Predictive Value of Positron Emission Tomography/Computed Tomography to Assess Early Treatment Response to Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade Without Chemotherapy for HER2-Positive Metastatic Breast Cancer: Are We Ready to Embrace This “Early Metabolic Look” Strategy?

Since the US Food and Drug Administration approval of trastuzumab in combination with a taxane in 1998, which revolutionized the management of human epidermal growth factor receptor 2 (HER2) –positive breast cancer, three other anti-HER2 therapies have been approved: lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1). With these, we can consider using combinations of two or more anti-HER2 therapies hoping to increase effectiveness or, alternatively, eliminate some chemotherapy while maintaining efficacy. Dual HER2 blockade with lapatinib or pertuzumab added to chemotherapy/trastuzumab was superior to trastuzumab alone in both the metastatic and neoadjuvant settings, but regimens without conventional chemotherapy have not been as fully explored. In the accompanying article, Lin et al report a nonrandomized phase II Translational Breast Cancer Research Consortium (TBCRC) trial conducted in 87 patients with HER2-positive metastatic breast cancer (MBC) treated with lapatinib plus trastuzumab without chemotherapy. That study demonstrated overall response rates of 50% and 22% in cohort 1 (no prior lines of trastuzumab for MBC; 1 year from adjuvant trastuzumab, if given) and cohort 2 (one to two lines of chemotherapy for MBC, including trastuzumab, and/or recurrence 1 year from adjuvant trastuzumab), respectively. Of note, 10% (four of 40) of the patients in cohort 1 remained on protocol therapy more than 3 years after study entry, although three of these patients were trastuzumab naive. The progression-free survival (PFS) was 7.4 months in cohort 1 and 5.3 months in cohort 2. The most common adverse events were diarrhea, fatigue, and rash. Notably, there were no grade 4 toxicities, and less than 10% had grade 3 toxicities. To place the efficacy results from that study in context, consider the additional data that have become available since trial accrual began in 2007. Three randomized trials have reported PFS and overall survival benefits for HER2-positive MBC, including the phase III EGF104900 (Lapatinib In Combination With Trastuzumab Versus Lapatinib Monotherapy In Subjects With HER2-positive TrastuzumabRefractory Metastatic Breast Cancer) trial in patients with HER2-positive trastuzumab-refractory MBC (median of three lines of trastuzumabbased chemotherapy). In addition, with significant survival benefit noted in the CLEOPATRA (A Study to Evaluate Pertuzumab Trastuzumab Docetaxel vs. Placebo Trastuzumab Docetaxel in Previously Untreated HER2-positive Metastatic Breast Cancer) and EMILIA (An Open-label Study of Trastuzumab Emtansine [T-DM1] vs Capecitabine Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) trials, pertuzumab and ado-trastuzumab emtansine are recommended in the firstand second-line metastatic setting by multiple clinical practice guidelines. Lapatinib plus trastuzumab could be a reasonable option upon disease progression on pertuzumab or T-DM1, given its acceptable toxicity profile and clinical activity.Thiscombinationcouldalsoplayanimportantroleinthefirst-or second-line setting for patients who have limited access to pertuzumab and/or T-DM1. The identification of so many new active agents for a distinct subtype of breast cancer over the past few years is cause for optimism. We have entered the era of precision medicine and moved away from the one-size-fits-all approach. At the same time, every advance opens new challenges, and we have yet to resolve how to reliably identify patients who might benefit the most from a particular targeted therapy. Historically, response assessment in the metastatic setting relies on identifying anatomic progression using the conventional response evaluation criteria for solid tumors (RECIST criteria), typically performed 8 to 12 weeks after the initiation of therapy. However, the JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 24 AUGUST 2