Down the Road for Breast Cancer

Introduction

Breast cancer, the most common malignancy in developed countries, manifests most often in women, but in rare instances can also occur in men.^1,2The National Cancer Institute estimates that in 2012, more than 225,000 new breast cancer cases in women and 2000 cases in men will occur, as well as 39,510 deaths attributed to breast cancer in women and 410 deaths in men.¹Due to improved screening and available treatment options, the 5-year survival rate for women diagnosed with breast cancer between 1999 and 2006 was 90%, compared with 75% for those diagnosed between 1975 and 1977.³Despite this increase in survival, advancements in the treatment of breast cancer are still needed. Forthcoming treatments for patients with breast cancer include new monocolonal antibodies, new tyrosine kinase inhibitors (TKIs), and progesterone receptor antagonists, among others which are currently being investigated in clinical trials.

Breast cancer develops in breast tissue, primarily the mammary gland ducts and lobules.¹Approximately 20% of regional stage disease cases will advance to metastatic breast cancer (MBC).²For patients with MBC, available treatment options include chemotherapy, endocrine therapy, monoclonal antibodies targeting growth factors, and TKIs, in addition to supportive measures.2 MBC is not considered a curable disease; therefore, goals of treatment include improving quality of life, prevention and palliation of symptoms, reduction of drug-related toxicities, and prolongation of survival.^2,4Several factors must be considered when choosing a treatment regimen. These factors include estrogen receptor (ER) and progesterone receptor (PR) status, human epidermal growth factor receptor (HER) 2/neu status, duration of the relapsefree interval since primary diagnosis and since completion of adjuvant therapy for breast cancer, location and extent of metastases, previous treatments used (Were they effective? Were they tolerated by the patient?), patient symptoms, patient preferences, expected adverse effects, and availability and access to treatments.²

Monoclonal Antibodies

Monoclonal antibodies being investigated for breast cancer include agents targeting vascular endothelial growth factor (VEGF), HER2, and CD3. HER2 is one of several receptors that its downstream signaling pathways promote cell proliferation and survival.⁴Overexpression of HER2 occurs in approximately 15% to 20% of breast cancers and has been linked to poor clinical outcomes. However, this has made it an attractive target for research and drug development.⁴Use of monoclonal antibodies engineered to target the HER2 receptor has been a particularly successful approach in the treatment of breast cancer. Specifically, the development of trastuzumab has been a significant advance represented in the treatment of breast cancer; however, cardiac toxicity, tumor resistance, and lack of effect on brain metastases limit its utility in therapy.

Further research has expanded the focus on the entire family of epidermal growth factor receptors (EGFRs) and signal transduction mechanisms. Another monoclonal antibody under development is pertuzumab, which has been characterized as a HER dimerization inhibitor and interacts with a different binding site than that of trastuzumab.⁵Dimerization between HER2 and HER3 has been shown to promote tumor progression through signal transduction via the PT3K/AK7 pathway.⁵Initial phase I and II trials evaluating pertuzumab showed it was well tolerated along with demonstrating positive results in trastuzumab-refractory patients.⁵Additionally, synergistic results were observed in another phase II trial using pertuzumab in combination with trastzumab.⁵The clinical evaluation of pertuzumab and trastuzumab (CLEOPATRA) is an ongoing, phase III randomized, double-blind, placebo-controlled trial evaluating the efficacyand safety of adding pertuzumab to current standard of care in patients with HER2-positive MBC in previously untreated patients with breast cancer.^5,6Hopefully, results from this study will shed more light on the effect of this agent.

