What is meant by targeted therapy?

The meaning of the term targeted therapy is open to wide interpretation. At its most basic level, targeted therapy might simply imply that a drug has a specific molecular target, but this is a very low-level definition, because all therapeutic agents have molecular targets. Saying that a taxane targets microtubules and is therefore targeted therapy renders the concept essentially trivial and meaningless.

Instead, the authors previously suggested that targeted therapy should have a broader and more inclusive meaning. Useful elements in defining targeted therapy might include the following:

• 1.
  

  The drug has a specific molecular target, which is the lowest level of meaning for targeted therapy. However, the idea is implied that the target should be a relatively specific one (ie, the more promiscuous the agent in its molecular targets, the less it should be considered a targeted therapy.

  
  
• 2.
  

  The target is biologically relevant (eg, part of the malignant phenotype) for specific cancers. The estrogen receptor (ER) is biologically relevant to the growth of specific human breast cancers, as is HER2. Replicating DNA is relevant to the malignant phenotype but is nonspecific (rendering most chemotherapeutics poor examples of targeted therapy).

  
  
• 3.
  

  The target is reproducibly measurable in individual patients. Tamoxifen is useful because estrogen receptor can be measured. Trastuzumab is useful because HER2 can be measured with some reliability using immunohistochemistry or fluorescence in situ hybridization. The robustness of the ability to assay a target therefore becomes of crucial importance. However, this does not necessarily imply that the target must always be measured. For instance, the presence of a B-cell lymphoma or of a chronic myelogenous leukemia routinely indicates the presence of the molecular target for these tumors.

  
  
• 4.
  

  The presence of that measurable target correlates with clinical benefit when the therapy is used. A targeted therapy used for every patient with breast cancer by definition cannot be targeted in any meaningful sense. Hormonal therapy only benefits patients who are estrogen receptor–positive, and trastuzumab’s real benefits are (probably) confined to patients with HER2-positive cancers.

Targeted therapy in the context of genomics

One of the profound revolutions in the understanding of breast cancer occurred in the past decade, with the realization that breast cancer was not a single disease but rather several diseases that happened to arise from the same organ. The new technology of cDNA microarrays allowed the examination of large numbers of expressed genes in human breast cancer. Bioinformatic exploration of relatively large patient cohorts for outcome end points such as disease-free and overall survival in the context of gene expression followed rapidly.

It became obvious breast cancer was, from a genetic standpoint, a collection of diseases. Unsupervised cluster analysis defined luminal, basal, cerbB2+, and “normal” breast subtypes (though the “normal” subtype may prove to have been artifactual). The luminal cancers (so called because their expression profile resembled that of luminal cells of milk ducts) were further divisible into A and B subtypes. These subtypes paralleled clinical subtypes long recognized by physicians. Luminal cancers show substantial overlap with ER-positive tumors, and, in their A and B subtypes, relatively hormone-sensitive and -insensitive ER-positive breast cancers. Basal cancers, in contrast, overlap with what so-called triple-negative” breast cancers (ER-, progesterone receptor [PR]–, and HER2-negative), and c-erbB2– (HER2) positive tumors were self-explanatory. Although clinicians might believe that unsupervised cluster analysis “told us what we already knew,” when these studies first became available physicians rarely considered basal tumors a biologically distinct subset, nor were they aware of distinct genomic subsets within the luminal (ER-positive) subgroup.

From a therapeutic standpoint, and for the point of this article, this genomic clustering offers an underlying biologic rationale for the basic approaches to systemic therapies in breast cancer, and more specifically for targeted therapy of breast cancer. We will not focus on hormonal therapy as a targeted therapy (although ER-targeted therapies are arguably the first targeted therapy in all of cancer medicine), but will instead focus on other existing and novel molecular targets with potential adjuvant benefits for early-stage breast cancer.

