Optimizing the management of her 2-positive early breast cancer : the clinical reality

s?&vmview=abst_detail_view&confID=65& abstractID=33873; cited May 11, 2010] 38. McArthur HL, Morris PG, Patil S, et al. Benefits of trastuzumab-ID=33873; cited May 11, 2010] 38. McArthur HL, Morris PG, Patil S, et al. Benefits of trastuzumabbased therapy for women with small, node-negative, her2-positive breast cancer [abstract 228]. Proc Am Soc Clin Oncol Breast Cancer Symp 2009;:. [Available online at: www.asco.org/ASCOv2/ Meetings/Abstracts?&vmview=abst_detail_view&confID=70& abstractID=40480; cited May 11, 2010] 39. Untch M, Gelber RD, Jackisch C, et al. Estimating the mag-ID=40480; cited May 11, 2010] 39. Untch M, Gelber RD, Jackisch C, et al. Estimating the magnitude of trastuzumab effects within patient subgroups in the hera trial. Ann Oncol 2008;19:1090–6. 40. Trudeau M, Madarnas Y, McCready D, Pritchard KI, Messersmith H, and the Breast Cancer Disease Site Group. The Role of Trastuzumab in Adjuvant and Neoadjuvant Therapy in Women with HER2/neu-Overexpressing Breast Cancer: A Clinical Practice Guideline. Evidence-based series 1-24. Section 1. Toronto: Cancer Care Ontario, Program in Evidence-Based Care; 2006. [Available online at: www.cancercare.on.ca/pdf/ pebc1-24s.pdf; cited April 27, 2010] 41. BC Cancer Agency (bcca). 041 Adjuvant Trastuzumab Therapy [Web page]. Vancouver, BC: bcca; 2009. [Available at: www. bccancer.bc.ca/HPI/CancerManagementGuidelines/Breast/ Management/041+Adjuvant+Trastuzumab+Therapy.htm; cited April 27, 2010] 42. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007;18:1133–44. 43. Mackey JR, Clemons M, Cote MA, et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian Trastuzumab Working Group. Curr Oncol 2008;15:24–35. OPTIMIZING THE MANAGEMENT OF HER2+ EBC


INTRODUCTION
About 23,000 new cases of breast cancer will be diagnosed in Canada in 2010 1 .The estimated 5400 annual deaths from breast cancer are second only to those from lung cancer as contributors to cancer-related mortality in the Canadian female population 1 .The majority of women diagnosed with breast cancer present with early-stage disease (>75%).In recent decades, a substantial decline in mortality among breast cancer patients has been attributed in part to advancements in adjuvant systemic therapy.
The outcome for early breast cancer (ebc) patients with her2 (human epidermal growth factor receptor 2)-positive disease has particularly improved since the end of the 1990s with the introduction of trastuzumab in this setting.Trastuzumab is a monoclonal antibody that binds to the extracellular domain of her2.
Several mechanisms of action underlie the antitumour effects of trastuzumab.Trastuzumab blocks her2-activated cell signalling, thereby reducing cell proliferation and restoring ability to undergo apoptosis by inhibiting the phosphatidylinositol 3 kinase/Akt pathway [2][3][4][5] , which increases cellular sensitivity to chemotherapy and radiotherapy 6 .Trastuzumab has also been shown to inhibit her2-regulated angiogenesis 3,[7][8][9] and, in preclinical models, to recruit the immune system through antibody-dependent cellular cytotoxicity, triggering activation of natural killer cell-mediated apoptosis [10][11][12] .In addition, trastuzumab has also been shown to prevent the formation of p95 her2 (a truncated active form of her2), which may lead to inhibition of tumour development 3,13 .
Optimizing the management of her2-positive early breast cancer: the clinical reality Based on efficacy data from six major randomized controlled clinical trials comparing adjuvant chemotherapy alone to adjuvant chemotherapy plus trastuzumab delivered either concurrently or in sequence, adjuvant trastuzumab has become an internationally accepted part of adjuvant systemic therapy for her2-positive ebc 14,15 .
Despite the clear benefits of adjuvant trastuzumab for the relevant patient population, there remain a number of clinical scenarios and questions in which the data are not as clear and controversy persists.For example, the 11th St. Gallen international expert consensus meeting was not able to provide a definitive recommendation regarding the use of anti-her2 therapy for patients with her2-positive node-negative tumours smaller than 1 cm in size, because of the absence of data to suggest an increased risk of disease recurrence or a significant benefit from treatment 14 .Also, the balance between cardiotoxic risk and adjuvant benefit from systemic chemotherapy continues to generate controversy.The 2010 National Comprehensive Cancer Network (nccn) guidelines recommend the need to balance the known cardiotoxicity risk of trastuzumab against the uncertain absolute benefits that may exist before considering trastuzumab treatment 15 .
The goal of this manuscript is to discuss the optimal utilization of adjuvant trastuzumab in the management of her2-positive ebc in the context of particularly common clinical scenarios: • Management of node-negative disease with tumours 1 cm or smaller in size • Management of her2-positive ebc across the spectrum of the disease (that is, nodal and steroid hormone receptor status, tumour size) • Timing of trastuzumab therapy with chemotherapy for early-stage disease: concurrent or sequential

