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Recent Advances in Targeted Therapy for Breast Cancer

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The advent of the “molecular era” in cancer treatment was marked by discovery of the Philadelphia (Ph) chromosome in 1960, the first chromosomal abnormality linked to a specific type of leukemia.^21,22 The Ph chromosome involves translocation of the ABL proto-oncogene normally found on chromosome 9 and the BCR gene on chromosome 22. It was demonstrated that the dysregulated ABL tyrosine kinase activity resulting from fusion protein expressed by the BCR-ABL gene was the pathogenic principle behind chronic myelogenous leukemia.²³ With a genetic target clearly identified, the process of drug development was allowed to proceed rationally with the goal of producing a drug that could block BCR-ABL.²³ The result of this work was imatinib, the first tyrosine kinase inhibitor approved for cancer treatment.

In line with the example of imatinib, trastuzumab, an antibody against the product of the HER2 oncogene, was approved for treatment of HER2-positive breast cancer. In this case, the clinical benefit conferred by the antibody appears to be limited to tumors with HER2 gene amplification. More recently, the next-generation tyrosine kinase inhibitor lapatinib has also been approved for treatment of HER2-positive breast cancer.²⁴ In addition, bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has been approved for the treatment of non-small cell lung cancer (NSCLC) and colorectal cancer and the tyrosine kinase inhibitor erlotinib, which binds epidermal growth factor receptor (EGFR), has been approved for the treatment of NSCLC.^25,26 The next-generation kinase inhibitors sunitinib, sorafenib, and temsirolimus, an inhibitor of the kinase mTOR, are indicated for the treatment of renal cell cancer (RCC).^27-29 Cetuximab, a chimeric monoclonal antibody against EGF, has been approved for the treatment of metastatic colorectal cancer, head and neck cancer, and panitumumab, a fully humanized monoclonal antibody against EGF, has been approved in colorectal cancer.^30-32

The numerous targeted agents in use and under development for various cancers illustrate the concept of molecular targeting in cancer therapy. Erlotinib owes its approval for NSCLC in good part to the discovery of EGFR mutations in lung cancer. Such mutations are present in 10% to 30% of patients with NSCLC and they may account for the majority of erlotinib activity in this disease.^33,34 Similarly, the efficacy of the kinase inhibitors sunitinib and sorafenib in RCC is predicated on their activity against the VEGF receptor, which is thought to play a central role in tumor angiogenesis in this cancer. The majority of renal cancers involve mutations that result in the inactivation of the von Hippel-Lindau tumor-suppressor gene (VHL). The VHL protein controls how much VEGF is produced by degrading the transcription factor hypoxia-inducible factor (HIF), which controls production of VEGF (Figure 3). With VHL inactivated in RCC, VEGF is overproduced and used for tumor maintenance.³⁵

One of the most exciting new targeted agents in breast cancer is the tyrosine kinase inhibitor lapatinib, an ATP mimetic that reversibly inhibits both the EGFR and HER2 kinases. Lapatinib has predominant activity against HER2-overexpressing cancer cells as well as clinical activity against newly diagnosed HER2-positive metastatic cancers. It has demonstrated clinical activity against HER2-positive cancers that have progressed on trastuzumab and it was approved based on that indication.³⁶ In a phase 1 study, it was shown to be safe when given in combination with trastuzumab.³⁷ One potential advantage of lapatinib is that it is a small molecule. In a pivotal phase 3 trial, when lapatinib was added to capecitabine, there was a small reduction in risk for progression in the CNS (Figure 4).^38,39 It is possible that the small size of lapatinib allows it to more readily enter the CNS and may account for the difference in risk for CNS progression.

In an extension arm of a phase 2 study of lapatinib as a single agent in patients with recurrent brain metastases from HER2-positive breast cancer, patients who had progressive disease in the CNS and/or elsewhere were offered the combination of lapatinib and capecitabine.40 Of the initial 49 patients who received the combination, 10 (20%) experienced a >50% reduction in volume of CNS metastases. In addition, more than 40% of patients experienced a > 20% reduction in volume of CNS disease. These results in a small group of patients raise the question of whether this response in progressive disease is attributable to the addition of capecitabine or the combination of lapatinib and capecitabine. Findings from the study also have implications for the continuation of anti-HER2 therapy upon disease progression.