Targeted therapy in the context of genomics

One of the profound revolutions in the understanding of breast cancer occurred in the past decade, with the realization that breast cancer was not a single disease but rather several diseases that happened to arise from the same organ. The new technology of cDNA microarrays allowed the examination of large numbers of expressed genes in human breast cancer. Bioinformatic exploration of relatively large patient cohorts for outcome end points such as disease-free and overall survival in the context of gene expression followed rapidly.

It became obvious breast cancer was, from a genetic standpoint, a collection of diseases. Unsupervised cluster analysis defined luminal, basal, cerbB2+, and “normal” breast subtypes (though the “normal” subtype may prove to have been artifactual). The luminal cancers (so called because their expression profile resembled that of luminal cells of milk ducts) were further divisible into A and B subtypes. These subtypes paralleled clinical subtypes long recognized by physicians. Luminal cancers show substantial overlap with ER-positive tumors, and, in their A and B subtypes, relatively hormone-sensitive and -insensitive ER-positive breast cancers. Basal cancers, in contrast, overlap with what so-called triple-negative” breast cancers (ER-, progesterone receptor [PR]–, and HER2-negative), and c-erbB2– (HER2) positive tumors were self-explanatory. Although clinicians might believe that unsupervised cluster analysis “told us what we already knew,” when these studies first became available physicians rarely considered basal tumors a biologically distinct subset, nor were they aware of distinct genomic subsets within the luminal (ER-positive) subgroup.

From a therapeutic standpoint, and for the point of this article, this genomic clustering offers an underlying biologic rationale for the basic approaches to systemic therapies in breast cancer, and more specifically for targeted therapy of breast cancer. We will not focus on hormonal therapy as a targeted therapy (although ER-targeted therapies are arguably the first targeted therapy in all of cancer medicine), but will instead focus on other existing and novel molecular targets with potential adjuvant benefits for early-stage breast cancer.

HER2-targeted therapy

The HER family of receptor tyrosine kinases plays an important role in breast cancer biology. These transmembrane receptor tyrosine kinases have a standard motif comprising an external (ligand-binding) domain, a transmembrane domain, and an internal tyrosine kinase domain. HER2 particularly has long attracted the attention of scientists because of its profound effect on tumor biology in the tumors in which it is amplified (approximately 15%–20% of patients with breast cancer). HER2 drives growth, invasion, and metastasis of breast cancers, and in the past its presence in a primary breast cancer was associated with increased risk for, and early death from, breast cancer.

In the mid-1990s, the concurrent development of reliable assays for HER2 overexpression (using immunohistochemistry) and amplification (using fluorescence in situ hybridization), and the development of the first agent targeting HER2 (the humanized monoclonal antibody trastuzumab), led to the first clinical trials specifically targeting HER2 in the metastatic setting. In a pivotal phase III trial in the front-line metastatic breast cancer setting, Slamon and colleagues showed that addition of trastuzumab to standard chemotherapy regimens improved both progression-free and overall survival.

This demonstration of the benefits of targeted therapy for HER2-positive metastatic disease led rapidly to the development of adjuvant therapy trials for HER2-positive early-stage breast cancer. Several large trials testing HER2-targeted therapy in the adjuvant setting have been presented, and provide stunning confirmation for the benefits of targeted therapy in the context of HER2-positive breast cancer. Two North American studies, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the North Central Cancer Treatment Group (NCCTG)–coordinated Intergroup trial N9831, merged their chemotherapy control arms (doxorubicin and cyclophosphamide followed by paclitaxel) in a comparison with the same regimens plus a year of trastuzumab for a joint analysis. They reported a highly significant 49% reduction in the risk for disease recurrence with sequential trastuzumab (4-year disease-free survival, 86% vs 73%; hazard ratio [HR], 0.51) and a 37% reduction in the risk of death (4-year overall survival, 93% vs 89%; HR, 0.63).

