Targeted Therapies in Breast Cancer: Challenging Questions from Oncology Nurses

Targeted Therapies in Breast Cancer: Focus on Clinical Research
Hope S. Rugo, MD
University of California San Francisco Comprehensive Cancer Center

Carefully controlled clinical studies have provided valuable insights regarding the optimal integration of targeted agents into the management of patients with breast cancer. The following questions were submitted by participants of previous IMER conferences and discussed at the symposium titled, Targeted Therapies in Breast Cancer: Challenging Questions from Oncology Nurses.

TARGETED THERAPIES IN THE METASTATIC SETTING
Would you continue to treat a patient with HER2-positive metastatic breast cancer with trastuzumab therapy following disease progression?
Several studies have examined this question, although primarily from a retrospective approach. In a study by Extra and colleagues (2006), women with HER2-overexpressing metastatic breast cancer that progressed during first-line trastuzumab therapy were divided into two groups, depending on whether they continued trastuzumab. With a median follow-up of 27.8 months, those who continued trastuzumab therapy experienced a significant survival benefit compared to those who discontinued trastuzumab (median overall survival [OS] not reached vs. 16.8 months; p < .0001). Because this was not a randomized trial, the patient groups may have been biased with respect to which patients were chosen to continue trastuzumab therapy. Nonetheless, this study demonstrated that at least a subset of patients may benefit from continued trastuzumab therapy. A nonrandomized extension of the pivotal trastuzumab trial (Tripathy et al., 2004) and a retrospective study (Fountzilas et al., 2003) both reported encouraging clinical benefit and no unexpected toxicities with trastuzumab therapy continued beyond disease progression. However, in the absence of positive data from a randomized clinical trial, continuing trastuzumab cannot be recommended for all patients. For those who have progressed while receiving single-agent trastuzumab, the addition of chemotherapy is a viable option. Based on its approval by the FDA for women who have progressed despite prior therapy with trastuzumab and chemotherapy, the combination of lapatinib and capecitabine should be considered for patients who have progressed on combination therapy.

What are the differences in the clinical applications of trastuzumab and lapatinib?
Trastuzumab, an anti-HER2 monoclonal antibody, has three indications for HER2-overexpressing breast cancer: in combination with paclitaxel for the first-line treatment of metastatic disease; as a single agent in recurrent metastatic disease; and in combination with chemotherapy for the adjuvant treatment of node-positive breast cancer (Herceptin® package insert, 2006). The pivotal trial of trastuzumab demonstrated that the addition of the agent to chemotherapy in patients previously untreated for HER2-overexpressing metastatic disease prolonged median overall survival by almost 5 months (25.1 vs. 20.3 months; p = .046; Slamon et al., 2001). Trastuzumab earned its single-agent indication based on a single-arm study evaluating its use in heavily pretreated patients with advanced disease. In this population, the agent produced a 15% response rate and a median OS of 13 months (Cobleigh et al., 1999). Trastuzumab's approval in the adjuvant setting was based on a 33% reduction in the risk of death (p = .015) observed when the agent was added to adjuvant chemotherapy (Romond et al., 2005).

Because the small molecule tyrosine kinase inhibitor (TKI) lapatinib was developed after the approval and widespread use of trastuzumab, its one indication thus far is for patients previously treated with trastuzumab. Specifically, lapatinib is approved for use in combination with capecitabine for the treatment of HER2-overexpressing metastatic breast cancer that has progressed despite treatment with an anthracycline, a taxane, and trastuzumab (Tykerb® prescribing information, 2007). The pivotal lapatinib trial demonstrated that the addition of lapatinib to capecitabine prolonged median time to progression (TTP) in these women by 4 months (8.4 months vs. 4.4 months; p < .001; Geyer et al., 2006). An updated report of this study presented at the 2007 annual meeting of the American Society of Clinical Oncology indicated that women in the lapatinib arm experienced a lower rate of disease progression in the central nervous system (CNS; 2% vs. 11%; p = .0445), suggesting that lapatinib can cross the blood-brain barrier and have a protective effect on the CNS (Geyer et al, 2007). Several clinical trials enrolling women with metastatic disease are now tracking the incidence of CNS metastases as a secondary objective in order to further study this potential benefit of lapatinib. Because of the large size of monoclonal antibodies, trastuzumab is unable to cross the blood-brain barrier, and therefore, would not be expected to provide protection from CNS metastases.