Development of Panel Suggestions
The authors of this paper met in Toronto for a one-day conference in June 2008.The panel reviewed results of the latest trials in the neoadjuvant, adjuvant, and metastatic settings.Based on updated trial information, suggestions were formulated for the neoadjuvant and metastatic settings and were subsequently published in 2009 16,17 .
With regard to the current manuscript, the panel reviewed the available evidence regarding adjuvant trastuzumab for ebc and identified ongoing controversies awaiting data from further or completed randomized clinical trials.Based on the panel's review and discussion of the updated clinical data, suggestions were formulated for a variety of clinical scenarios.A draft manuscript was initially written by a medical writer (BW) and was reviewed and revised by two main panel members (SuV and DR) and a breast cancer fellow (SL).The final manuscript was reviewed, revised, and approved by the remaining nine panel members (MC, SC, SD, JLe, JLa, JM, KP, LP, ShV).Published and presented clinical trial results available as of January 2010 were incorporated into the present document by SL.

Conflict of Interest Disclosures
Support for the initial meeting of the Canadian advisory panel and the development of the present manuscript was provided by an unrestricted educational grant from Hoffmann-La Roche Canada.The authors received an honorarium for attending the meeting, but not for writing the manuscript.The authors are solely responsible for the content of the manuscript, with no restrictions set by the sponsor.

OVERVIEW OF THE KEY TRIALS IN HER2-POSITIVE EARLY BREAST CANCER
Results from six large multicentre randomized controlled clinical trials evaluating the role of adjuvant trastuzumab in her2-positive ebc have been reported to date.These include the Herceptin Adjuvant (hera) trial 18 , the National Surgical Adjuvant Breast and Bowel Project (nsabp) B-31 trial 19,20 , the North Central Cancer Treatment Group (ncctg) N9831 trial 20,21 , the Breast Cancer International Research Group (bcirg) 006 trial 22 , the Finland Herceptin trial (finher) 23 , and the Protocol Adjuvant dans le Cancer du Sein (pacs-04) trial 24 .Together, these trials accrued more than 14,000 women and evaluated the addition of trastuzumab to varying chemotherapeutic strategies.These trials differed substantially with respect to study design (Figure 1), patient population (Table i), and chemotherapeutic backbones.Four trials demonstrated improved disease-free survival (dfs), and three demonstrated significantly improved overall survival (os, Table ii).Updated cardiac toxicity data from these trials indicate that the rate of this toxicity varies depending on the use of anthracyclines and whether trastuzumab is given in conjunction with or after chemotherapy (Table iii).

HERA Trial
The hera trial, an international phase iii multicentre randomized open-label three-arm study, randomized patients to 1 or 2 years of adjuvant trastuzumab or observation, subsequent to completion of a minimum of 4 cycles of adjuvant or neoadjuvant chemotherapy (Figure 1).Inclusion criteria included all her2-positive node-positive or node-negative disease with a tumour size greater than 1 cm 25 and left ventricular ejection fraction (lvef) of 55% or more as measured by echocardiography or multiple-gated acquisition (muga).A total of 5102 women participated in this  24 .* Multiple chemotherapy regimens were permitted.ebC = early breast cancer; Ct = chemotherapy; rt = radiation therapy; her2 = human epidermal growth factor receptor 2; fish = fluorescence in situ hybridization; ihC = immunohistochemistry; lVef = left ventricular ejection fraction; q3w = every three weeks; n+ = node positive; n-= node negative; aC = doxorubicin, cyclophosphamide; t = paclitaxel; h = trastuzumab; qw = every week; d = docetaxel; Cb = carboplatin; auC = area under the curve; Cish = chromogenic in situ hybridization; pgr = progesterone receptor; V = vinorelbine; feC = fluorouracil, epirubicin, cyclophosphamide; ed = epirubicin, docetaxel; et = epirubicin, paclitaxel.
trial with a primary endpoint of dfs and a secondary endpoint of os.At the interim analysis, with a median follow-up of 23.5 months, the unadjusted hazard ratio (hr) for risk of a dfs event with trastuzumab versus observation alone was 0.64 [95% confidence interval (ci): 0.54 to 0.76; p < 0.0001], corresponding to an absolute improvement in dfs of 6.3% (80.6% vs. 74.3%)at 3 years 26 .The unadjusted hr for risk of death at 3 years with trastuzumab versus observation was 0.66 (95% ci: 0.47 to 0.91; p = 0.0115), resulting in an absolute os benefit of 2.7% (92.4% vs. 89.7%) 26.
Recently, Gianni et al. presented updated data from the hera trial with a median follow-up time of 4 years (Table ii).The hr for risk of an event with trastuzumab versus observation was 0.76 (95% ci: 0.66 to 0.87; p < 0.0001), corresponding to an absolute dfs improvement of 6.4% (78.6% vs. 72.2%) 18.However, the observed absolute os benefit decreased from 2.7% at 3 years to 1.6% at 4 years and was no longer statistically significant (89.3% vs. 87.7%;hr: 0.85; 95% ci: 0.70 to 1.04; p = 0.1087).Potential explanations for the loss of survival benefit include • the crossover of 65% of control patients to adjuvant trastuzumab, resulting in an improved outcome in the observation arm; and • the apparent inferiority of sequencing adjuvant trastuzumab after chemotherapy rather than in combination with chemotherapy.

