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Updates in adjuvant systemic treatment of breast cancer
u p d a t e o n c a n c e r t h e r a p e u t i c s 2 ( 2 0 0 7 ) 193–199
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journal homepage: www.updateoncancer.com
Updates in adjuvant systemic treatment of breast cancer Heather L. McArthur ∗ , Clifford A. Hudis 1 Breast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, United States
a r t i c l e
i n f o
a b s t r a c t
Keywords:
Breast cancer is a significant public health burden with more than 200,000 new cases
Breast cancer
diagnosed in the United States each year. Although many incident cases represent local-
Early stage
ized disease, a significant proportion of women with early stage breast cancer eventually
Chemotherapy
experience a distant relapse and ultimately die of metastatic breast cancer complications.
Adjuvant
Consequently, investigators strive to improve the adjuvant treatment paradigm and thus, optimize outcomes for women with early stage breast cancer. Within the last year a study describing a decline in incident breast cancer cases in the United States was reported. In addition, the results from a number of notable adjuvant treatment studies were reported or updated. Innovations in taxane-containing strategies and dose dense chemotherapy strategies were prominently featured. In addition, a number of insights pertaining to the treatment of women with HER2-positive breast cancer were reported. An overview of selected recently reported studies will be reviewed here. © 2007 Elsevier Ltd. All rights reserved.
1.
Introduction
Breast cancer is global public health burden with more than one million new cases diagnosed worldwide [1] and more than 200,000 new cases diagnosed in the United States each year (American Cancer Society). Although an increasing proportion of new breast cancer diagnoses represent potentially curable early stage disease, a significant proportion of these women will experience a relapse. As a result, more than 40,000 breast cancer-related deaths are anticipated in the United States each year. Consequently, investigators strive to further delineate the pathophysiology of breast cancer and develop therapeutic innovations in order to minimize individual recurrence risk and optimize the potential for cure. Within the last year, a number of insights and therapeutic innovations in the management of early stage breast cancer were reported. Selected highlights will be reviewed here.
∗
2. Incident breast cancer cases in the United States One of the most highly publicized breast cancer-related studies within the past year reported a decline in incident breast cancer cases. At the 2006 San Antonio Breast Cancer Symposium (SABCS), Ravdin and colleagues demonstrated a sharp decline in age-adjusted incident breast cancer cases among women in the United States in 2003 compared with 2002 [2,3]. Although the incidence of new breast cancer diagnoses remained stable through 2004, an 8.6% decline in the ageadjusted annual incidence rate was observed from 2001. This decline was evident only for women 50 years of age or older and was more pronounced for women with estrogen-receptor positive (ER+) breast cancers compared to those with ERnegative disease. This trend was ascribed primarily to the early
Corresponding author. Tel.: +1 646 888 4551; fax: +1 646 888 4555. E-mail addresses: [email protected] (H.L. McArthur), [email protected] (C.A. Hudis). 1 Tel.: +1 646 888 4551; fax: +1 646 888 4555. 1872-115X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.uct.2007.11.001
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reports of the Women’s Health Initiative whereby deleterious effects of hormone replacement therapy were reported, resulting in a subsequent decline in hormone replacement therapy prescriptions among post-menopausal women in the United States [4]. In fact, after an increased incidence of coronary artery disease and incident breast cancer cases with hormone replacement therapy were reported in 2002, HRT use declined by 38% by the end of that year [5].
3.
In situ breast cancer
Pre-invasive breast cancers (either ductal or lobular carcinoma in situ) are indicators of increased risk for the development of invasive disease. As such, these lesions are potential targets for interventions aimed at reducing the rates of subsequent development of invasive cancers. Several relevant studies were reported at the 2007 American Society of Clinical Oncology (ASCO) annual meeting. In one study, investigators screened the Surveillance Epidemiology and End Results (SEER) database for incident in situ cases diagnosed between 1988 and 2003 [6]. Selected tumor and patient characteristics for the 88,285 identified incident cases were evaluated and outcomes reported. Of these, 66% and 12% represented DCIS and LCIS, respectively. Approximately one-third were treated with breast conserving surgery (BCS) alone, one-third with BCS with irradiation and one-third with total mastectomy. There was no difference in disease-specific survival demonstrated for women treated with BCS and irradiation compared with total mastectomy. These findings were consistent with the results of the Oxford overview meta-analysis [7]. Three National Surgical Adjuvant Breast and Bowel Project (NSABP) DCIS trials were also updated this year [8]. NSABP B17 evaluated BCS with or without irradiation; NSABP B24 evaluated BCS and irradiation followed by tamoxifen versus placebo; and NSABP B35 evaluated BCS and irradiation followed by tamoxifen versus anastrozole. As anticipated, the majority of observed recurrences among women with DCIS treated with BCS were ipsilateral breast tumor recurrences (IBTRs). The addition of radiotherapy conferred a 59% reduction in the risk of invasive IBTR. Few locoregional or distant failures were observed in the absence of an invasive-IBTR. In a combined analysis of B17 and B24, approximately one-half of IBTRs were invasive. However, only 0.84% of pts treated with BCS experienced a breast cancer-related death after developing an invasive IBTR.
4.
Advances in adjuvant chemotherapy
The optimal adjuvant chemotherapy strategy for women with early stage breast cancer has not yet been determined. In an ideal treatment paradigm, subgroups of women who derive significant benefit from a given treatment strategy would be clearly identified and offered treatment, while subgroups who derive no significant benefit would be spared the potentially deleterious effects of treatment. This type of individualized risk-benefit calculus is illustrated by the taxane example. The introduction of taxanes into the adjuvant treatment strategy represented a milestone in therapeutic innovation with
significant benefits demonstrated in a number of adequately powered randomized trials. However, taxane-containing regimens are also associated with significant rates of short and long-term toxicity. Thus, investigators strive to further characterize the risk-benefit calculus for subgroups of women with early stage breast cancer, so that taxane-based strategies may be tailored to the appropriate populations.