Is the incorporation of antiangiogenic agents standard treatment for metastatic breast cancer?
The first antiangiogenic agent to demonstrate success against breast cancer was the antivascular endothelial growth factor monoclonal antibody bevacizumab, although early trials combining it with capecitabine in heavily pretreated patients with metastatic disease showed no benefit (Miller Chap et al., 2005a). However, in the E2100 trial, bevacizumab was combined with paclitaxel for treatment in the first-line metastatic setting, and results showed that the addition of bevacizumab produced a significant increase in progression-free survival (11.0 months vs. 6.1 months; p < .001; Miller,Wang, et al., 2005). A 3-month improvement in OS was also observed, but this has not yet reached statistical significance, likely due to the small number of events that occurred at the time of this interim report. Two ongoing randomized trials are evaluating bevacizumab in combination with a variety of chemotherapy regimens for metastatic breast cancer in both the first-line (RIBBON1), and second-line (RIBBON2) settings. Bevacizumab has already received approval in Europe for the treatment of metastatic breast cancer, but FDA approval is pending an ongoing independent review of the E2100 data. Based on these data, bevacizumab is a reasonable option for the treatment of metastatic breast cancer, but it is premature to consider it a standard treatment. Other antiangiogenic agents are also being investigated as potential breast cancer therapies, including several multitargeted TKIs such as sunitinib, sorafenib, pazopanib, and axitinib. Aside from sunitinib, which is currently in phase III trials, these agents are early in development and will require time before their true potential can be determined.

What other targeted agents are under investigation in metastatic breast cancer?
Aside from multitargeted agents with antiangiogenic potential, other investigational agents include immunotoxins (e.g., trastuzumab- DM1), downstream pathway inhibitors, and various inhibitors of triple-negative breast cancer (eg, epidermal growth factor receptor, Src, PARP inhibitors).

TARGETED THERAPIES IN THE ADJUVANT SETTING
The overwhelming success of trastuzumab in the adjuvant setting has resulted in an explosion of clinical trials investigating the incorporation of targeted agents into adjuvant regimens. Although trastuzumab was recently approved by the FDA for use in this setting, questions remain concerning cardiac safety, optimal treatment duration, and combination with chemotherapy regimens. Other targeted agents under investigation in the adjuvant setting include lapatinib and bevacizumab.

Mrs. LP is a 35-year-old woman with breast cancer who is treated with lumpectomy and axillary node dissection. She has a 0.8-cm, node-negative, high-grade infiltrating ductal carcinoma with no lymphovascular invasion. The tumor is estrogen receptor-positive, progesterone receptor-negative, and HER2-overexpressing. How would you treat this patient?

a. Tamoxifen alone with radiation
b. Adjuvant chemotherapy alone followed by radiation
c. Adjuvant chemotherapy alone followed by tamoxifen and radiation
d. Adjuvant chemotherapy with trastuzumab followed by tamoxifen and radiation

On the surface, this appears to be an obvious answer, considering the dramatic improvement in survival produced by the addition of trastuzumab to adjuvant chemotherapy (Table 1). However, none of the adjuvant trastuzumab trials included patients with node-negative disease < 1 cm in size (Romond et al., 2005; Piccart-Gebhart et al., 2005; Slamon et al., 2006). In the absence of randomized clinical trial data on the outcomes of patients with tumors < 1 cm and node-negative disease, it is reasonable to provide Mrs. LP with the multimodality therapy shown in choice d.

How does the incorporation of trastuzumab into regimens for patients who have early stage HER2-overexpressing disease impact the use of radiation or hormone therapy, if at all?
In each of the adjuvant trials, both radiation and hormonal therapies were administered as needed. In none of the trials did the addition of trastuzumab have any negative impact on the efficacy or safety of either of these treatment modalities (Romond et al., 2005; Piccart-Gebhart et al., 2005; Slamon et al., 2006).

Should adjuvant chemotherapy regimens used in combination with trastuzumab always include an anthracycline?
The BCIRG 006 trial was the only adjuvant trastuzumab trial to address this question. As shown in the Figure, both the anthracyclinecontaining ACgTH regimen, and the nonanthracycline-containing TCH regimen were compared to the reference nontrastuzumabcontaining arm. Results from this trial demonstrated that TCH and ACgTH produce similar overall survival and that TCH is superior to the anthracycline-containing regimen with respect to cardiac safety (Table 2; Slamon et al., 2006). Therefore, both ACgTH and TCH are reasonable adjuvant trastuzumab regimens, with the TCH regimen possibly being more appropriate for patients at increased cardiac risk, including those older than 50 years of age, those with hypertension or a history of cardiac dysfunction, those with asymptomatic cardiac dysfunction at treatment initiation, and those with borderline normal cardiac function left ventricular ejection fraction (LVEF), 50% to 54% (Rastogi et al., 2007).