Joint Analysis of the NSABP B-31 and NCCTG N9831 Trials
The nsabp B-31 trial was a U.S.-based phase iii multicentre randomized open-label trial in her2-positive ebc that assessed the addition of trastuzumab to an anthracycline-based regimen [doxorubicin and cyclophosphamide followed by paclitaxel (ac→t) every 3 weeks for 4 cycles] with 1 year of trastuzumab [ac→th (Figure 1)].Trastuzumab was initiated concurrently with the first dose of paclitaxel 19 .The ncctg N9831 trial, a similar phase iii openlabel trial, explored the efficacy of 1 year adjuvant trastuzumab given concurrently with 12 doses of weekly paclitaxel versus after 12 doses of paclitaxel (ac→th→h vs. ac→t→h) in her2-positive ebc (Figure 1) 19 .Data from these two trials, referred to as the "joint analysis," were pooled to allow for an early non-protocol analysis with sufficient statistical power to compare the two similar regimens (ac→t vs. ac→th) 19 .The primary endpoint of the joint analysis was dfs, and the secondary endpoint was os.

BCIRG 006 Trial
The international bcirg 006 phase iii open-label trial, conducted in 42 countries, randomized patients with her2-positive ebc to observation or a 1-year course of trastuzumab in conjunction with taxane chemotherapy [doxorubicin and cyclophosphamide every 3 weeks for 4 cycles, followed by docetaxel every 3 weeks for 4 cycles (ac→d vs. ac→dh), Figure 1] 22 .The bcirg 006 trial also included a non-anthracycline third treatment arm with concurrent docetaxel, carboplatin, and trastuzumab (dcbh).The primary endpoint was dfs, and the secondary endpoint was os.
Recent data from the third planned analysis of bcirg 006 revealed dfs rates of 75% (ac→d), 84% (ac→dh), and 81% (dcbh) at 65 months of follow-up (Table ii) 22 .The hr, compared with the observation arm, for ac→dh was 0.64 (95% ci: 0.53 to 0.78; p < 0.001) and for dcbh was 0.75 (95% ci: 0.63 to 0.90; p = 0.04).The dfs in the two trastuzumab arms did not differ statistically (p = 0.21).Updated data show an os of 87% in the chemotherapy-only arm compared with 92% in the ac→dh arm (hr: 0.63; 95% ci: 0.48 to 0.81; p < 0.001) or 91% in the dcbh arm (hr: 0.77; 95% ci: 0.60 to 0.99; p = 0.038).Relative to the anthracyclinecontaining arms, dcbh continued to have a superior toxicity profile, including less acute toxicity, better c Reported as 5-year cumulative incidence of cardiac events [defined as definite or probable cardiac death and chf (dyspnea with normal activity or at rest, nyha class iii or iv, and absolute drop in lvef of more than 10% to below 55% or of more than 5% and below lower level of normal)].d Reported as 3-year cumulative incidence of cardiac events (defined as symptomatic chf, definite cardiac death, or probable cardiac death).e For patients with a greater than 10% relative lvef decline: n = 1018 (ac→d); n = 1042 (ac→dh); n = 1031 (dcbh).f Reported as a greater than 10% relative lvef decline.g Reported as grade 3 or 4 chf.h Reported as a greater than 20-percentage-point decrease in lvef from baseline at one or more lvef measurements after completion of chemotherapy.i Reported as a severe decline (absolute lvef < 45%, 45%-49%, and ≥15%).Pts = patients; lvef = left ventricular ejection fraction; sig.= significant; chf = congestive heart failure; hera = Herceptin Adjuvant study; h = trastuzumab; nsabp = National Surgical Adjuvant Breast and Bowel Project; a = doxorubicin; c = cyclophosphamide; t = paclitaxel; nr = not reported; ncctg = North Central Cancer Treatment Group; bcirg = Breast Cancer International Research Group; d = docetaxel; cb = carboplatin; finher = Finland Herceptin trial; v = vinorelbine; f = fluorouracil; e = epirubicin; ns = not specified; pacs = Protocol Adjuvant dans le Cancer du Sein.quality of life 31 , and lower rates of congestive heart failure (chf) and leukemia.Interesting and provocative data related to Topo2A (topoisomerase iia protein) were also presented, suggesting that the benefit from adjuvant trastuzumab was restricted to patients who were not Topo2A co-amplified.
Data analysis on her2-positive patients was further stratified based on specific chemotherapy regimen.Patients who received d→fec plus trastuzumab versus d→fec alone had a significantly higher ddfs rate (92.5% vs. 74.1%;hr: 0.32; 95% ci: 0.12 to 0.89; p = 0.029).In contrast, patients who took v→fec plus trastuzumab versus v→fec alone did not have a significantly different ddfs rate outcome (75.2% vs. 72.0%;hr: 0.92; 95% ci: 0.47 to 1.83; p = 0.82).Overall, investigators concluded that adjuvant docetaxel (not vinorelbine) improved ddfs and that trastuzumab is a safe and effective addition, justifying further investigation of a shortened duration of trastuzumab given the improved rfs that was shown with only 9 weeks of adjuvant trastuzumab.

