Ki67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor–positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.

PD-L1 (programmed cell death 1 ligand 1) expression is a major immune suppressive mechanism via engagement of the PD-1 (programmed cell death protein 1) and PD-L1 axis in non–small-cell lung cancer (NSCLC). After antigen recognition and activation of T cells through a T-cell receptor and major histocompatibility complex peptide-based interaction, PD-L1 can act as a coregulatory signal through binding of the inhibitory PD-1 receptor that ultimately leads to inactivation of lymphocytes and other immune cells.^1-3 Under certain circumstances, such as viral infections, this mechanism can act as a checkpoint to limit the immune response and avoid tissue damage.^4,5 This mechanism can also mediate immune tolerance as seen by placental trophoblastic expression, thereby preventing autoimmune-based destruction of this new immunologically foreign organ.^6-9 Similarly, tumor cells can evade the immune response through up-regulation of PD-L1, with diverse human malignant tumors showing elevated levels of PD-L1 protein, including NSCLC.^10-14

Patient response to checkpoint inhibitor immunotherapy has been considered to be exceptional.^1-3 The checkpoint inhibitor programmed cell death ligand 1 (PD-L1) is the target for 1 therapy approved by the US Food and Drug Administration (FDA) (atezolizumab), and its receptor, programmed cell death 1 (PD-1), is the target for 2 others (nivolumab and pembrolizumab). In registrational trials, each of these drugs has been tested with a companion diagnostic assay that has been independently designed and is based on a combination of a unique antibody with a custom-designed assay using proprietary reagents, protocols, and thresholds defining elevated expression of PD-L1. This scenario has led to a challenge for pathologists who seek to provide companion diagnostic testing but do not necessarily know which therapeutic agent will be selected by the oncologist for any given patient.