Do modifications in the scheduling or duration of trastuzumab therapy impact its efficacy when administered for the treatment of HER2-overexpressing early stage breast cancer?
The adjuvant trastuzumab trials tested different schedules of trastuzumab, with NSABP B-31 and NCCTG-N9831 using weekly trastuzumab concurrent with chemotherapy, HERA using every-3-week trastuzumab following chemotherapy, and BCIRG 006 using weekly dosing during chemotherapy and an every-3-week schedule thereafter. Despite these differences, the trials reported similar efficacies, suggesting that the more convenient every- 3- week schedule after chemotherapy is completed does not compromise patient outcome (Romond et al., 2005; Slamon et al., 2006).

The optimal duration of trastuzumab remains an unanswered question. The HERA trial is investigating 1 versus 2 years of trastuzumab, but the data in the 2-year arm are still immature (Piccart- Gebhart et al., 2005). The ongoing Protocol of Herceptin Adjuvant with Reduced Exposure (PHARE) trial will attempt to answer whether 6 months of trastuzumab achieves results comparable to 1 year of treatment.

How would you treat a patient with HER2-overexpressing early stage breast cancer who has only been treated with chemotherapy?
Because the success of adjuvant trastuzumab was only reported in 2005, many patients with HER2-overexpressing disease have received only chemotherapy in the adjuvant setting and may be candidates for additional treatment. For patients who completed adjuvant therapy several years ago, a reasonable option would be to provide no further therapy, since relapses peak within a few years of surgery. Adding 1 year of trastuzumab is a reasonable option for several patient populations, including those who have recently completed adjuvant chemotherapy, younger patients, and those with high-risk disease. No prospective clinical trials have tested delayed trastuzumab administration following chemotherapy, but positive results from the HERA trial (which provided trastuzumab following the completion of chemotherapy) confirm that trastuzumab does not need to be administered concurrently with chemotherapy to be effective (Piccart-Gebhart et al., 2005). One ongoing nonrandomized phase II study is investigating the delayed administration of trastuzumab in the adjuvant setting. The final option for patients who have not received adjuvant trastuzumab is to enroll them in the randomized phase III Tykerb® Evaluation After Chemothearpy (TEACH) trial, which is evaluating the addition of lapatinib for patients who have completed chemotherapy but have not received trastuzumab and have no evidence of disease.

Are bevacizumab and lapatinib being evaluated for early stage breast cancer?
Due to their successes in metastatic breast cancer, both bevacizumab and lapatinib are being tested in the adjuvant setting. Both agents are part of distinct phase III trials investigating their addition to standard adjuvant ACgT chemotherapy. Furthermore, the addition of several different bevacizumab schedules to ACgT (dosedense or standard) is being tested in two phase II trials. The abovementioned phase III TEACH trial is evaluating lapatinib following adjuvant chemotherapy. Multiple phase II trials testing the efficacy and safety of lapatinib in the adjuvant setting are ongoing as well.

Are targeted therapies being used in the neoadjuvant setting?
Similar to the adjuvant setting, a number of trials are currently evaluating bevacizumab and lapatinib in the neoadjuvant setting. Moreover, because trastuzumab is not approved for locally advanced disease, several studies are testing trastuzumab in this setting also. Trial designs include targeted agents in combination with chemotherapy, with hormonal therapy, and/or with other targeted agents. Neoadjuvant trials provide a unique window of opportunity in that surgery follows the treatment regimen of interest, allowing the pathological determination of tumor response, and the opportunity to evaluate molecular markers of response and resistance.

What is the future of targeted therapies in breast cancer?
Genomic and possibly even proteomic analysis will likely dominate the future of breast cancer research, allowing treatment decisions to be made rationally based on gene and/or protein expression patterns. This should allow the identification of subsets of breast cancer for specific therapies, either standard chemotherapy, or more likely, targeted therapy. The ultimate goal is to individualize treatment for each patient based on the genomic and proteomic tumor profiles, thereby increasing the likelihood of response to the chosen therapy and decreasing the administration of ineffective therapies. Strides have already been made in this direction, as illustrated by the development of molecular fingerprinting and initial attempts at dividing patients into subgroups with distinct outcomes, but much work remains to be completed.