PACS-04 Trial
The pacs-04 trial was a phase iii multicentre trial assessing the benefits of concomitant docetaxel and epirubicin for 6 cycles every 3 weeks versus fluorouracil, epirubicin, and cyclophosphamide for 6 cycles every 3 weeks, and a second randomization randomized her2-positive patients to sequential trastuzumab every 3 weeks for 1 year or observation (fec or ed vs. fec or ed → h, Figure 1) 24 .Patients had to have proven ebc with complete resection (T1, T2, T3) and be axillary node-positive.The primary endpoint was 3-year dfs.After a median follow-up of 47 months, there was no difference in dfs (77.9% vs. 80.9%; hr: 0.86; 95% ci: 0.61 to 1.22; p = 0.41) or os (96% vs. 95%; hr: 1.27; 95% ci: 0.68 to 2.38) between the observation and trastuzumab treatment groups (Table ii).

NODE-NEGATIVE DISEASE WITH TUMOURS 1 CM OR SMALLER
On the basis of the significant dfs and os benefits established in the pivotal trials discussed earlier, adjuvant trastuzumab is now considered standard of care for patients with her2-positive ebc.However, questions persist regarding the value of trastuzumab in specific subpopulations, notably node-negative patients with small tumours (≤1 cm-that is, T1a and T1b) because they generally have been considered to have low risk for disease recurrence.Node-negative patients with T1a (>0.1 cm and ≤0.5 cm) and T1b (>0.5 cm and ≤1 cm) tumours are commonly assumed to have a low risk of recurrence relative to patients with larger tumours.However, retrospective data from tertiary care cancer centres suggest that despite small size, these node-negative tumours (that is, ≤1 cm) are at a greater risk of recurrence if they are her2-positive (Table iv).
Black et al. examined the incidence of breast cancer outcomes in a group of 164 node-negative women with her2-positive tumours T2 or lower 35 .The incidences of breast cancer outcomes in her2negative tumours were not collected.Over a median period of 5 years of postsurgical follow-up, the incidences of distant metastasis, locoregional recurrence, and contralateral cancer were similar for patients with T1a-b (≤1 cm) her2-positive versus T1c (>1 cm and ≤2 cm) her2-positive tumours.Taken together, the incidences were 19%, 15%, and 23% for women with T1a-b, T1c, and T2 tumours respectively, suggesting that even T1 breast cancer is at a higher risk of recurrence in the context of her2-positive disease 35 .
In a nationwide population-based study in Finland, Joensuu et al. analyzed 852 unilateral node-negative T1 breast cancers (including 49 T1a and 264 T1b tumours) from the Finnish Cancer Registry 36 .Expression or amplification of her2 was determined by immunohistochemistry or chromogenic in situ hybridization respectively.Contrary to common perception, a tumour size of 10 mm or smaller was not uniformly associated with low risk for distant recurrence.Patients with T1b grade 2 or 3 tumours had a significantly decreased 9-year ddfs when the her2 protein was overexpressed [ddfs: 67% (n = 11) vs. 95% (n = 54); p = 0.003] or the gene was amplified [ddfs: 67% (n = 11) vs. 92% (n = 52); p = 0.006; In an independent analysis extending over 10 years of follow-up, Chia et al. reached similar conclusions 32 .Those authors examined rates of breast cancer-specific survival (bccs) and rfs using tissue microarray series consisting of 4444 invasive breast cancers, of which 2026 were pathologically node-negative and were deemed the study cohort.A majority of the breast cancers (61%, n = 1245) were stage i breast cancers, and the median tumour size was 2.0 cm (range: 0.1-9.9cm).Patients were categorized by the biological and morphological features of the tumours, including her2 and estrogen receptor (er) status, size, and grade, as well as by use of adjuvant therapy.Chia et al. found that her2positive and er-negative status both dramatically affected outcomes in the node-negative cohort.In the entire node-negative cohort (n = 2026), her2positive tumours versus her2-negative tumours had a significantly reduced 10-year rfs (65.9% vs. 75.5% respectively, p = 0.01), decreased distant rfs (drfs: 71.2% vs. 81.8%respectively; p = 0.004), poorer bccs (75.7% vs. 86.3%,p = 0.001), along with a shortened os trend (65% vs. 74.4%,p = 0.06).In patients who had a primary tumour size of 1 cm or smaller (n = 326, 16%), a similar trend demonstrating negative outcomes in her2-positive tumours was also shown (Table iv).