5. Taxane-containing chemotherapy strategies 5.1.
Efficacy of adjuvant taxane-containing regimens
Several independent studies have now reported improved outcomes for women with early stage breast cancer treated with adjuvant taxane-containing regimens. The overall efficacy of this strategy was recently confirmed in both a pooled analysis and a meta-analysis [9,10]. In the pooled analysis of 15,598 patients participating in nine adjuvant taxane trials, significant disease free survival (DFS) benefits were reported both overall (RR 0.86; p = .00001) and in the lymph node-positive subset (RR 0.84; p = 0.0001) [9]. Survival benefits were also reported both overall (RR 0.87; p = 0.0001) and in the lymph node-positive subset (RR: 0.84; 95% CI, 0.77–0.92; p = 0.0001). The absolute benefits in DFS and overall survival (OS) in favor of taxane-containing regimens ranged from 3.3% to 4.6% and from 2.0% to 2.8%, respectively. In a recently reported metaanalysis of 18,304 women participating in 12 adjuvant taxane studies, the hazard ratio (HR) for OS was 0.81 (p < 0.00001) in favor of the taxane-containing regimens [10]. Thus, the incorporation of taxanes into the adjuvant strategy confers significant overall survival benefits. Whether all subgroups, particularly women with node-negative disease, derive benefit from adjuvant taxane therapy remains uncertain. The metaanalysis on this topic by the Early Breast Cancer Trialists’ Collaborative Group is anticipated.
5.2.
Evaluation of taxane formulations
Determination of the ideal adjuvant taxane formulation, dose and schedule is also an active area of investigation. Eastern Cooperative Oncology Group (ECOG) 1199, for example, evaluated weekly versus q3 weekly schedules of paclitaxel (80 mg/m2 /dose versus 175 mg/m2 /dose, respectively) or docetaxel (35 mg/m2 /dose versus 100 mg/m2 /dose, respectively) after four cycles of q3 weekly adriamcycin/cyclophosphamide (AC) at conventional doses (60 and 600 mg/m2 /dose). Preliminary results were reported in 2005, with no significant benefit observed with either taxane or schedule [11]. However, a trend was observed toward a DFS benefit with weekly paclitaxel administration. In 2007, ECOG 1199 was updated for the 4950 women eligible for analysis after a median followup period of 63.8 months [12]. Despite the initial report in 2005 of a trend toward a DFS benefit with weekly paclitaxel administration, there was no difference with either taxane or schedule at the time of the updated analysis. However, significant differences were observed in the toxicity profiles of each regimen. For example, the incidence of grade 3/4 febrile neutropenia was 16% in the q3 weekly docetaxel arm ver-
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sus ≤1% in the other study arms. In an exploratory subset analysis, there was an apparent benefit with the weekly paclitaxel regimen in the hormone receptor-negative population and with the q3 weekly docetaxel regimen in the hormone receptor-positive population. Exploratory analyses, although provocative and hypothesis generating, must be interpreted with caution.
5.3.
Evaluation of taxane schedules
The role of sequencing in adjuvant anthracycline and taxane chemotherapy administration has also been investigated. Traditionally, when sequential adjuvant anthracycline-taxane therapy is planned, the anthracycline is typically administered prior to the taxane. This sequencing convention was recently challenged in a randomized phase II study evaluating 4 cycles of dose-dense docetaxel (75 mg/m2 ) before or after 4 cycles of conventional dose AC (60/600 mg/m2 ) [13]. Upfront docetaxel administration was associated with decreased dose reductions and superior relative dose intensity (RDI). However, whether the increased RDI will translate into improved efficacy is uncertain. Sequential versus concurrent anthracycline-taxane strategies have also been evaluated. In a recent phase III study, 617 patients with node-positive operable breast cancer were randomized to receive adjuvant epirubicin either sequentially or concurrently with either paclitaxel or docetaxel [14]. In an exploratory analysis, there was no significant DFS difference between the study arms. Furthermore, consistent with ECOG 1199, the superiority of a specific taxane was not demonstrated. In BIG 2-98, women with node positive breast cancer were randomized to one of four arms: A75 x4 → CMF x3, AC60/600 × 4 → CMFx3, A75 × 3 → T100 × 3 → CMF × 3 or AT 50/75 × 4 → CMF × 3 (where T = docetaxel) [15]. The results of this study were originally reported at ASCO 2006. Although the sequential A–T arm proved superior to the AT and A arms for DFS, there was no OS benefit observed with any of the evaluated regimens. This study was recently updated with a CNS substudy evaluating incident brain metastases detected postmortem [16]. In this substudy, although the taxane-containing strategies were associated with higher rates of abnormal CSF cytology and abnormal MRIs, no differences in CNS relapse rates at death between the taxane and non-taxane cohorts were observed.
5.4. Estrogen receptor (ER) expression and taxane efficacy The potential relationship between estrogen receptor (ER) expression and taxane efficacy was evaluated in a pooled analysis of 3490 patients participating in two very different Breast Cancer International Research Group studies: (BCIRG) 001 and PACS 01 [17–19]. In BCIRG 001, concurrent adjuvant docetaxel, adriamycin and cyclophosphamide (TAC) versus concurrent 5-fluourouracil, adriamycin and cyclophosphamide (FAC) was evaluated with 5-year DFS (75% versus 68%,) p = 0.001) and OS (87% versus 81%, p = 0.008) benefits demonstrated with the taxane-containing regimen [18]. In PACS 01, 6 cycles of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were compared to a sequential regimen of 3 cycles of FEC
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followed by 3 cycles of docetaxel (FEC-D) showing improved 5-year DFS (78.4% versus 73.2%, p = 0.011) and OS (90.7% versus 86.7%, p = 0.14) for the taxane-containing regimen [19]. In the recent analysis of pooled data from the two studies, DFS and OS benefits were reported for both the ER-positive and ER-negative cohorts [17]. Specifically, the hazard ratio for DFS was 0.69 versus 0.79 and the hazard ratio for death was 0.69 versus 0.70 for the ER-positive and ER-negative cohorts, respectively. However, the test for interaction between ER status and chemotherapy regimen was not statistically significant. Given that ER positivity has proven predictive of response to anthracycline-based chemotherapy in prior studies [20], these investigators also explored the predictive capacity of ER-positivity for taxane responsiveness. In this analysis, the relative efficacy of docetaxel did not appear to be significantly lower in patients with strongly ER-positive tumors compared to those with weakly or intermediately ER-positive tumors but the confounding effects of dose size, number, and specific drugs used limit the utility of this result except to say that a global taxane and hormone receptor interaction is unlikely to be absolute.
6.
