Despite having achieved a pCR in June, Carole experienced a rapid cutaneous relapse and neuropathic pain. On clinical examination in October 2010, she was found to have skin infiltration and a right axillary mass. Imaging showed right diffuse carcinomatous mastitis, and there was evidence of axillary and retroperitoneal para-aortic lymph-node involvement.
More than half of the audience suggested entering her into a clinical trial of a PARP inhibitor. Other options included platinum-based or taxane-based (docetaxel + capecitabine or gemcitabine; paclitaxel + bevacizumab) chemotherapy.
Expert opinion of Professor Lisa Carey
The heterogeneity described earlier for TNBC continues to manifest when the disease progresses to the metastatic stage. Slowly progressive or asymptomatic patients with small metastases present a different challenge from those with rapidly progressive, symptomatic disease, although in all cases the disease is not curable.
In asymptomatic patients, the goals of treatment are to control disease (i.e. to stop the tumour from growing, rather than trying to reduce tumour size) without exposing the patient to undue toxicity. In such patients, sequential single agents are the norm (if there is no appropriate clinical trial), and the choice depends on patient convenience, comorbidities and previous toxicities (95% of patients have already received neoadjuvant or adjuvant chemotherapy [29
]). Possible treatments include taxanes, anthracyclines (e.g. liposomal doxorubicin), capecitabine, platinum agents, other microtubule-directed agents, vinorelbine and gemcitabine.
In patients with rapidly progressive and symptomatic metastatic disease, there is little need to balance efficacy and tolerability of treatments, because the disease is likely to cause more toxicity than therapy would. The goal of treatment is to achieve a tumour response, and combination regimens always have higher response rates than single agents. Options include combinations involving bevacizumab, docetaxel + capecitabine, paclitaxel + gemcitabine, and ixabepilone + capecitabine.
As with the neoadjuvant and adjuvant settings, the jury is still out on the benefit of platinum-based treatments in the metastatic setting. Cisplatin monotherapy achieved only a 10% response rate in largely treatment-naive patients [30
]. Carboplatin monotherapy achieved a 17% response rate in patients who were largely pretreated with an EGFR inhibitor [31
]. Until the results of further clinical trials are available, platinum-based treatment should probably not be a standard of care, although it could be considered in later lines of treatment for metastatic TNBC.
Novel anticancer agents such as PARP inhibitors and iniparib are eliciting a great deal of interest currently, although none is yet available outside clinical trials. Most data are available for iniparib, which is provoking most excitement in the setting of sporadic (i.e. not BRCA1
-associated) TNBC. Iniparib does not possess characteristics typical of the PARP inhibitor class and investigations are currently in progress to elucidate its main mechanism of action. The recently published phase II study demonstrated that the addition of iniparib to gemcitabine + carboplatin improved the clinical benefit and survival of patients with metastatic TNBC, compared with chemotherapy alone, without significantly increased toxic effects () [32
]. However, in the pivotal phase III trial, iniparib demonstrated activity but did not meet the statistically rigorous primary endpoint [33
], although it is possible that subsets within the larger trial will demonstrate benefit; those analyses are ongoing.
Figure 3: Overall survival in patients with triple-negative breast cancer treated with gemcitabine + carboplatin with or without iniparib (adapted from ref. )
Questions that remain to be answered include: Is DNA damage stimulus needed in non-BRCA+ tumours? Might PARP inhibitors and iniparib work in any breast cancer or will the benefit be seen only in TNBC patients? What secondary effects might occur with prolonged prevention of DNA damage repair?