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HER2-Directed Treatment of Metastatic Breast Cancer: Unanswered QuestionsHow Can We Optimize Treatment of HER2-Positive Metastatic Breast Cancer? Despite significant progress in developing new treatments that significantly improve clinical outcomes for patients with HER2-positive breast cancer over the last 15 years, the need for additional unique therapies remains.
Trastuzumab emtansine, or T-DM1, is a HER2-specific antibody-drug conjugate consisting of trastuzumab covalently bound via a linker to DM1, a derivative of the microtubule inhibitor maytansine.[55] T-DM1 is internalized by the cancer cell, and the DM1 moiety is released into the cell, resulting in microtubule damage and cell death. A subsequent single-arm phase II study of T-DM1 enrolled 112 patients with HER2-positive MBC previously treated with HER2-targeted therapy. Neratinib is an oral, irreversible smallmolecule pan-HER receptor tyrosine kinase inhibitor with activity in preclinical studies.[64] An open-label, multicenter phase II trial enrolled 136 patients with HER2-positive MBC, 70 of whom had been previously treated with trastuzumab, and 66 of whom were trastuzumab-naive.
Afatinib is another oral, irreversible small molecule pan-HER tyrosine kinase inhibitor with demonstrated activity as monotherapy in a phase II study of 41 patients with HER2-positive MBC after disease progression on trastuzumab.[70] Four patients (11%) had a partial response, and 15 patients (37%) had stable disease. HER2 signaling has been associated with production of proangiogenic factors, including vascular endothelial growth factors (VEGFs) A, C, and D.[71] Bevacizumab (Avastin) is a humanized monoclonal antibody (IgG1) that blocks angiogenesis by binding to circulating VEGF A, preventing its binding to the VEGF receptor.
Therapeutic cancer vaccines designed to induce immune responses specific for HER2 are under active investigation for both early-stage and advanced HER2-positive breast cancer.[76] HER2-directed vaccine platforms that have been evaluated clinically include peptide-based vaccines, protein-based vaccines, plasmid DNA–based vaccines, dendritic cell–based vaccines, and vaccines that deliver HER2 in a viral or bacterial vector.
Understanding both the intricacies and the importance of HER2 signaling in breast cancers that overexpress HER2 has led to the development of several unique HER2-targeted drugs for the management of both early-stage and metastatic HER2-positive breast cancer. Therapies in the adjuvant setting like trastuzumab (Herceptin) and neratinib have shown more durable responses in patients with HER2+ breast cancer, as opposed to long-term treatment, said Mohammad Jahanzeb, MD, in an interview with Targeted Oncology. Some patients with early-stage HER2-positive breast cancer either progress on, or relapse very early after, adjuvant or neoadjuvant trastuzumab-based therapy, suggesting primary resistance to trastuzumab treatment.
Based on these data, an ongoing phase III study is evaluating the combination of pertuzumab and T-DM1 vs trastuzumab plus a taxane (docetaxel or paclitaxel) or T-DM1 alone (MARIANNE; NCT01120184). Single-agent neratinib (orally at 240 mg once daily) was associated with ORRs of 24% and 56% in the trastuzumab-pretreated and trastuzumab-naive groups, respectively.[65] Diarrhea was the most frequent adverse event, but was manageable with antidiarrheal agents and neratinib dose modifications. Prior to the approval of pertuzumab in combination with trastuzumab and docetaxel, the standard approach to the first-line treatment of HER2-positive metastatic disease was trastuzumab plus a taxane or vinorelbine, or lapatinib and capecitabine (for patients who had relapsed early after trastuzumab-based adjuvant therapy).
Emens receives research funding from Genentech, and has received honoraria for advisory board participation from Bristol-Myers Squibb. It is standard of care to administer 12 months of trastuzumab-based therapy in addition to chemotherapy, ideally concurrently," said Jahanzeb, medical director, Sylvester Comprehensive Cancer Center at Deerfield Beach. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET). Also, in virtually all patients with HER2-positive MBC, the disease eventually progresses; this highlights the need for new therapies that target HER2 signaling, but with distinct mechanisms of action. In addition, the toxicity profile favored the T-DM1 arm, with fewer grade 3 and 4 adverse events (41% vs 57%).
Ongoing trials are evaluating afatinib in combination with trastuzumab (NCT00950742), with letrozole (NCT00708214), and in the first-line setting with trastuzumab or lapatinib (NCT00826267).