Dose density
The dose dense strategy aims to optimize cell kill by sequentially eradicating the numerically dominant, rapidly proliferating cell populations followed by eradication of more indolent, resistant cells [21,22]. Since the reporting of significant survival benefits with the administration of dose dense adjuvant adriamycin, cyclophosphamide and paclitaxel in Cancer and Leukemia Group B (CALGB) 9741 [23,24], the dose dense strategy has been evaluated in a number of other settings. For example, the AGO trial of dose dense epirubicin, paclitaxel and cyclophosphamide (ETC) versus a conventional schedule of EC followed by T was recently reported [25]. In this study, 1284 women with “high risk,” node-positive early stage breast cancer were randomized to a sequential course of 3 cycles of E, T and C (150/225/2500 mg/m2 ) for a total of 9 cycles administered every 2 weeks with G-CSF support or 4 cycles of q3 weekly EC (90/600 mg/m2 ) followed by 4 cycles of q3 weekly T at 175 mg/m2 . After a median 62-month followup period, the dose dense strategy conferred significant OS benefits (82% versus 77%, p = 0.029). These results represent the most impressive survival benefits to date in this high risk population. However, the generalizability of these results is somewhat limited by the introduction of both dose density and dose intensity into the study schema. In the context of other studies, however, which have demonstrated a limited dose–response relationship for all three active components in the AGO regimen in the evaluated dose ranges, we can envision the study as delivering the same functional doses of the three drugs. Consequently, one may conclude that the dose dense schedule more than compensated for the decreased number of drug administrations. In another recently reported study of dose-density, National Cancer Institute of Canada (NCIC) MA.21, patients were stratified by nodal status, ER status and primary surgery to 6 cycles of oral cyclophosphamide, epirubicin and 5-fluorouracil (CEF), 4 cycles of adriamycin and cyclophos-
CEF = oral cyclophosphamide/epirubicin/5-fluorouracil; AC-T = adriamycin/cyclophosphamide and paclitaxel; EC-T = epirubicin/cyclophosphamide and paclitaxel; D = day.
N/A 175 mg/m2 IV D1 175 mg/m2 IV D1
Total (mg)
720 240 720 60 mg/m IV D1 and D8 60 mg/m2 IV D1 120 mg/m2 IV D1 CEF AC-T EC-T
q3w q3w q2w
6 8 10
2
Per cycle
Anthracycline Total cycles Schedule
Table 1 – National Cancer Institute of Canada (NCIC) MA.21 schema
A number of the pivotal adjuvant trastuzumab (Herceptin) trials, originally reported in 2005, were recently updated [27–30]. In HERA, women with node-positive or “high risk” node negative breast cancer were randomized to observation, 1 year of adjuvant trastuzumab or 2 years of trastuzumab after their primary chemotherapy [27]. In the experimental arms, trastuzumab was administered at an initial dose of 8 mg/kg and then 6 mg/kg every 3 weeks thereafter. In 2005, a significant 2-year DFS benefit was observed with 1 year of adjuvant trastuzumab compared with observation (85.8% versus 77.4%, respectively; p < 0.0001). In the recent update, after a median 2-year follow-up period, an OS benefit was reported [28]. Specifically, the unadjusted HR for the risk of death with trastuzumab compared with observation alone was 0.66 (p = 0.0115). Efficacy results from the 2-year trastuzumab treatment arm are still unreported. Similar results were observed in an update of the joint analysis of N9831 and NSABP B31. In these clinical trials, trastuzumab was administered concurrently with paclitaxel after four cycles of q3 weekly AC and then either weekly or q3 weekly, respectively, for a total 1 year duration of trastuzumab therapy [29,30]. In the updated analysis, Perez and colleagues confirmed that the previously reported benefits of trastuzumab therapy were sustained. Specifically, after a median follow-up period of 2.9 years, the reported 4-year DFS was 85.9% versus 73.1% and the reported 4-year OS was 92.6% versus 89.4% in favor of the trastuzumab study arms. Another pivotal adjuvant trastuzumab trial, BCIRG 006, was also updated [31,32]. In this study, patients were randomized to 4 cycles of AC followed by 4 cycles of docetaxel (AC-T), AC-T with trastuzumab initiated with docetaxel and administered for a total duration of 1 year (AC-TH), or 6 cycles of docetaxel/carboplatin with trastuzumab (TCH) administered concurrently and then administered for a total duration of 1 year. The results of a planned interim analysis were reported in 2005 with a HR of 0.49 (p < 0.0001) for AC-TH and 0.61 for TCH (p < 0.0002) compared with the control arm [31]. In an exploratory analysis, women with breast cancers exhibiting co-amplification of both HER2 and topoisomerase II␣, the DNA replication and recombination enzyme targeted by anthra-
Taxane
7. Advances in targeted therapy with trastuzumab
75 mg/m2 po D1–14 600 mg/m2 IV D1 830 mg/m2 IV D1
Cyclophos-phamide
5FU
phamide followed by 4 cycles of paclitaxel (AC-T) or a dose dense strategy of 6 cycles of epirubicin and cyclophosphamide followed by 4 cycles of paclitaxel (EC-T) administered every 2 weeks (Table 1) [26]. At the time of the first interim analysis, the adjusted 3-year RFS was 90.1%, 89.5% and 85.0%, for the CEF, EC-T and AC-T regimens, respectively. In an exploratory analysis, a non-significant trend favoring EC-T was observed when compared with CEF among the ER-negative subgroup (HR 0.78, p = 0.23). The superiority of CEF and dose-dense ECT for RFS compared with conventionally scheduled AC-T and the equivalence to date with either of the former regimens led the authors to conclude that taxanes may not be indicated for all patients. Further analyses with longer follow-up are anticipated.
500 mg/m2 D1 and D8 N/A N/A
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Regimen
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cyclines, appeared to derive a therapeutic advantage with anthracycline-trastuzumab therapy. Conversely, a differential benefit with anthracycline-trastuzumab therapy was not observed among women without this co-amplification. Thus, it was postulated that women without the co-amplification may be able to forgo the anthracycline component of these regimens, thereby avoiding the risk of cardiotoxicity associated with anthracycline-trastuzumab co-administration. In the recently reported second interim analysis, DFS benefits were sustained for both trastuzumab-containing arms (HR 0.61 for AC-TH versus AC-T and 0.67 for TCH versus AC-T), although the magnitude of the benefit was diminished compared with the first analysis [31,32]. Most notably, however, in the second interim analysis, the previously reported predictive capacity of HER2 and topoisomerase II␣ gene co-amplification was significantly diminished compared with the first interim analysis. Thus, whether there is a subset of women with HER2-positive breast cancer who may forgo anthracyclinecontaining regimens and the associated risk of cardiotoxicity remains uncertain.
8.
9.