A number of recent and ongoing studies have focused on the molecular determinants of resistance to anti-HER2 therapies. Berns and colleagues recently published the results of a large-scale RNA interference screen to identify genes involved in trastuzumab resistance in breast cancer.⁴¹ They found that knocking out the locus of PTEN resulted in resistance to trastuzumab in breast cancer cell lines. In a review of a database of tumors from 55 breast cancer patients treated with trastuzumab, they found that tumors that had low PTEN expression and/or an oncogenic mutation of PI3 kinase had a shorter time to progression after trastuzumab therapy (Figure 5). With the combined analysis of PTEN and PIK3CA, twice as many patients with elevated risk for progression were identified compared with analysis of PTEN alone. The study concluded that PI3K pathway activation may represent a valuable biomarker to select breast cancer patients who are likely to escape the action of trastuzumab.

Results from this study raise the question of how best to inhibit trastuzumab-resistant HER2-dependent breast cancer. One option is lapatinib. However, tumors with PI3 kinase mutations and PTEN loss also appear not to be less sensitive to lapatinib compared to tumors with wild-type PI3 kinase and PTEN. Preliminary results from an ex vivo experiment in which PIK3CA mutants (p110α^E545K, P110^H1047R) are overexpressed in SKBR-3 breast cancer cells demonstrate that these cells become resistant to lapatinib.

Another option is the trastuzumab-DM1 HER2 antibody-drug conjugate currently under development for the treatment of HER2-positive breast cancer. The conjugate is designed to join the binding activity of trastuzumab with delivery capability of a potent antimicrotubule agent. The use of DM1, which binds tubulin potently in HER2-expressing cells, theoretically improves the therapeutic window for trastuzumab. In addition, the molecule used to link the two agents has been engineered to potentially improve exposure to the conjugate while minimizing exposure to free DM1. Krop and colleagues reported results from an ongoing phase 1 study evaluating the safety and pharmacokinetics of the conjugate.⁴² At the time of reporting, 19 patients who had progressed on a trastuzumab regimen received trastuzumab-DM1. At the maximum tolerated dose, drug-related adverse events grade >2, including ST-elevations, thrombocytopenia, fatigue, and anemia, occurred infrequently and were generally manageable. Objective tumor responses have been reported in four of 16 patients treated at or below the maximum tolerated dose of trastuzumab-DM1. In three patients, these responses have been confirmed and maintained after 1.7 to 5.5 months of treatment. Based on these promising results, phase 2 trials in advanced HER2-positive breast cancer are being initiated.

Continuation of trastuzumab in combination with chemotherapy after failure of trastuzumab is being investigated in the Trastuzumab treatment Beyond Progression (TBP) study. This study is evaluating whether continuation of trastuzumab in progressive disease results in improved time to progression. von Minckwitz and colleagues reported results from the TBP study, which was conducted in 152 women with HER2-positive, locally advanced or metastatic breast cancer who had developed progressive disease after receiving trastuzumab with or without chemotherapy as adjuvant or first-line treatment for metastatic disease.⁴³ The patients were randomized to either capecitabine or capecitabine with a continuation of trastuzumab. The primary endpoint for the study was time to progression. A planned interim analysis including 112 evaluable patients showed a time to progression (TTP) of 33 weeks for the trastuzumab continuation regimen compared with 24 weeks for the regimen without trastuzumab. The hazard ratio was 0.82 (95% CI, 0.53–1.26) in favor of the trastuzumab continuation regimen. Although the difference between the two treatment groups did not reach significance, interim results suggest that treatment with trastuzumab beyond progression in addition to capecitabine may be superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after initial treatment with trastuzumab. Final results from the TBP study are forthcoming.

Another drug being evaluated for trastuzumab-resistant HER-positive breast cancer is the irreversible EGFR/HER2 tyrosine kinase inhibitor HKI-272. Results from a phase 1 study showed that HKI-272 had acceptable tolerability and promising antitumor activity.⁴⁴ Burstein and colleagues reported preliminary results from an ongoing open-label phase 2 study in patients with HER2-positive advanced breast cancer.⁴⁵ The study has two arms: one including patients who previously had inadequate responses to trastuzumab and the other including patients who had no prior treatment with trastuzumab. At the time of reporting, preliminary data were available for 97 patients, 61 in the trastuzumab failure arm and 36 in the trastuzumab naïve arm. There were few grade 3/4 adverse events. The most common adverse events were diarrhea, nausea, fatigue, and vomiting, which were mostly of mild-to-moderate severity. At 23 weeks, 97 patients were free of progression. Among patients who had failed prior trastuzumab therapy, progression-free survival (PFS) was 16 weeks. For patients with no prior trastuzumab therapy, PFS was 33 weeks. These preliminary data suggest that HKI-272 may be useful in HER2-positive patients with trastuzumab-resistant disease.

