RB1 or Retinoblastoma mutations and loss of retinoblastoma (Rb) expression are frequent but not always inevitable features of small cell lung cancer (SCLC). However, there is a lack of data on the incidence and profile of SCLC with intact wild-type Rb. In addition, there is a lack of clarity on the relative efficacy of immunohistochemistry and targeted next-generation sequencing (NGS) for Rb evaluation. Complete targeted NGS, including all exons of RB1 and Rb immunohistochemistry (IHC), was performed on 208 clinical SCLC samples.
A p16-high/cyclinD1-low profile was chosen as a marker of constitutive Rb insufficiency because of the well-established coordination of Rb/p16/cyclinD1 expression coordination. Wild-type Rb was expressed in 14 out of 208 SCLC (6%) and was associated with a distinct p16-low/cyclinD1-high profile. A combination of SCLC and non-SCLC (NSCLC) histology, as well as aggressive behavior, were linked to Rb-proficient SCLC. Only 29% of these tumors had CCND1 amplification, and they also had an abundance of CDKN2A mutations (50%), as well as changes characteristic of NSCLC (KEAP1, STK11, FGFR1).
The remaining 194 (p16-high/cyclinD1-low) of the 208 SCLC were Rb-deficient. This included 10 instances with mutant but expressed Rb and 184 patients with Rb loss (of which 29% lacked detectable RB1 changes by clinical NGS process). As far as researchers know, this is the largest study to date to investigate Rb by NGS and IHC in SCLC simultaneously, and it found a proficiency rate of 6%. According to pathologic and genetic evidence, the progenitors of Rb-competent SCLC are suspected to originate in NSCLC. CDK4/6 inhibitors may be useful in this aggressive subtype of SCLC due to the consistent upstream inactivation of Rb via CDKN2A/p16↓ and CCND1/cyclinD1↑. The study also sheds insight into the limitations of exon-only sequencing for RB1 interrogation and clarifies technical aspects of determining Rb status in clinical practice.