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Optimizing the Management of her2-Positive Early Breast Cancer: The Clinical Reality

Optimizing the Management of her2-Positive Early Breast Cancer: The Clinical Reality M E D I C A L O N C O L O G Y Optimizing the management of her 2-positive early breast cancer: the clinical reality † † Su. Verma MSEd MD,* S. Lavasani MD, ‡ † J. Mackey MD, K. Pritchard MD,* § §|| M. Clemons MB BS MD, S. Dent BSc MD, J. Latreille MDCM, J. Lemieux MSc MD,** †† §|| L. Provencher MA MD, Sh. Verma MD, ‡‡ §§ |||| S. Chia MD, B. Wang MSc, and D. Rayson MD ABSTRACT 1. INTRODUCTION Breast cancer positive for her 2 (human epidermal About 23,000 new cases of breast cancer will be growth factor receptor 2) is associated with a poor diagnosed in Canada in 2010 . The estimated prognosis for patients with both early-stage and 5400 annual deaths from breast cancer are second metastatic breast cancer. Trastuzumab has been shown only to those from lung cancer as contributors to to be effective and is now considered the standard cancer-related mortality in the Canadian female of care for early-stage patients with her 2-positive population . The majority of women diagnosed breast cancer. In that population, trastuzumab has with breast cancer present with early-stage disease been studied in six randomized clinical trials. Over- (>75%). In recent decades, a substantial decline in all, use of this agent leads to a significant reduction mortality among breast cancer patients has been in risk of disease recurrence and improvement in attributed in part to advancements in adjuvant sys- overall survival. Despite the strong evidence for the temic therapy. use of trastuzumab in managing her 2-positive early The outcome for early breast cancer (cbe ) patients breast cancer (ebc ), a number of clinical controver- with her 2 (human epidermal growth factor recep- sies remain. The authors of this paper undertook a tor 2)–positive disease has particularly improved review of the available scientific literature on adju - since the end of the 1990s with the introduction of vant trastuzumab to produce practical considerations trastuzumab in this setting. Trastuzumab is a mono- from Canadian oncologists. The panel focused their clonal antibody that binds to the extracellular domain discussion on five key areas: of her 2. Several mechanisms of action underlie the ● Management of node-negative disease with tu- antitumour effects of trastuzumab. Trastuzumab mours 1 cm or smaller in size blocks her 2-activated cell signalling, thereby ● Management of her 2-positive ebc across the reducing cell proliferation and restoring ability spectrum of the disease (that is, nodal and steroid to undergo apoptosis by inhibiting the phosphati- 2–5 hormone receptor status, tumour size) dylinositol 3 kinase/Akt pathway , which in- ● Timing of trastuzumab therapy with chemotherapy creases cellular sensitivity to chemotherapy and for early-stage disease: concurrent or sequential radiotherapy . Trastuzumab has also been shown 3,7–9 ● Treatment duration of trastuzumab for ebc to inhibit her 2-regulated angiogenesis and, in ● The role of non-anthracycline trastuzumab- preclinical models, to recruit the immune system based regimens through antibody-dependent cellular cytotoxicity, triggering activation of natural killer cell–mediated 10–12 KEY WORDS apoptosis . In addition, trastuzumab has also her 2 been shown to prevent the formation of p95 (a Adjuvant, early breast cancer, her 2-positive, node- truncated active form of her 2), which may lead to 3,13 negative, trastuzumab inhibition of tumour development . Copyright © 2010 Multimed Inc. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. Based on efficacy data from six major random - by two main panel members (SuV and DR) and a ized controlled clinical trials comparing adjuvant breast cancer fellow (SL). The final manuscript was chemotherapy alone to adjuvant chemotherapy reviewed, revised, and approved by the remaining plus trastuzumab delivered either concurrently or nine panel members (MC, SC, SD, JLe, JLa, JM, KP, in sequence, adjuvant trastuzumab has become an LP, ShV). Published and presented clinical trial results internationally accepted part of adjuvant systemic available as of January 2010 were incorporated into 14,15 therapy for her 2-positive ebc . the present document by SL. Despite the clear benet fi s of adjuvant trastuzumab for the relevant patient population, there remain a 1.2 Conflict of Interest Disclosures number of clinical scenarios and questions in which the data are not as clear and controversy persists. For Support for the initial meeting of the Canadian advi- example, the 11th St. Gallen international expert con- sory panel and the development of the present manu- sensus meeting was not able to provide a den fi itive rec - script was provided by an unrestricted educational ommendation regarding the use of anti-her 2 therapy grant from Hoffmann–La Roche Canada. The authors for patients with reh 2-positive node-negative tumours received an honorarium for attending the meeting, smaller than 1 cm in size, because of the absence of but not for writing the manuscript. The authors are data to suggest an increased risk of disease recurrence solely responsible for the content of the manuscript, or a significant benefit from treatment . Also, the with no restrictions set by the sponsor. balance between cardiotoxic risk and adjuvant benefit from systemic chemotherapy continues to generate 2. OVERVIEW OF THE KEY TRIALS IN HER2- controversy. The 2010 National Comprehensive Can- POSITIVE EARLY BREAST CANCER cer Network (nccn ) guidelines recommend the need to balance the known cardiotoxicity risk of trastuzumab Results from six large multicentre randomized con- against the uncertain absolute benefits that may exist trolled clinical trials evaluating the role of adjuvant before considering trastuzumab treatment . trastuzumab in her 2-positive ebc have been reported The goal of this manuscript is to discuss the to date. These include the Herceptin Adjuvant (hera ) optimal utilization of adjuvant trastuzumab in the trial , the National Surgical Adjuvant Breast and 19,20 management of her 2-positive ebc in the context of Bowel Project (nsabp ) B-31 trial , the North particularly common clinical scenarios: Central Cancer Treatment Group (ncctg ) N9831 20,21 trial , the Breast Cancer International Research ● Management of node-negative disease with tu- Group (bcirg ) 006 trial , the Finland Herceptin trial mours 1 cm or smaller in size (f inher ) , and the Protocol Adjuvant dans le Cancer ● Management of her 2-positive ebc across the du Sein (sca p -04) trial . Together, these trials accrued spectrum of the disease (that is, nodal and steroid more than 14,000 women and evaluated the addition hormone receptor status, tumour size) of trastuzumab to varying chemotherapeutic strate- ● Timing of trastuzumab therapy with chemotherapy gies. These trials differed substantially with respect to for early-stage disease: concurrent or sequential study design (Figure 1), patient population (Table i ), ● Treatment duration of trastuzumab for ebc and chemotherapeutic backbones. ● R o l e o f n o n - a n t h r a c y c l i n e t r a s t u z u m a b - Four trials demonstrated improved disease-free based regimens survival (dfs ), and three demonstrated significantly improved overall survival (os , Table ii ). Updated 1.1 Development of Panel Suggestions cardiac toxicity data from these trials indicate that the rate of this toxicity varies depending on the use The authors of this paper met in Toronto for a one-day of anthracyclines and whether trastuzumab is given in conference in June 2008. The panel reviewed results conjunction with or after chemotherapy (Table iii ). of the latest trials in the neoadjuvant, adjuvant, and metastatic settings. Based on updated trial informa- 2.1 HERA Trial tion, suggestions were formulated for the neoadjuvant and metastatic settings and were subsequently pub- The hera trial, an international phase iii multicentre 16,17 lished in 2009 . randomized open-label three-arm study, randomized With regard to the current manuscript, the panel patients to 1 or 2 years of adjuvant trastuzumab or reviewed the available evidence regarding adjuvant observation, subsequent to completion of a minimum trastuzumab for ebc and identified ongoing con - of 4 cycles of adjuvant or neoadjuvant chemotherapy troversies awaiting data from further or completed (Figure 1). Inclusion criteria included all her 2-pos- randomized clinical trials. Based on the panel’s itive node-positive or node-negative disease with a review and discussion of the updated clinical data, tumour size greater than 1 cm and left ventricular suggestions were formulated for a variety of clinical ejection fraction (vef l ) of 55% or more as measured scenarios. A draft manuscript was initially written by by echocardiography or multiple-gated acquisition a medical writer (BW) and was reviewed and revised (muga ). A total of 5102 women participated in this Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC Observation* Local invasive EBC Surgery + (neo)adjuvant CT ± RT One-year Trastuzumab HERA HER2+ (Central FISH/IHC 3+) (8 mg/kg  6 mg/kg, q3w) LVEF ≥55% Two-year Trastuzumab (8 mg/kg  6 mg/kg, q3w) N9831 Group A and B-31 Group 1 Paclitaxel 4 x AC (4 x 175 mg/m , q3w or AC  T 2 2 (60/600 mg/m , q3w) 12 x 80 mg/m , qw) Joint HER2+ (IHC 3+ or FISH) Analysis N+ or High Risk N– 4 x AC Paclitaxel AC  T+H 2 2 (60/600 mg/m , q3w) (4 x 175 mg/m , q3w or LVEF ≥ 50% 12 x 80 mg/m , qw) N9831 Group C B-31 and Group 2 One-year Trastuzumab (4 mg/kg  2 mg/kg, qw) Group A 4 x AC Paclitaxel 2 2 ACT (60/600 mg/m , q3w) (12 x 80 mg/m , qw) Group 1 4 x AC Paclitaxel 2 2 AC  T (60/600 mg/m , q3w) (4 x 175 mg/m , q3w OR 12 x 80 mg/m , qw) B-31 N9831 Group B 4 x AC Paclitaxel One-year Trastuzumab 2 2 4 x AC Paclitaxel ACT H (60/600 mg/m , q3w) (12 x 80 mg/m , qw) (4 mg/kg  2 mg/kg, qw) Group 2 2 2 (60/600 mg/m , q3w) (4 x 175 mg/m , q3w OR AC  TH 12 x 80 mg/m , qw) Group C 4 x AC Paclitaxel One-year Trastuzumab 2 2 ACTHH (4 mg/kg  2 mg/kg, qw) (60/600 mg/m , q3w) (12 x 80 mg/m , qw) One-year Trastuzumab (4 mg/kg  2 mg/kg, qw) 4 x AC 4 x Docetaxel ACD 2 2 (60/600 mg/m , q3w) (100 mg/m , q3w) 4 x AC 4 x Docetaxel ACDH 2 2 (60/600 mg/m , q3w) (100 mg/m , q3w) HER2+ (Central FISH) BCIRG 006 N+ or High Risk N– One-year Trastuzumab Stratified by nodes and (4 mg/kg  2 mg/kg, qw [in combination]; HR Status 6 mg/kg q3w [monotherapy after chemotherapy]) 6 x Docetaxel and Carboplatin (75 mg/m and AUC 6) DCbH One-year Trastuzumab (4 mg/kg  2 mg/kg, qw [in combination]; 6 mg/kg q3w [monotherapy after chemotherapy]) 3 x Docetaxel (100mg/m , q3w) or 3 x FEC D/V FEC 2 2 9 x Vinorelbine (25 mg/m , qw) (600/60/600 mg/m , q3w) HER2+ (IHC 2+ or 3+ and CISH) FinHer N+ or High Risk N–, >20 mm, 3 x Docetaxel (100mg/m , q3w) or 3 x FEC PgR–, no cardiac disease 2 2 9 x Vinorelbine (25 mg/m , qw) (600/60/600 mg/m , q3w) (D/V) H FEC Nine-week Trastuzumab (4 mg/kg  2 mg/kg, qw) 6 x FEC (500/100/500 mg/m , q3w) FEC/ED or HER2+ (IHC 2+ or 3+ and FISH) 6 x ET (75/75 mg/m , q3w) PACS-04 N+ LVEF ≥ 55% (if 50-55%, 6 x FEC (500/100/500 mg/m , q3w) One-year Trastuzumab cardiologist‘s approval required) FEC/ED  H or (8 mg/kg  6 mg/kg, q3w) 6 x ET (75/75 mg/m , q3w) After RT figure 1 Summary of trial designs (boxes not drawn to scale). The hera (Herceptin Adjuvant study) design was adapted from Piccart– 25 26 18 Gebhart et al. 2005 , Smith et al. 2007 , and Gianni et al. 2009 . The joint analysis [nsabp (National Surgical Adjuvant Breast and Bowel 19 20 Project) B-3, nCCtg (North Central Cancer Treatment Group) N9831] design was adapted from Romond et al. 2005 and Perez et al. 2007 . 27 22 The bCirg (Breast Cancer International Research Group) 006 design was adapted from Slamon et al. 2006 and Slamon et al. 2009 . The 28 23 f inher (Finland Herceptin trial) design was adapted from Joensuu et al. 2006 and Joensuu et al. 2009 . The aC p s (Protocol Adjuvant dans le Cancer du Sein)–04 design was adapted from Speilmann et al. 2009 . * Multiple chemotherapy regimens were permitted. ebC = early breast cancer; Ct = chemotherapy; rt = radiation therapy; her 2 = human epidermal growth factor receptor 2; fish = fluorescence in situ hybridization; ihC = immunohistochemistry; l Vef = 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; p gr = progesterone receptor; V = vinorelbine; feC = fluorouracil, epirubicin, cyclophosphamide; ed = epirubicin, docetaxel; et = epirubicin, paclitaxel. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. able t i Design and patient characteristics of adjuvant trastuzumab trials Trial short name Treatment regimen Pts Tumour size (%) Positive nodes (%) Positive hr status [total patients (n)] (h duration) (n) ≤2 cm >2 to ≤5 cm >5 cm na 0 1–3 ≥4 na [er or pr or both (%)] 25 a b hera (5102 ) Observation 1693 40 43 6 11 33 29 28 10 50 h (1 year) 1694 39 45 4 12 32 29 28 11 50 Joint analysis nsabp B-31 (2006 ) ac →t 1979 40 51 7 1 7 52 40 — 55 ncctg N9831 (3505 ) ac →t +h (1 year) 1989 38 52 9 1 7 53 40 — 54 bcirg 006 (3222) ac →d 1073 41 53 6 — 29 38 33 — 54 ac →dh (1 year) 1074 38 55 7 — 29 38 33 — 54 dc bh (1 year) 1075 40 54 6 — 29 39 33 — 54 23,28 d f inher (232) d /v →fec 116 30 70 — 0 22 50 28 — nr (d /v )h →fec (9 weeks) 116 40 59 — 1 10 55 34 — nr acs p -04 (528) fec or ed 268 49 51 (>2 cm) — (n=7) — 56 44 — 61 fec or ed →h 260 41 59 (>2 cm) — (n=1) — 60 40 — 58 Results were not reported for patients who were randomized to receive 2 years of trastuzumab. Multiple chemotherapy regimens were permitted. Not all patients were included in the joint analysis. 44% were er +; 29% were pr +. 50% were er +; 39% were pr +. h = trastuzumab; Pts = patients; an = not available; rh = hormone receptor; re = estrogen receptor; rp = progesterone receptor; areh = Herceptin Adjuvant study; pbasn = National Surgical Adjuvant Breast and Bowel Project; a = doxorubicin; c = cyclophosphamide; t = paclitaxel; gtccn = North Central Cancer Treatment Group; gricb = Breast Cancer International Research Group; d = docetaxel; c b = carboplatin; f inreh = Finland Herceptin trial; v = vinorelbine; acs p = Protocol Adjuvant dans le Cancer du Sein; f = fluorouracil; e = epirubicin; nr = not reported. trial with a primary endpoint of dfs and a secondary 2.2 Joint Analysis of the NSABP B-31 and NCCTG endpoint of os . At the interim analysis, with a median N9831 Trials follow-up of 23.5 months, the unadjusted hazard ratio (hr ) for risk of a dfs event with trastuzumab versus The pbasn B-31 trial was a U.S.-based phase iii mul- observation alone was 0.64 [95% confidence interval ticentre randomized open-label trial in reh 2-positive (ic ): 0.54 to 0.76; p < 0.0001], corresponding to an ab- ebc that assessed the addition of trastuzumab to solute improvement in sfd of 6.3% (80.6% vs. 74.3%) an anthracycline-based regimen [doxorubicin and at 3 years . The unadjusted hr for risk of death at cyclophosphamide followed by paclitaxel (ac →t ) 3 years with trastuzumab versus observation was 0.66 every 3 weeks for 4 cycles] with 1 year of trastu- (95% ci : 0.47 to 0.91; p = 0.0115), resulting in an zumab [ac →th (Figure 1)]. Trastuzumab was initi- 26 19 absolute os benefit of 2.7% (92.4% vs. 89.7%) . ated concurrently with the first dose of paclitaxel . Recently, Gianni et al. presented updated data The ncctg N9831 trial, a similar phase iii open- from the hera trial with a median follow-up time label trial, explored the efficacy of 1 year adjuvant of 4 years (Table ii ). The hr for risk of an event trastuzumab given concurrently with 12 doses of with trastuzumab versus observation was 0.76 weekly paclitaxel versus after 12 doses of paclitaxel (95% ci : 0.66 to 0.87; p < 0.0001), corresponding (ac →th →h vs. ac →t →h ) in her 2-positive ebc to an absolute dfs improvement of 6.4% (78.6% (Figure 1) . Data from these two trials, referred to vs. 72.2%) . However, the observed absolute os as the “joint analysis,” were pooled to allow for an benefit decreased from 2.7% at 3 years to 1.6% at early non-protocol analysis with sufc fi ient statistical 4 years and was no longer statistically significant power to compare the two similar regimens (ac →t (89.3% vs. 87.7%; hr : 0.85; 95% ci : 0.70 to 1.04; vs. ac →th ) . The primary endpoint of the joint p = 0.1087). Potential explanations for the loss of analysis was sfd , and the secondary endpoint was so . survival benefit include An efficacy update showed a significant difference in 4-year dfs rates for trastuzumab-treated patients ● the crossover of 65% of control patients to ad- (85.9% vs. 73.1%; adjusted hr : 0.48; 95% ci : 0.41 juvant trastuzumab, resulting in an improved to 0.57; p < 0.00001). The corresponding 4-year os outcome in the observation arm; and rates were 92.6% and 89.4%, respectively (rh : 0.65; ● the apparent inferiority of sequencing adjuvant 95% ci : 0.51 to 0.84; p = 0.0007) . trastuzumab after chemotherapy rather than in Updated data from the ncctg N9831 study pre- combination with chemotherapy. sented at the San Antonio Breast Cancer Symposium Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC ac ac nr nr nr nr th ac bcirg hr ac nsabp acs ac nr ac hr hera ac ncctg ci h t fec t t ed fec t ed th her ac ac dh hr ac h v d fec f ac h h d ac fec dc ac ac ac hr ii nsabp ncctg her t hera ncctg bcirg f p a d able acs Current OnCOlOgy —VOlume 17, n umber 4 Updated disease-free survival and overall survival Study short name Treatment regimen Pts Median follow-up Disease-free survival Overall survival Crossover [total pts (n)] ( duration) (n) (months) (%) 95% C p Value (%) 95% C p Value 18 b c Observation 1698 48 72 0.76 0.66 to 0.87 <0.0001 88 0.85 0.70 to 1.04 0.1087 65% of observation crossed over to (1 year) 1703 79 89 Joint analysis d e B-31 (2006 ) → 1979 35 73 0.48 0.41 to 0.57 <0.00001 89 0.65 0.51 to 0.84 0.0007 21% of → crossed over after N9831 (3505 ) initial efficacy report → + (1 year) 1989 86 93 in 2005 21 g g N9831 → 1087 72 0.70 0.57 to 0.86 0.0005 — 0.86 0.65 to 1.13 0.281 66 (5.5 years) 1097 80 — → → g g 954 80 0.77 0.61 to 0.96 0.019 — 0.79 0.59 to 1.08 0.135 64 (~5 years) → → 949 84 — 006 → 1073 65 75 1 87 1 2% of → crossed over → (1 year) 1074 84 0.64 0.53 to 0.78 <0.001 92 0.63 0.48 to 0.81 <0.001 to receive b (1 year) 1075 81 0.75 0.63 to 0.90 0.04 91 0.77 0.60 to 0.99 0.038 trastuzumab 23 h in / → 116 62 73 0.65 0.38 to 1.12 0.12 82 0.55 0.27 to 1.11 0.094 ( / ) → 115 83 91 (9 weeks) -04 or 268 47 78 0.86 0.61 to 1.22 0.41 96 1.27 0.68 to 2.38 or → 260 81 95 Hazard ratios are unadjusted. Multiple chemotherapy regimens were permitted. Based on 885 of the 1354 patients who were alive and disease-free on May 16, 2005. Not all patients were included in the joint analysis. Adjusted . Patients from → who received trastuzumab are still included in → for analysis. Investigators were conducting an intention-to-treat analysis. Disease-free and overall survival data are based on the following treatment arm comparisons: → versus → → and → → versus → → . Distant disease-free survival. Pts = patients; = trastuzumab; = hazard ratio; = confidence interval; = Herceptin Adjuvant study; = National Surgical Adjuvant Breast and Bowel Project; = doxorubicin; = cyclophosphamide; = paclitaxel; = North Central Cancer Treatment Group; = not reported; = Breast Cancer International Research Group; = docetaxel; b = carboplatin; in = Finland Herceptin trial; = vinorelbine; = fluorouracil; = epirubicin; = Protocol Adjuvant dans le Cancer du Sein. VERMA et al. able t iii Updated cardiac toxicity Trial short name Treatment regimen Pts Median l Vef (%) Symptomatic Cardiac (n) follow-up Required Pts with Chf death (months) at baseline sig. decrease (%) (n) 18 a hera Observation 1719 48 ≥55 0.8 0.2 1 h (1 year) 1682 3.7 2.0 0 29 c nsabp B-31 ac →t 898 60 ≥50 nr 0.9 1 ac →t +h (1 year) 947 nr 3.8 0 30 d ncctg N9831 ac →t 554 36 ≥50 4.5 0.3 1 ac →t →h 514 5.4 2.8 1 ac →t +h (1 year) 400 5.8 3.3 0 22 e f g bcirg 006 ac →d 1050 65 ≥50 11 0.7 0 e f g ac →dh (1 year) 1068 19 2.0 0 e f g dc bh (1 year) 1056 9 0.4 0 23 h f inher d /v →fec 116 62 ns 10.5 1.7 0 (d /v )h →fec (9 weeks) 115 6.8 0.9 0 24 i acs p -04 fec or ed 268 47 ≥50 2.6 0.4 0 fec or ed →h 260 11.1 1.5 0 Patients who crossed over are censored from the date that they started trastuzumab treatment. Severe chf [New York Heart Association (nyha ) class iii and iv ] was reported in 13 patients (0.8%). 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 vef l of more than 10% to below 55% or of more than 5% and below lower level of normal)]. Reported as 3-year cumulative incidence of cardiac events (defined as symptomatic chf , definite cardiac death, or probable cardiac death). For patients with a greater than 10% relative vef l decline: n = 1018 (ac →d ); n = 1042 (ac →dh ); n = 1031 (dc bh ). Reported as a greater than 10% relative vef l decline. Reported as grade 3 or 4 chf . Reported as a greater than 20-percentage-point decrease in vef l from baseline at one or more vef l measurements after completion of chemotherapy. Reported as a severe decline (absolute vef l < 45%, 45%–49%, and ≥15%). Pts = patients; vef l = 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; c b = carboplatin; f inher = Finland Herceptin trial; v = vinorelbine; f = fluorouracil; e = epirubicin; ns = not specified; acs p = Protocol Adjuvant dans le Cancer du Sein. (sabcs ) in December 2009 show continued improve- for 4 cycles, followed by docetaxel every 3 weeks for ment in dfs with the addition of sequential trastu- 4 cycles (ac →d vs. ac →dh ), Figure 1] . The bcirg zumab to chemotherapy: 80.1% in the sequential 006 trial also included a non-anthracycline third treat- arm versus 71.9% in the chemotherapy-only arm (rh : ment arm with concurrent docetaxel, carboplatin, and 0.70; 95% ci : 0.57 to 0.86; p = 0.0005; Table ii ) . trastuzumab (dc bh ). The primary endpoint was dfs , Comparison of the sequential arm with the concurrent and the secondary endpoint was os . arm showed a dfs of 79.8% versus 84.2% (hr : 0.77; Recent data from the third planned analysis of 95% ci : 0.61 to 0.96; p = 0.019; details discussed bcirg 006 revealed dfs rates of 75% (ac →d ), 84% later in this article). The 5-year follow-up did not (ac →dh ), and 81% (dc bh ) at 65 months of follow-up show any survival benefit for the sequential addition (Table ii ) . The hr , compared with the observation of trastuzumab to chemotherapy (hr : 0.86; 95% ci : arm, for ac →dh was 0.64 (95% ci : 0.53 to 0.78; p < 0.65 to 1.13; p = 0.281). 0.001) and for dc bh was 0.75 (95% ci : 0.63 to 0.90; p = 0.04). The sfd in the two trastuzumab arms did not 2.3 BCIRG 006 Trial differ statistically (p = 0.21). Updated data show an so of 87% in the chemotherapy-only arm compared with The international bcirg 006 phase iii open-label trial, 92% in the ca →hd arm (rh : 0.63; 95% ic : 0.48 to 0.81; conducted in 42 countries, randomized patients with p < 0.001) or 91% in the dc bh arm (hr : 0.77; 95% ci : reh 2-positive cbe to observation or a 1-year course of 0.60 to 0.99; p = 0.038). Relative to the anthracycline- trastuzumab in conjunction with taxane chemotherapy containing arms, dc bh continued to have a superior [doxorubicin and cyclophosphamide every 3 weeks toxicity profile, including less acute toxicity, better Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC 31 24 quality of life , and lower rates of congestive heart ed → h , Figure 1) . Patients had to have proven ebc failure (chf ) and leukemia. Interesting and provoca- with complete resection (T1, T2, T3) and be axillary tive data related to Topo2A (topoisomerase iia pro- node-positive. The primary endpoint was 3-year dfs . tein) were also presented, suggesting that the benefit After a median follow-up of 47 months, there was no from adjuvant trastuzumab was restricted to patients difference in sfd (77.9% vs. 80.9%; rh : 0.86; 95% ic : who were not Topo2A co-amplified. 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 2.4 f inher Trial trastuzumab treatment groups (Table ii ). The multicentre phase iii open-label f inher trial 3. NODE-NEGATIVE DISEASE WITH enrolled ebc patients (n = 1010) with axillary-node- TUMOURS 1 CM OR SMALLER positive or high-risk node-negative cancer . Patients were assigned to receive 3 cycles of docetaxel or On the basis of the significant dfs and os benefits vinorelbine every 3 weeks, followed by 3 cycles of established in the pivotal trials discussed earlier, fluorouracil, epirubicin, and cyclophosphamide ( d / adjuvant trastuzumab is now considered standard of v →fec ) every 3 weeks. Women with her 2-positive care for patients with her 2-positive ebc . However, breast cancer (n = 232) were further randomized to re- questions persist regarding the value of trastuzumab ceive or not to receive 9 weekly trastuzumab infusions in specific subpopulations, notably node-negative (4 mg/kg loading, 2 mg/kg maintenance; Figure 1). patients with small tumours (≤1 cm—that is, T1a and The primary endpoint was recurrence-free survival T1b) because they generally have been considered to (rfs ). At 3 years’ median follow-up, her 2-positive have low risk for disease recurrence. patients who received trastuzumab had a better rfs Node-negative patients with T1a (>0.1 cm and rate (89.3% vs. 77.6%; rh : 0.42; 95% ic : 0.21 to 0.83; ≤0.5 cm) and T1b (>0.5 cm and ≤1 cm) tumours are p = 0.01) and trend to improved so (96.3% vs. 89.7%; commonly assumed to have a low risk of recurrence rh : 0.41; 95% ic : 0.16 to 1.08; p = 0.07) than did those relative to patients with larger tumours. However, who did not receive trastuzumab . retrospective data from tertiary care cancer centres Recently, updated results from a median follow- suggest that despite small size, these node-negative up of 5 years were published , and her 2-positive tumours (that is, ≤1 cm) are at a greater risk of recur- patients who received trastuzumab continue to have rence if they are her 2-positive (Table iv ). a better distant dfs (ddfs ) rate (83.3% vs. 73.0%; Black et al. examined the incidence of breast unadjusted hr : 0.65; 95% ci : 0.38 to 1.12; p = 0.12) cancer outcomes in a group of 164 node-negative and os trend (91.3% vs. 82.3%; hr : 0.55; 95% ci : women with her 2-positive tumours T2 or lower . 