This protein contains sequences derived from both the intracellular and extracellular domains of HER2, and from GM-CSF.
The approval of pertuzumab in combination with trastuzumab and docetaxel has set a new standard of care for this patient population.
There was an unplanned analysis, and if you looked at those patients who had centrally confirmed HER2-positivity by FISH and with hormone receptor positivity, their benefit was actually 9%," said Jahanzeb.
Research on HER2-targeted therapy is extremely active, and novel agents continue to be developed at a rapid pace.
Thrombocytopenia and transaminitis were the most common grade 3 or higher adverse events associated with T-DM1. Vaccinated patients displayed evidence of new HER2-specific T-cell activity; one patient had a partial response, and three additional patients had stable disease for more than 1 year.
Importantly, this combination regimen is well tolerated and without increased cardiac toxicity. Jelovac has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. A more favorable toxicity profile was observed on the T-DM1 arm, with a lower incidence of grade 3 or 4 adverse events with T-DM1 vs trastuzumab and docetaxel (37% vs 75%). The FDA is reviewing these data for accelerated approval, with a decision expected in early 2013.
Grade 3 or greater side effects occurred in 44% of patients, most commonly hand-foot syndrome, diarrhea, and hypertension.
Dual-HER2 blockade was effective in both trastuzumab-pretreated and trastuzumab-naive patients, suggesting that trastuzumab-resistant HER2-positive breast cancers likely still depend on the HER2 signaling pathway. Once a good clinical response is achieved, it is reasonable to consider dropping docetaxel chemotherapy and continuing treatment with trastuzumab and pertuzumab. The role of pertuzumab in the second-line setting will be addressed by results of the PHEREXA trial.

The continuation of HER2 blockade remains an important component of therapy at disease progression, and therapy with lapatinib or novel agents available through clinical trials should be considered. Data from the EMILIA trial showed that T-DM1 has therapeutic potential for patients who progress on trastuzumab and a taxane, and T-DM1 is under active FDA review for accelerated approval. For patients with HER2-positive brain metastasis, lapatinib is currently the only FDA-approved HER2-targeted agent with documented activity; current data support the use of lapatinib and capecitabine in these patients.
An ongoing phase III study is evaluating addition of bevacizumab to carboplatin and paclitaxel plus trastuzumab for first-line treatment of HER2-positive MBC (Eastern Cooperative Oncology Group [ECOG] 1105; NCT00520975). Clinical and research efforts must focus on new ways to penetrate the blood-brain barrier and target HER2-positive disease within the CNS. Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites.
A coordinated strategy driven by the biology of the pathway will allow the full power of HER2-targeted therapy to be realized. Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Comparison of HER-2 overexpression in primary breast cancer and metastatic sites and its effect on biological targeting therapy of metastatic disease.
Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31.
Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.
Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer.
Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer.
Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study.
Docetaxel combined with trastuzumab is an active regimen in HER-2 3+ overexpressing and fluorescent in situ hybridization-positive metastatic breast cancer: a multi-institutional phase II trial.
Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. Phase II study of weekly docetaxel alone or in combination with trastuzumab in patients with metastatic breast cancer. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial. Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer - results of the eLEcTRA trial. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy.
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Efficacy and safety of lapatinib as first-line therapy for ErbB2-amplified locally advanced or metastatic breast cancer. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors.
Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.
Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.J Clin Oncol.
Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab.
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Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models.
Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy.
Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer.
Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy.
A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. Efficacy and safety of trastuzumab-DM1 versus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of randomized, multicenter, open-label phase 2 study (TDM4450G). Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase.
Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer.
Safety and efficacy of neratinib in combination with capecitabine in patients with ErbB2-positive breast cancer.
Efficacy and safety of neratinib (HKI-272) in combination with paclitaxel in HER2+ metastatic breast cancer. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma.
Final results of a phase II trial evaluating trastuzumab and bevacizumab as first line treatment of HER2-amplified advanced breast cancer. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Treatment with autologous antigen-presenting cells activated with the HER-2-based antigen lapuleucel-T: results of a phase I study of immunologic and clinical activity in HER-2-overexpressing breast cancer. Phase I clinical trial of HER-2-specific immunotherapy with concomitant HER-2 kinase inhibition. A feasibility study of combination therapy with trastuzumab (T), cyclophosphamide (CY), and an allogeneic GM-CSF-secreting breast tumor vaccine for the treatment of HER-2+ breast cancer.

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