Trastuzumab-mediated cardiotoxicity
Trastuzumab-mediated cardiotoxicity is an important clinical concern, particularly when trastuzumab is administered in conjunction with an anthracycline. A number of cardiac safety updates in the pivotal trastuzumab trials were recently reported. The N9831 investigators reported that no further cardiac events were observed at year 3 compared with year 1, with a cumulative incidence of cardiac events of 2.5% versus 0.2% in the trastuzumab versus control arms, respectively [30]. One cardiac death was observed in the control arm, but no cardiac events have been observed in the trastuzumab study arms to date. The NSABP B31 investigators reported similarly stable cardiac incident rates of 4.1% versus 0.8% at 3 years and 3.8% versus 0.9% at 5 years with trastuzumab versus not, respectively [34]. These investigators also proposed a clinical prediction model for trastuzumab mediated cardiac events incorporating age, anti-hypertensive medication status and baseline left ventricular ejection fraction. The resulting cardiac risk score aims to predict cumulative risk of incident cardiac events with anthracycline-trastuzumab therapy.
HER2 expression and chemosensitivity
Investigators endeavor to identify subsets of women who benefit from specific chemotherapy regimens. In a recent pooled analysis of the subset analyses from seven randomized control trials, Gennari and coworkers reported a 29% reduction in relapse risk and a 27% reduction in risk of death among adjuvant trastuzumab-na¨ıve, anthracycline-treated women with HER2-overexpressing breast cancer when compared with the non-overexpressing cohort [33]. The authors concluded that the superiority of anthracycline-containing adjuvant chemotherapy regimens appear to be limited to the HER2-overexpressing cohort. There was no observed residual effect of anthracycline-based chemotherapy over non-anthracycline-based chemotherapy among women with HER2-negative breast cancers. The enhanced sensitivity of HER2-overexpressing breast cancers to anthracyclines is postulated to reflect, in part, co-amplification of HER2 and topoisomerase II␣. Although the impact of coamplification is not yet well defined, these efforts reflect the evolving paradigm shift in adjuvant management strategies, whereby chemotherapy recommendations are increasingly tailored to the biology of individual tumors. Importantly, these data were derived entirely in the pre-trastuzumab era and their significance in settings where the antibody is routinely administered is uncertain.
10.
HER2 status determination
Significant controversy has recently arisen around HER2 status determination. HER2 status is currently determined by measuring HER2 protein expression by immunohistochemistry (IHC) and/or HER2 gene amplification by fluorescence in situ hybridization (FISH). It is reasonable to expect that an increase in the levels of the trastuzumab target, namely the HER2 receptor, would confer additional therapeutic benefit. Conversely, it is reasonable to expect that trastuzumab therapy would confer no significant benefits in the absence of HER2 amplification or overexpression. However, a recent analysis of the central HER2 testing performed in the large, randomized North American adjuvant trastuzumab trial, NSABP B31, suggested that the benefits seen with adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors [35]. In NSABP B31, women were eligible for enrollment if they had IHC 3+ or FISH+ HER2-positive breast cancer as determined centrally or at an approved reference lab [29]. For the 1795 enrolled patients, 174 (9.7%) of tumors were originally classified as HER2-positive but later proved IHC-negative and FISH-negative for HER2 on central lab review. However, a consistent DFS benefit was observed in every subset of women on the study, including those women with IHC-negative, FISH-
Table 2 – HER2 testing and RR in NSABP B31 study of adjuvant trastuzumab Category FISH+ FISH− IHC 3+ IHC− (0, 1+, 2+) FISH− IHC− Reprinted with permission [35].
N (ACT/ACTH) 1588 (789/799) 207 (114/93) 1488 (740/748) 299 (161/138) 174 (92/82)
N of events ACT/ACTH 160/85 23/8 151/82 32/10 20/7
RR (95% CI)
p-value
0.47 (0.36–0.61) 0.40 (0.18–0.89) 0.48 (0.37–0.63) 0.32 (0.16–0.65) 0.34 (0.14–0.80)
<0.0001 0.026 <0.0001 0.0017 0.014
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negative HER2 status on central review (RR 0.34, p = 0.014) (Table 2). These findings may seem discordant with prior studies such as CALGB 9840, which demonstrated no benefit with trastuzumab therapy in women with HER2-normal breast cancer in the metastatic setting but in the latter study patients were randomized only after their local lab first identified them as non-overexpressing [36]. The critical distinction is that the patients randomized on the adjuvant trials were first called positive by their local labs and later called negative centrally. Hence, potential explanations for the NSABP B31 data include the possibility of false negative results on central lab testing, problems with or hetereogeneity within the specimens provided for evaluation or some as yet undetermined biologic explanation. Until this issue is fully elucidated, and given the significant survival improvements demonstrated in the adjuvant trastuzumab trials, it is reasonable to offer adjuvant trastuzumab to any woman whose breast cancer has ever been reported as HER2-positive, even in the face of discordant results from another lab. To facilitate decisions regarding HER2 testing, the ASCO published guidelines on this topic earlier this year.
11.
Conclusions
Although the incidence of one type of early stage breast cancer appears to be on the decline in the United States, the optimal treatment paradigm for all types has not yet been determined. Until we are able to successfully cure all women with early stage disease, ongoing refinements of current management strategies are anticipated. Recently, successful variations of taxane-containing regimens and applications of the dose dense strategy have been reported. Furthermore, there has been a reassuring stabilization of cumulative trastuzumabmediated cardiotoxicity events in the adjuvant setting with longer follow-up. However, the identification of biological breast cancer features that accurately predict responsiveness to conventional chemotherapy and/or targeted therapy remains an ongoing area of investigation. We hope that further insights into the pathophysiology of breast cancer will permit further refinements of the adjuvant systemic therapy paradigm. As a consequence, it is anticipated that adjuvant therapy recommendations will become increasingly tailored to the affected individual and the biology of their cancer.
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(ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). In: San Antonio Breast Cancer Symposium. San Antonio; 2004. Norton L, Simon R, Brereton J, Bogden A. Predicting the course of Gompertzian growth. Nature 1976;264:542–5. Norton L. A Gompertzian model of human breast cancer growth. Cancer Res 1988;48:7067–71. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21(8):1431–9. Hudis C, Citron M, Berry D, et al. Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. In: San Antonio Breast Cancer Symposium. San Antonio; 2005. Moebus VJ, Lueck HJ, Thomssen C, et al. Dose-dense sequential chemotherapy with epirubicin (E), paclitaxel (T) and cyclophosphamide (C) (ETC) in comparison to conventional dosed chemotherapy in high-risk breast cancer patients (≥4 + LN). Mature results of an AGO-trial. In: San Antonio Breast Cancer Symposium. San Antonio; 2006. Burnell M, Levine M, Chapman JA, et al. A randomized trial of CEF versus dose dense EC followed by paclitaxel versus AC followed by paclitaxel in women with node positive or high risk node negative breast cancer, NCIC CTG MA.21: results of an interim analysis. In: San Antonio Breast Cancer Symposium. San Antonio; 2006. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–72. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007;369(9555):29–36. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353(16):1673–84.