0.27 to 1.11; p = 0.094) than do those who received The incidences of breast cancer outcomes in her 2- chemotherapy alone (Table ii ). negative tumours were not collected. Over a median Data analysis on her 2-positive patients was period of 5 years of postsurgical follow-up, the inci- further stratified based on specific chemotherapy dences of distant metastasis, locoregional recurrence, regimen. Patients who received d →fec plus trastu- and contralateral cancer were similar for patients with zumab versus d →cef alone had a signic fi antly higher T1a–b (≤1 cm) her 2-positive versus T1c (>1 cm and ddfs rate (92.5% vs. 74.1%; hr : 0.32; 95% ci : 0.12 ≤2 cm) her 2-positive tumours. Taken together, the to 0.89; p = 0.029). In contrast, patients who took incidences were 19%, 15%, and 23% for women with v →fec plus trastuzumab versus v →fec alone did T1a–b, T1c, and T2 tumours respectively, suggesting not have a significantly different ddfs rate outcome that even T1 breast cancer is at a higher risk of recur- (75.2% vs. 72.0%; hr : 0.92; 95% ci : 0.47 to 1.83; p = rence in the context of her 2-positive disease . 0.82). Overall, investigators concluded that adjuvant In a nationwide population-based study in Finland, docetaxel (not vinorelbine) improved ddfs and that Joensuu et al. analyzed 852 unilateral node-negative trastuzumab is a safe and effective addition, justify- T1 breast cancers (including 49 T1a and 264 T1b ing further investigation of a shortened duration of tumours) from the Finnish Cancer Registry . Expres- trastuzumab given the improved rfs that was shown sion or amplic fi ation of reh 2 was determined by immu- with only 9 weeks of adjuvant trastuzumab. nohistochemistry or chromogenic in situ hybridization respectively. Contrary to common perception, a tumour 2.5 PACS-04 Trial size of 10 mm or smaller was not uniformly associated with low risk for distant recurrence. Patients with T1b The acs p -04 trial was a phase iii multicentre trial as- grade 2 or 3 tumours had a significantly decreased sessing the benet fi s of concomitant docetaxel and epi - 9-year ddfs when the her 2 protein was overexpressed rubicin for 6 cycles every 3 weeks versus u fl orouracil, [ddfs : 67% (n = 11) vs. 95% (n = 54); p = 0.003] or epirubicin, and cyclophosphamide for 6 cycles every the gene was amplified [ ddfs : 67% (n = 11) vs. 92% 3 weeks, and a second randomization randomized (n = 52); p = 0.006; Table iv ]. reh 2-positive patients to sequential trastuzumab every In an independent analysis extending over 10 3 weeks for 1 year or observation (fec or ed vs. fec or years of follow-up, Chia et al. reached similar Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. able t iv Recurrence-free survival and distant recurrence-free survival in patients with node-negative disease based on human epidermal growth factor receptor 2 [her 2 (erbB2)] status Reference Tumour Follow-up her 2 Hormonal Survival (%) size (years) status status Recurrence-free Distant recurrence- free (cm) (n) her 2+ her 2– her 2+ her 2– 36 a Finnish Population Study 0.6–1 9.5 Amplification: — — — 67 92 12 positive, 95 56 negative; expression: 12 positive, 60 negative 32,c British Columbia Tissue Microarray 0.6–1 10 13 Positive, — 68 82 212 negative nr p=0.312 MD Anderson Cancer Center ≤1 5 98 Positive, — 77 94 86 97 867 negative hr : 2.68 hr : 5.3 95% ci : 1.44 to 5.0 95% ci : 2.23 to 12.62 p=0.002 p=0.0002 European Institute of Oncology ≤1 5 79 Positive, Positive 92 99 158 negative hr : 5.2 nr 95% ci : 1.0 to 25.9 p=0.013 Absence of her 2 amplification ( p=0.006). Absence of her 2 expression (p=0.003). This subgroup did not receive any adjuvant systemic therapy. her 2+ = positive for the human epidermal growth factor 2; her 2– = negative for the human epidermal growth factor 2; nr = not reported; hr = hazard ratio; ci = confidence interval. conclusions . Those authors examined rates of Recently, Gonzalez–Angulo et al. also assessed breast cancer–specific survival ( bccs ) and rfs using the rfs and drfs rates of women (n = 965) with her 2- tissue microarray series consisting of 4444 invasive positive node-negative ebc with tumours 1 cm or breast cancers, of which 2026 were pathologically smaller . Patients were identified from the Breast node-negative and were deemed the study cohort. Cancer Management System database of the MD A majority of the breast cancers (61%, n = 1245) Anderson Cancer Center (1990 to 2002). At a median were stage i breast cancers, and the median tumour follow-up of 74 months, there were 72 recurrences, size was 2.0 cm (range: 0.1–9.9 cm). Patients were including 34 distant recurrences. The 5-year sfr rates categorized by the biological and morphological were 77.1% in the her 2-positive group and 93.7% features of the tumours, including reh 2 and estrogen in the her 2-negative group (p < 0.0001). The 5-year receptor (er ) status, size, and grade, as well as by sfrd rates were 86.4% in the reh 2-positive group and use of adjuvant therapy. Chia et al. found that her 2- 97.2% in the her 2-negative group (p < 0.0001). Pa- positive and er -negative status both dramatically tients (n = 350) from two European centres using the affected outcomes in the node-negative cohort. In same inclusion criteria and similar follow-up times the entire node-negative cohort (n = 2026), her 2- were also analyzed as a validation set. The validation positive tumours versus her 2-negative tumours had set showed similar results. The authors concluded a signic fi antly reduced 10-year sfr (65.9% vs. 75.5% that her 2-positive T1a–b N0 M0 tumours have a respectively, p = 0.01), decreased distant rfs (drfs : significant risk of relapse and should be considered 71.2% vs. 81.8% respectively; p = 0.004), poorer for systemic anti-her 2 adjuvant therapy. bccs (75.7% vs. 86.3%, p = 0.001), along with a Curigliano et al. performed a retrospective study shortened os trend (65% vs. 74.4%, p = 0.06). In on 150 patients with T1a–b N0 reh 2-positive tumours patients who had a primary tumour size of 1 cm or (T1a: n = 85; T1b: n = 65) who did not receive tras- smaller (n = 326, 16%), a similar trend demonstrat- tuzumab treatment . After a median follow-up of ing negative outcomes in reh 2-positive tumours was 4.6 years, sfd was assessed. In patients with hormone also shown (Table iv ). receptor–positive disease, 5-year sfd was signic fi antly Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC worse in reh 2-positive patients versus reh 2-negative hormone receptor status, but 97% of the trastuzumab patients (92% vs. 99%; hr : 5.2; 95% ci : 1.0 to 25.9; cohort received chemotherapy compared to only 57% p = 0.013; Table iv ) . However, no difference was of patients in the non-trastuzumab cohort. seen in patients with hormone receptor–negative disease (91% vs. 92%; hr : 1.2; 95% ci : 0.3 to 4.7; 4. PANEL SUGGESTIONS FOR TREATMENT IN p = 0.091). Overall, the hr associated with her 2 ADJUVANT THERAPY overexpression was 2.4 (95% ci : 0.9 to 6.5; p = 0.09) in hormone receptor–positive and –negative patients. 4.1 Considerations in the Management of Node- The os in patients with her 2-positive T1a–bN0 Negative Disease with Tumours 1 cm or Smaller disease was similar regardless of hormone receptor status (p = 0.93). 4.1.1 Suggestions While the foregoing retrospective analyses sug- The biology of her 2-positive disease supersedes the gest that women in the her 2-positive cohort with T1 size of the tumour when considering use of trastu- tumours are at an increased risk of recurrence, there zumab in the adjuvant setting. is little information available to assess the benefits Trastuzumab may be considered for women with of either chemotherapy alone or in combination with node-negative T1b (0.5–1.0 cm) tumours that also have trastuzumab for this subset. additional high-risk prognostic factors such as young To date, support for improved outcomes with age, presence of lymphovascular invasion, grade iii trastuzumab is available for node-negative patients cancers, or negative hormone receptor status. taken as a whole. In the case of node-negative pa- The potential cardiac toxicity associated with the tients with the smallest tumours (T1a–b), support selected regimen always has to be weighed with the po- for trastuzumab treatment comes from retrospective tential benefits from chemotherapy and trastuzumab. single-institution practice studies, and while such patients were eligible for the bcirg 006 trial, there is 4.1.2 Discussion no information available specific to this subset from In the opinion of the panel, her 2-positivity rep- this trial. resents an important prognostic factor and one of Recently, Rodrigues et al. conducted a retrospec- several biological markers that appear to be as- tive analysis on the efficacy of adjuvant trastuzumab sociated with disease recurrence and other adverse in 96 patients with her 2-positive node-negative in- outcomes, even in the context of smaller tumours vasive breast carcinoma with T1a or T1b tumours . and node-negative disease. These biological features Chemotherapy [anthracycline (n = 20), taxane (n = should be considered carefully when deciding on 2), sequential anthracycline/taxane (n = 18), and adjuvant therapy. concurrent anthracycline–taxane (n = 1)] was given Most panel members indicated that they would to 43% (n = 41) of the patients. Forty patients, mainly not consider trastuzumab when treating node-negative those with a poor prognosis (based on high mitotic patients with T1mic (≤0.1 cm) or T1a tumours, but index, high grade, and hormone-receptor negativity), they all agreed that this treatment might be justified 32–36 received adjuvant trastuzumab, most in combination in her 2-positive T1b tumours . The panel also with chemotherapy (n = 37). The other 56 patients agreed that other factors suggesting a high recurrence with mainly good prognoses did not receive adjuvant risk such as high tumour grade, lymphovascular inva- trastuzumab. No recurrences occurred in patients who sion, er –negative status and young age should also received trastuzumab, while 5 occurred in patients be taken into consideration. who did not receive trastuzumab. Among the 5 recur- rences, 4 originated in tumours that were hormone 4.2 Management of HER2-positive EBC Across the receptor–negative or high grade (or both). Based on Spectrum of Disease these data, the investigators concluded that patients with node-negative disease with tumours 1 cm or 4.2.1 Suggestion smaller have a high risk of metastatic recurrence Trastuzumab should serve as the standard of care in and should be treated with adjuvant trastuzumab or women with reh 2-positive cbe , with consideration for included in her 2-targeted adjuvant trials, or both. disease and patient characteristics such as nodal status, A retrospective study of 495 her 2-positive early- hormone receptor status, and tumour size (>1 cm). stage breast cancers with 2-cm or smaller node-negative tumours was done at the Memorial Sloan–Kettering 4.2.2 Discussion 18,25,26 Cancer Center. Two cohorts of patients from the pre- The majority of the trials discussed earlier (areh , 19,20 19,21 22 and post-trastuzumab eras were compared for dfs . ncctg N9831 , nsabp B-31 , bcirg 006 , and There was a statistically significant difference noted f inher ) demonstrate dfs benefits of trastuzumab in dfs in these two cohorts (p = 0.007). Six deaths treatment in patients with her 2-positive ebc . These were reported in the pre-trastuzumab era versus only outcomes were similar across most studies, despite one death in the trastuzumab cohort. The two groups differences in the chemotherapeutic regimens with were balanced with respect to age, size of tumour, and which trastuzumab was tested. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. In the recently published pre-planned subgroup characteristics. However, recent data suggest that the analysis of the hera study, Untch et al. confirmed the concurrent approach incorporating anthracyclines, benefit of trastuzumab in her 2-positive ebc across while slightly more cardiotoxic, may be associated various subgroups . For each of the subpopulations with superior efficacy. defined by nodal or hormone receptor status, trastu - zumab treatment was associated with a statistically 4.3.2 Discussion significant increase in 3-year dfs where patient num- A review of the outcomes from the pivotal trials bers were sufc fi ient. Furthermore, the extent of trastu - described earlier suggests that trastuzumab’s sfd ben- zumab’s sfd benet fi was highly consistent across these efits are seen in her 2-positive ebc , whether it is used subpopulations, as judged by the calculated hr for concurrently with the taxane part of chemotherapy dfs events. In particular, subpopulations with lower or is initiated upon completion of chemotherapy. The intrinsic risk of disease recurrence (node-negative position adopted in 2007 and maintained in 2009 by patients and node-negative patients with T1 tumours) the St. Gallen panel was that the two approaches are 14,42 experienced an improvement in dfs similar to that equally acceptable . seen in the broader reh 2-positive cbe population (rh s More recent data suggest that concurrent ap- were approximately 0.5–0.6 in all cases). proaches are more effective . At the sabcs 2009 In the joint analysis of the pbasn B-31 and the cn - meeting, the 60-month follow-up of the gtccn N9831 ctg N9831 trials, trastuzumab’s dfs benefit was also trial was reported. While there continues to be a observed across all subgroups (including age, nodal dfs benefit of sequential trastuzumab ( ac →t →h ) status, hormone receptor status, tumour size, and over chemotherapy alone (ac →t ), the dfs benefit tumour grade) because preliminary analysis showed was superior for the concurrent trastuzumab arm an increase in 4-year dfs in the trastuzumab arm (hr (ac →th →h ) relative to the sequential trastuzumab ranges from 0.22 to 0.80) . arm (hr : 0.77; 95% ci : 0.61 to 0.96; p = 0.019; Recent data from the third planned analysis of Table ii ). This result did not cross the boundary the node-negative population of the bcirg 006 trial for statistical significance, which was pre-set at a showed a significant increase in dfs , both with the p value of 0.00116. The os was not significantly ac →dh regimen (93% vs. 85%; hr : 0.47; 95% ci : improved with sequential trastuzumab relative to 0.28 to 0.77; p = 0.003) and the dc bh regimen (90% chemotherapy alone (hr : 0.86; 95% ci : 0.65 to 1.13; vs. 85%; hr : 0.64; 95% ci : 0.41 to 1.01; p = 0.057). p = 0.281). The investigators recommended the Similarly, there was an increase in os in the ac →dh concurrent use of trastuzumab with chemotherapy group (97% vs. 93%; hr : 0.38; 95% ci : 0.17 to 0.87; (ca →ht →h ) given the risk–benet fi ratio and 4% ab - p = 0.02) and the dc bh group (96% vs. 93%; hr : 0.56; solute improvement in dfs . Also, the acs p -04 trial, 95% ci : 0.27 to 1.13; p = 0.11) . which examined the role of sequential trastuzumab Subgroup analyses were not presented in the (cef /ce →h ), did not show a signic fi ant improvement f inher and acs p -04 trials. in dfs or os . While provocative, these results were This trastuzumab benefit has been recognized in by no means conclusive, because the acs p -04 trial various clinical practice guidelines published since included only a small sample size of 502 patients the pivotal trial results became available. The nccn with her 2-positive disease, and the results do not guidelines on breast cancer recommend the use of correspond with the dfs benefits seen in the other trastuzumab as an appropriate adjuvant therapy in all trials incorporating sequential trastuzumab (hera , patients with reh 2-positive tumours larger than 1 cm as ncctg N9831, and so on). a category 1 recommendation . Similar support for the In trials incorporating a concurrent approach, use of trastuzumab in node-positive and node-negative os benefits are consistently seen where trastuzumab her 2-positive breast cancers (with some restrictions) is given concurrently with taxanes, either in a non- can be found in guidelines from Cancer Care Ontario anthracycline based regimen (that is, dc bh ) or after (node-positive or high-risk node-negative breast can- completion of anthracyclines (nsabp B-31, ncctg cers only) , the BC Cancer Agency (node-positive or 9831, bcirg 006). node-negative with tumours ≥T1c and other features to qualify for chemotherapy) , and the St. Gallen expert 4.4 Treatment Duration of Trastuzumab for EBC consensus group (patients who satisfy the inclusion criteria used in the trials may be considered) . 4.4.1 Suggestion The phase iii randomized studies support the standard 4.3 Timing of Trastuzumab Therapy with use of trastuzumab for 1 year (that is, 18 cycles when Chemotherapy for Early-Stage Disease: given every 3 weeks), regardless of the chemotherapy Concurrent or Sequential regimen employed. 4.3.1 Suggestion 4.4.2 Discussion The decision to use either approach is at the cli- The optimal duration of treatment with trastuzumab nician’s discretion based on patient and disease is unknown. The majority of the pivotal trials on Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC trastuzumab use in ebc have required patients to be the individual cardiovascular risk balanced with the given trastuzumab treatment for a total of 1 year anticipated individual risk of relapse. (Table ii ). The areh study included an arm evaluating The bcirg 006 trial does not demonstrate any 2-year treatment, but safety and efc fi acy data will not advantage to anthracyclines in the population without 18,25,26 be reported until 2011 . The f inher trial gave Topo2 co-amplification, but no validated clinical as - a total of 9 weekly trastuzumab infusions, and at a say is available to assist in this decision. The bcirg median follow-up of 5 years, her 2-positive patients 006 data now suggest superior efficacy results in the who received trastuzumab continue to have a bet- anthracycline-based regimen. Consequently, clini- ter ddfs rate and os trend than those who received cians may need to be more selective in choosing the chemotherapy alone (Table i ) . Although these non-anthracycline trastuzumab regimen (dc bh ), and data are promising, it must be noted that the overall perhaps it should no longer be considered a de facto sample size was small (n = 232). Results from larger standard of care. randomized clinical trials such as sold (Synergism or Long Duration) and phare (Protocol of Herceptin 5. CARDIOTOXICITY Adjuvant with Reduced Exposure), assessing 9 weeks or 6 months of trastuzumab treatment respectively, Two years ago, a similar Canadian panel of seven and the 2-year hera data will shed more light on the oncologists and two cardiologists met for a full-day optimal duration of trastuzumab. In the absence of conference and developed recommendations in the strong data, there is no need to diverge from the ap- assessment and management of cardiac complica- proved 1-year treatment duration. This is in agreement tions during adjuvant trastuzumab therapy . First, 15 40 with guidelines from nccn , Cancer Care Ontario , the authors outlined risk factors that exclude patients and the BC Cancer Agency . from trastuzumab treatment such as existing heart failure or vef l below 50% (or both) and risk factors 4.5 The Role of Non-Anthracycline that require special consideration such as ischemic Trastuzumab-Based Regimens heart disease, significant valvulopathy, and a pre- trastuzumab baseline vefl of 50%–55%. Second, 4.5.1 Suggestion the panel concluded that there were insufficient data The choice between anthracycline-based adjuvant to make formal statements about the cardiotoxicity trastuzumab regimens and the dc bh regimen should of concurrent versus sequential regimens and that be based on the individual risk of cardiac toxicity. evidence existed to suggest that anthracycline-free regimens have a lesser incidence of cardiac toxicity. 4.5.2 Discussion Updated cardiac toxicity results from the gtccn 9831 The need for anthracyclines when giving trastuzumab trial (Table iii ) do suggest a slightly greater cardiac and chemotherapy-based treatment has been contro- toxicity risk with the concurrent approach compared versial. In the initial reports from the bcirg 006 trial, with the sequential approach (incidence of symptom- there was clear indication that the two trastuzumab- atic chf : 3.3% vs. 2.8%) . Patients with ebc should containing arms (ac →dh and dc bh ) had very similar be treated with trastuzumab treatment for 1 year clinical benefits . However, weighing the safety (less only if disease recurs) until further evidence risks (cardiotoxicity and leukemia risk) associated suggests otherwise. Third, the panel emphasized the with the anthracycline-based arm (ac →dh ), the need to assess cardiac function before trastuzumab non-anthracycline arm (dc bh ) seems to be a more treatment by using echocardiography or muga scan favourable choice. to establish baseline and subsequent vef l readings The bcirg 006 trial was recently updated at sabcs (3, 6, 9, and 12 months). After trastuzumab therapy, 2009, and again, both trastuzumab-containing arms annual monitoring should be considered in patients had better dfs and os than the control arm, and the who experienced cardiac symptoms or a greater two trastuzumab arms did not differ statistically in than 10% absolute asymptomatic decline in vefl . dfs although numerically the results favoured the Finally, the panel established a detailed “stop/restart” ac →dh arm . The data combining dfs events with algorithm for both symptomatic and asymptomatic life-threatening toxicities (chf and treatment-related left ventricular dysfunction based on the Canadian leukemia) now favour the ac →dh arm. There is no Cardiovascular Society recommendations. Details of doubt that the non-anthracycline regimen (dc bh ) is pharmacotherapy options and duration of treatment the safest regimen with respect to cardiotoxicity (in- for cardiotoxicity were outlined, and guidelines for cidence: 0.4% New York Heart Association grades 3 the decision to re-initiate were discussed . and 4 fhc vs. 2.0% fhc with ca →hd ); however, while the efficacy results of dc bh and ac →dh do not dif- 6. CONCLUSIONS fer statistically, the 5-year dfs numerically favours ca →hd . Consequently, the clinical decision to pursue Trastuzumab has emerged as the key component an anthracycline or non-anthracycline adjuvant tras- of care in women with her 2-positive ebc . Clinical tuzumab regimen should be made in the context of findings from several large trials, representing more Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. than 14,000 individual patients, have established sig- pathways: implications for her 2-targeted antibody therapy. nificant dfs and os benefits of trastuzumab treatment. Oncogene 2006;25:6986–96. The benefits of trastuzumab are seen regardless of 9. Klos KS, Zhou X, Lee S, et al. Combined trastuzumab and pa- other patient characteristics such as age or of tumour clitaxel treatment better inhibits ErbB-2-mediated angiogenesis characteristics such as hormone positivity or nodal in breast carcinoma through a more effective inhibition of Akt status. The benefit of trastuzumab for node-negative than either treatment alone. Cancer 2003;98:1377–85. ebc patients with small tumours (for example, T1a 10. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc tumours) remains to be fully established. 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Curr Oncol Breast Cancer Res Treat 2007;106(suppl 1):. [Available 2008;15:24–35. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. Correspondence to: Sunil Verma, University of To- Centre Intégré de cancérologie de la Montérégie, ronto and Sunnybrook Health Sciences Centre, 2075 Université de Sherbrooke, and Réseau Cancer Bayview Avenue, Room T2 045, Toronto, Ontario Montérégie, Longueuil, QC. M4N 3M5. ** Unité de recherche en santé des populations, E-mail: sunil.verma@sunnybrook.ca Centre de Recherche du Centre Hospitalier afl fi ié universitaire de Québec, Quebec City, QC. †† * University of Toronto, Toronto, ON. Hôpital du Saint-Sacrement, Quebec City, QC. † ‡‡ Sunnybrook Health Sciences Centre, Toronto, ON. British Columbia Breast Tumour Group, British Division of Medical Oncology, Department of Columbia Cancer Agency–Vancouver Centre, Oncology, University of Alberta, Cross Cancer Vancouver, BC. §§ Institute, Edmonton, AB. Remedy Communications, Toronto, ON. § |||| Division of Medical Oncology, The Ottawa Hos- Atlantic Clinical Cancer Research Unit (ACCRU) pital Cancer Centre, Ottawa, ON. and QEII Cancer Care Program, QEII Health Sci- || University of Ottawa, Ottawa, ON. ences Centre, Halifax, NS. Current OnCOlOgy —VOlume 17, n umber 4 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Oncology Multidisciplinary Digital Publishing Institute

Optimizing the Management of her2-Positive Early Breast Cancer: The Clinical Reality

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Abstract