Recently, Gonzalez-Angulo et al. also assessed the rfs and drfs rates of women (n = 965) with her2positive node-negative ebc with tumours 1 cm or smaller 33 .Patients were identified from the Breast Cancer Management System database of the MD Anderson Cancer Center (1990 to 2002).At a median follow-up of 74 months, there were 72 recurrences, including 34 distant recurrences.The 5-year rfs rates were 77.1% in the her2-positive group and 93.7% in the her2-negative group (p < 0.0001).The 5-year drfs rates were 86.4% in the her2-positive group and 97.2% in the her2-negative group (p < 0.0001).Patients (n = 350) from two European centres using the same inclusion criteria and similar follow-up times were also analyzed as a validation set.The validation set showed similar results.The authors concluded that her2-positive T1a-b N0 M0 tumours have a significant risk of relapse and should be considered for systemic anti-her2 adjuvant therapy.
Curigliano et al. performed a retrospective study on 150 patients with T1a-b N0 her2-positive tumours (T1a: n = 85; T1b: n = 65) who did not receive trastuzumab treatment 34 .After a median follow-up of 4.6 years, dfs was assessed.In patients with hormone receptor-positive disease, 5-year dfs was significantly VERMA et al. c This subgroup did not receive any adjuvant systemic therapy.her2+ = positive for the human epidermal growth factor 2; her2-= negative for the human epidermal growth factor 2; nr = not reported; hr = hazard ratio; ci = confidence interval.
The os in patients with her2-positive T1a-bN0 disease was similar regardless of hormone receptor status (p = 0.93).
While the foregoing retrospective analyses suggest that women in the her2-positive cohort with T1 tumours are at an increased risk of recurrence, there is little information available to assess the benefits of either chemotherapy alone or in combination with trastuzumab for this subset.
To date, support for improved outcomes with trastuzumab is available for node-negative patients taken as a whole.In the case of node-negative patients with the smallest tumours (T1a-b), support for trastuzumab treatment comes from retrospective single-institution practice studies, and while such patients were eligible for the bcirg 006 trial, there is no information available specific to this subset from this trial.
Recently, Rodrigues et al. conducted a retrospective analysis on the efficacy of adjuvant trastuzumab in 96 patients with her2-positive node-negative invasive breast carcinoma with T1a or T1b tumours 37 .Chemotherapy [anthracycline (n = 20), taxane (n = 2), sequential anthracycline/taxane (n = 18), and concurrent anthracycline-taxane (n = 1)] was given to 43% (n = 41) of the patients.Forty patients, mainly those with a poor prognosis (based on high mitotic index, high grade, and hormone-receptor negativity), received adjuvant trastuzumab, most in combination with chemotherapy (n = 37).The other 56 patients with mainly good prognoses did not receive adjuvant trastuzumab.No recurrences occurred in patients who received trastuzumab, while 5 occurred in patients who did not receive trastuzumab.Among the 5 recurrences, 4 originated in tumours that were hormone receptor-negative or high grade (or both).Based on these data, the investigators concluded that patients with node-negative disease with tumours 1 cm or smaller have a high risk of metastatic recurrence and should be treated with adjuvant trastuzumab or included in her2-targeted adjuvant trials, or both.
A retrospective study of 495 her2-positive earlystage breast cancers with 2-cm or smaller node-negative tumours was done at the Memorial Sloan-Kettering 38 Cancer Center.Two cohorts of patients from the preand post-trastuzumab eras were compared for dfs.There was a statistically significant difference noted in dfs in these two cohorts (p = 0.007).Six deaths were reported in the pre-trastuzumab era versus only one death in the trastuzumab cohort.The two groups were balanced with respect to age, size of tumour, and hormone receptor status, but 97% of the trastuzumab cohort received chemotherapy compared to only 57% of patients in the non-trastuzumab cohort.