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[30] Perez EA, Romond EH, Suman VJ, et al. Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. Proc ASCO 2007;25(18S):512. [31] Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. In: San Antonio Breast Cancer Symposium. San Antonio; 2005. [32] Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC → T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC → TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients. In: San Antonio Breast Cancer Symposium. San Antonio; 2006. [33] Gennari A, Sormani MP, Puntoni M, Bruzzi P. A pooled analysis on the interaction between HER-2 expression and responsiveness of breast cancer to adjuvant chemotherapy. In: San Antonio Breast Cancer Symposium. San Antonio; 2006. [34] Rastogi P, Jeong J, Geyer CE, et al. Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC) → paclitaxel (T) vs. AC → T with trastuzumab(H). Proc ASCO 2007;25(18S):LBA513. [35] Paik S, Kim C, Jeong J, et al. Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors: central testing results from NSABP B-31. Proc ASCO 2007;25(18S):511. [36] Seidman AD, Berry D, Cirrincione C, et al. CALGB:9840 Phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3 h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. Proc ASCO 2004;22(14S):512.
available at www.sciencedirect.com
journal homepage: www.updateoncancer.com
Updates in adjuvant systemic treatment of breast cancer Heather L. McArthur ∗ , Clifford A. Hudis 1 Breast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, United States
a r t i c l e
i n f o
a b s t r a c t
Keywords:
Breast cancer is a significant public health burden with more than 200,000 new cases
Breast cancer
diagnosed in the United States each year. Although many incident cases represent local-
Early stage
ized disease, a significant proportion of women with early stage breast cancer eventually
Chemotherapy
experience a distant relapse and ultimately die of metastatic breast cancer complications.
Adjuvant
Consequently, investigators strive to improve the adjuvant treatment paradigm and thus, optimize outcomes for women with early stage breast cancer. Within the last year a study describing a decline in incident breast cancer cases in the United States was reported. In addition, the results from a number of notable adjuvant treatment studies were reported or updated. Innovations in taxane-containing strategies and dose dense chemotherapy strategies were prominently featured. In addition, a number of insights pertaining to the treatment of women with HER2-positive breast cancer were reported. An overview of selected recently reported studies will be reviewed here. © 2007 Elsevier Ltd. All rights reserved.
1.
Introduction
Breast cancer is global public health burden with more than one million new cases diagnosed worldwide [1] and more than 200,000 new cases diagnosed in the United States each year (American Cancer Society). Although an increasing proportion of new breast cancer diagnoses represent potentially curable early stage disease, a significant proportion of these women will experience a relapse. As a result, more than 40,000 breast cancer-related deaths are anticipated in the United States each year. Consequently, investigators strive to further delineate the pathophysiology of breast cancer and develop therapeutic innovations in order to minimize individual recurrence risk and optimize the potential for cure. Within the last year, a number of insights and therapeutic innovations in the management of early stage breast cancer were reported. Selected highlights will be reviewed here.
∗
2. Incident breast cancer cases in the United States One of the most highly publicized breast cancer-related studies within the past year reported a decline in incident breast cancer cases. At the 2006 San Antonio Breast Cancer Symposium (SABCS), Ravdin and colleagues demonstrated a sharp decline in age-adjusted incident breast cancer cases among women in the United States in 2003 compared with 2002 [2,3]. Although the incidence of new breast cancer diagnoses remained stable through 2004, an 8.6% decline in the ageadjusted annual incidence rate was observed from 2001. This decline was evident only for women 50 years of age or older and was more pronounced for women with estrogen-receptor positive (ER+) breast cancers compared to those with ERnegative disease. This trend was ascribed primarily to the early
Corresponding author. Tel.: +1 646 888 4551; fax: +1 646 888 4555. E-mail addresses: [email protected] (H.L. McArthur), [email protected] (C.A. Hudis). 1 Tel.: +1 646 888 4551; fax: +1 646 888 4555. 1872-115X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.uct.2007.11.001
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reports of the Women’s Health Initiative whereby deleterious effects of hormone replacement therapy were reported, resulting in a subsequent decline in hormone replacement therapy prescriptions among post-menopausal women in the United States [4]. In fact, after an increased incidence of coronary artery disease and incident breast cancer cases with hormone replacement therapy were reported in 2002, HRT use declined by 38% by the end of that year [5].
3.
In situ breast cancer
Pre-invasive breast cancers (either ductal or lobular carcinoma in situ) are indicators of increased risk for the development of invasive disease. As such, these lesions are potential targets for interventions aimed at reducing the rates of subsequent development of invasive cancers. Several relevant studies were reported at the 2007 American Society of Clinical Oncology (ASCO) annual meeting. In one study, investigators screened the Surveillance Epidemiology and End Results (SEER) database for incident in situ cases diagnosed between 1988 and 2003 [6]. Selected tumor and patient characteristics for the 88,285 identified incident cases were evaluated and outcomes reported. Of these, 66% and 12% represented DCIS and LCIS, respectively. Approximately one-third were treated with breast conserving surgery (BCS) alone, one-third with BCS with irradiation and one-third with total mastectomy. There was no difference in disease-specific survival demonstrated for women treated with BCS and irradiation compared with total mastectomy. These findings were consistent with the results of the Oxford overview meta-analysis [7]. Three National Surgical Adjuvant Breast and Bowel Project (NSABP) DCIS trials were also updated this year [8]. NSABP B17 evaluated BCS with or without irradiation; NSABP B24 evaluated BCS and irradiation followed by tamoxifen versus placebo; and NSABP B35 evaluated BCS and irradiation followed by tamoxifen versus anastrozole. As anticipated, the majority of observed recurrences among women with DCIS treated with BCS were ipsilateral breast tumor recurrences (IBTRs). The addition of radiotherapy conferred a 59% reduction in the risk of invasive IBTR. Few locoregional or distant failures were observed in the absence of an invasive-IBTR. In a combined analysis of B17 and B24, approximately one-half of IBTRs were invasive. However, only 0.84% of pts treated with BCS experienced a breast cancer-related death after developing an invasive IBTR.
4.
