The molecular deciphering of triple-negative breast cancer has become a strong research goal. Studies presented at the 33rd Annual San Antonio Breast Cancer Symposium moved the field forward, revealing distinct genetic subtypes within the triple-negative breast cancer classification and suggesting that not all triple-negative tumors may be unfavorable. The findings may help to individualize therapy some day-though they also suggest there will be no magic bullet.

Unique Gene Ontologies

In a study that drew much attention at a poster discussion session, Brian Lehmann, PhD, and Joshua Bauer, PhD, from the laboratory of Jennifer Pietenpol, PhD, at the Vanderbilt-Ingram Cancer Center, Nashville, showed triple-negative breast cancer to be quite a heterogeneous disease based on the results of a transcriptome analysis in which six distinct biologic subtypes of triple-negative breast cancer were identified.¹ Dr. Lehmann and his colleagues further linked these subtypes to potential therapeutic strategies.

"We compiled an extensive triple-negative breast cancer transcriptome dataset from 21 independent breast cancer studies. We analyzed 386 triple-negative breast cancer gene-expression profile training sets and identified six stable clusters that display unique gene-expression patterns and gene ontologies," Dr. Lehmann reported.

The investigators identified two basal-like subtypes characterized by cell cycle and DNA damage response genes; two mesenchymal-like subtypes enriched in cell differentiation, epithelial-mesenchymal transition, and growth factor pathways; an immunomodulatory subgroup defined by immune cell surface antigens, receptors, and signal transduction genes; and a luminal subgroup driven by androgen-receptor signaling.

"Using tumor gene-expression signatures, we identified representative cell lines to model each of the subgroups and also pharmacologically targeted prominent signaling pathways," he said.

Through the treatment of xenografts of these triple-negative breast cancer tumor subtypes, they found that basal-like triple-negative disease is sensitive to cisplatin, mesenchymal-like triple-negative breast cancers may preferentially respond to Src and PI3K/mTOR inhibitors, and the luminal subtype is sensitive to the androgen-receptor antagonist bicalutamide and to HSP90 inhibitors.

"The data generated in this study have significant value for target selection in drug discovery, clinical trial design, and selection of biomarkers that will enable the alignment of patients with triple-negative breast cancer to the appropriate targeted therapy," Dr. Lehmann said.

Subtypes with Good Prognosis

Similarly, German investigators evaluated 28 breast cancer datasets and identified a dozen molecular phenotypes upon 579 triple-negative breast cancer samples.² This is the largest analysis of all available gene-expression data on triple-negative breast cancer, according to Achim Rody, MD, of Goethe University, Frankfurt, Germany.

"Triple-negative breast cancers represent molecularly and clinically distinct subtypes," Dr. Rody said. The analysis showed 73% to be basal-like tumors. The rest were classified into phenotypes according to gene function, ie, immune activity, angiogenesis, proliferation, apocrine activity, inflammation, and others.

Clinical prognosis was associated with genetic subtype. There were no outcome differences between basal-like tumors and non-basal-like tumors. However, high B-cell (immune system) and low IL-8 (inflammation) metagene expression identified a subset of patients (32% of all tumors) with a favorable prognosis and a 5-year event-free survival of 84%.

"In the multivariate analysis, only the metagene ratio and lymph node status were significant predictors of triple-negative breast cancer in our cohort," he noted, adding that inhibition of the related pathways might provide new therapeutic approaches.

High MYC Signature, Worse Outcomes

Focusing on a single oncogene transcription factor-MYC-investigators from the University of California, San Francisco, demonstrated that triple-negative breast tumors with high expression of MYC had worse clinical outcomes.³

MYC is known to be associated with poorly differentiated aggressive tumors, and the genomic locus is amplified in 20% to 50% of all breast tumors. From gene-expression arrays on 149 patients in the I-SPY trial, MYC was found to be abundant in triple-negative breast cancers. Patients with tumors that had high MYC signatures had worse outcomes in the trial. Disease-free survival at 5 years was approximately 95% for patients with low MYC, compared with 80% in the setting of intermediate expression and 55% with high MYC expression, reported Andrei Goga, MD, PhD.

MYC pathway activation is another predictor of poor outcome beyond triple-negative status. In a multivariate analysis considering receptor status and MYC pathway activation as a continuous variable, triple-negative status carried a hazard ratio of 1.5, but the hazard ratio for MYC pathway activation is 16.7, he said.

The MYC pathway can be targeted via inhibition of cyclin-dependent kinase (CDK1), which upregulates the proapoptotic Bcl2 family member BIM. Exploiting the synthetic lethal interaction between MYC overexpression and

CDK1 inhibition induces cell death in triple-negative breast cancer cells and regression of tumor xenografts. The CDK1 inhibitor SCH-727965, currently in phase II trials, has shrunk tumors in mouse models of triple-negative breast cancer. ■

References

1. Lehmann BD, Bauer JA, Chen X, et al: Transcriptome analysis of triple negative breast cancers identifies six distinct biological subgroups and reveals therapeutic strategies. 33rd Annual San Antonio Breast Cancer Symposium. Abstract PD01-07. Presented December 9, 2010.

2. Rody A, Karn T, Liedtke C, et al: Identification of a clinically relevant gene signature in triple negative and basal-like breast cancer. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S5-5. Presented December 11, 2010.

3. Goga A, Horiuchi D, Kusdra L, et al: Synthetic-lethality of triple-negative breast cancers via the MYC oncogene pathway. 33rd Annual San Antonio Breast Cancer Symposium. Abstract S5-4. Presented December 11, 2010.