Yara Abdou, MD
DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefit for patients with HER2-low metastatic breast cancer. This phase 3 study by Modi and colleagues enrolled 557 patients with hormone receptor (HR)–negative or HR-positive breast cancer and centrally confirmed HER2 low expression in those who had been previously treated with one or two prior lines of chemotherapy for metastatic breast cancer. Patients with HR-positive breast cancer were required to have endocrine therapy–refractory disease. Patients were randomized in a 2:1 ratio to receive either an antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), or the physician's choice of standard chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nanoparticle albumin–bound paclitaxel [nab-paclitaxel]). Among all 557 patients, T-DXd improved median progression-free survival (PFS) by 4.8 months (9.9 vs 5.1 months; hazard ratio [HR] 0.50; P < .001) and median overall survival (OS) by 6.6 months (23.4 vs 16.8 months; HR 0.64; P = .0010) compared with standard single-agent chemotherapy. Among the 494 (88.7%) HR-positive patients, the median PFS was 10.1 months in the T-DXd group and 5.4 months in the chemotherapy group (HR 0.51; P < .001). Median OS was 23.9 months and 17.5 months, respectively (HR 0.64; P = .003) . The rates of grade 3 or higher adverse events were lower with T-DXd than with standard chemotherapy (52.6% vs 67.4%, respectively), although higher rates of drug-related interstitial lung disease or pneumonitis were noted in the T-DXd arm (12.1% vs 0.1%). Lung toxicity continues to be an important safety concern with T-DXd . These practice-changing results open the door to a new treatment option for a substantial group of patients with HER2-low disease and support the need to reclassify HER2-low as a new targetable subset of breast cancer, distinct from HER-negative (HER2-0), and to acquire an understanding of the clinical characteristics of and prognosis for these patients.
Tarantino and colleagues evaluated the biologic and prognostic significance of HER2-low expression in breast cancer and investigated the association between HR status and HER2-low expression. Among 5235 patients with HER2-0 invasive breast cancer, HR expression was significantly more common among HER2-low tumors than among HER2-0 tumors (90.6% vs 81.8%; P < .001). The rate of HER2-low tumors increased progressively as estrogen receptor (ER) expression increased (40.1% of ER-negative, 46.3% of ER-low, 55.2% of ER-moderate, 57.8% of ER-high, and 62.1% of ER-very high [ie, ER > 95%] tumors; P < .001). Among 675 patients receiving neoadjuvant chemotherapy, higher pathologic complete response (pCR) rates were seen among those with HER2-0 tumors (26.8% vs 16.6%; P = .002), although no statistically significant differences in pCR rates were noted between HER2-low and HER2-0 tumors when analyzed by HR and ER status. In contrast to the findings of Modi and colleagues , this analysis saw no prognostic significance in terms of survival outcomes for HER2-low expression among patients who had HR-positive or HER2-0 tumors, suggesting that HER2-low breast cancer may not be a distinct biologic subtype. Further studies are needed to clarify whether HER2-low breast cancer needs to be considered separately in practice.
Immunotherapy, particular checkpoint inhibitors, has revolutionized the treatment of many solid tumors. However, their role in HER2-positive breast cancer remains unclear. IMpassion050 is a double-blind, randomized, phase 3 study evaluating the efficacy and safety of adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) antibody, to neoadjuvant standard of care (chemotherapy + pertuzumab + trastuzumab [PH]) for high-risk, HER2-positive early breast cancer (EBC). In the study by Huober and colleagues , 454 patients with a primary tumor > 2 cm and histologically confirmed positive lymph node status (N1-3) were randomly assigned in a 1:1 ratio to the atezolizumab or placebo group with dose-dense doxorubicin or cyclophosphamide, followed by paclitaxel and PH. In the adjuvant setting, patients continued atezolizumab or placebo and PH to complete 1 year of HER2-targeted therapy; those with residual disease could switch to trastuzumab emtansine with atezolizumab or placebo. At clinical cutoff (February 5, 2021), rates of pCR in the atezolizumab group vs placebo group were similar among all patients in the study (62.4% vs 62.7%; P = .9551) and in the PD-L1–positive population (64.2% vs 72.5%; P = .1846). Treatment-related grade 3-4 adverse events occurred more frequently in the atezolizumab group compared with the placebo group, both during the neoadjuvant treatment phase (47.3% vs 42.2%) and the adjuvant treatment phase (13.4% vs 9.8%).
In summary, the phase 3 I Mpassion050 trial showed no significant improvement in pCR with the addition of atezolizumab to neoadjuvant therapy in patients with high-risk, HER2-positive EBC, including those with PD-L1–positive tumors. At this time, PH and chemotherapy remain the standard of care in this patient population. Longer follow-up is needed in respect to the long-term effect of atezolizumab in this setting .