Triple-negative breast cancer has recently received much media attention with the publication of the Cancer Genome study in Nature with its molecular characterization and relation to ovarian cancer (2012;490:61-70). At this year's San Antonio Breast Cancer Symposium, ER-positive breast cancer still took front stage, where the most talked about and potentially practice-changing news was the findings from the ATLAS study of adjuvant tamoxifen and updated results for large trials focusing on HER2 disease. As for triple-negative metastatic breast cancer (TN MBC), though, unfortunately there was no major practice-changing news. Rather, the spotlight was on the continued quest to better understand the molecular driver pathways of triple-negative disease and identify therapeutic targets.
Three major impressions from this year's meeting with respect to TN MBC:
1. There were no practice-changing key findings from large trials: The majority of the large trials presented in the oral and poster sessions focused on ER-positive (e.g., ATLAS and LEA) and HER2-positive ( e.g., HERA and PHARE) or neoadjuvant/adjuvant (BEATRICE) trials. TN MBC was addressed in subset analysis in the “Phase III, Open-Label, Randomized, Multicenter Study of Eribulin Mesylate Versus Capecitabine in Patients with Locally Advanced or Metastatic Breast Cancer Previously Treated with Anthracyclines and Taxanes” oral presentation (S6-6).
This study involved 1,102 patients with locally advanced or metastatic breast cancer with three or fewer prior chemotherapy regimens, and with prior taxane and anthracycline exposure. Patients were randomized to either eribulin or capecitabine at the FDA-approved doses and schedules. The study found no significant increases in either progression-free or overall survival, although there was a trend toward improved overall survival or eribulin—15.9 vs. 14.5 months (HR = 0.879, p = 0.056). This observation is reminiscent of the overall result in the EMBRACE trial comparing eribulin with treatment of physician's choice, but warrants further study.
2. Targeting “BRCAness” in Triple-Negative Metastatic Breast Cancer: This year's oral and poster presentations continued on the theme of targeting “BRCAness” in TN MBC, exploiting the feature of DNA repair deficiency with use of platinum chemotherapy and inhibitors of poly-ADP-ribose polymerase (PARP).
Phase I and II trials were reported evaluating the use of platinum in combination with other agent(s). A Phase II trial of RAD 001 (oral mTOR inhibitor) and carboplatin in TN MBC preliminarily reported a clinical benefit rate of 41 percent, with mature analysis still pending (P5-20-01).
Additionally, there was a proposed approach to create “BRCAness” with the addition of other agents such as a histone deacetylase (HDAC) inhibitor in triple-negative disease motivated by preclinical data (S3-7), with other reports of biomarker studies to define a group of patients who may benefit from this therapeutic approach. The impact of BRCA1/2 mutational status with respect to outcome was examined among TN MBC patients in the TBCRC009 multicenter Phase II trial of cisplatin or carboplatin (whose initial preliminary result was reported at the ASCO 2011 Annual Meeting).
An exploratory analysis showed that 11 patients with BRCA1/2 mutations had higher relative risks than the 65 patients with BRCA wild-type (54.6% vs. 26.2%, p = 0.0506) (PD09-03) did, but there was no difference in progression-free survival. Another study proposed that perhaps “BRCAness” in TN disease may also be evaluated by the level of BRCA expression or epigenetic gene-silencing status, which may explain how sporadic (non-BRCA mutation associated) TN disease may respond to platinum therapy.
Sharma et al presented a study analyzing BRCA ‘insufficiency’ (which was defined as low BRCA expression level or promoter methylation) in addition to BRCA mutational status to predict after platinum therapy among triple-negative patients who underwent neoadjuvant therapy (PD09-02). In this study, “BRCA insufficient” TN patients had improved overall survival. At a median follow-up of 48 months, the overall survival rate was 91 percent for BRCA1-insufficient patients compared with 56 percent for BRCA1-sufficient patients (p = 0.025) (PD09-02).
The key to this therapeutic approach may be that we need to better define and select those subsets of TN patients whose disease is driven by “BRCAness.”
3. Exploring molecular pathways for new therapeutic targets: Driven by advances in molecular genomic data, the evaluation of different pathways for therapeutic targets in TN MBC was a major focus of research at the meeting.
There were several targetable pathways that appeared to be associated with TN. Justin Balko in an oral presentation nicely summarized potential target pathways by examining residual disease following neoadjuvant chemotherapy for non-metastatic TNBC. These included components of the PI3K/mTOR pathway (including PTEN, PI3K), DNA-repair pathway (BRCA1/2), RAS/MAPK pathway (with RAF/MEK targets), cell cycle regulators (potentially targetable with CDK inhibitors, aurora kinase inhibitors), and growth factor receptors (EGFR, FGFR4, IGFR, MET).
Examples of trials that are ongoing with targeted therapies include a multicenter Phase II trial of BKM120 (oral PI3K inhibitor) and a multicenter randomized Phase II trial of tivozanib with paclitaxel (OT2-3-06 and OT2-3-11). Additionally, Ron Bose presented data on HER2-mutational analysis among HER2-negative (IHC, FISH) patients where preclinical data suggest a potential for HER2-targeted therapy among this population, with a planned multicenter Phase II trial of neratinib based on mutational analysis (S5-6). The importance of these pathways and mutations as major oncogenic drivers in TN MBC await further clarification in ongoing trials.
Overall, it is encouraging to note steady progress toward unraveling the key molecular pathways that drive various subtypes of triple-negative metastatic breast cancer. This will hopefully lead to less toxic targeted therapy better matched to specific subgroups of patients who will derive the most benefit.
It is increasingly important for clinicians to keep current with molecular genetic as it translates into patient-care settings. The molecular pathways cannot remain in the realm of research laboratories, or as nostalgic mementos of our collegiate and medical school educations. Clinical medical oncologists are at the front line to inform and educate patients who may be interested in participating in the clinical trials that are instrumental to our breaking the therapeutic barriers that currently exist in this molecular subtype of breast cancer.