Triple-negative Phenotype in Metastatic Breast Cancer – Where Do We Stand in Terms of Treatment?

European Oncological Disease, 2007;1(2):52-3

Treatment of breast cancer has come a long way. The recent elucidation of distinctive molecular breast cancer subtypes through gene expression profiling has shed light on the heterogeneous clinical behaviour and outcomes of seemingly alike morphological breast cancers.1 This information could be translated in the scenario of clinical trials and clinical practice as a streamlined approach for targeting specific molecular defects on cancer cells that are thought to drive tumour cell progression. A subpopulation emerging as having particularly poor prognosis is those patients who have disease that is receptor-negative for oestrogen, progestin and human epidermal growth factor receptor 2 (HER2 or HER2neu – triple-negative disease).The lack of these targets obviates any consideration regarding use of hormone therapies or HER2- targeted agents.

So, how should we approach this orphan disease? The awareness that these patients benefit less from current treatments than other populations is increasing among researchers, and new clinical trials are being designed to investigate responsiveness to treatment in this patient population. Chemotherapy represents the gold standard treatment for these patients. In this article, we will provide some guidelines on how to properly use chemotherapy in the metastatic setting and evaluate whether there is room for combining chemotherapy with biological agents in an HER2-negative population in clinical practice.

The decision as to which type of chemotherapy/regimen should be given to patients with metastatic breast cancer as first-line chemotherapy should be based on the individual (i.e. performance status, biological age and co-morbidities) and their specific disease characteristics (i.e. tumour burden and disease-free interval) and take into account prior treatments received in the adjuvant setting, as well as patient preference. Attaining longer survival is certainly a primary aim when treating metastatic patients. However, physicians should not overlook treatment-related toxicity as it can have a detrimental impact on quality of life.2 For this reason an aggressive polychemotherapy regimen should be proposed only for a specific subgroup of patients, namely symptomatic patients with rapidly progressive disease in whom a prompt response is necessary (see Table 1).3

In the last few years, data from two phase III trials comparing singleagent chemotherapy with polychemotherapy have been published. O’Shaughnessy et al. randomised a total of 511 anthracycline pre-treated patients with advanced breast cancer to receive docetaxel 100mg/m2 or docetaxel 75mg/m2 on day one, plus capecitabine 1,250mg/m2 on days one to 14 every three weeks.4 The primary endpoint of the study was time to disease progression (TTP). The addition of capecitabine to docetaxel resulted in increased response rate (RR) (42 versus 30%), prolongation of TTP (6.1 versus 4.2 months) and longer survival (median survival 14.5 versus 11.5 months). This improvement in efficacy was counterbalanced by an increase in the incidence of side effects such as hand–foot syndrome, stomatitis and diarrhoea in the combination arm. Overall, grade 3 adverse events were reported in 49 and 71% of patients in the single-agent and combination arms, respectively. An analysis of post-study therapy showed that only 17% of patients treated with single-agent docetaxel received capecitabine at progression.

  1. Sorlie T, Perou CM, Tibshirami S, et al., Proc Natl Acad Sci U S A, 2001;98(19):10869–74.
  2. Smith I, Semin Oncol, 2006;33(Suppl. 2):S2–5.
  3. Ocana A, Hortobagy GN, Esyeva FJ, Clin Breast Cancer, 2006;6(6):495–504.
  4. O’Shaughnessy J, Miles D, Vukelja S, et al., J Clin Oncol, 2002;20:2812–23.
  5. Albain KS, Nag S, Calderillo-Ruiz G, et al., J Clin Oncol, 2004;22(Suppl. 14):A510.
  6. Piccart MJ, Burzykowski T, Buyse M, et al., Eur J Cancer, 2006;4:178, abstract 434.
  7. Schneider BP, Miller KD, J Clin Oncol, 2005;23(8): 1782–90.
  8. Ferrara N, Kerbel RS, Nature, 2005;438:967–74.
  9. Miller KD, Wang M, Gralow J, et al., A randomised phase III trial of paclitaxel versus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer, San Antonio Meeting, 2005; abstract 3.
  10. Sledge G, Miller K, Moisa C, Gradishar W, J Clin Oncol, 2007;25(18S):35s, abstract 1013.
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