Advances in adjuvant chemotherapy
The optimal adjuvant chemotherapy strategy for women with early stage breast cancer has not yet been determined. In an ideal treatment paradigm, subgroups of women who derive significant benefit from a given treatment strategy would be clearly identified and offered treatment, while subgroups who derive no significant benefit would be spared the potentially deleterious effects of treatment. This type of individualized risk-benefit calculus is illustrated by the taxane example. The introduction of taxanes into the adjuvant treatment strategy represented a milestone in therapeutic innovation with
significant benefits demonstrated in a number of adequately powered randomized trials. However, taxane-containing regimens are also associated with significant rates of short and long-term toxicity. Thus, investigators strive to further characterize the risk-benefit calculus for subgroups of women with early stage breast cancer, so that taxane-based strategies may be tailored to the appropriate populations.
5. Taxane-containing chemotherapy strategies 5.1.
Efficacy of adjuvant taxane-containing regimens
Several independent studies have now reported improved outcomes for women with early stage breast cancer treated with adjuvant taxane-containing regimens. The overall efficacy of this strategy was recently confirmed in both a pooled analysis and a meta-analysis [9,10]. In the pooled analysis of 15,598 patients participating in nine adjuvant taxane trials, significant disease free survival (DFS) benefits were reported both overall (RR 0.86; p = .00001) and in the lymph node-positive subset (RR 0.84; p = 0.0001) [9]. Survival benefits were also reported both overall (RR 0.87; p = 0.0001) and in the lymph node-positive subset (RR: 0.84; 95% CI, 0.77–0.92; p = 0.0001). The absolute benefits in DFS and overall survival (OS) in favor of taxane-containing regimens ranged from 3.3% to 4.6% and from 2.0% to 2.8%, respectively. In a recently reported metaanalysis of 18,304 women participating in 12 adjuvant taxane studies, the hazard ratio (HR) for OS was 0.81 (p < 0.00001) in favor of the taxane-containing regimens [10]. Thus, the incorporation of taxanes into the adjuvant strategy confers significant overall survival benefits. Whether all subgroups, particularly women with node-negative disease, derive benefit from adjuvant taxane therapy remains uncertain. The metaanalysis on this topic by the Early Breast Cancer Trialists’ Collaborative Group is anticipated.
5.2.
Evaluation of taxane formulations
Determination of the ideal adjuvant taxane formulation, dose and schedule is also an active area of investigation. Eastern Cooperative Oncology Group (ECOG) 1199, for example, evaluated weekly versus q3 weekly schedules of paclitaxel (80 mg/m2 /dose versus 175 mg/m2 /dose, respectively) or docetaxel (35 mg/m2 /dose versus 100 mg/m2 /dose, respectively) after four cycles of q3 weekly adriamcycin/cyclophosphamide (AC) at conventional doses (60 and 600 mg/m2 /dose). Preliminary results were reported in 2005, with no significant benefit observed with either taxane or schedule [11]. However, a trend was observed toward a DFS benefit with weekly paclitaxel administration. In 2007, ECOG 1199 was updated for the 4950 women eligible for analysis after a median followup period of 63.8 months [12]. Despite the initial report in 2005 of a trend toward a DFS benefit with weekly paclitaxel administration, there was no difference with either taxane or schedule at the time of the updated analysis. However, significant differences were observed in the toxicity profiles of each regimen. For example, the incidence of grade 3/4 febrile neutropenia was 16% in the q3 weekly docetaxel arm ver-
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sus ≤1% in the other study arms. In an exploratory subset analysis, there was an apparent benefit with the weekly paclitaxel regimen in the hormone receptor-negative population and with the q3 weekly docetaxel regimen in the hormone receptor-positive population. Exploratory analyses, although provocative and hypothesis generating, must be interpreted with caution.
5.3.
Evaluation of taxane schedules
The role of sequencing in adjuvant anthracycline and taxane chemotherapy administration has also been investigated. Traditionally, when sequential adjuvant anthracycline-taxane therapy is planned, the anthracycline is typically administered prior to the taxane. This sequencing convention was recently challenged in a randomized phase II study evaluating 4 cycles of dose-dense docetaxel (75 mg/m2 ) before or after 4 cycles of conventional dose AC (60/600 mg/m2 ) [13]. Upfront docetaxel administration was associated with decreased dose reductions and superior relative dose intensity (RDI). However, whether the increased RDI will translate into improved efficacy is uncertain. Sequential versus concurrent anthracycline-taxane strategies have also been evaluated. In a recent phase III study, 617 patients with node-positive operable breast cancer were randomized to receive adjuvant epirubicin either sequentially or concurrently with either paclitaxel or docetaxel [14]. In an exploratory analysis, there was no significant DFS difference between the study arms. Furthermore, consistent with ECOG 1199, the superiority of a specific taxane was not demonstrated. In BIG 2-98, women with node positive breast cancer were randomized to one of four arms: A75 x4 → CMF x3, AC60/600 × 4 → CMFx3, A75 × 3 → T100 × 3 → CMF × 3 or AT 50/75 × 4 → CMF × 3 (where T = docetaxel) [15]. The results of this study were originally reported at ASCO 2006. Although the sequential A–T arm proved superior to the AT and A arms for DFS, there was no OS benefit observed with any of the evaluated regimens. This study was recently updated with a CNS substudy evaluating incident brain metastases detected postmortem [16]. In this substudy, although the taxane-containing strategies were associated with higher rates of abnormal CSF cytology and abnormal MRIs, no differences in CNS relapse rates at death between the taxane and non-taxane cohorts were observed.
5.4. Estrogen receptor (ER) expression and taxane efficacy The potential relationship between estrogen receptor (ER) expression and taxane efficacy was evaluated in a pooled analysis of 3490 patients participating in two very different Breast Cancer International Research Group studies: (BCIRG) 001 and PACS 01 [17–19]. In BCIRG 001, concurrent adjuvant docetaxel, adriamycin and cyclophosphamide (TAC) versus concurrent 5-fluourouracil, adriamycin and cyclophosphamide (FAC) was evaluated with 5-year DFS (75% versus 68%,) p = 0.001) and OS (87% versus 81%, p = 0.008) benefits demonstrated with the taxane-containing regimen [18]. In PACS 01, 6 cycles of adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were compared to a sequential regimen of 3 cycles of FEC
195
followed by 3 cycles of docetaxel (FEC-D) showing improved 5-year DFS (78.4% versus 73.2%, p = 0.011) and OS (90.7% versus 86.7%, p = 0.14) for the taxane-containing regimen [19]. In the recent analysis of pooled data from the two studies, DFS and OS benefits were reported for both the ER-positive and ER-negative cohorts [17]. Specifically, the hazard ratio for DFS was 0.69 versus 0.79 and the hazard ratio for death was 0.69 versus 0.70 for the ER-positive and ER-negative cohorts, respectively. However, the test for interaction between ER status and chemotherapy regimen was not statistically significant. Given that ER positivity has proven predictive of response to anthracycline-based chemotherapy in prior studies [20], these investigators also explored the predictive capacity of ER-positivity for taxane responsiveness. In this analysis, the relative efficacy of docetaxel did not appear to be significantly lower in patients with strongly ER-positive tumors compared to those with weakly or intermediately ER-positive tumors but the confounding effects of dose size, number, and specific drugs used limit the utility of this result except to say that a global taxane and hormone receptor interaction is unlikely to be absolute.
