Triple negative breast cancer – molecular basics and clinical impact

Molecular taxonomy of breast cancer

Rather than a homogeneous entity, breast cancer is increasingly understood as a heterogeneous mixture of individual subtypes that differ with regard to molecular, pathological and clinical features. Expression of estrogen receptor (ER) and progesterone receptor (PR) as well as HER2 constitute the major determinants of these subtypes and distinguish (a) HER2-positiv, (b) ER-positive/HER2-negative and (c) triple negative breast cancers (TNBC). The latter are characterized by the lack of expression of each of the three receptors. TNBC is highly concordant to the basal-like breast cancer which has previously characterized by high-throughput gene expression analysis (GeneChips; Perou et al. Nature 2000).

Clinical characteristics of triple negative breast cancer

TNBC is particularly prevalent among African American and Hispanic women and commonly of high grade (Liedtke et al. J. Clin. Oncol. 2008). It is particularly common among patients with somatic BRCA-1-mutations (Sorlie et al. PNAS 2003), although it has to be acknowledged that this association is not reciprocal: in fact the majority of patients with TNBC do not carry a BRCA-1-mutation. Patients with TNBC suffer from a particularly unfavorable prognosis despite higher response rate to neoadjuvant chemotherapy (NACT) compared to the remaining breast cancer subtypes (Liedtke et al. J Clin Oncol 2008). This phenomenon has been demonstrated similarly for patients with basal-like breast cancer and been referred to as „triple negative paradox“ (Carey et al. Clin Cancer Res 2007).

This phenomenon, however, can be explained. In fact, we have recently shown that patients with TNBC showed an increased rate of high grade tumors. High grade is a positive predictor for increased response to chemotherapy, but also predicts unfavorable prognosis. Furthermore, patients with TNBC carry an increased risk of visceral metastases. Visceral metastases predict for a worse prognosis compared to osseous metastases (Imkampe et al. Eur J Surg Oncol. 2007). Most importantly, patients with an optimal response to NACT (pathological complete response, pCR) had an excellent prognosis regardless of whether they had TNBC or not. In contrast, patients who had residual disease had significantly better survival if they were diagnosed with non-TNBC rather than TNBC. It seems plausible that the latter is due to a lack of therapeutic options for patients with TNBC. To date those patients are offered chemotherapy only, where as patient with non-TNBC may receive endocrine therapy and/or trastuzumab.

These results illustrate the need for developing additional therapeutic options for patients with TNBC. Thus, clinical as well as basic research efforts should aim for optimization of current treatments as well as implementation of new therapies.

Treatment of TNBC:

To date chemotherapy has been regarded as the main stem of TNBC systemic therapy (Goldhirsch et al. Ann Oncol. 2007). However, as demonstrated above, not all patients benefit from this increased chemotherapy sensitivity. Particularly patients with TNBC who recur after primary (adjuvant or neoadjuvant) systemic therapy need additional therapeutic tools to improve their prognosis. The following concepts may improve prognosis of patients with TNBC:

(A) Optimizing response rates through specifically tailored systemic regimens (i.e. through implementation of biomarkers/multigene predictors)

It has been suggested that addition of a taxane to an anthracycline therapy may result in a survival benefit particularly among patients with TNBC (Hayes et al. N Engl J Med. 2007). Furthermore, patients with BRCA-1-Mutation carry an insufficient ability to repair DNA damages (Kennedy et al. J Natl Cancer Inst 2004). Thus, patients with TNBC and BRCA-1-Mutation may derive particular benefit from DNA-damaging agents such as platinum derivatives. Furthermore, recent translational studies suggest that multigene predictors should soon allow for individualizing systemic breast cancer therapy according to the molecular signature of given cancer (Hess et al., J Clin Oncol. 2006).

(2) Identification and implementation of novel targeted therapies specifically for TNBC

Recently, we performed gene expression profiling of 294 fine needle aspiration samples of breast cancer patients Using the Affymetrix U133A GeneChip system. As many as 1,871 probesets were overexpressed among TNBC (n=73) compared to non-TNBC (n=221, P-value, FDR<0.00001); these genes mapped to well-established oncogenic pathways. 62% and 21% of these genes were also overexpressed in TNBC cases in an independent human and cell line dataset, respectively (p<0.05) (Liedtke et al., Proc AACR 2008) Each of the corresponding genes constitutes a potential novel target that may serve as a basis to develope novel therapeutic agents for TNBC. For instance, the Gamma-Aminobutyric Acid (Gaba) A Receptor subunit Pi (GABA pi) is significantly overexpressed in TNBC compared to non-TNBC. In fact, si-RNA mediated knockdown of GABA pi results in decreased proliferation of GABA pi-positive breast cancer cells in vitro. (Tordai et al., Proc AACR 2007)

To date, translational as well as preliminary clinical evidence suggest several novel agents such as

• PARP inhibitors (Farmer et al. Nature 2005)

• antiangiogenic agents such as bevazizumab (Miller et al. N Engl J Med. 2007)

• androgen receptor antagonists (Doane et al., Oncogene 2006)

• agents targeting EGFR (i.e. erlotinib) (Hoadley et al. BMC Genomics. 2007) or src (i.e. dasatinib) (Finn et al. Breast Cancer Res Treat. 2007)

Conclusion:

Patients with TNBC carry an unfavorable prognosis despite increased response to NACT. To reduce the probability of disease recurrence, highly effective (chemotherapy) regimens are warranted to prevent TNBC disease recurrence. Patients with TNBC carry an increased risk of visceral metastasis; consequently patient with TNBC may benefit from intensified aftercare focusing on visceral disease recurrence. Novel clinical trials should aim for increased therapeutic efficacy of current breast cancer therapeutics through (a) optimal sequencing, duration and dosage and (b) supplementation by novel therapeutic agents.

References:

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