As mentioned above, resistance to trastuzumab has remained a difficult therapeutic challenge to overcome in the treatment of breast cancer. In development is a unique agent that combines the fungal toxin DM1 (maytansine) and trastuzumab through a chemically derived conjugation.⁵This novel approach has given renewed

hope to improving outcomes and overcoming resistance. The mechanism of action of this drug does not rely on signal transduction, but simply the overexpression of HER2.⁵Trastuzumab primarily acts as a carrier agent to deliver maytansine, which is a potent cytotoxic agent acting as an inhibitor of cellular microtubule assembly.⁵Multiple phase II and phase III trials are under way. A phase II trial comparing trastuzumab-DM1 with trastuzumab/ docetaxel has reported preliminary results. While relative risks were comparable between the 2 arms, recent evidence suggests progression-free survival (PFS) was significantly longer in the trastuzumab- DM1 study group. Further research is ongoing with 2 phase III trials studying trastuzumab-DM1 in patients with MBC. EMILIA is an open-label study evaluating capecitabine (CAP)/lapatinib against trastuzumab-DM1 in patients that have previously received trastuzumab.⁷In another approach, MARIANNE is a phase III trial studying 3 treatment groups as firstline therapy for HER2-positive MBC. One treatment group includes the use of trastuzumab plus a taxane with the second utilizing trastuzumab-DM1 and pertuzumab. The final treatment group will examine the use of trastuzumab-DM1 alone.⁸

Two additional monoclonal antibodies under development include ramucirumab and ertumaxomab. Ramucirumab blocks the interaction between all known VEGFs and VEGFR-2, which has been shown to inhibit angiogenesis and tumor growth in preclinical studies with VEGF-A.⁹In contrast to bevacizumab that targets only VEGF-A, ramucirumab could theoretically inhibit angiogenesis more effectively. Additionally, it is believed that the toxicity profile for ramucirumab will be more favorable due to its specificity and lack of off-target toxicities as seen with the TKIs. The primary side effects that have been identified include hypertension, vascular thrombotic events, and

proteinuria, which are consistent with other agents targeting this same pathway. 9 Ongoing studies of ramucirumab include phase II studies evaluating ramucirumab/CAP and ramucirumab/eribulin as well as a phase III randomized, doubleblind study evaluating PFS of ramucirumab/ docetaxel compared with docetaxel monotherapy in treatment-naïve patients with HER2-negative, unresectable, locally recurrent breast cancer or MBC.^10-12Ertumaxomab has been developed to target both HER2 receptors and the CD3 antigen that is expressed on T-cells. Aggregation and activation of T-cells, macrophages, dendritic cells, and natural killer cells results from the formation of the HER2- ertumaxomab-CD3 complex.⁵This leads to tumor cell death via phagocytosis, and phase I studies have demonstrated a wide range of activity against HER-2—positive cell lines.5 Phase II trials in MBC in patients that had already received trastuzumab further support the evaluation of ertumaxomab in future studies.5 In this study median time to progression (TTP) was 65.5 days. Most adverse effects were mild or moderate, usually resolving in 1 day. The most frequently observed adverse effects were pyrexia, headache, chills, and vomiting.¹³

Insulin-like growth factor type-1 receptor (IGF-1R) aids cell proliferation and survival and is overexpressed in many tumor types.¹⁴Cixutumumab is an IGF-1R monoclonal antibody. Researchers believe combining cixutumumab with mammalian target of rapamycin (mTOR) inhibitors may enhance the effects of mTOR inhibition. A phase I study evaluating the tolerability and activity of the mTOR inhibitor temsirolimus with cixutumumab demonstrated the combination was tolerable in patients with advanced cancer.¹⁵An ongoing phase II study is investigating whether cixutumumab with or without antiestrogen therapy increases PFS in patients with hormone receptor (HR)-positive advanced breast cancer (ABC) or MBC who have progressed disease on antiestrogen therapy.¹⁶

Tyrosine Kinase Inhibitors

In 2007, the US Food and Drug Administration (FDA) approved lapatinib, the first TKI for use in ABC or MBC in combination with CAP.^17,18Since that time, there has been intense study utilizing this drug class. Research has resulted in numerous targets being identified.¹⁹Although significant results have been seen with response rate (RR), PFS, and TTP, improvements in overall survival (OS) have not improved with the addition of lapatinib to therapeutic regimens. Understanding the complex nature of cancer and signaling pathways, it is not unexpected that redundant mechanisms exist that can overcome targeted inhibition using a single agent.²⁰Using combinations to avoid dose-limiting toxicities, metronomic dosing, and single agents targeted at multiple receptors are all strategies under review to improve effectiveness and ultimately OS. Due to their small molecular weight, many of the TKIs theoretically can cross the blood-brain barrier, unlike larger monoclonal antibodies such as trastuzumab.¹⁷This pharmacokinetic advantage is being studied in patients specifically with brain metastasis.¹⁷