M E D I C A L O N C O L O G Y Optimizing the management of her 2-positive early breast cancer: the clinical reality † † Su. Verma MSEd MD,* S. Lavasani MD, ‡ † J. Mackey MD, K. Pritchard MD,* § §|| M. Clemons MB BS MD, S. Dent BSc MD, J. Latreille MDCM, J. Lemieux MSc MD,** †† §|| L. Provencher MA MD, Sh. Verma MD, ‡‡ §§ |||| S. Chia MD, B. Wang MSc, and D. Rayson MD ABSTRACT 1. INTRODUCTION Breast cancer positive for her 2 (human epidermal About 23,000 new cases of breast cancer will be growth factor receptor 2) is associated with a poor diagnosed in Canada in 2010 . The estimated prognosis for patients with both early-stage and 5400 annual deaths from breast cancer are second metastatic breast cancer. Trastuzumab has been shown only to those from lung cancer as contributors to to be effective and is now considered the standard cancer-related mortality in the Canadian female of care for early-stage patients with her 2-positive population . The majority of women diagnosed breast cancer. In that population, trastuzumab has with breast cancer present with early-stage disease been studied in six randomized clinical trials. Over- (>75%). In recent decades, a substantial decline in all, use of this agent leads to a significant reduction mortality among breast cancer patients has been in risk of disease recurrence and improvement in attributed in part to advancements in adjuvant sys- overall survival. Despite the strong evidence for the temic therapy. use of trastuzumab in managing her 2-positive early The outcome for early breast cancer (cbe ) patients breast cancer (ebc ), a number of clinical controver- with her 2 (human epidermal growth factor recep- sies remain. The authors of this paper undertook a tor 2)–positive disease has particularly improved review of the available scientific literature on adju - since the end of the 1990s with the introduction of vant trastuzumab to produce practical considerations trastuzumab in this setting. Trastuzumab is a mono- from Canadian oncologists. The panel focused their clonal antibody that binds to the extracellular domain discussion on five key areas: of her 2. Several mechanisms of action underlie the ● Management of node-negative disease with tu- antitumour effects of trastuzumab. Trastuzumab mours 1 cm or smaller in size blocks her 2-activated cell signalling, thereby ● Management of her 2-positive ebc across the reducing cell proliferation and restoring ability spectrum of the disease (that is, nodal and steroid to undergo apoptosis by inhibiting the phosphati- 2–5 hormone receptor status, tumour size) dylinositol 3 kinase/Akt pathway , which in- ● Timing of trastuzumab therapy with chemotherapy creases cellular sensitivity to chemotherapy and for early-stage disease: concurrent or sequential radiotherapy . Trastuzumab has also been shown 3,7–9 ● Treatment duration of trastuzumab for ebc to inhibit her 2-regulated angiogenesis and, in ● The role of non-anthracycline trastuzumab- preclinical models, to recruit the immune system based regimens through antibody-dependent cellular cytotoxicity, triggering activation of natural killer cell–mediated 10–12 KEY WORDS apoptosis . In addition, trastuzumab has also her 2 been shown to prevent the formation of p95 (a Adjuvant, early breast cancer, her 2-positive, node- truncated active form of her 2), which may lead to 3,13 negative, trastuzumab inhibition of tumour development . Copyright © 2010 Multimed Inc. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. Based on efficacy data from six major random - by two main panel members (SuV and DR) and a ized controlled clinical trials comparing adjuvant breast cancer fellow (SL). The final manuscript was chemotherapy alone to adjuvant chemotherapy reviewed, revised, and approved by the remaining plus trastuzumab delivered either concurrently or nine panel members (MC, SC, SD, JLe, JLa, JM, KP, in sequence, adjuvant trastuzumab has become an LP, ShV). Published and presented clinical trial results internationally accepted part of adjuvant systemic available as of January 2010 were incorporated into 14,15 therapy for her 2-positive ebc . the present document by SL. Despite the clear benet fi s of adjuvant trastuzumab for the relevant patient population, there remain a 1.2 Conflict of Interest Disclosures number of clinical scenarios and questions in which the data are not as clear and controversy persists. For Support for the initial meeting of the Canadian advi- example, the 11th St. Gallen international expert con- sory panel and the development of the present manu- sensus meeting was not able to provide a den fi itive rec - script was provided by an unrestricted educational ommendation regarding the use of anti-her 2 therapy grant from Hoffmann–La Roche Canada. The authors for patients with reh 2-positive node-negative tumours received an honorarium for attending the meeting, smaller than 1 cm in size, because of the absence of but not for writing the manuscript. The authors are data to suggest an increased risk of disease recurrence solely responsible for the content of the manuscript, or a significant benefit from treatment . Also, the with no restrictions set by the sponsor. balance between cardiotoxic risk and adjuvant benefit from systemic chemotherapy continues to generate 2. OVERVIEW OF THE KEY TRIALS IN HER2- controversy. The 2010 National Comprehensive Can- POSITIVE EARLY BREAST CANCER cer Network (nccn ) guidelines recommend the need to balance the known cardiotoxicity risk of trastuzumab Results from six large multicentre randomized con- against the uncertain absolute benefits that may exist trolled clinical trials evaluating the role of adjuvant before considering trastuzumab treatment . trastuzumab in her 2-positive ebc have been reported The goal of this manuscript is to discuss the to date. These include the Herceptin Adjuvant (hera ) optimal utilization of adjuvant trastuzumab in the trial , the National Surgical Adjuvant Breast and 19,20 management of her 2-positive ebc in the context of Bowel Project (nsabp ) B-31 trial , the North particularly common clinical scenarios: Central Cancer Treatment Group (ncctg ) N9831 20,21 trial , the Breast Cancer International Research ● Management of node-negative disease with tu- Group (bcirg ) 006 trial , the Finland Herceptin trial mours 1 cm or smaller in size (f inher ) , and the Protocol Adjuvant dans le Cancer ● Management of her 2-positive ebc across the du Sein (sca p -04) trial . Together, these trials accrued spectrum of the disease (that is, nodal and steroid more than 14,000 women and evaluated the addition hormone receptor status, tumour size) of trastuzumab to varying chemotherapeutic strate- ● Timing of trastuzumab therapy with chemotherapy gies. These trials differed substantially with respect to for early-stage disease: concurrent or sequential study design (Figure 1), patient population (Table i ), ● Treatment duration of trastuzumab for ebc and chemotherapeutic backbones. ● R o l e o f n o n - a n t h r a c y c l i n e t r a s t u z u m a b - Four trials demonstrated improved disease-free based regimens survival (dfs ), and three demonstrated significantly improved overall survival (os , Table ii ). Updated 1.1 Development of Panel Suggestions cardiac toxicity data from these trials indicate that the rate of this toxicity varies depending on the use The authors of this paper met in Toronto for a one-day of anthracyclines and whether trastuzumab is given in conference in June 2008. The panel reviewed results conjunction with or after chemotherapy (Table iii ). of the latest trials in the neoadjuvant, adjuvant, and metastatic settings. Based on updated trial informa- 2.1 HERA Trial tion, suggestions were formulated for the neoadjuvant and metastatic settings and were subsequently pub- The hera trial, an international phase iii multicentre 16,17 lished in 2009 . randomized open-label three-arm study, randomized With regard to the current manuscript, the panel patients to 1 or 2 years of adjuvant trastuzumab or reviewed the available evidence regarding adjuvant observation, subsequent to completion of a minimum trastuzumab for ebc and identified ongoing con - of 4 cycles of adjuvant or neoadjuvant chemotherapy troversies awaiting data from further or completed (Figure 1). Inclusion criteria included all her 2-pos- randomized clinical trials. Based on the panel’s itive node-positive or node-negative disease with a review and discussion of the updated clinical data, tumour size greater than 1 cm and left ventricular suggestions were formulated for a variety of clinical ejection fraction (vef l ) of 55% or more as measured scenarios. A draft manuscript was initially written by by echocardiography or multiple-gated acquisition a medical writer (BW) and was reviewed and revised (muga ). A total of 5102 women participated in this Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC Observation* Local invasive EBC Surgery + (neo)adjuvant CT ± RT One-year Trastuzumab HERA HER2+ (Central FISH/IHC 3+) (8 mg/kg  6 mg/kg, q3w) LVEF ≥55% Two-year Trastuzumab (8 mg/kg  6 mg/kg, q3w) N9831 Group A and B-31 Group 1 Paclitaxel 4 x AC (4 x 175 mg/m , q3w or AC  T 2 2 (60/600 mg/m , q3w) 12 x 80 mg/m , qw) Joint HER2+ (IHC 3+ or FISH) Analysis N+ or High Risk N– 4 x AC Paclitaxel AC  T+H 2 2 (60/600 mg/m , q3w) (4 x 175 mg/m , q3w or LVEF ≥ 50% 12 x 80 mg/m , qw) N9831 Group C B-31 and Group 2 One-year Trastuzumab (4 mg/kg  2 mg/kg, qw) Group A 4 x AC Paclitaxel 2 2 ACT (60/600 mg/m , q3w) (12 x 80 mg/m , qw) Group 1 4 x AC Paclitaxel 2 2 AC  T (60/600 mg/m , q3w) (4 x 175 mg/m , q3w OR 12 x 80 mg/m , qw) B-31 N9831 Group B 4 x AC Paclitaxel One-year Trastuzumab 2 2 4 x AC Paclitaxel ACT H (60/600 mg/m , q3w) (12 x 80 mg/m , qw) (4 mg/kg  2 mg/kg, qw) Group 2 2 2 (60/600 mg/m , q3w) (4 x 175 mg/m , q3w OR AC  TH 12 x 80 mg/m , qw) Group C 4 x AC Paclitaxel One-year Trastuzumab 2 2 ACTHH (4 mg/kg  2 mg/kg, qw) (60/600 mg/m , q3w) (12 x 80 mg/m , qw) One-year Trastuzumab (4 mg/kg  2 mg/kg, qw) 4 x AC 4 x Docetaxel ACD 2 2 (60/600 mg/m , q3w) (100 mg/m , q3w) 4 x AC 4 x Docetaxel ACDH 2 2 (60/600 mg/m , q3w) (100 mg/m , q3w) HER2+ (Central FISH) BCIRG 006 N+ or High Risk N– One-year Trastuzumab Stratified by nodes and (4 mg/kg  2 mg/kg, qw [in combination]; HR Status 6 mg/kg q3w [monotherapy after chemotherapy]) 6 x Docetaxel and Carboplatin (75 mg/m and AUC 6) DCbH One-year Trastuzumab (4 mg/kg  2 mg/kg, qw [in combination]; 6 mg/kg q3w [monotherapy after chemotherapy]) 3 x Docetaxel (100mg/m , q3w) or 3 x FEC D/V FEC 2 2 9 x Vinorelbine (25 mg/m , qw) (600/60/600 mg/m , q3w) HER2+ (IHC 2+ or 3+ and CISH) FinHer N+ or High Risk N–, >20 mm, 3 x Docetaxel (100mg/m , q3w) or 3 x FEC PgR–, no cardiac disease 2 2 9 x Vinorelbine (25 mg/m , qw) (600/60/600 mg/m , q3w) (D/V) H FEC Nine-week Trastuzumab (4 mg/kg  2 mg/kg, qw) 6 x FEC (500/100/500 mg/m , q3w) FEC/ED or HER2+ (IHC 2+ or 3+ and FISH) 6 x ET (75/75 mg/m , q3w) PACS-04 N+ LVEF ≥ 55% (if 50-55%, 6 x FEC (500/100/500 mg/m , q3w) One-year Trastuzumab cardiologist‘s approval required) FEC/ED  H or (8 mg/kg  6 mg/kg, q3w) 6 x ET (75/75 mg/m , q3w) After RT figure 1 Summary of trial designs (boxes not drawn to scale). The hera (Herceptin Adjuvant study) design was adapted from Piccart– 25 26 18 Gebhart et al. 2005 , Smith et al. 2007 , and Gianni et al. 2009 . The joint analysis [nsabp (National Surgical Adjuvant Breast and Bowel 19 20 Project) B-3, nCCtg (North Central Cancer Treatment Group) N9831] design was adapted from Romond et al. 2005 and Perez et al. 2007 . 27 22 The bCirg (Breast Cancer International Research Group) 006 design was adapted from Slamon et al. 2006 and Slamon et al. 2009 . The 28 23 f inher (Finland Herceptin trial) design was adapted from Joensuu et al. 2006 and Joensuu et al. 2009 . The aC p s (Protocol Adjuvant dans le Cancer du Sein)–04 design was adapted from Speilmann et al. 2009 . * Multiple chemotherapy regimens were permitted. ebC = early breast cancer; Ct = chemotherapy; rt = radiation therapy; her 2 = human epidermal growth factor receptor 2; fish = fluorescence in situ hybridization; ihC = immunohistochemistry; l Vef = 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; p gr = progesterone receptor; V = vinorelbine; feC = fluorouracil, epirubicin, cyclophosphamide; ed = epirubicin, docetaxel; et = epirubicin, paclitaxel. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. able t i Design and patient characteristics of adjuvant trastuzumab trials Trial short name Treatment regimen Pts Tumour size (%) Positive nodes (%) Positive hr status [total patients (n)] (h duration) (n) ≤2 cm >2 to ≤5 cm >5 cm na 0 1–3 ≥4 na [er or pr or both (%)] 25 a b hera (5102 ) Observation 1693 40 43 6 11 33 29 28 10 50 h (1 year) 1694 39 45 4 12 32 29 28 11 50 Joint analysis nsabp B-31 (2006 ) ac →t 1979 40 51 7 1 7 52 40 — 55 ncctg N9831 (3505 ) ac →t +h (1 year) 1989 38 52 9 1 7 53 40 — 54 bcirg 006 (3222) ac →d 1073 41 53 6 — 29 38 33 — 54 ac →dh (1 year) 1074 38 55 7 — 29 38 33 — 54 dc bh (1 year) 1075 40 54 6 — 29 39 33 — 54 23,28 d f inher (232) d /v →fec 116 30 70 — 0 22 50 28 — nr (d /v )h →fec (9 weeks) 116 40 59 — 1 10 55 34 — nr acs p -04 (528) fec or ed 268 49 51 (>2 cm) — (n=7) — 56 44 — 61 fec or ed →h 260 41 59 (>2 cm) — (n=1) — 60 40 — 58 Results were not reported for patients who were randomized to receive 2 years of trastuzumab. Multiple chemotherapy regimens were permitted. Not all patients were included in the joint analysis. 