One ongoing phase 2 study is evaluating the combination of the heat shock protein inhibitor (HSP90) tanespimycin and trastuzumab in patients with HER2-positive trastuzumab-refractory metastatic breast cancer.⁴⁶ Inhibition of HSP90 activity results in degradation of HSP90 client proteins including the HER2 receptor. In a previous phase 1 study, the combination of tanespimycin and trastuzumab resulted in an overall clinical benefit rate of 53%. At the time of reporting, 20 had been enrolled in the phase 2 study. Thirteen patients were evaluable for efficacy. Five patients had objective tumor responses in a population of heavily pretreated patients. Drug-related adverse events included fatigue (50%), diarrhea (38%), dizziness (31%), headache (25%), and dyspnea (19%). Grade 3 drug-related adverse events were seen in three patients and one patient withdrew from the study due to drug-related toxicity.

Other agents being investigated for usefulness in trastuzumab-resistant HER2-positive breast cancer are inhibitors of PI3K and AKT, insulin-like growth factor I receptor (IGF-IR), mTOR, ADAM metalloproteases (ADAM 10/17), and the SRC tyrosine kinase.^47-50

With many potential options existing for the treatment of trastuzumab-resistant HER2-positive breast cancer, what is the best strategy for determining the most effective option? One possibility is to do head-to-head comparisons in randomized phase 2 trials, in which each treatment is compared with chemotherapy plus trastuzumab (or with chemotherapy alone for the trastuzumab-DC1 conjugate) in a metastatic setting. Perhaps these trials would also have a third lapatinib arm. Such studies may not require a large number of patients in each arm to determine whether further evaluation is warranted. Patient selection for each study might benefit from what is already known about the sensitivity of molecular targets to the agents in question and focus on populations with HER2 overexpression.

Triple-Negative Breast Cancer

Breast cancer is increasingly emerging as a heterogeneous group of tumors, with distinct subtypes defined according to histopathologic features, genetic mutations, and gene-expression profiles. Breast cancers that lack HER2 amplification as well as ER and PR expression are termed “triple-negative” tumors. Kreike and colleagues recently evaluated the gene expression profile and histopathology of 97 triple-negative breast cancer tumors in an effort to define triple-negative tumor subgroups and determine risk for developing progressive disease.⁵¹ Unsupervised hierarchical clustering with 7,770 significantly regulated genes was performed to clarify differences in gene expression among the sample of triple-negative tumors. Low HER2 and ER cluster expression as well as high basal cluster expression were evident. Fifty percent of the tumors were positive for p53 staining. All of triple-negative tumors were basal-like breast carcinomas, with five distinct subtypes. Multivariate analysis demonstrated that histopathologic factors including a large amount of lymphocytic infiltrate and absence of central fibrosis within tumors were independently associated with survival free of distant metastasis.

Results from two trials with EGFR antagonists in triple-negative breast cancer were recently reported. Carey and colleagues reported results from a randomized phase 2 study of cetuximab.⁵² The study randomized patients to one of two treatment arms: cetuximab alone with carboplatin added upon progression or cetuximab plus carboplatin throughout. Cetuximab alone was well-tolerated but had a low single agent response rate so failed criteria for ongoing study. Rapid progression in this population may have limited evaluation of efficacy. The second arm with the combination of cetuximab and carboplatin is ongoing. O’Shaughnessy and colleagues reported preliminary results from a randomized phase 2 study of the combination of irinotecan and carboplatin with or without cetuximab in patients with metastatic breast cancer.⁵³ The study randomized 163 patients to receive either irinotecan followed by carboplatin with or without cetuximab. In this preliminary analysis, the overall rate of response was 30% for the group that received only irinotecan and carboplatin versus 49% for the group that received irinotecan and carboplatin plus cetuximab. There were no differences in overall survival or progression-free survival between the two groups. The group receiving cetuximab had higher rates of toxicities than the group without. This preliminary analysis suggests that the addition of cetuximab to the combination of irinotecan and carboplatin does not improve treatment outcome and is associated with greater toxicity.

While results from studies of EFGR antagonists in triple-negative breast cancer have been overall negative—other studies have investigated inhibition of the SRC kinase. One preclinical study evaluated dasatinib, a small molecular kinase inhibitor of both SRC and ABL proteins, in 39 human breast cancer cell lines.⁵⁴ Eight out of 39 cell lines were highly sensitive to dasatinib and 10 cell lines had moderate sensitivity. The cell lines that were most sensitive to dasatinib were of the basal-type and/or those that had undergone an epithelial-to-mesenchymal transition. Breast cancer cell lines of the luminal subtype were largely resistant to dasatinib. These results were confirmed by another study using breast cancer cell lines to identify potential candidate molecular markers that might predict dasatinib sensitivity. The study found the triple-negative breast cancer subtype to be a potential marker for dasatinib sensitivity.⁵⁴ Based on these data, trials of dasatinib in triple-negative breast cancer have been initiated.⁵⁵