E-Updates in the Adjuvant Treatment of Breast Cancer, Volume 2Updates on Chemotherapeutic Options and Targeted Therapies
Table of Contents
IntroductionGene-Profiling Techniques Permit Refinements to Conventional Adjuvant Treatment RecommendationsInnovations in Anthracycline-Based Adjuvant RegimensInnovations in Taxane-Containing Chemotherapy StrategiesAdvances in Targeted TherapyCardiac Safety with Novel Adjuvant StrategiesConclusion
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Perhaps the most profound changes in our approach to adjuvant therapy in the past decade have been driven by changes in the understanding of breast cancer biology. Genomic analyses have suggested that some therapeutic interventions (hormonal and HER2-targeting therapy) have a solid basis in the treatment of certain subsets of breast cancer, and also have made it clear that breast cancer should be considered a collection of diseases rather than a solitary disease. While genomic analyses have allowed for more precision in treating breast cancer, several questions apply to all tumor subtypes: who should be treated; and what are the optimal agents, sequences, and durations of treatment?
To answer these questions, we are pleased to introduce the second volume of our CME series E-Updates in the Adjuvant Treatment of Breast Cancer. You have before you the first of two E-Updates presented to you between now and the end of the year on the adjuvant treatment of breast cancer. This first issue by Dr. Heather L. McArthur, Special Fellow from Memorial Sloan-Kettering Cancer Center, focuses on updates on chemotherapeutic options and targeted therapies-namely, a number of notable innovations in the adjuvant treatment paradigm, including scheduling, drug delivery, and targeted therapy innovations. The upcoming issue will address updates on hormonal therapies, informing about the current role of tamoxifen and aromatase inhibitors.
These reviews should allow you as the clinician to make practical treatment decisions while being informed of current research and evolving practice guidelines. The upcoming issue will address updates on hormonal therapies and the current roles of tamoxifen and aromatase inhibitors. Please write to us at: email@example.com.
Chau T. Dang, MD and Clifford A. Hudis, MD
AC = doxorubicin and cyclophosphamide
AC-T = doxorubicin and cyclophosphamide followed by paclitaxel
ALLTO = Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation
BCIRG = Breast Cancer International Research Group
CAF or FAC = cyclophosphamide, doxorubicin, and 5-fluorouracil
CALGB = Cancer and Leukemia Group B
CEF or FEC = cyclophosphamide, epirubicin, and 5-fluorouracil
CMF = cyclophosphamide, methotrexate, and 5-fluorouracil
EBCTCG = Early Breast Cancer Trialists' Collaborative Group
EC = epirubicin and cyclophosphamide
ECOG = Eastern Cooperative Oncology Group
EC-T = epirubicin and cyclophosphamide followed by paclitaxel
FAC = 5-fluorouracil, doxorubicin, and cyclophosphamide
FEC-D = 5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel
HERA = Herceptin Adjuvant trial
NCIC = National Cancer Institute of Canada
NSABP = National Surgical Adjuvant Breast and Bowel
PACS = French Adjuvant Study Group
TAC = docetaxel administered concurrently with doxorubicin and cyclophosphamide
TC = docetaxel and cyclophosphamide
TCH = docetaxel, carboplatin with trastuzumab followed by trastuzumab monotherapy for 1 year of trastuzumab
Globally, breast cancer is a significant public health issue, with more than 200,000 new cases diagnosed in the United States and more than one million new cases diagnosed worldwide each year.[1,2] In a highly publicized study, an 8.6% decline in the age-adjusted annual rate of incident breast cancer cases was observed among American women between 2001 and 2004.[3,4] However, despite this decline and the increasing proportion of early-stage diagnoses, a significant proportion of women with potentially curable early-stage disease ultimately experience a distant relapse and die of metastatic breast cancer-related complications. Thus, to optimize outcomes for women with early-stage breast cancer, investigators strive to improve cure rates and ideally minimize treatment-related toxicity through therapeutic innovation. To this end, a number of notable innovations in the adjuvant treatment paradigm, including scheduling, drug delivery, and targeted therapy innovations have recently been reported.