Afatinib and neratinib utilize the same targets as lapatinib, but in contrast to lapatinib irreversibly bind and inhibit the EGFR and HER2 receptors.20 In theory, they have a therapeutic advantage, as kinase activity would be eliminated until a new receptor could be created.²⁰Both drugs are currently in phase III development with favorable results from phase II studies.²¹Both drugs are orally active and share diarrhea as the primary dose-limiting toxicity. However, it should be noted that dose-limiting skin rashes were also associated with afatinib.²⁰

Other targets of TKIs being heavily studied are the VEGF family of receptors in an attempt to halt angiogenesis.²²Angiogenesis is believed to be integral to the growth and metastasis of solid tumors based on the theory that neovascularization is necessary to support oxygen and nutrient needs.²²Unfortunately, recent phase III studies involving sunitinib showed either inferior or comparable outcomes with increased toxicities, such as anorexia, fatigue, mucositis, diarrhea, and nausea.^22,23These results have effectively halted drug development for MBC.^22,23Although these initial results have been discouraging, other VEGFR inhibitors have shown promise in recent trials. Sorafenib is an orally bioavailable pan-VEGFR inhibitor that also inhibits RAF kinase and platelet-derived growth factor receptor (PDGFR), giving it both antiproliferative and anti-angiogenic properties.²²In early trials studying patients with breast cancer who had been previously treated, it was shown to have limited effectiveness as the sole therapeutic agent. However, in combination with other chemotherapeutic agents, phase IIb trials showed significant improvements in overall outcomes.²²

Additional VEGF inhibitors under investigation include pazopanib and axitinib. Both molecules have proven inhibitory activity against all identified forms of VEGFR, as well as PDGFR and c-KIT. Results from a recent phase II trial in combination with docetaxel in patients with MBC showed significant improvements in RR, but failed to show a significant difference in median TTP against placebo.^21,22Pazopanib, another multi-target TKI, is being evaluated in combination with lapatinib in a phase II trial as a first-line therapy for HER2-positive breast cancer and in a phase III trial for HER2- positive inflammatory breast cancer. Initial results from the phase II trial indicate a better RR and 12-week PFS with combination therapy.^21,22A phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with MBC did not demonstrate a statistically significant difference in TTP.²⁴

Other multitargeted TKIs under development include cediranib, motesanib (AMG-706), and vandetanib, but early trials have shown added toxicity with limited results.^21,22Further studies are needed to determine the place of TKIs in breast cancer.

Poly (ADP-ribose) Polymerase Inhibitors

In determining effective cell targets for chemotherapeutic drugs, research has increasingly focused on analysis of the receptor profile of healthy cells versus cancerous cells.²¹The genetic profile and receptor expression of the cancer being treated is becoming more important in determining which drugs will lead to successful outcomes.¹⁸Triple negative breast cancer (TNBC) is one of the more aggressive, lethal, and subsequently difficult to treat cancer subtypes.²⁵Characterized through immunochemistry as lacking the ER, PR, and HER2 genes, TNBC does not respond to mainstay endocrine therapy, leaving limited therapeutic options.^25,26TNBC accounts for approximately 15% of all breast cancers and has been associated with poorer clinical outcomes.^21,25,26Although a small subset of patients respond extremely well to chemotherapy and have a good prognosis, frequently patients relapse and subsequently have a short median time of survival.^25,26As many as 10% of breast cancer cases can be attributed to a hereditary mutation in genes that encode proteins integral to DNA repair, BRAC1 or BRAC2.²¹Patients with mutations in these genes are more likely to have TNBC and are consequently not good candidates for currently available customized therapy.²¹