PANEL SUGGESTIONS FOR TREATMENT IN ADJUVANT THERAPY
4.1 Considerations in the Management of Node-Negative Disease with Tumours 1 cm or Smaller

Suggestions
The biology of her2-positive disease supersedes the size of the tumour when considering use of trastuzumab in the adjuvant setting.
Trastuzumab may be considered for women with node-negative T1b (0.5-1.0 cm) tumours that also have additional high-risk prognostic factors such as young age, presence of lymphovascular invasion, grade iii cancers, or negative hormone receptor status.
The potential cardiac toxicity associated with the selected regimen always has to be weighed with the potential benefits from chemotherapy and trastuzumab.

Discussion
In the opinion of the panel, her2-positivity represents an important prognostic factor and one of several biological markers that appear to be associated with disease recurrence and other adverse outcomes, even in the context of smaller tumours and node-negative disease.These biological features should be considered carefully when deciding on adjuvant therapy.
Most panel members indicated that they would not consider trastuzumab when treating node-negative patients with T1mic (≤0.1 cm) or T1a tumours, but they all agreed that this treatment might be justified in her2-positive T1b tumours [32][33][34][35][36] .The panel also agreed that other factors suggesting a high recurrence risk such as high tumour grade, lymphovascular invasion, er-negative status and young age should also be taken into consideration.

Suggestion
Trastuzumab should serve as the standard of care in women with her2-positive ebc, with consideration for disease and patient characteristics such as nodal status, hormone receptor status, and tumour size (>1 cm).
OPTIMIZING THE MANAGEMENT OF HER2+ EBC In the recently published pre-planned subgroup analysis of the hera study, Untch et al. confirmed the benefit of trastuzumab in her2-positive ebc across various subgroups 39 .For each of the subpopulations defined by nodal or hormone receptor status, trastuzumab treatment was associated with a statistically significant increase in 3-year dfs where patient numbers were sufficient.Furthermore, the extent of trastuzumab's dfs benefit was highly consistent across these subpopulations, as judged by the calculated hr for dfs events.In particular, subpopulations with lower intrinsic risk of disease recurrence (node-negative patients and node-negative patients with T1 tumours) experienced an improvement in dfs similar to that seen in the broader her2-positive ebc population (hrs were approximately 0.5-0.6 in all cases).
In the joint analysis of the nsabp B-31 and the ncctg N9831 trials, trastuzumab's dfs benefit was also observed across all subgroups (including age, nodal status, hormone receptor status, tumour size, and tumour grade) because preliminary analysis showed an increase in 4-year dfs in the trastuzumab arm (hr ranges from 0.22 to 0.80) 20 .
Subgroup analyses were not presented in the finher and pacs-04 trials.
This trastuzumab benefit has been recognized in various clinical practice guidelines published since the pivotal trial results became available.The nccn guidelines on breast cancer recommend the use of trastuzumab as an appropriate adjuvant therapy in all patients with her2-positive tumours larger than 1 cm as a category 1 recommendation 15 .Similar support for the use of trastuzumab in node-positive and node-negative her2-positive breast cancers (with some restrictions) can be found in guidelines from Cancer Care Ontario (node-positive or high-risk node-negative breast cancers only) 40 , the BC Cancer Agency (node-positive or node-negative with tumours ≥T1c and other features to qualify for chemotherapy) 41 , and the St. Gallen expert consensus group (patients who satisfy the inclusion criteria used in the trials may be considered) 14 .

Timing of Trastuzumab Therapy with
Chemotherapy for Early-Stage Disease: Concurrent or Sequential

Suggestion
The decision to use either approach is at the clinician's discretion based on patient and disease characteristics.However, recent data suggest that the concurrent approach incorporating anthracyclines, while slightly more cardiotoxic, may be associated with superior efficacy.

Discussion
A review of the outcomes from the pivotal trials described earlier suggests that trastuzumab's dfs benefits are seen in her2-positive ebc, whether it is used concurrently with the taxane part of chemotherapy or is initiated upon completion of chemotherapy.The position adopted in 2007 and maintained in 2009 by the St. Gallen panel was that the two approaches are equally acceptable 14,42 .
More recent data suggest that concurrent approaches are more effective 21 .At the sabcs 2009 meeting, the 60-month follow-up of the ncctg N9831 trial was reported.While there continues to be a dfs benefit of sequential trastuzumab (ac→t→h) over chemotherapy alone (ac→t), the dfs benefit was superior for the concurrent trastuzumab arm (ac→th→h) relative to the sequential trastuzumab arm (hr: 0.77; 95% ci: 0.61 to 0.96; p = 0.019; Table ii).This result did not cross the boundary for statistical significance, which was pre-set at a p value of 0.00116.The os was not significantly improved with sequential trastuzumab relative to chemotherapy alone (hr: 0.86; 95% ci: 0.65 to 1.13; p = 0.281).The investigators recommended the concurrent use of trastuzumab with chemotherapy (ac→th→h) given the risk-benefit ratio and 4% absolute improvement in dfs 21 .Also, the pacs-04 trial, which examined the role of sequential trastuzumab (fec/ec→h), did not show a significant improvement in dfs or os 24 .While provocative, these results were by no means conclusive, because the pacs-04 trial included only a small sample size of 502 patients with her2-positive disease, and the results do not correspond with the dfs benefits seen in the other trials incorporating sequential trastuzumab (hera, ncctg N9831, and so on).
In trials incorporating a concurrent approach, os benefits are consistently seen where trastuzumab is given concurrently with taxanes, either in a nonanthracycline based regimen (that is, dcbh) or after completion of anthracyclines (nsabp B-31, ncctg 9831, bcirg 006).

