NCCN VERSION 2 2015

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MS-37

NCCN Guidelines Index

Breast Cancer Table of Contents

Discussion

NCCN Guidelines Version 2.2015

Breast Cancer

Adjuvant HER2-Targeted Therapy

The panel recommends HER2-targeted therapy in patients with HER2

positive tumors (see

Principles of HER2 Testing

). Trastuzumab is a

humanized monoclonal antibody with specificity for the extracellular

domain of HER2.

343

Results of several randomized trials testing

trastuzumab as adjuvant therapy have been reported.

221-226,344-346

NSABP B-31 patients with HER2-positive, node-positive breast cancer

were randomly assigned to 4 cycles of AC every 3 weeks followed by

paclitaxel for 4 cycles every 3 weeks or the same regimen with 52

weeks of trastuzumab commencing with paclitaxel. In the NCCTG

N9831 trial, patients with HER2-positive breast cancer that was

node-positive, or node-negative, with primary tumors greater than 1 cm

in size if ER- and PR-negative or greater than 2 cm in size if ER- or

PR-positive, were similarly randomized except that paclitaxel was given

by a low-dose weekly schedule for 12 weeks and a third arm delayed

trastuzumab until the completion of paclitaxel.

The B-31 and NCCTG N9831 trials have been jointly analyzed with the

merged control arms for both trials compared with the merged arms

using trastuzumab begun concurrently with paclitaxel. There were 4045

patients included in the joint analysis performed at 3.9 years median

follow-up. A 48% reduction in the risk of recurrence (HR 0.52; 95% CI,

0.45–0.60;

< .001) and a 39% reduction in the risk of death (HR 0.61;

95% CI, 0.50–0.75; log-rank

= .001) were documented.

345

Similar

significant effects on DFS were observed when results of the NSABP

B-31 and NCCTG N9831 trials were analyzed separately. Cardiac

toxicity was increased in patients treated with trastuzumab.

224,347,348

the adjuvant trastuzumab trials, the rates of grade III/IV congestive

heart failure (CHF) or cardiac-related death in patients receiving

treatment regimens containing trastuzumab ranged from 0% (FinHer

trial) to 4.1% (NSABP B-31 trial).

221,222,224,226,347,348

The frequency of

cardiac dysfunction appears to be related to both age and baseline left

ventricular ejection fraction. An analysis of data from N9831 showed the

3-year cumulative incidence of CHF or cardiac death to be 0.3%, 2.8%,

and 3.3% in the arms of the trial without trastuzumab, with trastuzumab

following chemotherapy, and with trastuzumab initially combined with

paclitaxel, respectively.

347

The acceptable rate of significant cardiac

toxicity observed in the trastuzumab adjuvant trials in part reflects

rigorous monitoring for cardiac dysfunction. Furthermore, concerns

have been raised regarding the long-term cardiac risks associated with

trastuzumab therapy based on results of follow-up evaluations of

cardiac function in patients enrolled in some of these trials.

349,350

A third trial (HERA) (N = 5081) tested trastuzumab for 1 or 2 years

compared to none following all local therapy and a variety of standard

chemotherapy regimens in patients with node-positive disease or

node-negative disease with tumor ≥1 cm.

222

At a median follow-up of

one year, a 46% reduction in the risk of recurrence was reported in

those who received trastuzumab compared with those who did not (HR

0.54; 95%, CI 0.43–0.67;

< .0001), no difference in OS, and

acceptable cardiac toxicity were reported. The 2-year data indicate that

1 year of trastuzumab therapy is associated with an OS benefit when

compared with observation (HR for risk of death = 0.66; 95% CI, 0.47–

0.91;

= .0115).

351

After this initial analysis, patients randomized to

chemotherapy alone were allowed to cross over to receive trastuzumab.

Intent-to-treat analysis including a crossover patient was reported at

4-year median follow-up.

346

The primary endpoint of DFS continued to

be significantly higher in the trastuzumab-treated group (78.6%) versus

the observation group (72.2; HR 0.76; 95%, CI 0.66–0.87;

< .0001).

At a median follow-up of 8 years, the study reported no significant

difference in DFS, a secondary endpoint, in patients treated with