cancers (Mol. Oncol. 2011;5:5-23). These subtypes often have distinctly different behavior and treatment responses.
We are also learning more about the overlap between triple negativity and mutation of the BRCA1 tumor suppressor gene. About 90% of BRCA1-mutated breast cancers have a triple-negative phenotype. But interestingly, most triple-negative tumors have normal BRCA1 function. Recent data suggest that a subset of these tumors may have posttranslational modifications that affect BRCA1 function, so if you look for the DNA mutation, you won’t find it. Sporadic basal-like tumors and hereditary BRCA1 tumors have a similar phenotype, so a defect in BRCA1 may have a role in these sporadic basal-like tumors.
Recent clinical trials are adding to our arsenal several new drugs – and a few old ones – from different classes that target vulnerabilities of triple-negative breast cancer and offer promise for improving outcomes in this hard-to-treat disease.
Cytotoxic Chemotherapeutic Agents
We know that triple-negative tumors are sensitive to cytotoxic chemotherapy, especially in the neoadjuvant and adjuvant settings.
Recognition that there is a defect in DNA repair in BRCA1 tumors and at least some triple-negative tumors has generated interest in the use of DNA-damaging agents such as platinums. The pathologic complete response rate to neoadjuvant cisplatin has been around 75% in BRCA1 tumors, but just 15% to 16% in sporadic triple-negative tumors, suggesting selective sensitivity to platinum-based agents in the former. An ongoing randomized phase II neoadjuvant trial is looking at this issue more closely, using carboplatin and bevacizumab (NCT00861705), and we hope that the results of this study will help us to better understand the responsiveness to platinums in sporadic triple-negative breast cancer.
Ixabepilone (Ixempra), an approved agent for the treatment of metastatic and locally advanced breast cancer, also appears promising. A pooled analysis of data from women with pretreated advanced triple-negative disease treated in a pair of phase III trials testing addition of ixabepilone to capecitabine showed a doubling of response rate and progression-free survival (San Antonio Breast Cancer Symposium 2008. Abstract 3057). But the combination also had substantial toxicity, so there is now more interest in using ixabepilone alone and farther out, in patients having multidrug-resistant disease.
EGFR Inhibitors
The epidermal growth factor receptor (EGFR) is upregulated in many triple-negative breast cancers, making this an attractive treatment target. Unfortunately, trials combining cetuximab (Erbitux) with carboplatin or with carboplatin-irinotecan have found small or no improvement in outcomes, along with added toxicity.
But the BALI-1 trial in patients with triple-negative metastatic breast cancer found a doubling of the overall response rate and progression-free survival with addition of cetuximab to cisplatin (SABCS 2010 meeting, Abstract PD01-01), although this trial did not meet its primary end point). We are waiting anxiously to see data from correlative markers obtained from these patients’ primary and metastatic tumors.
The bottom line here is that patient selection will be critical if we are going to pursue EGFR blockade in triple-negative disease.
PARP Inhibitors
There has been tremendous interest in using inhibitors of poly(ADP-ribose polymerase) or PARP, which interfere with the repair of DNA damage, in triple-negative disease. Trials to date have had mixed results and provided some valuable lessons.
A randomized phase II trial among patients with triple-negative metastatic breast cancer found that adding iniparib, an investigational PARP inhibitor, to gemcitabine-carboplatin dramatically improved progression-free and overall survival (N. Engl. J. Med. 2011;364:205-14). But the subsequent, far larger randomized phase III trial using the same regimens did not meet either of these end points (ASCO 2011 meeting. Abstract 1007).
This was very surprising and made us realize that patient selection of disease may have a significant impact on evaluation of outcome parameters. Triple-negative breast cancer is a heterogeneous disease, and we didn’t understand it well enough. In addition, we did not have enough data to understand the clinical activity of backbone in triple-negative breast cancer; in fact, patients treated with gemcitabine-carboplatin alone had a better response and PFS than expected.