Suggestion
The phase iii randomized studies support the standard use of trastuzumab for 1 year (that is, 18 cycles when given every 3 weeks), regardless of the chemotherapy regimen employed.

Discussion
The optimal duration of treatment with trastuzumab is unknown.The majority of the pivotal trials on trastuzumab use in ebc have required patients to be given trastuzumab treatment for a total of 1 year (Table ii).The hera study included an arm evaluating 2-year treatment, but safety and efficacy data will not be reported until 2011 18,25,26 .The finher trial gave a total of 9 weekly trastuzumab infusions, and at a median follow-up of 5 years, her2-positive patients who received trastuzumab continue to have a better ddfs rate and os trend than those who received chemotherapy alone (Table i) 23 .Although these data are promising, it must be noted that the overall sample size was small (n = 232).Results from larger randomized clinical trials such as sold (Synergism or Long Duration) and phare (Protocol of Herceptin Adjuvant with Reduced Exposure), assessing 9 weeks or 6 months of trastuzumab treatment respectively, and the 2-year hera data will shed more light on the optimal duration of trastuzumab.In the absence of strong data, there is no need to diverge from the approved 1-year treatment duration.This is in agreement with guidelines from nccn 15 , Cancer Care Ontario 40 , and the BC Cancer Agency 41 .

The Role of Non-Anthracycline
Trastuzumab-Based Regimens

Suggestion
The choice between anthracycline-based adjuvant trastuzumab regimens and the dcbh regimen should be based on the individual risk of cardiac toxicity.

Discussion
The need for anthracyclines when giving trastuzumab and chemotherapy-based treatment has been controversial.In the initial reports from the bcirg 006 trial, there was clear indication that the two trastuzumabcontaining arms (ac→dh and dcbh) had very similar clinical benefits 27 .However, weighing the safety risks (cardiotoxicity and leukemia risk) associated with the anthracycline-based arm (ac→dh), the non-anthracycline arm (dcbh) seems to be a more favourable choice.The bcirg 006 trial was recently updated at sabcs 2009, and again, both trastuzumab-containing arms had better dfs and os than the control arm, and the two trastuzumab arms did not differ statistically in dfs although numerically the results favoured the ac→dh arm 22 .The data combining dfs events with life-threatening toxicities (chf and treatment-related leukemia) now favour the ac→dh arm.There is no doubt that the non-anthracycline regimen (dcbh) is the safest regimen with respect to cardiotoxicity (incidence: 0.4% New York Heart Association grades 3 and 4 chf vs. 2.0% chf with ac→dh); however, while the efficacy results of dcbh and ac→dh do not differ statistically, the 5-year dfs numerically favours ac→dh.Consequently, the clinical decision to pursue an anthracycline or non-anthracycline adjuvant trastuzumab regimen should be made in the context of the individual cardiovascular risk balanced with the anticipated individual risk of relapse.
The bcirg 006 trial does not demonstrate any advantage to anthracyclines in the population without Topo2 co-amplification, but no validated clinical assay is available to assist in this decision.The bcirg 006 data now suggest superior efficacy results in the anthracycline-based regimen.Consequently, clinicians may need to be more selective in choosing the non-anthracycline trastuzumab regimen (dcbh), and perhaps it should no longer be considered a de facto standard of care.