Gene-Profiling Techniques Permit Refinements to Conventional Adjuvant Treatment Recommendations
Breast cancer is a heterogeneous disease with significant diversity in natural history and responsiveness to therapy, with at least five distinct molecular subtypes identified to date. Ideally, specific adjuvant therapy recommendations would be tailored to the biology of an individual's tumor. Consequently, significant efforts have been undertaken to identify the subsets of women who are likely to derive benefit from specific conventional chemotherapy and targeted treatment strategies. Moreover, with a tailored approach, women who are unlikely to derive benefit could be spared the potentially deleterious effects of therapy.
One of the most notable innovations in tailored therapy has been the successful development of gene-expression profiling. The Oncotype DX 21-gene assay, for example, was developed and validated in two NSABP studies. It incorporates 16 cancer-related genes (including the estrogen receptor and HER2 genes) and 5 reference genes identified from a panel of 250 candidate genes to generate an expression profile, which, in turn, is converted into a recurrence risk score. As initially reported, the test enabled stratification of women with node-negative, tamoxifen-treated, early-stage breast cancer into "low-," "intermediate-," or "high-" risk categories, with associated 10-year distant recurrence rates of 6.8%, 14.3%, and 30.5%, respectively.
In the validation study, women with low-risk scores did not derive additional benefit from conventional chemotherapy, whereas women with high-risk scores derived significant benefit. Thus, some women with large, node-negative, hormone-sensitive breast cancers who might historically have received a recommendation for systemic therapy based on tumor size alone, but who are identified as low risk by gene profiling, may forego the short- and long-term toxicity associated with chemotherapy. Furthermore, women with small, node-negative, hormone-sensitive tumors who might not have conventionally received a recommendation for chemotherapy as a consequence of their small tumor size, but who are now identified as at a high risk of recurrence by gene profiling, can mitigate this risk with systemic therapy.
This approach has more recently been validated in women with node-positive, hormone-sensitive breast cancer, a group for whom adjuvant systemic chemotherapy has historically been considered standard of care based on the overall high rate of recurrence with nodal involvement. In this study, 1,477 postmenopausal women were treated with tamoxifen with or without CAF chemotherapy. The impact of risk stratification by Oncotype DX in this node-positive population proved consistent with the results observed in the node-negative populations. Consistent results have also been reported with other European gene-profiling techniques, including the 70-gene MammaPrint and the 76-gene Rotterdam signatures, although these techniques require fresh-frozen tissue, which is not typically available in the United States.[8-10]
Notably, in both node-negative and node-positive patients, the optimal treatment strategy for women at "intermediate" risk by gene profiling remains uncertain. Consequently, the TAILORRx trial is currently randomizing women with intermediate- risk scores by Oncotype DX to receive hormone therapy alone or in combination with chemotherapy, and a parallel study with MammaPrint is ongoing in Europe. It is hoped that further innovations in gene-profiling techniques will permit further refinements to adjuvant therapy recommendations.
Innovations in Anthracycline-Based Adjuvant Regimens
The incorporation of the anthracyclines, epirubicin and doxorubicin, into adjuvant treatment strategies represents a significant milestone in adjuvant therapy innovation. As evidenced by numerous adequately powered phase III studies, the efficacy of anthracyclines has since been confirmed with the reporting of the 2005 EBCTCG meta-analysis. In this study, individual patient data for almost 150,000 women participating in 194 randomized chemotherapy or hormone therapy trials that began by 1995 were evaluated.
In an indirect analysis of anthracycline-based therapy with FAC or FEC versus nonanthracycline-based chemotherapy with CMF, data from 14,000 women were included. Compared with conventional CMF chemotherapy, the anthracycline-based regimens conferred significant recurrence and survival benefits. Specifically, 6 months of anthracycline-based therapy was associated with an 11% reduction in recurrence risk (recurrence rate ratio, .89; P = .001) and a 16% improvement in breast cancer-specific survival (breast cancer death rate ratio, .84; P = .00001) compared with CMF. Furthermore, the impact of anthracycline-based therapy was consistent for older and younger cohorts. Accordingly, investigators have since built on these anthracycline foundations with the incorporation of taxanes, improvements in scheduling and drug delivery, and innovations in targeted therapies.
