1Division of Hematology/Oncology, Comprehensive Breast Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA
2Internal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
Dr Brufsky works as a consultant for Puma and Roche pharmaceutical companies. Dr Raychaudhuri has no relevant financial relationships to disclose.
J Clin Pathways. 2018;4(5):40-41. doi:10.25270/JCP.2018.06.00026
Journal of Clinical Pathways is pleased to present a new section called “CME Corner,” which will highlight, when available, relevant continuing medical education (CME) opportunities deemed to be of use to readers. Articles will include an overview of a specific area where leaders have determined there to be an educational need, and a link to the available CME program will be provided.
HER2+ breast cancer is a clinically distinct entity, due to the striking efficacy of targeted HER2 drugs, both in early stage and metastatic breast cancer (MBC). In the early 1980s, HER2 gene amplification, resulting in excess HER2 protein in breast cancer cells, was discovered to stimulate excess cell growth and division. High levels of the HER2 protein were expressed in about 20% of breast cancers, which was associated with a higher risk of metastases and relapse, and reduced overall survival.1
Trastuzumab (Herceptin; Genentech) is a HER2 specific monoclonal antibody against the HER2 protein. In 1998 trastuzumab received Food and Drug Administration (FDA) approval for therapy in combination with cytotoxic chemotherapy of HER2 positive metastatic breast cancer overexpressing the HER2 protein based on a randomized clinical trial which demonstrated dramatic improvements in progression free survival (PFS) and overall survival (OS) over chemotherapy alone.2,3 In November 2006, the FDA expanded the indication for trastuzumab to adjuvant therapy in combination with cytotoxic chemotherapy for early-stage breast cancer overexpressing the HER2 protein after 2 large randomized adjuvant trials demonstrated that trastuzumab added to chemotherapy improved 5-year disease free survival (DFS) in stages I through III breast cancer by almost 20% over chemotherapy alone.4
Other novel anti-HER2 therapies have also changed clinical practice. Pertuzumab (Perjeta; Genentech) is a monoclonal antibody to the HER2 protein that blocks dimerization on the cell surface of HER2 and HER3, resulting in growth inhibition. Preclinical data suggested that pertuzumab would be synergistic with trastuzumab.5 A large randomized clinical trial (CLEOPATRA) demonstrated substantial improvements in PFS and OS when pertuzumab was added to trastuzumab (THP), and docetaxel over trastuzumab and docetaxel alone as therapy for HER2 positive MBC. The 5-year survival of patients on THP was 60 months, and represents substantial progress in turning this subset of MBC into a chronic, stable disease with long-term survival.6 Additionally, randomized clinical trials in the neoadjuvant setting adding pertuzumab to standard trastuzumab-containing chemotherapy regimens (NEOSPHERE, TRYPHANEA) as therapy for locally advanced HER2+ early-stage breast cancer have resulted in better complete pathologic response as surgery, and superior 5-year DFS. A recent study (APHINITY) demonstrated that the addition of pertuzumab to trastuzumab containing regimens as adjuvant therapy for HER2+ early-stage breast cancer results in modest improvements in 4 year DFS over trastuzumab-based therapy alone.7
Ado-trastuzumab emtansine (Kadcyla; Genentech) is a novel antibody drug conjugate linking emtansine (a cytotoxic microtuble inhibitor) to trastuzumab. The low doses of emtansine coupled with direction of the therapy to HER2 overexpressing cancer cells results in effective therapy with less toxicity than standard agents. A large randomized trial comparing ado-trastuzumab emtansine to capecitabine and lapatinib (Tykerb; Novartis) therapy (EMILIA) demonstrated substantial improvements in PFS and OS with ado-trastuzumab emtansine, and far less toxicity in women with progressive metastatic HER2+ MBC.8 Ado-trastuzumab emtansine is the current standard of care for progressive HER2+ MBC.
Newer anti HER2 therapies and strategies seek to improve on these impressive results. HER2 tyrosine kinase inhibitors (TKIs) seek to inhibit the intracellular portion of the HER2 protein and block downstream signalling. Lapatinib has already been approved for this use in combination with capecitabine chemotherapy, and multiple other HER2 TKIs [pyrotinib, tucatinib, and neratinib (Nerlynx; Puma Biotechnology)] are currently under clinical investigation. Neratinib, when added as extended adjuvant therapy to existing trastuzumab-based adjuvant therapy for early-stage HER2+ breast cancer, improved 5-year DFS in a randomized clinical trial,9 and was recently approved for this use by the FDA.