Poly ADP ribose polymerase 1 (PARP1) is part of a family of enzymes that help maintain genomic integrity in cells.²⁶Inhibitors of this enzyme are under development, as scientific analysis has determined that PARP is upregulated in breastcancer, as well as many other cancers.²¹It is theorized that cancer cells already have defects in 1 DNA repair mechanism, and thus attacking an upregulated compensatory pathway would be an effective treatment strategy. This theory has been validated in preclinical studies involving tumor cell lines with BRAC mutations.^25,26Through inhibition of the PARP enzyme, the strategy known as synthetic lethality is leveraged to cause cell death. Synthetic lethality refers to the situation in which cell death occurs due to the loss of 2 gene products, whereas the loss of one or the other would not have a detrimental effect.^25,27Additionally, PARP inhibition is theorized to enhance the cytotoxicity of DNA, damaging radiation treatment and chemotherapy.²⁵Preclinical studies involving iniparib and veliparib in combination with ionizing radiation, as well chemotherapy such as carboplatin, had supported the theory that PARP inhibitors potentiate the effects of DNA-damaging therapeutic agents.²⁵

Although early phase I and phase II trials involving olaparib, veliparib, and iniparib have all shown promise, results from recent phase III trial involving iniparib in patients with triple negative MBC have been disappointing.^21,25,26Benefit appears to be limited to patients with confirmed BRAC1 or BRAC2 mutations, but further studies will help determine the primary role of PARP inhibitors in breast cancer.²⁶Adverse events that have been reported include nausea and fatigue; however, severe toxicities related to myelosuppression have also been documented.26 Both olaparib and veliparib are orally bioavailable, while iniparib is given intravenously.²⁵

mTOR Inhibitors

Letrozole and anastrozole, both aromatase inhibitors, are the mainstay of therapy in patients with HR-positive ABC in postmenopausal patients. The problem

with these agents is that not all patients will respond to their effects and others ultimately relapse due to acquired resistance.²⁸One potential mechanism of resistance is thought to be due to the mTOR signaling pathway, with evidence suggesting an association involving the mTOR pathway and ER signaling. The mTOR inhibitors are being studied to determine their effect on assisting endocrine therapies to increase their effectiveness. Everolimus, ridaforolimus (formerly deforolimus), and temsirolimus are mTOR inhibitors being studied in breast cancer. A phase III randomized trial of 724 patients with HR-positive ABC with recurrence or progression while receiving an aromatase inhibitor evaluated the effect of everolimus/exemestane versus exemestane monotherapy on PFS. The investigators determined PFS to be increased by 4 months for patients receiving therapy with everolimus/exemestane. At the time the manuscript was submitted it was too early to determine OS; however, at that time 10.7% of patients in the combination group had died, compared with 13% receiving monotherapy.²⁸Based upon the results of this study, everolimus was approved by the FDA in July for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer in combination with exemestane after failing letrozole or anastrozole therapy.²⁹

PIK3CA mutations have been associated with ER-positive breast cancer. An open label phase II study evaluating temsirolimus in patients with MBC hypothesized that patients with a PIK3CA mutation would respond to temsirolimus; however, the results of the study demonstrated a minimal effect in this subset of patients.³⁰Another phase II study that proposed letrozole with 10 mg daily or 30 mg intermittent temsirolimus showed tolerability and clinical activity and early results suggested better PFS with combination arms.³¹Unfortunately, HORIZON, a phase III study evaluating letrozole with temsirolimus, was terminated early because it was believed the combination treatment was unlikely to achieve the targeted level of efficacy compared with letrozole alone.³²Ongoing studies with temsirolimus include a phase I/II study evaluating combination treatment with neratinib in patients with HER2-amplified MBC or TNBC and a phase I/II trial of cixutumumab and temsirolimus in patients with locally recurrent or MBC.^33,34A phase II study involving ridaforolimus with dalotuzumab in ER—positive breast cancer is ongoing.³⁵

