NCCN VERSION 2 2015

The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

MS-18

NCCN Guidelines Index

Breast Cancer Table of Contents

Discussion

NCCN Guidelines Version 2.2015

Breast Cancer

preoperative systemic therapy to evaluate disease responsiveness have

not been well studied.

159

Preoperative Systemic Therapy in HER2-Positive Patients

In women with HER2-positive tumors treated with neoadjuvant

chemotherapy, the addition of neoadjuvant trastuzumab to paclitaxel

followed by chemotherapy with FEC

(fluorouracil/epirubicin/cyclophosphamide) was associated with an

increase in the pCR rate from 26% to 65.2% (

= .016).

160

Thus, the

incorporation of trastuzumab into neoadjuvant chemotherapy regimens

appears important in HER2-positive tumors.

161

The GeparQuinto phase III trial led by the German Breast Group

studied 620 women with untreated, HER2-positive, primary invasive

breast cancer.

162

Patients were randomized to receive 4 cycles of

epirubicin/cyclophosphamide followed by docetaxel administered

concurrently with either trastuzumab or lapatinib. The primary endpoint,

pCR, was achieved in 30.3% of patients who received trastuzumab plus

chemotherapy compared with 22.7% of patients who received lapatinib

plus chemotherapy (odds ratio 0.68 [95% CI, 0.47–0.97];

< .04).

162

Edema and dyspnea occurred more frequently in the trastuzumab

group, while diarrhea and skin rash occurred more frequently in the

lapatinib group.

The NeoALTTO trial randomized 455 patients with HER2-positive

primary breast cancer to receive lapatinib plus paclitaxel, trastuzumab

plus paclitaxel, or a combination of lapatinib and trastuzumab plus

paclitaxel.

163

The results showed that the pCR rate was 51.3% (95% CI,

43.1–59.5) in the lapatinib plus trastuzumab combination arm compared

to a rate of 24.7% (CI, 18.1–32.3) for the lapatinib arm and 29.5% ( CI,

22.4–37.5) for the trastuzumab arm. The difference in pCR rate

between the lapatinib plus trastuzumab arm compared to the

trastuzumab arm was statistically significant (difference 21.1%, 9.1–

34.2,

= .0001). The pCR rate difference between the lapatinib and

trastuzumab arms was not statistically significant

(difference -4.8%, -17.6–8.2;

= .34).

163

Grade 3/4 liver enzyme

abnormalities occurred more frequently with trastuzumab plus lapatinib

or lapatinib alone compared to trastuzumab alone.

163

Updated

preliminary

data presented at the 2013 San Antonio Breast Cancer

Symposium demonstrated that patients achieving pCR had better

outcome compared with patients not achieving pCR.

164

These studies

thus confirm that the use of HER2-targeted therapy is important in the

preoperative treatment of HER2-positive primary breast cancer. There

remains significant uncertainty regarding the optimal regimen of

HER2-targeting. The NeoALTTO study results confirm the potential of

dual HER2-targeted therapy in the neoadjuvant setting.

Pertuzumab is a recombinant, humanized, monoclonal antibody that

inhibits the ligand-dependent dimerization of HER2 and its downstream

signaling. Pertuzumab and trastuzumab bind to different epitopes of

HER2 receptor and have complementary mechanisms of action. When

administered together in HER2-positive tumor models and in humans,

they provide a greater overall anti-tumor effect than either alone.

165,166

Since the combination of pertuzumab and trastuzumab showed

significant OS benefit in the metastatic setting,

167

it was examined in the

neoadjuvant setting as well.

168,169

The FDA recently granted accelerated approval for pertuzumab in

combination with trastuzumab and docetaxel as neoadjuvant treatment

for patients with HER2-positive, early-stage breast cancer, including

patients with tumors greater than 2 cm in diameter (≥T2) or node

positive (≥N1). The accelerated approval was based on the results of

two phase II trials, the NeoSphere trial,

169

and the TRYPHAENA study

168

that showed significant improvement in pCR in patients receiving