6.
Dose density
The dose dense strategy aims to optimize cell kill by sequentially eradicating the numerically dominant, rapidly proliferating cell populations followed by eradication of more indolent, resistant cells [21,22]. Since the reporting of significant survival benefits with the administration of dose dense adjuvant adriamycin, cyclophosphamide and paclitaxel in Cancer and Leukemia Group B (CALGB) 9741 [23,24], the dose dense strategy has been evaluated in a number of other settings. For example, the AGO trial of dose dense epirubicin, paclitaxel and cyclophosphamide (ETC) versus a conventional schedule of EC followed by T was recently reported [25]. In this study, 1284 women with “high risk,” node-positive early stage breast cancer were randomized to a sequential course of 3 cycles of E, T and C (150/225/2500 mg/m2 ) for a total of 9 cycles administered every 2 weeks with G-CSF support or 4 cycles of q3 weekly EC (90/600 mg/m2 ) followed by 4 cycles of q3 weekly T at 175 mg/m2 . After a median 62-month followup period, the dose dense strategy conferred significant OS benefits (82% versus 77%, p = 0.029). These results represent the most impressive survival benefits to date in this high risk population. However, the generalizability of these results is somewhat limited by the introduction of both dose density and dose intensity into the study schema. In the context of other studies, however, which have demonstrated a limited dose–response relationship for all three active components in the AGO regimen in the evaluated dose ranges, we can envision the study as delivering the same functional doses of the three drugs. Consequently, one may conclude that the dose dense schedule more than compensated for the decreased number of drug administrations. In another recently reported study of dose-density, National Cancer Institute of Canada (NCIC) MA.21, patients were stratified by nodal status, ER status and primary surgery to 6 cycles of oral cyclophosphamide, epirubicin and 5-fluorouracil (CEF), 4 cycles of adriamycin and cyclophos-
CEF = oral cyclophosphamide/epirubicin/5-fluorouracil; AC-T = adriamycin/cyclophosphamide and paclitaxel; EC-T = epirubicin/cyclophosphamide and paclitaxel; D = day.
N/A 175 mg/m2 IV D1 175 mg/m2 IV D1
Total (mg)
720 240 720 60 mg/m IV D1 and D8 60 mg/m2 IV D1 120 mg/m2 IV D1 CEF AC-T EC-T
q3w q3w q2w
6 8 10
2
Per cycle
Anthracycline Total cycles Schedule
Table 1 – National Cancer Institute of Canada (NCIC) MA.21 schema
A number of the pivotal adjuvant trastuzumab (Herceptin) trials, originally reported in 2005, were recently updated [27–30]. In HERA, women with node-positive or “high risk” node negative breast cancer were randomized to observation, 1 year of adjuvant trastuzumab or 2 years of trastuzumab after their primary chemotherapy [27]. In the experimental arms, trastuzumab was administered at an initial dose of 8 mg/kg and then 6 mg/kg every 3 weeks thereafter. In 2005, a significant 2-year DFS benefit was observed with 1 year of adjuvant trastuzumab compared with observation (85.8% versus 77.4%, respectively; p < 0.0001). In the recent update, after a median 2-year follow-up period, an OS benefit was reported [28]. Specifically, the unadjusted HR for the risk of death with trastuzumab compared with observation alone was 0.66 (p = 0.0115). Efficacy results from the 2-year trastuzumab treatment arm are still unreported. Similar results were observed in an update of the joint analysis of N9831 and NSABP B31. In these clinical trials, trastuzumab was administered concurrently with paclitaxel after four cycles of q3 weekly AC and then either weekly or q3 weekly, respectively, for a total 1 year duration of trastuzumab therapy [29,30]. In the updated analysis, Perez and colleagues confirmed that the previously reported benefits of trastuzumab therapy were sustained. Specifically, after a median follow-up period of 2.9 years, the reported 4-year DFS was 85.9% versus 73.1% and the reported 4-year OS was 92.6% versus 89.4% in favor of the trastuzumab study arms. Another pivotal adjuvant trastuzumab trial, BCIRG 006, was also updated [31,32]. In this study, patients were randomized to 4 cycles of AC followed by 4 cycles of docetaxel (AC-T), AC-T with trastuzumab initiated with docetaxel and administered for a total duration of 1 year (AC-TH), or 6 cycles of docetaxel/carboplatin with trastuzumab (TCH) administered concurrently and then administered for a total duration of 1 year. The results of a planned interim analysis were reported in 2005 with a HR of 0.49 (p < 0.0001) for AC-TH and 0.61 for TCH (p < 0.0002) compared with the control arm [31]. In an exploratory analysis, women with breast cancers exhibiting co-amplification of both HER2 and topoisomerase II␣, the DNA replication and recombination enzyme targeted by anthra-
Taxane
7. Advances in targeted therapy with trastuzumab
75 mg/m2 po D1–14 600 mg/m2 IV D1 830 mg/m2 IV D1
Cyclophos-phamide
5FU
phamide followed by 4 cycles of paclitaxel (AC-T) or a dose dense strategy of 6 cycles of epirubicin and cyclophosphamide followed by 4 cycles of paclitaxel (EC-T) administered every 2 weeks (Table 1) [26]. At the time of the first interim analysis, the adjusted 3-year RFS was 90.1%, 89.5% and 85.0%, for the CEF, EC-T and AC-T regimens, respectively. In an exploratory analysis, a non-significant trend favoring EC-T was observed when compared with CEF among the ER-negative subgroup (HR 0.78, p = 0.23). The superiority of CEF and dose-dense ECT for RFS compared with conventionally scheduled AC-T and the equivalence to date with either of the former regimens led the authors to conclude that taxanes may not be indicated for all patients. Further analyses with longer follow-up are anticipated.