44% were er +; 29% were pr +. 50% were er +; 39% were pr +. h = trastuzumab; Pts = patients; an = not available; rh = hormone receptor; re = estrogen receptor; rp = progesterone receptor; areh = Herceptin Adjuvant study; pbasn = National Surgical Adjuvant Breast and Bowel Project; a = doxorubicin; c = cyclophosphamide; t = paclitaxel; gtccn = North Central Cancer Treatment Group; gricb = Breast Cancer International Research Group; d = docetaxel; c b = carboplatin; f inreh = Finland Herceptin trial; v = vinorelbine; acs p = Protocol Adjuvant dans le Cancer du Sein; f = fluorouracil; e = epirubicin; nr = not reported. trial with a primary endpoint of dfs and a secondary 2.2 Joint Analysis of the NSABP B-31 and NCCTG endpoint of os . At the interim analysis, with a median N9831 Trials follow-up of 23.5 months, the unadjusted hazard ratio (hr ) for risk of a dfs event with trastuzumab versus The pbasn B-31 trial was a U.S.-based phase iii mul- observation alone was 0.64 [95% confidence interval ticentre randomized open-label trial in reh 2-positive (ic ): 0.54 to 0.76; p < 0.0001], corresponding to an ab- ebc that assessed the addition of trastuzumab to solute improvement in sfd of 6.3% (80.6% vs. 74.3%) an anthracycline-based regimen [doxorubicin and at 3 years . The unadjusted hr for risk of death at cyclophosphamide followed by paclitaxel (ac →t ) 3 years with trastuzumab versus observation was 0.66 every 3 weeks for 4 cycles] with 1 year of trastu- (95% ci : 0.47 to 0.91; p = 0.0115), resulting in an zumab [ac →th (Figure 1)]. Trastuzumab was initi- 26 19 absolute os benefit of 2.7% (92.4% vs. 89.7%) . ated concurrently with the first dose of paclitaxel . Recently, Gianni et al. presented updated data The ncctg N9831 trial, a similar phase iii open- from the hera trial with a median follow-up time label trial, explored the efficacy of 1 year adjuvant of 4 years (Table ii ). The hr for risk of an event trastuzumab given concurrently with 12 doses of with trastuzumab versus observation was 0.76 weekly paclitaxel versus after 12 doses of paclitaxel (95% ci : 0.66 to 0.87; p < 0.0001), corresponding (ac →th →h vs. ac →t →h ) in her 2-positive ebc to an absolute dfs improvement of 6.4% (78.6% (Figure 1) . Data from these two trials, referred to vs. 72.2%) . However, the observed absolute os as the “joint analysis,” were pooled to allow for an benefit decreased from 2.7% at 3 years to 1.6% at early non-protocol analysis with sufc fi ient statistical 4 years and was no longer statistically significant power to compare the two similar regimens (ac →t (89.3% vs. 87.7%; hr : 0.85; 95% ci : 0.70 to 1.04; vs. ac →th ) . The primary endpoint of the joint p = 0.1087). Potential explanations for the loss of analysis was sfd , and the secondary endpoint was so . survival benefit include An efficacy update showed a significant difference in 4-year dfs rates for trastuzumab-treated patients ● the crossover of 65% of control patients to ad- (85.9% vs. 73.1%; adjusted hr : 0.48; 95% ci : 0.41 juvant trastuzumab, resulting in an improved to 0.57; p < 0.00001). The corresponding 4-year os outcome in the observation arm; and rates were 92.6% and 89.4%, respectively (rh : 0.65; ● the apparent inferiority of sequencing adjuvant 95% ci : 0.51 to 0.84; p = 0.0007) . trastuzumab after chemotherapy rather than in Updated data from the ncctg N9831 study pre- combination with chemotherapy. sented at the San Antonio Breast Cancer Symposium Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC ac ac nr nr nr nr th ac bcirg hr ac nsabp acs ac nr ac hr hera ac ncctg ci h t fec t t ed fec t ed th her ac ac dh hr ac h v d fec f ac h h d ac fec dc ac ac ac hr ii nsabp ncctg her t hera ncctg bcirg f p a d able acs Current OnCOlOgy —VOlume 17, n umber 4 Updated disease-free survival and overall survival Study short name Treatment regimen Pts Median follow-up Disease-free survival Overall survival Crossover [total pts (n)] ( duration) (n) (months) (%) 95% C p Value (%) 95% C p Value 18 b c Observation 1698 48 72 0.76 0.66 to 0.87 <0.0001 88 0.85 0.70 to 1.04 0.1087 65% of observation crossed over to (1 year) 1703 79 89 Joint analysis d e B-31 (2006 ) → 1979 35 73 0.48 0.41 to 0.57 <0.00001 89 0.65 0.51 to 0.84 0.0007 21% of → crossed over after N9831 (3505 ) initial efficacy report → + (1 year) 1989 86 93 in 2005 21 g g N9831 → 1087 72 0.70 0.57 to 0.86 0.0005 — 0.86 0.65 to 1.13 0.281 66 (5.5 years) 1097 80 — → → g g 954 80 0.77 0.61 to 0.96 0.019 — 0.79 0.59 to 1.08 0.135 64 (~5 years) → → 949 84 — 006 → 1073 65 75 1 87 1 2% of → crossed over → (1 year) 1074 84 0.64 0.53 to 0.78 <0.001 92 0.63 0.48 to 0.81 <0.001 to receive b (1 year) 1075 81 0.75 0.63 to 0.90 0.04 91 0.77 0.60 to 0.99 0.038 trastuzumab 23 h in / → 116 62 73 0.65 0.38 to 1.12 0.12 82 0.55 0.27 to 1.11 0.094 ( / ) → 115 83 91 (9 weeks) -04 or 268 47 78 0.86 0.61 to 1.22 0.41 96 1.27 0.68 to 2.38 or → 260 81 95 Hazard ratios are unadjusted. Multiple chemotherapy regimens were permitted. Based on 885 of the 1354 patients who were alive and disease-free on May 16, 2005. Not all patients were included in the joint analysis. Adjusted . Patients from → who received trastuzumab are still included in → for analysis. Investigators were conducting an intention-to-treat analysis. Disease-free and overall survival data are based on the following treatment arm comparisons: → versus → → and → → versus → → . Distant disease-free survival. Pts = patients; = trastuzumab; = hazard ratio; = confidence interval; = Herceptin Adjuvant study; = National Surgical Adjuvant Breast and Bowel Project; = doxorubicin; = cyclophosphamide; = paclitaxel; = North Central Cancer Treatment Group; = not reported; = Breast Cancer International Research Group; = docetaxel; b = carboplatin; in = Finland Herceptin trial; = vinorelbine; = fluorouracil; = epirubicin; = Protocol Adjuvant dans le Cancer du Sein. VERMA et al. able t iii Updated cardiac toxicity Trial short name Treatment regimen Pts Median l Vef (%) Symptomatic Cardiac (n) follow-up Required Pts with Chf death (months) at baseline sig. decrease (%) (n) 18 a hera Observation 1719 48 ≥55 0.8 0.2 1 h (1 year) 1682 3.7 2.0 0 29 c nsabp B-31 ac →t 898 60 ≥50 nr 0.9 1 ac →t +h (1 year) 947 nr 3.8 0 30 d ncctg N9831 ac →t 554 36 ≥50 4.5 0.3 1 ac →t →h 514 5.4 2.8 1 ac →t +h (1 year) 400 5.8 3.3 0 22 e f g bcirg 006 ac →d 1050 65 ≥50 11 0.7 0 e f g ac →dh (1 year) 1068 19 2.0 0 e f g dc bh (1 year) 1056 9 0.4 0 23 h f inher d /v →fec 116 62 ns 10.5 1.7 0 (d /v )h →fec (9 weeks) 115 6.8 0.9 0 24 i acs p -04 fec or ed 268 47 ≥50 2.6 0.4 0 fec or ed →h 260 11.1 1.5 0 Patients who crossed over are censored from the date that they started trastuzumab treatment. Severe chf [New York Heart Association (nyha ) class iii and iv ] was reported in 13 patients (0.8%). 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 vef l of more than 10% to below 55% or of more than 5% and below lower level of normal)]. Reported as 3-year cumulative incidence of cardiac events (defined as symptomatic chf , definite cardiac death, or probable cardiac death). For patients with a greater than 10% relative vef l decline: n = 1018 (ac →d ); n = 1042 (ac →dh ); n = 1031 (dc bh ). Reported as a greater than 10% relative vef l decline. Reported as grade 3 or 4 chf . Reported as a greater than 20-percentage-point decrease in vef l from baseline at one or more vef l measurements after completion of chemotherapy. Reported as a severe decline (absolute vef l < 45%, 45%–49%, and ≥15%). Pts = patients; vef l = 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; c b = carboplatin; f inher = Finland Herceptin trial; v = vinorelbine; f = fluorouracil; e = epirubicin; ns = not specified; acs p = Protocol Adjuvant dans le Cancer du Sein. (sabcs ) in December 2009 show continued improve- for 4 cycles, followed by docetaxel every 3 weeks for ment in dfs with the addition of sequential trastu- 4 cycles (ac →d vs. ac →dh ), Figure 1] . The bcirg zumab to chemotherapy: 80.1% in the sequential 006 trial also included a non-anthracycline third treat- arm versus 71.9% in the chemotherapy-only arm (rh : ment arm with concurrent docetaxel, carboplatin, and 0.70; 95% ci : 0.57 to 0.86; p = 0.0005; Table ii ) . trastuzumab (dc bh ). The primary endpoint was dfs , Comparison of the sequential arm with the concurrent and the secondary endpoint was os . arm showed a dfs of 79.8% versus 84.2% (hr : 0.77; Recent data from the third planned analysis of 95% ci : 0.61 to 0.96; p = 0.019; details discussed bcirg 006 revealed dfs rates of 75% (ac →d ), 84% later in this article). The 5-year follow-up did not (ac →dh ), and 81% (dc bh ) at 65 months of follow-up show any survival benefit for the sequential addition (Table ii ) . The hr , compared with the observation of trastuzumab to chemotherapy (hr : 0.86; 95% ci : arm, for ac →dh was 0.64 (95% ci : 0.53 to 0.78; p < 0.65 to 1.13; p = 0.281). 0.001) and for dc bh was 0.75 (95% ci : 0.63 to 0.90; p = 0.04). The sfd in the two trastuzumab arms did not 2.3 BCIRG 006 Trial differ statistically (p = 0.21). Updated data show an so of 87% in the chemotherapy-only arm compared with The international bcirg 006 phase iii open-label trial, 92% in the ca →hd arm (rh : 0.63; 95% ic : 0.48 to 0.81; conducted in 42 countries, randomized patients with p < 0.001) or 91% in the dc bh arm (hr : 0.77; 95% ci : reh 2-positive cbe to observation or a 1-year course of 0.60 to 0.99; p = 0.038). Relative to the anthracycline- trastuzumab in conjunction with taxane chemotherapy containing arms, dc bh continued to have a superior [doxorubicin and cyclophosphamide every 3 weeks toxicity profile, including less acute toxicity, better Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC 31 24 quality of life , and lower rates of congestive heart ed → h , Figure 1) . Patients had to have proven ebc failure (chf ) and leukemia. Interesting and provoca- with complete resection (T1, T2, T3) and be axillary tive data related to Topo2A (topoisomerase iia pro- node-positive. The primary endpoint was 3-year dfs . tein) were also presented, suggesting that the benefit After a median follow-up of 47 months, there was no from adjuvant trastuzumab was restricted to patients difference in sfd (77.9% vs. 80.9%; rh : 0.86; 95% ic : who were not Topo2A co-amplified. 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 2.4 f inher Trial trastuzumab treatment groups (Table ii ). The multicentre phase iii open-label f inher trial 3. NODE-NEGATIVE DISEASE WITH enrolled ebc patients (n = 1010) with axillary-node- TUMOURS 1 CM OR SMALLER positive or high-risk node-negative cancer . Patients were assigned to receive 3 cycles of docetaxel or On the basis of the significant dfs and os benefits vinorelbine every 3 weeks, followed by 3 cycles of established in the pivotal trials discussed earlier, fluorouracil, epirubicin, and cyclophosphamide ( d / adjuvant trastuzumab is now considered standard of v →fec ) every 3 weeks. Women with her 2-positive care for patients with her 2-positive ebc . However, breast cancer (n = 232) were further randomized to re- questions persist regarding the value of trastuzumab ceive or not to receive 9 weekly trastuzumab infusions in specific subpopulations, notably node-negative (4 mg/kg loading, 2 mg/kg maintenance; Figure 1). patients with small tumours (≤1 cm—that is, T1a and The primary endpoint was recurrence-free survival T1b) because they generally have been considered to (rfs ). At 3 years’ median follow-up, her 2-positive have low risk for disease recurrence. patients who received trastuzumab had a better rfs Node-negative patients with T1a (>0.1 cm and rate (89.3% vs. 77.6%; rh : 0.42; 95% ic : 0.21 to 0.83; ≤0.5 cm) and T1b (>0.5 cm and ≤1 cm) tumours are p = 0.01) and trend to improved so (96.3% vs. 89.7%; commonly assumed to have a low risk of recurrence rh : 0.41; 95% ic : 0.16 to 1.08; p = 0.07) than did those relative to patients with larger tumours. However, who did not receive trastuzumab . retrospective data from tertiary care cancer centres Recently, updated results from a median follow- suggest that despite small size, these node-negative up of 5 years were published , and her 2-positive tumours (that is, ≤1 cm) are at a greater risk of recur- patients who received trastuzumab continue to have rence if they are her 2-positive (Table iv ). a better distant dfs (ddfs ) rate (83.3% vs. 73.0%; Black et al. examined the incidence of breast unadjusted hr : 0.65; 95% ci : 0.38 to 1.12; p = 0.12) cancer outcomes in a group of 164 node-negative and os trend (91.3% vs. 82.3%; hr : 0.55; 95% ci : women with her 2-positive tumours T2 or lower . 