Table 1.
Efficacy of HER2-directed therapy in HER2 low patients—from testing flaw to the investigational arm.
| Clinical Trial | Phase | N | Setting | Study Population | Treatment in the Investigational Arm/Control Arm | Efficacy of Anti-HER2 Therapy * HER2 Low Patients |
|---|---|---|---|---|---|---|
| Slamon et al., 2001 [46] | 3 | 469 | Advanced/metastatic; 2nd- or 3rd-line |
HER2 2+ and 3+ BC (IHC) | Trastuzumab + chemotherapy vs. chemotherapy | mOS ITT 25.1 vs. 20.3 months |
| * ISH not carried out | * Not reported | |||||
| Vogel CL et al., 2002 [45] | 2 | 114 | Advanced/metastatic; 1st-line |
HER2 2+ and 3+ BC (IHC) | Trastuzumab monotherapy, single arm | ORR ITT 26% |
| 79 patients (ISH+) 29 patients (ISH−) |
* ORR HER2 ISH-positive vs. HER2 ISH-negative 34% vs. 7% | |||||
| Romond EH et al., 2005 [48] NSABP B-31 NCCTG N9831 |
Both phase 3 | 3351 | Early/adjuvant | HER2 3+ or HER2-amplified as determined by ISH | Trastuzumab + chemotherapy vs. chemotherapy | HR for DFS 0.48; p < 0.0001 * carried out by Paik S et al., [50] * carried out Perez et al., [51] |
| Paik S et al., 2008 [50] | Subanalysis | 1787 | Early/adjuvant | NSABP trial B-31 | Trastuzumab + chemotherapy vs. chemotherapy | HER2-positive—HR for DFS 0.47 (0.37–0.62), p < 0.001 |
| 174 pts reclassified to HER2-negative | * HER2-negative—HR for DFS 0.34 (0.14–0.80), p = 0.014 | |||||
| Perez EA et al., 2010 [51] | Subanalysis | 1783 | Early/adjuvant | N9831 | Trastuzumab + chemotherapy vs. chemotherapy | HER2 positive—HR for DFS 0.46, 0.49, and 0.45 (IHC 3+, HER2/CEP17 ≥ 2.0, both) |
| 103 pts reclassified as HER2-negative | * HER2 negative—HR for DFS 0.69, 0.54, and 0.51, p = 0.26, 0.12, and 0.14 (IHC 0 to 2+, HER2/CEP17 < 2.0, both) | |||||
| Fehrenbacher L et al., 2020 [54] | 3 | 3270 | Early/adjuvant | HER2-low BC | Trastuzumab + chemotherapy vs. chemotherapy | * IDFS 89.8% vs. 89.2% (HR 0.98; 95% CI, 0.76 to 1.25; p = 0.85) |
| Filho OM et al., 2021 [61] | 2 | 164 | Early/neoadjuvant | HER2-positive BC | TDM1 + pertuzumab, single arm | * pCR non-heterogeneous vs. heterogeneous |
| * 10% pts reclassified as HER2-heterogeneous (ISH) | 43.4% vs. 10% | |||||
| Banerji et al., 2021 [21] | 1 | 99 | Advanced/metastatic, heavily pretreated patients |
HER2-positive, HER2-low BC | Trastuzumab–duocarmazine; single arm | ORR HER2-positive BC 33% * ORR HER2-low ER+ 28% * ORR HER2-low ER- 40% |
| Modi S. et al., 2020 [22] | 1b | 54 | Advanced/metastatic heavily pretreated patients |
HER2-low BC | Trastuzumab–deruxtecan; single arm | * ORR 37% mDoR (95% CI, 8.8 mo to not evaluable) |
| Modi S. et al., 2022 [66] DESTINY-Breast04 |
3 | 557 | Advanced/metastatic ≥2nd-line |
HER2-low BC | Trastuzumab–deruxtecan vs. physician’s choice | * mPFS 9.9 vs. 5.1 mo (HR 0.50; p < 0.001) * mOS 23.4 vs. 16.8 mo (HR 0.64; p = 0.001) |
* referring to the HER2 Low Patient group.