These results were confirmed by the Herceptin Adjuvant (HERA) trial, in which 5090 women with HER2-positive (node-negative or -positive) early breast cancer underwent standard adjuvant chemotherapy and then were randomly assigned to either observation or the addition of trastuzumab for 1 or 2 years after completion of the cytotoxic chemotherapy regimen chosen by their oncologist. A significant reduction in disease-free survival (36%) and a significant improvement in overall survival (34%) was reported.

Subsequently, the BCIRG 006 study examined the role of non–anthracycline-based chemotherapy in combination with trastuzumab. Patients receiving trastuzumab in the context of anthracycline-based chemotherapy clearly experience an increased risk for congestive heart failure, and preclinical studies have suggested that non–anthracycline-based combinations had significant activity. The Breast Cancer International Research Group (BCIRG) 006 trial compared two anthracycline-containing regimens (doxorubicin/cyclophosphamide [AC] followed by docetaxel with or without trastuzumab) versus a non–anthracycline trastuzumab combination (carboplatin plus docetaxel and trastuzumab [CTH]) in 3222 women with HER2-positive early breast cancer. Both trastuzumab-containing arms were superior to the non-trastuzumab arm, and no significant efficacy difference between the 2 trastuzumab-containing arms was observed (with an HR for disease-free survival of 0.67 and 0.61 for AC/docetaxel/trastuzumab and TCH, respectively).

The debate regarding the benefit of anthracyclines in HER2-positive breast cancer continues to vex oncologists. It was first hypothesized that HER2-positive tumors are more sensitive to anthracyclines. However this was not confirmed in the preclinical setting. Pegram and colleagues tested the sensitivity of HER2-overexpressing cell lines to doxorubicin and found that HER2 overexpression alone did not predict for doxorubicin sensitivity. More recently, the topoisomerase II alpha gene amplification was also studied, given anthracyclines’ principle role as topoisomerase II alpha inhibitors. The topoisomerase II alpha gene is located on the long arm of chromosome 17 near the HER2 gene. Topoisomerase II alpha amplification correlates strongly with HER2 overexpression. Several retrospective studies in the metastatic setting suggested that topoisomerase II alpha amplification is a predictor of anthracycline response, and results of the control arm of the BCIRG 006 adjuvant trial (ie, in the absence of trastuzumab) seemed to confirm this. Because BCIRG 006 was not powered to compare anthracycline and non–anthracycline trastuzumab-containing regimens, no solid prospective data show which approach (if either) is preferred. Both anthracycline and non-anthracycline approaches fall within the current standard of care.

The proper duration of treatment in the adjuvant setting remains unanswered. The four larger clinical trials (NSABP B-31, N9831, HERA, and BCIRG 006) have used at least 1 year of adjuvant trastuzumab. The results of the HERA trial arms of 1 versus 2 years of adjuvant trastuzumab are awaited. In contrast, the smaller FinHer trial suggested that as little as 9 weeks might provide the same efficacy with less toxicity, which in turn has led to trials examining a shorter duration of therapy. Current practice uses a standard 1-year regimen.

Although trastuzumab-based regimens remain the standard of care in the adjuvant HER2 setting, newer agents have entered the HER2 arena. Lapatinib is an oral small molecule receptor tyrosine kinase inhibitor of both epidermal growth factor receptor and HER2. Preclinical data suggest that it is synergistic with trastuzumab against HER2-positive breast cancer. It was recently approved for advanced HER2-positive metastatic breast cancer, because it showed activity in trastuzumab-refractory metastatic disease in combination with capecitabine in a large phase III randomized trial. Lapatinib’s role is currently being examined in the adjuvant setting in the international, multi-group Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, which randomizes patients undergoing standard chemotherapy approaches to receive either trastuzumab, lapatinib, the combination of the two drugs, or their sequential use.