500 mg/m2 D1 and D8 N/A N/A
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Regimen
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cyclines, appeared to derive a therapeutic advantage with anthracycline-trastuzumab therapy. Conversely, a differential benefit with anthracycline-trastuzumab therapy was not observed among women without this co-amplification. Thus, it was postulated that women without the co-amplification may be able to forgo the anthracycline component of these regimens, thereby avoiding the risk of cardiotoxicity associated with anthracycline-trastuzumab co-administration. In the recently reported second interim analysis, DFS benefits were sustained for both trastuzumab-containing arms (HR 0.61 for AC-TH versus AC-T and 0.67 for TCH versus AC-T), although the magnitude of the benefit was diminished compared with the first analysis [31,32]. Most notably, however, in the second interim analysis, the previously reported predictive capacity of HER2 and topoisomerase II␣ gene co-amplification was significantly diminished compared with the first interim analysis. Thus, whether there is a subset of women with HER2-positive breast cancer who may forgo anthracyclinecontaining regimens and the associated risk of cardiotoxicity remains uncertain.
8.
9.
Trastuzumab-mediated cardiotoxicity
Trastuzumab-mediated cardiotoxicity is an important clinical concern, particularly when trastuzumab is administered in conjunction with an anthracycline. A number of cardiac safety updates in the pivotal trastuzumab trials were recently reported. The N9831 investigators reported that no further cardiac events were observed at year 3 compared with year 1, with a cumulative incidence of cardiac events of 2.5% versus 0.2% in the trastuzumab versus control arms, respectively [30]. One cardiac death was observed in the control arm, but no cardiac events have been observed in the trastuzumab study arms to date. The NSABP B31 investigators reported similarly stable cardiac incident rates of 4.1% versus 0.8% at 3 years and 3.8% versus 0.9% at 5 years with trastuzumab versus not, respectively [34]. These investigators also proposed a clinical prediction model for trastuzumab mediated cardiac events incorporating age, anti-hypertensive medication status and baseline left ventricular ejection fraction. The resulting cardiac risk score aims to predict cumulative risk of incident cardiac events with anthracycline-trastuzumab therapy.
HER2 expression and chemosensitivity
Investigators endeavor to identify subsets of women who benefit from specific chemotherapy regimens. In a recent pooled analysis of the subset analyses from seven randomized control trials, Gennari and coworkers reported a 29% reduction in relapse risk and a 27% reduction in risk of death among adjuvant trastuzumab-na¨ıve, anthracycline-treated women with HER2-overexpressing breast cancer when compared with the non-overexpressing cohort [33]. The authors concluded that the superiority of anthracycline-containing adjuvant chemotherapy regimens appear to be limited to the HER2-overexpressing cohort. There was no observed residual effect of anthracycline-based chemotherapy over non-anthracycline-based chemotherapy among women with HER2-negative breast cancers. The enhanced sensitivity of HER2-overexpressing breast cancers to anthracyclines is postulated to reflect, in part, co-amplification of HER2 and topoisomerase II␣. Although the impact of coamplification is not yet well defined, these efforts reflect the evolving paradigm shift in adjuvant management strategies, whereby chemotherapy recommendations are increasingly tailored to the biology of individual tumors. Importantly, these data were derived entirely in the pre-trastuzumab era and their significance in settings where the antibody is routinely administered is uncertain.
10.
HER2 status determination
Significant controversy has recently arisen around HER2 status determination. HER2 status is currently determined by measuring HER2 protein expression by immunohistochemistry (IHC) and/or HER2 gene amplification by fluorescence in situ hybridization (FISH). It is reasonable to expect that an increase in the levels of the trastuzumab target, namely the HER2 receptor, would confer additional therapeutic benefit. Conversely, it is reasonable to expect that trastuzumab therapy would confer no significant benefits in the absence of HER2 amplification or overexpression. However, a recent analysis of the central HER2 testing performed in the large, randomized North American adjuvant trastuzumab trial, NSABP B31, suggested that the benefits seen with adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors [35]. In NSABP B31, women were eligible for enrollment if they had IHC 3+ or FISH+ HER2-positive breast cancer as determined centrally or at an approved reference lab [29]. For the 1795 enrolled patients, 174 (9.7%) of tumors were originally classified as HER2-positive but later proved IHC-negative and FISH-negative for HER2 on central lab review. However, a consistent DFS benefit was observed in every subset of women on the study, including those women with IHC-negative, FISH-
Table 2 – HER2 testing and RR in NSABP B31 study of adjuvant trastuzumab Category FISH+ FISH− IHC 3+ IHC− (0, 1+, 2+) FISH− IHC− Reprinted with permission [35].
N (ACT/ACTH) 1588 (789/799) 207 (114/93) 1488 (740/748) 299 (161/138) 174 (92/82)
N of events ACT/ACTH 160/85 23/8 151/82 32/10 20/7
RR (95% CI)
p-value
0.47 (0.36–0.61) 0.40 (0.18–0.89) 0.48 (0.37–0.63) 0.32 (0.16–0.65) 0.34 (0.14–0.80)
<0.0001 0.026 <0.0001 0.0017 0.014
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negative HER2 status on central review (RR 0.34, p = 0.014) (Table 2). These findings may seem discordant with prior studies such as CALGB 9840, which demonstrated no benefit with trastuzumab therapy in women with HER2-normal breast cancer in the metastatic setting but in the latter study patients were randomized only after their local lab first identified them as non-overexpressing [36]. The critical distinction is that the patients randomized on the adjuvant trials were first called positive by their local labs and later called negative centrally. Hence, potential explanations for the NSABP B31 data include the possibility of false negative results on central lab testing, problems with or hetereogeneity within the specimens provided for evaluation or some as yet undetermined biologic explanation. Until this issue is fully elucidated, and given the significant survival improvements demonstrated in the adjuvant trastuzumab trials, it is reasonable to offer adjuvant trastuzumab to any woman whose breast cancer has ever been reported as HER2-positive, even in the face of discordant results from another lab. To facilitate decisions regarding HER2 testing, the ASCO published guidelines on this topic earlier this year.
11.
Conclusions
Although the incidence of one type of early stage breast cancer appears to be on the decline in the United States, the optimal treatment paradigm for all types has not yet been determined. Until we are able to successfully cure all women with early stage disease, ongoing refinements of current management strategies are anticipated. Recently, successful variations of taxane-containing regimens and applications of the dose dense strategy have been reported. Furthermore, there has been a reassuring stabilization of cumulative trastuzumabmediated cardiotoxicity events in the adjuvant setting with longer follow-up. However, the identification of biological breast cancer features that accurately predict responsiveness to conventional chemotherapy and/or targeted therapy remains an ongoing area of investigation. We hope that further insights into the pathophysiology of breast cancer will permit further refinements of the adjuvant systemic therapy paradigm. As a consequence, it is anticipated that adjuvant therapy recommendations will become increasingly tailored to the affected individual and the biology of their cancer.
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