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Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Physicians' Education Resource®, LLC designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1.5 Contact Hours.

Acknowledgement of Commercial Support

This activity is supported by an educational grant from Puma Biotechnology.

Community Practice Connections™: Optimizing Outcomes in HER2-Positive Breast Cancer: Emerging Evidence and Practical Strategies in Early Stage Treatment Settings

Release Date: May 31, 2018
Expiration Date: May 31, 2019
Media: Internet - based


Activity Overview

As opportunities to improve outcomes for your patients with early stage HER2-positive breast cancer continue to emerge with new pharmacologic options, it is important for you to be able to maintain state of the art clinical care. Keeping up with the sheer volume and pace of clinical evidence presentations may be difficult for any clinician, and we would like to offer an educational resource to assist with the application of these data to the real-world clinical scenarios that you encounter with your patients with HER2-positive breast cancer. It is our belief that this resource will help you to develop a deeper understanding of several topics, including the latest information on adjuvant treatment for HER2-positive breast cancer, methods to characterize HER2-positive breast cancer that can inform decision-making with your patients, and evidence from clinical trials that may help in your development of treatment sequencing strategies. We have incorporated video interviews that feature insights from leading experts in the field of managing patients with HER2-positive breast cancer, in order to help enhance your knowledge base and hone your approaches to patient management.

Acknowledgment of Commercial Support

This activity is supported by an educational grant from Puma Biotechnology.

Instructions for This Activity and Receiving Credit

  • You will need to login to participate in the activity.
  • Each presentation may contain an interactive question(s). You may move forward through the presentation; however, you may not go back to change answers or review videos/content until you finish the presentation.
  • At the end of the activity, “educational content/video files” will be available for your reference.
  • In order to receive a CME/CE certificate, participants must complete the activity.
  • Complete the posttest and pass with a score of 70% or higher, complete the evaluation and then click on request for credit. Participants may immediately download a CME/CE certificate upon completion of these steps.

Target Audience

This activity is directed toward medical oncologists, surgeons, pathologists and fellows. Nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other health care professionals interested in the treatment of breast cancer are invited to participate.

Learning Objectives

At the conclusion of this activity, you should be better prepared to:

  1. Relate the rationale underlying the recent development of strategies for the adjuvant treatment of HER2-positive breast cancer
  2. Delineate methods to properly characterize HER2-positive breast cancer to inform optimized decision making in patients with early-stage disease
  3. Explain outcomes from landmark recent clinical trials conducted in patients with HER2-positive breast cancer that have evaluated adjuvant treatment approaches
  4. Apply evidence from key clinical trials to inform decision making concerning the sequencing of adjuvant therapies in the care of patients with early-stage HER2-positive breast cancer

Faculty, Staff, and Planners' Disclosures


Kimberly L. Blackwell, MD
Professor of Medicine
Assistant Professor of Radiation Oncology
Duke University Medical Center
Durham, NC

Disclosure: Grant Research Support: Celgene, Genentech, Pfizer, Novartis; Consultant: Astra Zeneca, Celgene, Celltrion Healthcare, Celldex Therapeutics, Eisai, Eli Lilly, Genentech, Mylan GmbH, Novartis, Pfizer, Pierian Biosciences, Puma, Roche, Syndax, Visante, Seattle Genetics

Adam M. Brufsky, MD, PhD
Professor of Medicine
Associate Chief, Division of Hematology/Oncology
Co-Director, Comprehensive Breast Cancer Center
Associate Director, Translational Investigation
University of Pittsburgh
Pittsburgh, PA

Disclosure: Consultant: Puma, Roche

Hope S. Rugo, MD, FASCO
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
University of California San Francisco Helen Diller Family Comprehensive Cancer Center
San Francisco, CA

Disclosure: Grant Research Support: Genentech, Mylan, Puma

Debu Tripathy, MD
Professor and Chair, Department of Breast Medical Oncology
The University of Texas MD Anderson Cancer Center
Houston, TX

Disclosure: No relevant financial relationships with commercial interests to disclose.

The staff of PER® have no relevant financial relationships with commercial interests to disclose.

Disclosure Policy and Resolution of Conflicts of Interest (COI)

As a sponsor accredited by the ACCME, it is the policy of PER® to ensure fair balance, independence, objectivity, and scientific rigor in all of its CME/CE activities. In compliance with ACCME guidelines, PER® requires everyone who is in a position to control the content of a CME/CE activity to disclose all relevant financial relationships with commercial interests. The ACCME defines “relevant financial relationships” as financial relationships in any amount occurring within the past 12 months that creates a COI.

Additionally, PER® is required by ACCME to resolve all COI. PER® has identified and resolved all COI prior to the start of this activity by using a multistep process.

Off-Label Disclosure and Disclaimer

This CME/CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE activity is for continuing medical and nursing education purposes only, and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any of the companies that provided commercial support for this activity.

