NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

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% ( P = .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]; P < .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, P = .0001). The pCR rate difference between the lapatinib and trastuzumab arms was not statistically significant (difference -4.8%, -17.6–8.2; P = .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

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