Accreditation Statement

This activity has been designated to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-13-009-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 70% minimum passing score and complete the evaluation at http://education.nccn.org/node/24674; and 4) view/print certificate.

Release date: July 12, 2013; Expiration date: July 12, 2014

Learning Objectives:

Upon completion of this activity, participants will be able to:

• Integrate into professional practice the updates to NCCN Guidelines for Breast Cancer

• Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Breast Cancer

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Pertuzumab

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 the HER2 receptor and have complementary mechanisms of action. Therefore, the rationale for administering the drugs together is to achieve a more powerful blockage of the HER2 pathway. This was demonstrated to be true in tumor models and in humans, wherein combining pertuzumab with trastuzumab provided a greater overall antitumor effect than either alone.^8,9

In a randomized, double-blind, phase III study (CLEOPATRA), 808 women with HER2-positive metastatic breast cancer were randomized to receive trastuzumab and docetaxel with or without pertuzumab as their first-line treatment.¹⁰ The results demonstrated a 6.1-month improvement in median progression-free survival with the addition of pertuzumab (12.4 vs 18.5 months; hazard ratio [HR] for progression or death, 0.62; 95% CI, 0.51-0.75; P<.001). In addition, a strong trend was seen toward an overall survival benefit with pertuzumab, with a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.52-0.84; P=.0008). The median overall survival was 37.6 months in the nonpertuzumab group and had not yet been reached at the time of analysis in the group treated with pertuzumab.¹¹ Notably, no significant difference was seen in health-related quality of life or toxicities between the treatment arms, including no increase in either symptomatic or asymptomatic cardiac dysfunction.^12,13

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NCCN Guidelines Insights: Breast Cancer, Version 3.2013

Version 2.2013 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 7; 10.6004/jnccn.2013.0098

Phase II trials have also assessed the activity and tolerability for pertuzumab, pertuzumab with trastuzumab, and other regimens combining pertuzumab and trastuzumab together with other active cytotoxics, such as paclitaxel and vinorelbine^14,15 (ClinicalTrials.gov identifier: NCT01276041). Phase III trials of pertuzumab plus chemotherapy without trastuzumab have not been reported.

Pertuzumab has antitumor activity in patients beyond the first-line setting. The results of a multicenter, open-label, single-arm, phase II study show that the combination of pertuzumab and trastuzumab is active and well tolerated in patients with HER2-positive metastatic breast cancer that has progressed on prior trastuzumab therapy. The trial reported an objective response rate of 24.2% and a clinical benefit rate of 50%.¹⁶ To determine whether the clinical benefit seen in the study was from pertuzumab alone or was a result of the combined effect of pertuzumab and trastuzumab, a cohort of 29 patients whose disease progressed during prior trastuzumab-based therapy received pertuzumab monotherapy until progressive disease or unacceptable toxicity. Of these, 17 patients with disease progression continued to receive pertuzumab with the addition of trastuzumab. In the 29 patients who received pertuzumab monotherapy, the objective response and clinical benefit rates reported were 3.4% and 10.3%, respectively, whereas in the 17 patients who received dual blockade after progression on pertuzumab, the objective response rate and clinical benefit rate were 17.6% and 41.2%, respectively.¹⁷

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NCCN Guidelines Insights: Breast Cancer, Version 3.2013

Version 2.2013 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 7; 10.6004/jnccn.2013.0098

Further research is expected to determine the ideal sequencing strategy for anti-HER2 therapy. NCCN Recommendations: Based on the available data, the NCCN Breast Cancer Panel recommends pertuzumab plus trastuzumab in combination with a taxane as a preferred option for first-line treatment of patients with HER2-positive metastatic breast cancer (see BINV-21, page 756). Pertuzumab plus trastuzumab in combination with docetaxel is a category 1 recommendation, and in combination with paclitaxel is a category 2A recommendation (see BINV-O 1 of 7, page 757, and BINV-O 4 of 7, page 758, for dosing schedule).

For patients with disease progression after treatment with trastuzumab-based therapy without pertuzumab, the NCCN Breast Cancer Panel recommends considering a line of therapy containing both trastuzumab plus pertuzumab with or without a cytotoxic agent (eg, vinorelbine or taxane; see BINV-21, page 756).

T-DM1

T-DM1 is a first-in-class antibody-drug conjugate. Through a stable linker, the HER-2 targeting antitumor portion of trastuzumab is conjugated with the microtubule-inhibitory agent DM1 (derivative of maytansine). Therefore, T-DM1 delivers its antitumor activity to HER2-overexpressing cells through combining the specificity of trastuzumab with cytotoxicity of maytansine, thus increasing the therapeutic index.¹⁸

A recent randomized, multicenter, open-label, phase III study (EMILIA) showed overall and progression-free survival benefits for T-DM1 compared with the combination of lapatinib and capecitabine in patients with HER2-positive or metastatic breast cancer previously treated with a taxane-trastuzumab regimen.¹⁹ The median progression-free survival (assessed by independent review) with T-DM1 was 9.6 months versus 6.4 months with lapatinib plus capecitabine; the HR for progression or death from any cause was 0.65 (95% CI, 0.55-0.77; P<.001). The stratified HR for death from any cause with T-DM1 versus lapatinib plus capecitabine was 0.62 (95% CI, 0.48-0.81; P=.0005).¹⁹ Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1 (frequency >25%), whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine.¹⁹ NCCN Recommendations: Based on the available data, the NCCN Breast Cancer Panel recommends T-DM1 as a preferred option for treatment of patients with HER2-positive metastatic breast cancer who were previously treated with a trastuzumab-based regimen (see BINV-21, page 756, and BINV-O 5 of 7, page 759, for dosing schedule).