Progesterone Antagonists

The role of progesterone in breast cancer is controversial; however, evidence suggests selective PR antagonists may prevent tumor progression. The first PR

antagonist on the market was mifepristone, which is not used for the treatment of breast cancer, but instead termination of intrauterine pregnancy.³⁶Lonaprisan is an orally bioavailable type III PR antagonist that differs from mifepristone due to its purely antagonistic effects. Unlike mifepristone, lonaprisan does not convert to a progesterone agonist when exposed to protein kinase A activators and is highly receptor selective.^37,38An in vitro study demonstrated lonaprisan strongly inhibited cell proliferation of breast cancer cell lines by blocking them in the G0/ G1 phase. Additionally, lonaprisan also induced a biological aging-like phenotype.³⁸A phase II study investigating the efficacy, safety, and tolerability of lonaprisan 25 mg versus 100 mg daily as a second-line endocrine therapy for postmenopausal women with HR-positive MBC randomized 69 patients and was completed in April 2011. The primary end point of the study was not met, thus suggesting lonaprisan had limited activity as second-line endocrine therapy in MBC.³⁹

Pegylated Liposomal Doxorubicin

A study evaluating a non-anthracycline regimen in early HER2-positive breast cancer found estimated disease-free survival rates at 5 years were highest in the group of patients receiving doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks with 52 weeks of trastuzumab.⁴⁰Unfortunately, combination anthracycline plus trastuzumab therapies have been limited due to the cardiotoxic effects of these drugs.⁴¹Pegylated liposomal doxorubicin (PLD) contains doxorubicin molecules encapsulated in a bilayer sphere of lipids, which is surrounded by a dense layer of polyethylene glycol. The size of the liposomes prevents the doxorubicin from entering the heart and gastrointestinal tract and selectively deposits the liposome into the tumor.⁴²PLD is an approved treatment in Europe as monotherapy for MBC in patients at risk of heart problems, but it has not received FDA approval in the United States.⁴³A phase II study evaluating PLD plus carboplatin versus PLD plus carboplatin and trastuzumab demonstrated better median OS durations (33 months) and better median PFS (10 months) with the PLD, carboplatin, and trastuzumab treatment. Grades 3/4 treatment-related toxic effects in this group were neutropenia (35%), thrombocytopenia (17%), and fatigue (13%); however, minimal cardiac toxicity was noted.⁴⁴A phase III study demonstrated that PLD and CAP had similar TTP when used as first-line therapy in patients with MBC; however, patients administered PLD had better tolerability than patients receiving CAP.⁴⁵Several studies evaluating PLD in various types of patients with breast cancer are ongoing.⁴⁶

Conclusion

Over the past 2 decades, major advances have been seen in the detection, prevention, and treatment of breast cancer, with mortality steadily declining. Numerous new drugs are under development and new targets continue to be identified to focus research efforts. Although early detection and preventative strategies, such as lifestyle modification, remain critical strategies in the overall battle against breast cancer, significant results have been reported from recent drug studies, providing hope to patients who have failed currently available treatments. Based on the literature, it is becoming more apparent that tailored therapies will continue to grow based on the increased understanding of the mechanisms of oncogenesis and causes of drug resistance. A patient’s tumor receptor profile (ie, HER2, PR, ER) and genetic markers, such as BRAC1 and BRAC2, have helped to ensure successful treatment strategies. PARP inhibitors have shown limited success in patients specifically with BRAC mutations and, to date, TKIs have had mixed results; however, toxicity remains a concern. The monoclonal antibodies appear to have the greatest potential for coming to market in the short term. Pertuzumab has been recently approved for use with trastuzumab, paving the way for the approval of novel chemotherapy conjugate trastuzumab- DM1. If the results from trials translate to clinical practice, this is likely to improve to PFS with limited or no increases in OS. With an 18-month course of treatment with trastuzumab/pertuzumab estimated at approximately $187,000 (more than $10,000 per month) and 28 days of everolimus being $7500, results over the long term and additional clinical trials should be watched closely.47,48 Other agents are expected to be costly as well. Given the FDA’s decision to revoke the breast cancer indication for bevacizumab, caution is warranted in order to fully understand the side-effect profiles and efficacy of these drugs in the postapproval phase.Author Affiliations:Our Lady of the Lake Regional Medical Center (MMM), Baton Rouge, LA; and University of Louisiana at Monroe College of Pharmacy—Baton Rouge Campus (BLM), Baton Rouge, LA.

Funding Source:None.

Author Disclosures:Dr M. M. Mohundro reports receiving payment for involvement in the preparation of this manuscript. Dr B. L. Mohundro reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

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Down the Road for Breast Cancer