Innovations in Taxane-Containing Chemotherapy StrategiesEfficacy of Adjuvant Taxane-Containing Regimens
Numerous large, randomized trials have now reported improved outcomes with taxane-containing regimens in women with early-stage breast cancer. The overall efficacy of adjuvant taxane-containing strategies with either paclitaxel or docetaxel (Taxotere) was confirmed in both a pooled analysis and a meta-analysis.[12,13]
In the pooled analysis, nine adjuvant taxane trials were evaluated and outcomes reported. For the 15,598 evaluated patients, significant disease-free survival (DFS) and overall survival (OS) improvements were reported both overall (DFS relative risk ratio, .86; P = .00001; OS relative risk ratio, .87; P = .0001) and in the node-positive subset (DFS relative risk ratio, .84; P = .0001; OS relative risk ratio, .84; P = .0001). The absolute DFS benefits ranged from 3.3% to 4.6%, and the absolute OS benefits ranged from 2.0% to 2.8% in favor of the taxane-containing strategies.
In the meta-analysis, outcomes for 18,304 women participating in 12 adjuvant taxane studies were evaluated. The results proved similar to those reported in the pooled analysis, with a significant hazard ratio (HR) for survival of .81 (P < .00001) in favor of the taxane-containing strategies. Therefore, these two large studies confirmed the significant survival benefits to be derived with taxane-containing strategies overall. However, these analyses were not able to adequately address the question of benefit in specific subsets. It is hoped that the forthcoming EBCTCG meta-analysis will provide clarity on this issue.
Evaluation of Taxanes and Taxane Scheduling
There has been long-standing controversy regarding the superiority of paclitaxel versus docetaxel and the influence of scheduling. Consequently, ECOG 1199 randomized almost 5,000 women to receive conventionally dosed every-3-weekly AC for 4 cycles followed by either weekly paclitaxel for 12 cycles, every-3-weekly paclitaxel for 4 cycles, weekly docetaxel for 12 cycles, or every-3-weekly docetaxel for 4 cycles.[14,15]
After a median 5-year follow-up period, there was a significant improvement in DFS with weekly paclitaxel (HR, 1.27; P = .006) and with every-3-weekly docetaxel (HR, 1.23; P = .02) compared with standard every-3-weekly paclitaxel therapy. A modest, nonsignificant improvement in DFS was observed with weekly docetaxel (HR, 1.09; P = .29) compared with standard every-3-weekly paclitaxel therapy. Significant improvements in OS were also reported for weekly paclitaxel (HR, 1.32; P = .01) compared with every-3-weekly paclitaxel, but no significant OS improvements were observed with the other experimental arms. Thus, 12 cycles of weekly paclitaxel proved superior to 12 cycles of weekly docetaxel and to either taxane administered in an every-3-weekly schedule for 4 cycles. Notably, however, weekly paclitaxel has not yet been compared with other established strategies such as every-2-weekly (or dose-dense) AC-T.
Taxane Sensitivity in Specific Subsets
Anthracyclines and taxanes are the most active agents in breast cancer treatment and therefore represent the cornerstones of modern chemotherapy strategies. However, anthracycline administration is associated with a small but significant long-term risk of cardiotoxicity and acute myelogenous leukemia. Thus, this risk must be carefully weighed against the potential benefits of therapy when making individualized chemotherapy recommendations.
Furthermore, some subsets of patients may be able to forego an anthracycline when a taxane is being administered. This issue was recently addressed in part in US Oncology 9735, wherein 1,016 women with node-positive or node-negative breast cancer were randomized after definitive surgery to receive 4 cycles of every-3-weekly AC at conventional doses or 4 cycles of every-3-weekly TC (75/600 mg/m2).[16,17] When the study was first reported after a median 5-year follow-up period, a significant improvement in DFS (86% vs 81%; P = .027), but not OS, was reported. At a recent update, after a median 7-year follow-up period, the previously reported DFS benefits were sustained (81% for TC vs 75% for AC; P = .033); and a statistically significant improvement in OS (87% for TC vs 82% for AC; P = .032) was reported. In unplanned analyses, no interaction of hormone receptor status or HER2 status with treatment was observed.