Novel approaches: anti–vascular endothelial growth factor therapy

Evidence for a role of angiogenesis (new blood vessel formation) in breast cancer is derived from several independent lines of evidence. Beginning in the early 1990s, evidence emerged that tumor microvessel density in human breast cancers was associated with an increased risk for relapse and death. Proangiogenic factors are readily measurable in early breast cancers, and vascular endothelial growth factor (VEGF) in particular is associated with an increased risk for recurrence and death in patients with early-stage breast cancer. Increased VEGF production by breast cancers is also associated with an increased risk for brain and visceral metastasis. HER2 amplification is also associated with increased VEGF production in human breast cancers, suggesting this important breast cancer subtype as a particular target of interest.

The improved understanding of VEGF biology suggested several potential means of targeting the VEGF system. The VEGFs are a family of five related glycoproteins (VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor) that act through three type III receptor tyrosine kinases (VEGFR-1, VEGFR2, VEGFR-3); in addition the neuropilins (NP1 and NP2) act as coreceptors for the VEGFRs, increasing the binding affinity of VEGF to VEGFR tyrosine kinase receptor. The functional effects of VEGF depend on which ligand-receptor complex is activated.

The VEGF axis may be attacked in multiple ways, including (among FDA-approved agents) ligand-binding agents (eg, bevacizumab), agents interfering with the VEGF receptor tyrosine kinase (eg, sunitinib, sorafenib), agents interfering with downstream effectors of VEGF activity (eg, mammalian target of rapamycin [mTOR] inhibitors), and agents that indirectly affect angiogenesis through modulation of VEGF production (eg, HER2-targeting agents).

Of these approaches, ligand inhibition with bevacizumab is currently the only FDA- and European Medicines Agency (EMEA)–approved agent for metastatic breast cancer. This approval is based on two randomized controlled trials. E2100 randomized women to receive paclitaxel alone or in combination with bevacizumab as front-line therapy for HER2-negative metastatic disease, and the AVADO trial randomized a similar patient population to receive docetaxel alone or in combination with bevacizumab at one of two doses. Both trials showed a statistically significant improvement in progression-free survival. Neither showed a significant improvement in overall survival, although both were relatively poorly powered to show a survival advantage. Other phase II metastatic trials have suggested that patients HER2-positive advanced breast cancer might benefit from the combination of anti-VEGF therapies with anti-HER2 therapies.

Based on the results in advanced disease, adjuvant trials have been initiated in both HER2-negative and HER2-positive populations. E5103 randomizes women with lymph node–positive and high-risk lymph node–negative disease to receive either a backbone chemotherapy regimen (AC followed by paclitaxel) alone or in combination with bevacizumab (administered either for the duration of chemotherapy or for a total of a year of therapy). The BEvacizumab and Trastuzumab Adjuvant Therapy in HER2-positive Breast Cancer (BETH) trial randomizes patients with HER2-positive breast cancer to undergo either a standard chemotherapy/trastuzumab combination or the same with bevacizumab. Both are large, well-powered trials with primary disease-free survival end points and secondary overall survival end points.

Whether bevacizumab (or other VEGF-targeting agents) can legitimately be called targeted therapy is currently uncertain. Although the molecular target (VEGF) is well defined and readily measurable, a specific subpopulation benefiting from anti-VEGF therapy cannot currently be defined. Early investigations suggested that specific single nucleotide polymorphism variants of VEGF may be associated with clinical benefit in the metastatic setting, an observation that is currently being examined as part of the large E5103 adjuvant bevacizumab proof-of-concept trial.

Concerns have been raised regarding the potential benefits of anti-VEGF therapy in the adjuvant setting. The vasculature of micrometastases and overt metastases may differ significantly, and therefore benefits seen in the overt metastatic setting may not translate to the adjuvant setting. Preclinical studies in some animal models of micrometastatic disease have suggested that anti-VEGF therapy may actually promote the development of metastases, although these models are open to question on several grounds. Finally, the adjuvant colorectal NSABP C-08 trial failed to show a statistically significant clinical benefit regarding its primary disease-free survival end point. The results of ongoing adjuvant bevacizumab trials are therefore awaited with some trepidation.