Systemic therapy for early‐stage HER2‐positive breast cancers: Time for a less‐is‐more approach?

Abstract

Trastuzumab-based chemotherapy has dramatically improved outcomes for patients with all stages of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Additional HER2-directed agents that have recently been approved are also expected to improve outcomes. Patients with small, lymph node-negative, HER2-positive breast cancers who are treated with trastuzumabbased chemotherapy demonstrate especially favorable responses, with 5-year recurrence rates of <5%. In this review, recent data regarding response rates among patients with early-stage HER2-positive breast cancer treated with trastuzumab-based chemotherapy are discussed. This review supports future studies of the possible omission of chemotherapy in a subset of patients with HER2-positive cancers, specifically those that coexpress hormone receptors. INTRODUCTIONApproximately 25% of breast cancers overexpress the human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase. HER2-positive cancers are characterized by an aggressive clinical course with a high propensity for distant metastases within 5 years of diagnosis. 1,2 The use of trastuzumab-based chemotherapy has dramatically improved outcomes for patients with all stages of HER2-positive breast cancer. [3][4][5][6] The median survival for patients with metastatic, HER2-positive breast cancer is approximately 3 years 7 ; survival is expected to increase even further because of the approval of additional HER2-directed agents. 8,9 Adjuvant trials have demonstrated significant reductions in disease recurrence and improvements in survival for patients with early-stage, HER2-positive breast cancers who are treated with trastuzumabbased chemotherapy. 3,5,6 There has been increased interest in the use of neoadjuvant HER2-directed agents with chemotherapy using pathologic complete response (pCR) as a surrogate for long-term outcome. For example, the combination of pertuzumab, trastuzumab, and docetaxel was recently approved in the preoperative setting for patients with HER2-positive breast cancers. 10 Some retrospective analyses of patients with small HER2-positive cancers have demonstrated worse outcomes compared with those achieved in patients with other breast cancer subtypes. 11,12 In contrast, the results of other studies have indicated that outcomes are more favorable, with low recurrence rates reported in patients with small HER2-positive breast cancers. Although patients with these cancers were underrepresented in the pivotal adjuvant trials, a recent metaanalysis of these trials has demonstrated favorable outcomes for patients with small HER2-positive breast cancers who were treated with adjuvant trastuzumab-based chemotherapy. 13 The meta-analysis further demonstrated that the addition of trastuzumab to chemotherapy improves outcomes in these patients compared with chemotherapy alone. 14 Recent adjuvant trials evaluated the addition of other targeted agents, including bevazicumab and lapatinib, to trastuzumab-based chemotherapy; these trials included a larger percentage of ...

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial

“… 13 Although these differences may simply be spurious findings due to the exploratory nature of the subgroup analyses, they are more likely explained by HER2 and estrogen-receptor crosstalk. 28 , 29 The existence of bidirectional crosstalk between HER2 and estrogen-receptor pathways 30 means that estrogen-receptor signaling may be activated with inhibition of HER2 alone. 28 The ExteNET study in the early-disease setting permitted endocrine therapy in hormone receptor–positive patients, 13 whereas NALA and I-SPY, 27 which combined neratinib with a chemotherapeutic agent, did not include concomitant endocrine therapy for hormone receptor–positive disease, as this is not recommended in the advanced setting.…”

A data- and model-driven approach for cancer treatment

“…For example, the human epidermal growth factor receptor 2 (HER2), a proto-oncogene encoding the HER2 (alias ERBB2) tyrosine kinase receptor, is used as a biomarker for selecting treatment options. The use of HER2-directed agents such as the monoclonal antibody therapy trastuzumab and pertuzumab, has dramatically improved breast cancer patient outcomes in all stages of the disease [3,4]. However, although these methods have enriched the treatment toolkit by enabling stratification of patients into subgroups of potential responders, they only test for alterations in a limited number of genes (those present on the panel) and still only provide a treatment option for those patients who happen to carry the selected markers-typically only a small fraction of the cases [e.g., 25% of breast cancers overexpress HER2; 15% of lung cancer patients carry alterations in epidermal growth factor receptor (EGFR) or receptor tyrosine kinase proto-oncogene 1 (ROS1)], limiting the overall impact of single biomarker strategies [5].…”

“…4 Cancer treatment boards can be informed by a data and model approach as part of the current patient diagnostic and therapy selection process. 4 The data-and model-driven approach to personalized oncology is already being tested in pilot clinical studies. 4 Further model development and optimization is required to ensure specificity, accuracy, and sensitivity of model predictions.…”

Trastuzumab in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Results of a Prospective, Noninterventional Study on Routine Treatment Between 2006 and 2012 in Germany

“…Although approximately 10,000 patients were randomly assigned to these studies, only approximately 1,000 of them were age 60 years or older . Moreover, patient cohorts with small or low‐risk tumors or those with significant concomitant diseases were excluded .…”