Consequently, many clinicians now recommend TC for patients with HER2-normal breast cancer who are likely to derive benefit from adjuvant chemotherapy but for whom the potential for anthracycline-mediated cardiotoxicity is a concern. Notably, however, TC was associated with more clinically significant events of febrile neutropenia in both older and younger cohorts than was AC. Furthermore, since the inception of US Oncology 9735, several regimens (including AC-T) have demonstrated superiority to AC and have not yet been evaluated against TC. It is anticipated that the ongoing "TIC TAC" study evaluating 6 cycles of TC versus 6 cycles of TAC in women with operable HER2-normal breast cancer will provide further insights.
Whether estrogen receptor status is a predictor for response to taxane therapy was explored in a pooled analysis of 3,490 patients participating in BCIRG 001 and PACS 01.[18,19] In BCIRG 001, women were randomized to receive 6 cycles of TAC versus 6 cycles of concurrent FAC. Improvements in 5-year DFS (75% vs 68%; P = .001) and OS (87% vs 81%; P = .008) were reported in favor of the taxane-containing strategy. In PACS 01, women were randomized to receive 6 cycles of FEC or 3 cycles of FEC followed by 3 cycles of docetaxel (FEC-D). Consistent with the BCIRG 001 results, 5-year DFS (78.4% vs 73.2%; P = .011) and OS (90.7% vs 86.7%; P = .14) benefits were reported in favor of the taxane-containing strategy.
In the analysis of data pooled from both studies, DFS and OS benefits were observed with the taxane-containing strategies for both ER (estrogen receptor)-positive and ER-negative cohorts (although there was no significant difference in the test for interaction between ER status and chemotherapy regimen). Furthermore, there was no difference in relative efficacy for docetaxel-treated patients with strongly ER-positive tumors compared with those with weakly or intermediately ER-positive tumors. However, interpretability of these analyses is limited in part by the confounding effects of dose size, the number of taxane cycles administered, and the inherent differences in the control and experimental arms. Because the taxane-hormone receptor interaction is unlikely to be absolute, it is hoped that the upcoming EBCTCG meta-analysis will be adequately powered to provide clarity on the issue of taxane sensitivity in specific subsets.
Dose-dense Strategies. The Norton-Simon model predicted that tumor cell kill could be optimized by sequentially eradicating the numerically dominant, rapidly proliferating cell populations and then more indolent, resistant cells.[22,23] This strategy was first evaluated in CALGB 9741, a large randomized trial of conventionally scheduled every-3-weekly AC-T versus every-2-weekly (dose-dense) AC-T versus sequentially administered every-2-weekly or every-3-weekly A-C-T.[24,25] The every-2-weekly AC-T regimen proved superior to the conventionally scheduled regimen for OS, and consequently, the dose-dense strategy has now been evaluated in a number of other settings. For example, phase II studies of every-2-weekly EC followed by 4 cycles of every-2-weekly paclitaxel (EC-T) and every-2-weekly CMF have shown that dose-dense strategies may be safely administered with growth factor support.
The efficacy of dose-dense strategies has also been demonstrated in numerous adequately powered phase III randomized studies. For example, in NCIC MA.21, women aged 60 years or younger with node-positive or "high-risk" node-negative breast cancer were randomized to receive 6 cycles of every-3-weekly oral CEF, 4 cycles of every-3-weekly AC followed by 4 cycles of every-3-weekly paclitaxel (AC-T), or 6 cycles of dose-dense EC-T. At the interim analysis, the adjusted 3-year relapse free survival (RFS) was 90.1%, 89.5%, and 85.0%, for the CEF, EC-T, and AC-T regimens, respectively. In an exploratory analysis, every-3-weekly AC-T proved inferior to both CEF and dose-dense EC-T (HR, 1.67; P = .007; HR, 2.15; P = .0002, respectively), although the latter regimens were associated with increased rates of febrile neutropenia, thromboembolic events, and delayed cardiotoxicity compared with AC-T. These results are consistent with other adequately powered randomized studies of dose-dense strategies. The investigators also concluded that given the equivalence of CEF with dose-dense EC-T, taxanes may not be necessary in selected patients; however, further studies of taxane sensitivity in subsets are warranted.