CARDIOTOXICITY
Two years ago, a similar Canadian panel of seven oncologists and two cardiologists met for a full-day conference and developed recommendations in the assessment and management of cardiac complications during adjuvant trastuzumab therapy 43 .First, the authors outlined risk factors that exclude patients from trastuzumab treatment such as existing heart failure or lvef below 50% (or both) and risk factors that require special consideration such as ischemic heart disease, significant valvulopathy, and a pretrastuzumab baseline lvef of 50%-55%.Second, the panel concluded that there were insufficient data to make formal statements about the cardiotoxicity of concurrent versus sequential regimens and that evidence existed to suggest that anthracycline-free regimens have a lesser incidence of cardiac toxicity.Updated cardiac toxicity results from the ncctg 9831 trial (Table iii) do suggest a slightly greater cardiac toxicity risk with the concurrent approach compared with the sequential approach (incidence of symptomatic chf: 3.3% vs. 2.8%) 30 .Patients with ebc should be treated with trastuzumab treatment for 1 year (less only if disease recurs) until further evidence suggests otherwise.Third, the panel emphasized the need to assess cardiac function before trastuzumab treatment by using echocardiography or muga scan to establish baseline and subsequent lvef readings (3, 6, 9, and 12 months).After trastuzumab therapy, annual monitoring should be considered in patients who experienced cardiac symptoms or a greater than 10% absolute asymptomatic decline in lvef.Finally, the panel established a detailed "stop/restart" algorithm for both symptomatic and asymptomatic left ventricular dysfunction based on the Canadian Cardiovascular Society recommendations.Details of pharmacotherapy options and duration of treatment for cardiotoxicity were outlined, and guidelines for the decision to re-initiate were discussed 43 .

CONCLUSIONS
Trastuzumab has emerged as the key component of care in women with her2-positive ebc.Clinical findings from several large trials, representing more OPTIMIZING THE MANAGEMENT OF HER2+ EBC than 14,000 individual patients, have established significant dfs and os benefits of trastuzumab treatment.The benefits of trastuzumab are seen regardless of other patient characteristics such as age or of tumour characteristics such as hormone positivity or nodal status.The benefit of trastuzumab for node-negative ebc patients with small tumours (for example, T1a tumours) remains to be fully established.However, all her2-positive node-positive patients and nodenegative patients with T1b or larger tumours should be considered for trastuzumab treatment because they remain at greater risk of disease recurrence.Clinicians should also always consider the potential risk of cardiac toxicity of systemic treatments, and as a result, an appropriate trastuzumab-based regimen should be chosen based on thorough assessment of cardiac toxicity risk factors.A single year of trastuzumab treatment should be initiated concurrently with the taxane part of chemotherapy for most patients unless cardiac concerns trigger a consideration for a sequential approach or a non-anthracycline regimen alternative.

DATE OF AUTHOR SUGGESTIONS
The panel suggestions were completed in April 2010.

•
Treatment duration of trastuzumab for ebc•Role of non-anthracycline trastuzumabbased regimens nCCtg (North Central Cancer Treatment Group) N9831] design was adapted from Romond et al. 2005 19 and Perez et al. 2007 20 .The bCirg (Breast Cancer International Research Group) 006 design was adapted from Slamon et al. 2006 27 and Slamon et al. 2009 22 .The finher (Finland Herceptin trial) design was adapted from Joensuu et al. 2006 28 and Joensuu et al. 2009 23 .The paCs (Protocol Adjuvant dans le Cancer du Sein)-04 design was adapted from Speilmann et al. 2009

table i
Design and patient characteristics of adjuvant trastuzumab trials ≥4 na [er or pr or both (%)] a Results were not reported for patients who were randomized to receive 2 years of trastuzumab.bMultiple chemotherapy regimens were permitted.cNot all patients were included in the joint analysis.d44% were er+; 29% were pr+.e 50% were er+; 39% were pr+.h = trastuzumab; Pts = patients; na = not available; hr = hormone receptor; er = estrogen receptor; pr = progesterone receptor; hera = Herceptin Adjuvant study; nsabp = National Surgical Adjuvant Breast and Bowel Project; a = doxorubicin; c = cyclophosphamide; t = paclitaxel; ncctg = North Central Cancer Treatment Group; bcirg = Breast Cancer International Research Group; d = docetaxel; cb = carboplatin; finher = Finland Herceptin trial; v = vinorelbine; pacs = Protocol Adjuvant dans le Cancer du Sein; f = fluorouracil; e = epirubicin; nr = not reported.tableiiUpdated disease-free survival and overall survival b Multiple chemotherapy regimens were permitted.c Based on 885 of the 1354 patients who were alive and disease-free on May 16, 2005.d Not all patients were included in the joint analysis.e Adjusted hr.f Patients from ac→t who received trastuzumab are still included in ac→t for analysis.Investigators were conducting an intention-to-treat analysis.g Disease-free and overall survival data are based on the following treatment arm comparisons: ac→t

table iii
Updated cardiac toxicity a Patients who crossed over are censored from the date that they started trastuzumab treatment.bSeverechf [New York Heart Association (nyha) class iii and iv] was reported in 13 patients (0.8%).

table iv
Recurrence-free survival and distant recurrence-free survival in patients with node-negative disease based on human epidermal growth factor receptor 2 [her2 (erbB2)] status a Absence of her2 amplification (p=0.006).b Absence of her2 expression (p=0.003).