PER Pulse Recap™

PER Pulse Recap (1 of 3)

In approximately 20% of primary breast cancers, there is amplification and/or overexpression of the human epidermal growth factor receptor 2 (HER2) gene.1 According to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations, HER2 status should be established for all patients with primary invasive breast cancer.1 This testing helps to guide therapeutic direction, and it is imperative to have an accurate assessment in order to optimize patient outcomes.
Although most HER2 tests are definitive, the possibility of equivocal testing does exist. Common testing techniques include assessment of immunohistochemistry (IHC) score or in situ hybridization (ISH). An initial equivocal test should be followed by reflex testing on the same specimen using the alternative test, or an alternative specimen if the pathologist has concerns about the initially tested specimen.1
The NSABP B-47 study is currently assessing patients who have node-positive or high-risk, node-negative breast cancer that has a HER2 status of 1+ or 2+ by IHC, but not amplified by fluorescence in situ hybridization (FISH).2 It is designed to test the hypothesis that patients who are HER2-negative may benefit from adjuvant trastuzumab, as suggested by the NSABP B-31 study.3
Of note, ASCO guidelines pertaining to the use of biomarkers to guide decisions on adjuvant therapy for women with early-stage, invasive breast cancer have been published recently.4 For patients with known HER2+ breast cancer, the guidelines recommend that clinicians not use several reviewed assays.4
For additional commentary about these topics and others, visit to access more resources from the 34th Annual Miami Breast Cancer Conference®, including downloadable slides from the meeting.
1. Wolff AC, Hammond ME, Jicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3397-4013.
2. Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer (NCT01275677). Accessed May 1, 2017.
3. Pogue-Geile KL, Kim C, Jeong J-H, et al. Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31. J Natl Cancer Inst. 2013;105(23):1782-1788.
4. Harris LN, Ismaila N, McShane LM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(10):1134-1150.

PER Pulse Recap (2 of 3)

Several landmark trials have laid the foundation for the current adjuvant therapy standard of chemotherapy plus 12 months of trastuzumab in patients with early-stage, HER2+ breast cancer. These include HERA, NSABP B-31, NCCTG N9831, and BCIRG 006.1-4
Strategies to improve adjuvant therapy‒associated outcomes for patients with early-stage, HER2+ breast cancer have recently undergone exploration, assessing potential modifications of the standard treatment regimen.5 Although many patients with HER2+ breast cancer have seen great improvement with the incorporation of trastuzumab, not all patients do well, either due to resistance to treatment or side effects with standard approaches.6
The combination of adding trastuzumab to the adjuvant nonanthracycline regimen of docetaxel plus cyclophosphamide for patients with early-stage, HER2-amplified breast cancer has been assessed in a single-group, open-label, phase II study. In this study, 2-year overall survival (OS) was noted to be 99.5%, and 2-year disease-free survival (DFS) was 97.8% for patients with TOP2A-amplified disease.7 The 2-year OS was 98.8% and the 2-year DFS was 97.9% for patients with TOP2A-nonamplified disease. The authors concluded that a 4-cycle treatment regimen of docetaxel and cyclophosphamide with trastuzumab may be an adjuvant option for women with lower-risk, early-stage, HER2-amplified breast cancer.7  
The BETH study8 was a randomized phase III study that assessed the influence of the addition of bevacizumab to adjuvant chemotherapy. The study showed that bevacizumab did not improve invasive DFS or OS in patients with high-risk, HER2+ breast cancer.8 Other studies, such as ALTTO, ExteNET, APHINITY, and TEACH, have assessed different combinations in the adjuvant setting.9-12 
In the adjuvant setting, the use of lapatinib as monotherapy or in combination with trastuzumab has been assessed in both the ALTTO and TEACH trials.9,10 The ExteNET study11 assessed the use of neratinib after a year of adjuvant trastuzumab. Recent data suggest that, particularly for patients with estrogen receptor‒positive cancer, there is a benefit to the addition of neratinib for an additional year.11,13 There is approximately a 5.5% difference in favor of adding neratinib. Gastrointestinal side effects are common, particularly diarrhea. Most recently, the APHINITY study,12 which assessed the addition of pertuzumab to trastuzumab and chemotherapy in the adjuvant setting for early-stage, HER2+ breast cancer, has been reported to have met its primary endpoint of DFS.
For additional commentary about these topics and others, visit to access more resources from the 34th Annual Miami Breast Cancer Conference®, including downloadable slides from the meeting.
1. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021-1028.
2. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32: 3744-3752.
3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.
4. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365: 1273-1283.
5. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14(8):741-748.
6. Joensuu H. Escalating and de-escalating treatment in HER2-positive early breast cancer. Cancer Treat Rev. 2017;52:1-11.
7. Jones SE, Collea R, Paul D, et al. Aduvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013;14(11):1121-1128.
8. Slamon DL, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer. Presented at: the 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio,TX. Abstract S1-03.
9. Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol. 2016;34(10):1034-1042.
10. Goss PE, Smith IE, O’Shaughnessy J, et al. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(1):88-96.
11. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377.
12. The ASCO Post. Phase III APHINITY Study: Adjuvant Pertuzumab/Trastuzumab/Chemotherapy Increased Invasive Disease–Free Survival in HER2-Positive Breast Cancer. Accessed May 4, 2017.
13. Loibl S, Gianni L. HER2-positive breast cancer [published online December 6, 2016]. Lancet. 2016. DOI:

PER Pulse Recap (3 of 3)

When considering the use of neoadjuvant therapy for patients with HER2+ breast cancer, it is important to weigh the advantages and disadvantages of adjuvant versus neoadjuvant approaches. Accurate staging is imperative. The neoadjuvant approach may improve the rates of adequate surgical resection, particularly in breast-conserving surgery for patients who are stage 2 or higher.1 Clinical investigation has shown that pathologic complete response (pCR) at surgery has an association with improvements in disease-free survival (DFS) and overall survival (OS).2
Several other studies have assessed the HER2 dual blockade role with lapatinib and trastuzumab versus trastuzumab alone in the neoadjuvant setting for treatment of HER2+ breast cancer, including NeoALTTO, CALGB 40601, NSABP-B41, EORTC 10054, TRIO-US B07, and CHER-LOB.3-8 A meta-analysis of these 6 studies found that dual blockade with lapatinib and trastuzumab plus chemotherapy is active only in HER2+, hormone receptor‒negative (HR-negative) cancer treated with taxane monochemotherapy.9
The NeoSphere study10 assessed the potential of dual HER2 blockade with pertuzumab and trastuzumab. In this study, patients were randomized 1:1:1:1 to receive 1 of 4 different preoperative regimens for 12 weeks: docetaxel plus trastuzumab; docetaxel plus trastuzumab plus pertuzumab; trastuzumab plus pertuzumab; or docetaxel plus pertuzumab. Patients in the group that received docetaxel plus trastuzumab plus pertuzumab had a significantly greater rate of pCR than patients who received trastuzumab plus docetaxel (P=.0141).10 At 5-year follow-up of the NeoSphere study, the addition of pertuzumab to trastuzumab plus docetaxel suggested benefit with respect to progression-free survival and DFS.11
The TRYPHAENA study12 assessed the combination of pertuzumab with 6 cycles of different neoadjuvant chemotherapy regimens for patients with early and advanced HER2+ breast cancer.  In arm A, patients received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) plus trastuzumab plus pertuzumab ×3 followed by docetaxel plus trastuzumab plus pertuzumab ×3. In arm B, patients received FEC ×3 followed by docetaxel plus trastuzumab plus pertuzumab ×3. In arm C, patients received docetaxel plus carboplatin plus trastuzumab (TCH) plus pertuzumab ×6. Pathologic complete response rates were comparable, with 61.6% for arm A, 57.3% for arm B, and 66.2% for arm C. Patients were noted to have a low rate of symptomatic left ventricular systolic dysfunction with anthracycline combinations.12
Many agents are known to augment the effectiveness of antibody-based therapy and are also being assessed. The I-SPY 2 platform trial was designed to assess several treatment regimens in combination with standard neoadjuvant chemotherapy for high-risk, clinical stage II or III breast cancer, in order to assess the effect on rate of pCR.13,14 As a part of this study, neratinib was evaluated versus control for 10 biomarker signatures. Neratinib attained a prespecified efficacy threshold with regard to patients with HER2+, HR-negative disease. For patients with HER2+, HR-negative cancer, the mean estimated pCR rate was 56% for the group treated with neratinib compared with 33% for controls.14
For additional commentary about these topics and others, visit to access more resources from the 34th Annual Miami Breast Cancer Conference®, including downloadable slides from the meeting.
1. Tripathy D. Using neoadjuvant therapy for breast cancer in clinical practice: when and how? Breast Cancer Res Treat. 2012;132(3):775-777.
2. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172.
3. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379(9816): 633-640.
4. Carey LA, Berry DA, Cirrincione CT, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016;34(6):542-549.
5. Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(12):1183-1192.
6. Bonnefoi H, Jacot W, Saghatchian M, et al. Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. Ann Oncol. 2015;26(2):325-332.
7. Hurvitz S, Miller J, Dichmann R, et al. Final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/or lapatinib in patients with HER2+ breast cancer (TRIO-US B07). Cancer Res. 2013;73(abstr S1-02).
8. Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol. 2012;30(16):1989-1995.
9. Clavarezza M, Puntoni M, Gennari A, et al. Dual block with lapatinib and trastuzumab versus single-agent trastuzumab combined with chemotherapy as neoadjuvant treatment of HER2-positive breast cancer: a meta-analysis of randomized trials. Clin Cancer Res. 2016;22(18):4594-4603.
10. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.
11. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800.
12. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013; 24:2278-2284.
13. Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375(1):23-24.
14. Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375(1):11-22.

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