[BLOG]: Emerging targets in triple-negative breast cancer

Triple-negative breast cancer (TNBC) represents just under 15% of all breast cancer (BC) cases, according to IMS’ epidemiologic analysis. It carries a bleaker prognosis than other forms of BC. These facts are well-known. Much else about the disease is unknown, however; indeed, it’s probably a mistake to think of TNBC cancer as “a” disease at all.

TNBC tumors are “triple” negative because their cells lack estrogen receptors, progesterone receptors, and the HER2 oncogene. Where these biomarkers are present, BC can be handled with antiestrogenic therapies or anti-HER2 monoclonal antibodies (MAbs). But when it comes to TNBC, oncologists have no FDA-approved targeted drugs in their arsenal; just chemotherapy, which has limited success against metastatic TNBC.

Genotyping is beginning to unlock the molecular secrets of TNBC. This analysis will eventually locate new druggable targets. But it’s doubtful that these will be broad targets; instead, the emerging picture is one of confusing variety. It’s not going to be a one-size-fits-all solution for TNBC but rather a variety of different approaches, each tailored to a different subgroup within the patient pool.

Consider the poly ADP ribose polymerase (PARP) inhibitors. A few years ago, targeting PARP was believed to be a potential game changer in TNBC. These hopes were dashed when Sanofi’s iniparib failed to meet its clinical endpoint in a phase 3 trial in 2011. Nevertheless, the concept has been revived, and 4 companies (AbbVie, AstraZeneca, BioMarin, Tesaro) now have PARP inhibitors in phase 3 development.

But these new trials are ignoring most of the TNBC population and focusing in on the small subset of TNBC patients with germline mutations in the BRCA1 and BRCA2 genes. Blocking PARP in these patients may indeed bring game-changing results against tumor cells.

The catch? These patients are a small minority of the TNBC population; perhaps 15%, according to an analysis published at the American Society of Clinical Oncology (ASCO) 2014 meeting.¹ A larger proportion of TNBC patients may have mutations somewhere in the BRCA pathway and thus also be potential responders. But PARP inhibitors, if approved, will certainly be niche medicines. This approach can yield fruit: in lung cancer, Pfizer successfully markets its ALK-inhibitor Xalkori (crizotinib), although the relevant mutation is seen in only about 5% of patients. This approach, however, depends on precise patient stratification based on reliable biomarkers and companion diagnostics.

Another current pivotal trial in TNBC is that of Celldex’s antibody-drug conjugate glembatumumab vedotin (CDX-011), which binds to the proprietary antigen glycoprotein (gp)NMB. Celldex’s trial is focused on a gpNMB-overexpressing subset of TNBC patients. It is difficult to gauge how much of the patient population would fall into this subset. If glembatumumab vedotin achieves major clinical gains, testing for this antigen could conceivably become common practice.

What of targets with potentially wide scope in TNBC? One possibility is the androgen receptor. Although estrogen and progesterone receptors have traditionally formed the focus for hormonal therapy in BC, androgen receptors are believed to be present in an even larger subset of patients. What’s more, antiandrogen therapy is already established as a key tool for managing prostate cancer.

So the drugs (eg, Xtandi [enzalutamide], Astellas and Medivation) already exist and have reached phase 2 in BC trials. TNBC is the likely development focus within BC, because the other TNBC treatment options are poor. Data are limited so far, but the androgen receptor is definitely on the radar as a molecular target. Oncologists report that they are already informally testing for the receptor in the diagnostic work-up (although some have said it is less prevalent than the literature would suggest).

Another new target firmly on the radar across the oncology world is programmed death receptor-1 (PD-1). After sensational early clinical trial results the first 2 PD-1 inhibitors, Merck’s Keytruda (pembrolizumab) and Bristol-Myers Squibb’s Opdivo (nivolumab), are already available in certain markets. By binding PD-1, these drugs can enable the immune system to mount an attack on tumor cells, which seems highly effective in malignant melanoma, a particularly immunogenic tumor type.

PD-1 inhibitors are also moving rapidly toward approval in solid organ tumors, starting with lung cancer. Oncologists are anticipating a major impact in TNBC, but only limited early data are available so far. Here, there is no clear biomarker that might delineate the patients who will respond best. Although PD-ligand 1 (PD-L1) is being used as a biomarker in certain trials, the parameters for PD-L1 presence are defined differently by various parties with no consensus on a meaningful threshold.

The ability to better subset TNBC might also lead to a more effective redeployment of the existing drug arsenal. Roche’s Avastin (bevacizumab) is believed to have some limited efficacy in TNBC, but the drug may have high efficacy in a particular patient subset yet to be identified from the data. Results published at the European Society for Medical Oncology (ESMO) 2014 meeting hinted that the MAb could play an effective role in maintenance therapy or increase the effectiveness of chemotherapy in metastatic disease.²

Particular chemotherapies may also come to the fore in certain TNBC patient subsets; for example, there is some evidence that platinum-based chemotherapy may be optimal for TNBC patients with BRCA mutations.

Many such hints are now accumulating in the clinical literature for TNBC, but at present the gloomy prognosis and the unmet need remain. The increasingly subtle elucidation of the disease’s complex heterogeneity, however, is beginning to allow us for the first time to know our enemy. TNBC is currently defined by what it is not; soon we may begin to understand what it is and how best to fight it.

Mr Evans is an oncology specialist with IMS Health Disease Analytics.

References

1. De Greve J, De Brakeleer S, Desmedt C, et al. Frequent BRCA1/2 and BARD1 germline mutations in triple-negative breast cancer patients. J Clin Oncol. 2014;32(suppl; abstr 1107):5s.

2. ESMO 2014. Efficacy and safety of bevacizumab in the randomised phase III IMELDA and TANIA clinical trials. European Society for Medical Oncology (ESMO) 2014 Congress. Madrid, Spain. September 28, 2014.

http://www.esmo.org/Conferences/ESMO-2014-Congress/News-Articles/Bevacizumab-Maintenance-in-HER2-Negative-Metastatic-Breast-Cancer. Accessed October 20, 2014.

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