0.27 to 1.11; p = 0.094) than do those who received The incidences of breast cancer outcomes in her 2- chemotherapy alone (Table ii ). negative tumours were not collected. Over a median Data analysis on her 2-positive patients was period of 5 years of postsurgical follow-up, the inci- further stratified based on specific chemotherapy dences of distant metastasis, locoregional recurrence, regimen. Patients who received d →fec plus trastu- and contralateral cancer were similar for patients with zumab versus d →cef alone had a signic fi antly higher T1a–b (≤1 cm) her 2-positive versus T1c (>1 cm and ddfs rate (92.5% vs. 74.1%; hr : 0.32; 95% ci : 0.12 ≤2 cm) her 2-positive tumours. Taken together, the to 0.89; p = 0.029). In contrast, patients who took incidences were 19%, 15%, and 23% for women with v →fec plus trastuzumab versus v →fec alone did T1a–b, T1c, and T2 tumours respectively, suggesting not have a significantly different ddfs rate outcome that even T1 breast cancer is at a higher risk of recur- (75.2% vs. 72.0%; hr : 0.92; 95% ci : 0.47 to 1.83; p = rence in the context of her 2-positive disease . 0.82). Overall, investigators concluded that adjuvant In a nationwide population-based study in Finland, docetaxel (not vinorelbine) improved ddfs and that Joensuu et al. analyzed 852 unilateral node-negative trastuzumab is a safe and effective addition, justify- T1 breast cancers (including 49 T1a and 264 T1b ing further investigation of a shortened duration of tumours) from the Finnish Cancer Registry . Expres- trastuzumab given the improved rfs that was shown sion or amplic fi ation of reh 2 was determined by immu- with only 9 weeks of adjuvant trastuzumab. nohistochemistry or chromogenic in situ hybridization respectively. Contrary to common perception, a tumour 2.5 PACS-04 Trial size of 10 mm or smaller was not uniformly associated with low risk for distant recurrence. Patients with T1b The acs p -04 trial was a phase iii multicentre trial as- grade 2 or 3 tumours had a significantly decreased sessing the benet fi s of concomitant docetaxel and epi - 9-year ddfs when the her 2 protein was overexpressed rubicin for 6 cycles every 3 weeks versus u fl orouracil, [ddfs : 67% (n = 11) vs. 95% (n = 54); p = 0.003] or epirubicin, and cyclophosphamide for 6 cycles every the gene was amplified [ ddfs : 67% (n = 11) vs. 92% 3 weeks, and a second randomization randomized (n = 52); p = 0.006; Table iv ]. reh 2-positive patients to sequential trastuzumab every In an independent analysis extending over 10 3 weeks for 1 year or observation (fec or ed vs. fec or years of follow-up, Chia et al. reached similar Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. able t iv Recurrence-free survival and distant recurrence-free survival in patients with node-negative disease based on human epidermal growth factor receptor 2 [her 2 (erbB2)] status Reference Tumour Follow-up her 2 Hormonal Survival (%) size (years) status status Recurrence-free Distant recurrence- free (cm) (n) her 2+ her 2– her 2+ her 2– 36 a Finnish Population Study 0.6–1 9.5 Amplification: — — — 67 92 12 positive, 95 56 negative; expression: 12 positive, 60 negative 32,c British Columbia Tissue Microarray 0.6–1 10 13 Positive, — 68 82 212 negative nr p=0.312 MD Anderson Cancer Center ≤1 5 98 Positive, — 77 94 86 97 867 negative hr : 2.68 hr : 5.3 95% ci : 1.44 to 5.0 95% ci : 2.23 to 12.62 p=0.002 p=0.0002 European Institute of Oncology ≤1 5 79 Positive, Positive 92 99 158 negative hr : 5.2 nr 95% ci : 1.0 to 25.9 p=0.013 Absence of her 2 amplification ( p=0.006). Absence of her 2 expression (p=0.003). This subgroup did not receive any adjuvant systemic therapy. her 2+ = positive for the human epidermal growth factor 2; her 2– = negative for the human epidermal growth factor 2; nr = not reported; hr = hazard ratio; ci = confidence interval. conclusions . Those authors examined rates of Recently, Gonzalez–Angulo et al. also assessed breast cancer–specific survival ( bccs ) and rfs using the rfs and drfs rates of women (n = 965) with her 2- tissue microarray series consisting of 4444 invasive positive node-negative ebc with tumours 1 cm or breast cancers, of which 2026 were pathologically smaller . Patients were identified from the Breast node-negative and were deemed the study cohort. Cancer Management System database of the MD A majority of the breast cancers (61%, n = 1245) Anderson Cancer Center (1990 to 2002). At a median were stage i breast cancers, and the median tumour follow-up of 74 months, there were 72 recurrences, size was 2.0 cm (range: 0.1–9.9 cm). Patients were including 34 distant recurrences. The 5-year sfr rates categorized by the biological and morphological were 77.1% in the her 2-positive group and 93.7% features of the tumours, including reh 2 and estrogen in the her 2-negative group (p < 0.0001). The 5-year receptor (er ) status, size, and grade, as well as by sfrd rates were 86.4% in the reh 2-positive group and use of adjuvant therapy. Chia et al. found that her 2- 97.2% in the her 2-negative group (p < 0.0001). Pa- positive and er -negative status both dramatically tients (n = 350) from two European centres using the affected outcomes in the node-negative cohort. In same inclusion criteria and similar follow-up times the entire node-negative cohort (n = 2026), her 2- were also analyzed as a validation set. The validation positive tumours versus her 2-negative tumours had set showed similar results. The authors concluded a signic fi antly reduced 10-year sfr (65.9% vs. 75.5% that her 2-positive T1a–b N0 M0 tumours have a respectively, p = 0.01), decreased distant rfs (drfs : significant risk of relapse and should be considered 71.2% vs. 81.8% respectively; p = 0.004), poorer for systemic anti-her 2 adjuvant therapy. bccs (75.7% vs. 86.3%, p = 0.001), along with a Curigliano et al. performed a retrospective study shortened os trend (65% vs. 74.4%, p = 0.06). In on 150 patients with T1a–b N0 reh 2-positive tumours patients who had a primary tumour size of 1 cm or (T1a: n = 85; T1b: n = 65) who did not receive tras- smaller (n = 326, 16%), a similar trend demonstrat- tuzumab treatment . After a median follow-up of ing negative outcomes in reh 2-positive tumours was 4.6 years, sfd was assessed. In patients with hormone also shown (Table iv ). receptor–positive disease, 5-year sfd was signic fi antly Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC worse in reh 2-positive patients versus reh 2-negative hormone receptor status, but 97% of the trastuzumab patients (92% vs. 99%; hr : 5.2; 95% ci : 1.0 to 25.9; cohort received chemotherapy compared to only 57% p = 0.013; Table iv ) . However, no difference was of patients in the non-trastuzumab cohort. seen in patients with hormone receptor–negative disease (91% vs. 92%; hr : 1.2; 95% ci : 0.3 to 4.7; 4. PANEL SUGGESTIONS FOR TREATMENT IN p = 0.091). Overall, the hr associated with her 2 ADJUVANT THERAPY overexpression was 2.4 (95% ci : 0.9 to 6.5; p = 0.09) in hormone receptor–positive and –negative patients. 4.1 Considerations in the Management of Node- The os in patients with her 2-positive T1a–bN0 Negative Disease with Tumours 1 cm or Smaller disease was similar regardless of hormone receptor status (p = 0.93). 4.1.1 Suggestions While the foregoing retrospective analyses sug- The biology of her 2-positive disease supersedes the gest that women in the her 2-positive cohort with T1 size of the tumour when considering use of trastu- tumours are at an increased risk of recurrence, there zumab in the adjuvant setting. is little information available to assess the benefits Trastuzumab may be considered for women with of either chemotherapy alone or in combination with node-negative T1b (0.5–1.0 cm) tumours that also have trastuzumab for this subset. additional high-risk prognostic factors such as young To date, support for improved outcomes with age, presence of lymphovascular invasion, grade iii trastuzumab is available for node-negative patients cancers, or negative hormone receptor status. taken as a whole. In the case of node-negative pa- The potential cardiac toxicity associated with the tients with the smallest tumours (T1a–b), support selected regimen always has to be weighed with the po- for trastuzumab treatment comes from retrospective tential benefits from chemotherapy and trastuzumab. single-institution practice studies, and while such patients were eligible for the bcirg 006 trial, there is 4.1.2 Discussion no information available specific to this subset from In the opinion of the panel, her 2-positivity rep- this trial. resents an important prognostic factor and one of Recently, Rodrigues et al. conducted a retrospec- several biological markers that appear to be as- tive analysis on the efficacy of adjuvant trastuzumab sociated with disease recurrence and other adverse in 96 patients with her 2-positive node-negative in- outcomes, even in the context of smaller tumours vasive breast carcinoma with T1a or T1b tumours . and node-negative disease. These biological features Chemotherapy [anthracycline (n = 20), taxane (n = should be considered carefully when deciding on 2), sequential anthracycline/taxane (n = 18), and adjuvant therapy. concurrent anthracycline–taxane (n = 1)] was given Most panel members indicated that they would to 43% (n = 41) of the patients. Forty patients, mainly not consider trastuzumab when treating node-negative those with a poor prognosis (based on high mitotic patients with T1mic (≤0.1 cm) or T1a tumours, but index, high grade, and hormone-receptor negativity), they all agreed that this treatment might be justified 32–36 received adjuvant trastuzumab, most in combination in her 2-positive T1b tumours . The panel also with chemotherapy (n = 37). The other 56 patients agreed that other factors suggesting a high recurrence with mainly good prognoses did not receive adjuvant risk such as high tumour grade, lymphovascular inva- trastuzumab. No recurrences occurred in patients who sion, er –negative status and young age should also received trastuzumab, while 5 occurred in patients be taken into consideration. who did not receive trastuzumab. Among the 5 recur- rences, 4 originated in tumours that were hormone 4.2 Management of HER2-positive EBC Across the receptor–negative or high grade (or both). Based on Spectrum of Disease these data, the investigators concluded that patients with node-negative disease with tumours 1 cm or 4.2.1 Suggestion smaller have a high risk of metastatic recurrence Trastuzumab should serve as the standard of care in and should be treated with adjuvant trastuzumab or women with reh 2-positive cbe , with consideration for included in her 2-targeted adjuvant trials, or both. disease and patient characteristics such as nodal status, A retrospective study of 495 her 2-positive early- hormone receptor status, and tumour size (>1 cm). stage breast cancers with 2-cm or smaller node-negative tumours was done at the Memorial Sloan–Kettering 4.2.2 Discussion 18,25,26 Cancer Center. Two cohorts of patients from the pre- The majority of the trials discussed earlier (areh , 19,20 19,21 22 and post-trastuzumab eras were compared for dfs . ncctg N9831 , nsabp B-31 , bcirg 006 , and There was a statistically significant difference noted f inher ) demonstrate dfs benefits of trastuzumab in dfs in these two cohorts (p = 0.007). Six deaths treatment in patients with her 2-positive ebc . These were reported in the pre-trastuzumab era versus only outcomes were similar across most studies, despite one death in the trastuzumab cohort. The two groups differences in the chemotherapeutic regimens with were balanced with respect to age, size of tumour, and which trastuzumab was tested. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. In the recently published pre-planned subgroup characteristics. However, recent data suggest that the analysis of the hera study, Untch et al. confirmed the concurrent approach incorporating anthracyclines, benefit of trastuzumab in her 2-positive ebc across while slightly more cardiotoxic, may be associated various subgroups . For each of the subpopulations with superior efficacy. defined by nodal or hormone receptor status, trastu - zumab treatment was associated with a statistically 4.3.2 Discussion significant increase in 3-year dfs where patient num- A review of the outcomes from the pivotal trials bers were sufc fi ient. Furthermore, the extent of trastu - described earlier suggests that trastuzumab’s sfd ben- zumab’s sfd benet fi was highly consistent across these efits are seen in her 2-positive ebc , whether it is used subpopulations, as judged by the calculated hr for concurrently with the taxane part of chemotherapy dfs events. In particular, subpopulations with lower or is initiated upon completion of chemotherapy. The intrinsic risk of disease recurrence (node-negative position adopted in 2007 and maintained in 2009 by patients and node-negative patients with T1 tumours) the St. Gallen panel was that the two approaches are 14,42 experienced an improvement in dfs similar to that equally acceptable . seen in the broader reh 2-positive cbe population (rh s More recent data suggest that concurrent ap- were approximately 0.5–0.6 in all cases). proaches are more effective . At the sabcs 2009 In the joint analysis of the pbasn B-31 and the cn - meeting, the 60-month follow-up of the gtccn N9831 ctg N9831 trials, trastuzumab’s dfs benefit was also trial was reported. While there continues to be a observed across all subgroups (including age, nodal dfs benefit of sequential trastuzumab ( ac →t →h ) status, hormone receptor status, tumour size, and over chemotherapy alone (ac →t ), the dfs benefit tumour grade) because preliminary analysis showed was superior for the concurrent trastuzumab arm an increase in 4-year dfs in the trastuzumab arm (hr (ac →th →h ) relative to the sequential trastuzumab ranges from 0.22 to 0.80) . arm (hr : 0.77; 95% ci : 0.61 to 0.96; p = 0.019; Recent data from the third planned analysis of Table ii ). This result did not cross the boundary the node-negative population of the bcirg 006 trial for statistical significance, which was pre-set at a showed a significant increase in dfs , both with the p value of 0.00116. The os was not significantly ac →dh regimen (93% vs. 85%; hr : 0.47; 95% ci : improved with sequential trastuzumab relative to 0.28 to 0.77; p = 0.003) and the dc bh regimen (90% chemotherapy alone (hr : 0.86; 95% ci : 0.65 to 1.13; vs. 85%; hr : 0.64; 95% ci : 0.41 to 1.01; p = 0.057). p = 0.281). The investigators recommended the Similarly, there was an increase in os in the ac →dh concurrent use of trastuzumab with chemotherapy group (97% vs. 93%; hr : 0.38; 95% ci : 0.17 to 0.87; (ca →ht →h ) given the risk–benet fi ratio and 4% ab - p = 0.02) and the dc bh group (96% vs. 93%; hr : 0.56; solute improvement in dfs . Also, the acs p -04 trial, 95% ci : 0.27 to 1.13; p = 0.11) . which examined the role of sequential trastuzumab Subgroup analyses were not presented in the (cef /ce →h ), did not show a signic fi ant improvement f inher and acs p -04 trials. in dfs or os . While provocative, these results were This trastuzumab benefit has been recognized in by no means conclusive, because the acs p -04 trial various clinical practice guidelines published since included only a small sample size of 502 patients the pivotal trial results became available. The nccn with her 2-positive disease, and the results do not guidelines on breast cancer recommend the use of correspond with the dfs benefits seen in the other trastuzumab as an appropriate adjuvant therapy in all trials incorporating sequential trastuzumab (hera , patients with reh 2-positive tumours larger than 1 cm as ncctg N9831, and so on). a category 1 recommendation . Similar support for the In trials incorporating a concurrent approach, use of trastuzumab in node-positive and node-negative os benefits are consistently seen where trastuzumab her 2-positive breast cancers (with some restrictions) is given concurrently with taxanes, either in a non- can be found in guidelines from Cancer Care Ontario anthracycline based regimen (that is, dc bh ) or after (node-positive or high-risk node-negative breast can- completion of anthracyclines (nsabp B-31, ncctg cers only) , the BC Cancer Agency (node-positive or 9831, bcirg 006). node-negative with tumours ≥T1c and other features to qualify for chemotherapy) , and the St. Gallen expert 4.4 Treatment Duration of Trastuzumab for EBC consensus group (patients who satisfy the inclusion criteria used in the trials may be considered) . 4.4.1 Suggestion The phase iii randomized studies support the standard 4.3 Timing of Trastuzumab Therapy with use of trastuzumab for 1 year (that is, 18 cycles when Chemotherapy for Early-Stage Disease: given every 3 weeks), regardless of the chemotherapy Concurrent or Sequential regimen employed. 4.3.1 Suggestion 4.4.2 Discussion The decision to use either approach is at the cli- The optimal duration of treatment with trastuzumab nician’s discretion based on patient and disease is unknown. The majority of the pivotal trials on Current OnCOlOgy —VOlume 17, n umber 4 OPTIMIZING THE MANAGEMENT OF HER2+ EBC trastuzumab use in ebc have required patients to be the individual cardiovascular risk balanced with the given trastuzumab treatment for a total of 1 year anticipated individual risk of relapse. (Table ii ). The areh study included an arm evaluating The bcirg 006 trial does not demonstrate any 2-year treatment, but safety and efc fi acy data will not advantage to anthracyclines in the population without 18,25,26 be reported until 2011 . The f inher trial gave Topo2 co-amplification, but no validated clinical as - a total of 9 weekly trastuzumab infusions, and at a say is available to assist in this decision. The bcirg median follow-up of 5 years, her 2-positive patients 006 data now suggest superior efficacy results in the who received trastuzumab continue to have a bet- anthracycline-based regimen. Consequently, clini- ter ddfs rate and os trend than those who received cians may need to be more selective in choosing the chemotherapy alone (Table i ) . Although these non-anthracycline trastuzumab regimen (dc bh ), and data are promising, it must be noted that the overall perhaps it should no longer be considered a de facto sample size was small (n = 232). Results from larger standard of care. randomized clinical trials such as sold (Synergism or Long Duration) and phare (Protocol of Herceptin 5. CARDIOTOXICITY Adjuvant with Reduced Exposure), assessing 9 weeks or 6 months of trastuzumab treatment respectively, Two years ago, a similar Canadian panel of seven and the 2-year hera data will shed more light on the oncologists and two cardiologists met for a full-day optimal duration of trastuzumab. In the absence of conference and developed recommendations in the strong data, there is no need to diverge from the ap- assessment and management of cardiac complica- proved 1-year treatment duration. This is in agreement tions during adjuvant trastuzumab therapy . First, 15 40 with guidelines from nccn , Cancer Care Ontario , the authors outlined risk factors that exclude patients and the BC Cancer Agency . from trastuzumab treatment such as existing heart failure or vef l below 50% (or both) and risk factors 4.5 The Role of Non-Anthracycline that require special consideration such as ischemic Trastuzumab-Based Regimens heart disease, significant valvulopathy, and a pre- trastuzumab baseline vefl of 50%–55%. Second, 4.5.1 Suggestion the panel concluded that there were insufficient data The choice between anthracycline-based adjuvant to make formal statements about the cardiotoxicity trastuzumab regimens and the dc bh regimen should of concurrent versus sequential regimens and that be based on the individual risk of cardiac toxicity. evidence existed to suggest that anthracycline-free regimens have a lesser incidence of cardiac toxicity. 4.5.2 Discussion Updated cardiac toxicity results from the gtccn 9831 The need for anthracyclines when giving trastuzumab trial (Table iii ) do suggest a slightly greater cardiac and chemotherapy-based treatment has been contro- toxicity risk with the concurrent approach compared versial. In the initial reports from the bcirg 006 trial, with the sequential approach (incidence of symptom- there was clear indication that the two trastuzumab- atic chf : 3.3% vs. 2.8%) . Patients with ebc should containing arms (ac →dh and dc bh ) had very similar be treated with trastuzumab treatment for 1 year clinical benefits . However, weighing the safety (less only if disease recurs) until further evidence risks (cardiotoxicity and leukemia risk) associated suggests otherwise. Third, the panel emphasized the with the anthracycline-based arm (ac →dh ), the need to assess cardiac function before trastuzumab non-anthracycline arm (dc bh ) seems to be a more treatment by using echocardiography or muga scan favourable choice. to establish baseline and subsequent vef l readings The bcirg 006 trial was recently updated at sabcs (3, 6, 9, and 12 months). After trastuzumab therapy, 2009, and again, both trastuzumab-containing arms annual monitoring should be considered in patients had better dfs and os than the control arm, and the who experienced cardiac symptoms or a greater two trastuzumab arms did not differ statistically in than 10% absolute asymptomatic decline in vefl . dfs although numerically the results favoured the Finally, the panel established a detailed “stop/restart” ac →dh arm . The data combining dfs events with algorithm for both symptomatic and asymptomatic life-threatening toxicities (chf and treatment-related left ventricular dysfunction based on the Canadian leukemia) now favour the ac →dh arm. There is no Cardiovascular Society recommendations. Details of doubt that the non-anthracycline regimen (dc bh ) is pharmacotherapy options and duration of treatment the safest regimen with respect to cardiotoxicity (in- for cardiotoxicity were outlined, and guidelines for cidence: 0.4% New York Heart Association grades 3 the decision to re-initiate were discussed . and 4 fhc vs. 2.0% fhc with ca →hd ); however, while the efficacy results of dc bh and ac →dh do not dif- 6. CONCLUSIONS fer statistically, the 5-year dfs numerically favours ca →hd . Consequently, the clinical decision to pursue Trastuzumab has emerged as the key component an anthracycline or non-anthracycline adjuvant tras- of care in women with her 2-positive ebc . Clinical tuzumab regimen should be made in the context of findings from several large trials, representing more Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. than 14,000 individual patients, have established sig- pathways: implications for her 2-targeted antibody therapy. nificant dfs and os benefits of trastuzumab treatment. Oncogene 2006;25:6986–96. The benefits of trastuzumab are seen regardless of 9. Klos KS, Zhou X, Lee S, et al. Combined trastuzumab and pa- other patient characteristics such as age or of tumour clitaxel treatment better inhibits ErbB-2-mediated angiogenesis characteristics such as hormone positivity or nodal in breast carcinoma through a more effective inhibition of Akt status. The benefit of trastuzumab for node-negative than either treatment alone. Cancer 2003;98:1377–85. ebc patients with small tumours (for example, T1a 10. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc tumours) remains to be fully established. However, receptors modulate in vivo cytoxicity against tumor targets. all her 2-positive node-positive patients and node- Nat Med 2000;6:443–6. negative patients with T1b or larger tumours should 11. Gennari R, Menard S, Fagnoni F, et al. Pilot study of the be considered for trastuzumab treatment because they mechanism of action of preoperative trastuzumab in patients remain at greater risk of disease recurrence. Clinicians with primary operable breast tumors overexpressing reh 2. Clin should also always consider the potential risk of car- Cancer Res 2004;10:5650–5. diac toxicity of systemic treatments, and as a result, 12. Arnould L, Gelly M, Penault–Llorca F, et al. Trastuzumab- an appropriate trastuzumab-based regimen should be based treatment of her 2-positive breast cancer: an antibody- chosen based on thorough assessment of cardiac toxic- dependent cellular cytotoxicity mechanism? Br J Cancer ity risk factors. 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Curr Oncol Breast Cancer Res Treat 2007;106(suppl 1):. [Available 2008;15:24–35. Current OnCOlOgy —VOlume 17, n umber 4 VERMA et al. Correspondence to: Sunil Verma, University of To- Centre Intégré de cancérologie de la Montérégie, ronto and Sunnybrook Health Sciences Centre, 2075 Université de Sherbrooke, and Réseau Cancer Bayview Avenue, Room T2 045, Toronto, Ontario Montérégie, Longueuil, QC. M4N 3M5. ** Unité de recherche en santé des populations, E-mail: sunil.verma@sunnybrook.ca Centre de Recherche du Centre Hospitalier afl fi ié universitaire de Québec, Quebec City, QC. †† * University of Toronto, Toronto, ON. Hôpital du Saint-Sacrement, Quebec City, QC. † ‡‡ Sunnybrook Health Sciences Centre, Toronto, ON. British Columbia Breast Tumour Group, British Division of Medical Oncology, Department of Columbia Cancer Agency–Vancouver Centre, Oncology, University of Alberta, Cross Cancer Vancouver, BC. §§ Institute, Edmonton, AB. Remedy Communications, Toronto, ON. § |||| Division of Medical Oncology, The Ottawa Hos- Atlantic Clinical Cancer Research Unit (ACCRU) pital Cancer Centre, Ottawa, ON. and QEII Cancer Care Program, QEII Health Sci- || University of Ottawa, Ottawa, ON. ences Centre, Halifax, NS. Current OnCOlOgy —VOlume 17, n umber 4

Journal

Current OncologyMultidisciplinary Digital Publishing Institute

Published: Aug 1, 2010

Keywords: adjuvant; early breast cancer; her2-positive; node-negative; trastuzumab

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