Advances in Targeted Therapy HER2-Targeted Therapy with Trastuzumab
Several pivotal adjuvant trastuzumab (Herceptin) trials have been updated.[29-34] For example, in the HERA study, after primary chemotherapy, women with node-positive or "high-risk" node-negative HER2-positive breast cancer were randomized to undergo observation, 1 year of trastuzumab, or 2 years of trastuzumab. Although the results of the 2-year trastuzumab arm have not yet been reported, the benefits of 1 year of trastuzumab were initially reported in 2005. There were significant 2-year DFS benefits to 1 year of trastuzumab compared with observation (85.8% vs 77.4%, respectively; P < .0001). In a recent update, the DFS benefits were sustained, and significant OS benefits were also reported (HR, .66; P = .0115). The joint analysis of NSABP B31 and N9831, wherein women were randomized to receive chemotherapy with or without concurrent trastuzumab and then trastuzumab monotherapy for 1 year of therapy, was also updated.[31,32] In the updated analysis, the DFS and OS benefits originally reported in 2005 were sustained after a median follow-up of 2.9 years.
In BCIRG 006, patients with node-positive or "high-risk" node-negative HER2-positive breast cancer were randomized to receive 4 cycles of AC followed by 4 cycles of docetaxel; AC-docetaxel with concurrent trastuzumab and trastuzumab monotherapy for 1 year; or 6 cycles of TCH.[33,34] In the second interim analysis, sustained DFS benefits for both trastuzumab-containing arms compared with the control arm (HR, 0.61 and 0.67, respectively) were reported. Although the magnitude of the DFS benefits in BCIRG 006 was diminished compared with initial reports, a small but significant OS benefit in favor of the trastuzumab-containing regimens was now observed. Thus, consistent benefits have been reported with chemotherapy and trastuzumab across all pivotal adjuvant trastuzumab studies. However, as chemotherapy foundations continue to improve, novel strategies for evaluating adjuvant trastuzumab are anticipated. For example, trastuzumab administered in combination with standard dose-dense chemotherapy strategies (including AC-T) has recently been evaluated and proved to be safe.
Given the success of HER2-targeted therapy with trastuzumab in the adjuvant setting, and the benefits observed with other HER2-targeted agents including the tyrosine kinase inhibitor lapatinib (Tykerb), hsp90 inhibitors, and other HER2-targeted monoclonal antibodies such as pertuzumab in the metastatic setting, there has been considerable interest in evaluating these strategies in the adjuvant setting. Lapatinib is an orally available HER1- and HER2-targeted tyrosine kinase inhibitor and is currently US Food and Drug Administration (FDA) approved in combination with capecitabine(Xeloda) for the treatment of women with HER2-positive, pretreated, metastatic breast cancer. Consequently, many phase II studies of adjuvant lapatinib were undertaken. However, in one recent report of every-2-weekly AC followed by weekly paclitaxel with trastuzumab and continuous lapatinib followed by maintenance trastuzumab-lapatinib for 1 year of targeted therapy, the rate of diarrhea, a well-documented sequela of lapatinib therapy, proved unacceptable. Furthermore, in a metastatic study, the combination of paclitaxel with lapatinib was associated with a 2.7% incidence of fatal adverse events, many of which were ascribed to diarrhea-associated sepsis, versus 0.6% with paclitaxel alone.
Therefore, it is anticipated that investigators will incorporate stringent guidelines for the management of lapatinib-related diarrhea in the ongoing phase III adjuvant trastuzumab trials. The international ALLTO study is currently randomizing women with operable HER2-positive breast cancer to receive conventional chemotherapy with trastuzumab alone, lapatinib alone, or the combination. It is hoped that this study will provide insights into the efficacy and tolerability of single-agent versus combination HER2-targeted therapy in the adjuvant setting and that consequently, not only will the treatment algorithm be refined for the 20%–30% of women with HER2-positive breast cancer, but it will also provide head-to-head trastuzumab-lapatinib data, which might be extrapolated to refine treatment recommendations for metastatic breast cancer.
Antiangiogenic Therapy with Bevacizumab
Bevacizumab (Avastin) is a humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF) and is FDA approved in combination with paclitaxel in the metastatic setting as a result of reports of improved progression-free survival compared with paclitaxel alone. However, bevacizumab may be more effective when targeting minimal residual disease in the adjuvant setting. Because it was not known whether bevacizumab administered in combination with conventional chemotherapy would increase the risk of cardiotoxicity, several phase II adjuvant studies with a primary endpoint of cardiac safety have been undertaken.