Targeted HER2 therapies are generally well tolerated. Trastuzumab is associated with a low risk of cardiotoxicity requiring periodic monitoring by echocardiograms.10 Pertuzumab is associated with diarrhea and rash in fewer than 10% of patients.11 HER2 TKIs such as neratinib and lapatinib are also associated with a 10% to 15% incidence of grade 3 diarrhea.12 The CONTROL study addressed this issue with neratinib, and demonstrated that loperamide reduced the incidence, severity, and duration of associated diarrhea. Adding colestipol or budesonide further reduced frequency and duration of diarrhea in this trial, suggesting further strategies to reduce this side effect.13
Outcomes in HER2+ breast cancer have clearly improved with the use of novel HER2 targeted therapies. Assessing the value of these therapies can be measured as a balance of the clinical costs and benefits to the patient in terms of survival benefit, toxicities, and quality of life. Several studies from the United States, Canada, Australia, and Europe suggest adjuvant trastuzumab for HER2+ breast cancer is cost-effective, as the current costs of novel anti-HER2 therapies are several thousand dollars per quality-adjusted life year gained.14 Nonetheless, identification of subsets of patients who would benefit from de-escalation of treatment without compromising patient care could possibly improve this cost-effectiveness. Recent data from a phase 2 study of 12 weeks of adjuvant trastuzumab and paclitaxel in women with HER2+ node negative early-stage breast cancer, where a 4-year DFS of 97% was demonstrated with minimal toxicity and decreased costs, suggest that such de-escalation is possible.15,16 Additionally, recent data from a large randomized UK trial (PERSEPHONE) suggest that 6 months of adjuvant trastuzumab is noninferior to 12 months,17 potentially providing support for further de-escalation of therapy without compromising efficacy.
With the introduction of multiple biosimilar traztuzumab products in the United States within the next 18 months, it is expected that costs can be further decreased with no detriment to the substantial clinical benefit this agent provides.
The CME program titled "Examining Clinical and Cost Implications of HER+ Breast Cancer Care in a New Era of Value-Based Care: Biosimilars, Clinical Pathways, and Precision Medicine" is provided by the North American Center for Continuing Medical Education, LLC (NACCME). NACCME is owned by HMP, the publisher of Journal of Clinical Pathways.
1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
2. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14(3):737-744.
3. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER-2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17(9):2639-2648.
4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
5. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res. 2004;64(7):2343-2346.
6. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
7. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER-2 positive breast cancer. N Engl J Med. 2017;377(2):122-131.
8. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791.
9. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700.
10. Onitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics and risk factors. Ther Adv Drug Saf. 2014;5(4):154-166.
11. Swain SM, Schneeweiss A, Gianni L, et al. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol. 2017;28(4):761-768.
12. Moy B, Goss PE. Lapatinib-associated toxicity and practical management recommendations. Oncologist. 2007;12(7):756-765.
13. Ustaris F, Saura C, Palma JD, et al. Effective management and prevention of neratinib-induced diarrhea. Am J Hem Onc. 2015;11(11):13-22.
14. Nixon NA, Hannouf MB, Verma S. A review of the value of human epidermal growth factor receptor 2 (HER2)-targeted therapies in breast cancer. Eur J Cancer. 2018;89: 72-81.
15. Guarneri V, Frassoldati A, Bruzzi P, et al. Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of Trastuzumab in patients with HER2-positive breast cancer. Clin Breast Cancer. 2008;8(5):453-456.
16. Clarke CS, Hunter RM, Shemilt I, Serra-Sastre V. Multi-arm cost-effectiveness analysis (CEA) comparing different durations of adjuvant trastuzumab in early breast cancer, from the English NHS payer perspective. PLoS One. 2017;12(3):e0172731.
17. Earl HM, Hiller L, Vallier A, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results [ASCO abstract 506]. J Clin Oncol. 36, 2018;36:(suppl).