In ECOG 2104, for example, women were randomized to receive dose-dense AC-T with bevacizumab initiated either concurrently with AC or concurrently with paclitaxel; the regimen proved feasible. In another study, 4 cycles of every-2-weekly AC followed by 4 cycles of nanoparticle-albumin bound paclitaxel (nab-P), a novel taxane formulation, with concurrent bevacizumab followed by maintenance bevacizumab for 1 year of VEGF-targeted therapy was evaluated in women with HER2-normal operable breast cancer; the regimen proved to be safe.
Correlative studies exploring the relationship between serial blood pressure and plasma renin activity measurements and the incidence of bevacizumab-mediated hypertension, a well-documented sequela of bevacizumab administration, have also recently been reported. Blood pressure and plasma renin activity measurements over time did not appear to be predictors of the development of hypertension, although baseline systolic and mean arterial pressures did. A phase III study of AC-T chemotherapy with or without bevacizumab in women with node-positive or high-risk node-negative HER2-normal breast cancer (ECOG 5103) is ongoing. It is anticipated that the results of this study will provide further insights into the role of bevacizumab in the adjuvant setting and ideally, through correlative studies, insights into the mechanisms of various bevacizumab-mediated toxicities including hypertension.
Cardiac Safety with Novel Adjuvant Strategies
Anthracyclines are one of the most active agents in breast cancer. However, administration of anthracyclines is also associated with significant short- and long-term risks of irreversible cardiotoxicity, which often manifests clinically as congestive heart failure. This risk may be further increased with the administration of selected targeted therapies including trastuzumab or bevacizumab.
In the pivotal study of dose-dense treatment, CALGB 9741, the risk of grade 3 or 4 cardiac events with every-2-weekly AC-T was 1%, versus 2.5% with the conventionally scheduled regimen.[24,25] However, in the pivotal North American adjuvant trastuzumab trials, a 6.7% cardiac event rate resulting in study withdrawal was observed after 4 cycles of every-3-weekly AC.
To further evaluate cardiac safety with the dose-dense AC strategy, investigators at Memorial Sloan-Kettering Cancer Center pooled data from three sequential adjuvant pilot studies. In each of these studies, dose-dense AC was administered with or without bevacizumab, and cardiac safety was the primary endpoint. Notably, no withdrawals due to asymptomatic left ventricular ejection fraction (LVEF) declines in the 214 evaluable patients were observed. Therefore, adjuvant dose-dense AC does not appear to be associated with significant short-term changes in LVEF when administered alone or in combination with bevacizumab and is expected to remain a foundation for many future studies of novel targeted agents.
Key Points• Gene-profiling techniques are making it possible to identify the subsets of women with breast cancer who are likely to derive benefit from specific chemotherapy and targeted treatment strategies.
• Some subsets of patients may be able to forego an anthracycline when a taxane is being administered, although more clarity on this issue may come from an upcoming meta-analysis.
• Consistent benefits have been reported with chemotherapy and trastuzumab across all pivotal adjuvant trastuzumab studies.
• Adjuvant dose-dense AC does not appear to be associated with significant short-term changes in LVEF when administered alone or in combination with bevacizumab and is expected to remain a foundation for many future studies of novel targeted agents.
Although improvements in the incidence rates of breast cancer have recently been reported in the United States, a significant proportion of women with early-stage disease still experience a distant relapse and ultimately die of metastatic breast cancer-related complications despite adequate locoregional and systemic therapy. Consequently, to optimize outcomes for women with early-stage breast cancer, ongoing therapeutic innovations are critical. Recently, notable strides have been made in individualizing treatment recommendations through advances in gene profiling; administration of conventional chemotherapy regimens through innovations in drugs, scheduling, and delivery; and the successful translation of observations in basic science into clinical benefits through targeted therapies. It is anticipated that further insights into the pathophysiology of breast cancer and the identification of specific subtypes will ultimately permit further refinements to the adjuvant treatment paradigm. In turn, it is hoped that treatments that are increasingly tailored to the biology of an individual's tumor will ultimately result in improved outcomes, and ideally, even cures, for all women with early-stage breast cancer.
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