Discussion

The known genomic landscape of SCLC classically features high frequencies of RB1 and TP53 mutation which were recapitulated in this study.7–10 Additional alterations identified in this study involve a wide variety of recognised cancer-related genes, and impact a series of genomic pathways that have been previously linked to development and progression of SCLC.7–10 By comparison with other solid tumour types, including NSCLC,11 the frequency of potentially actionable genomic alterations in SCLC is lower with an average of 0.98 actionable GA per patient. Around 50% of the SCLC patients in this series harboured at least one actionable genomic alteration. Not only does SCLC feature a lower frequency of actionability than other types of lung cancer such as adenocarcinoma,11 the long tail of altered genes in SCLC and the resulting wide panorama of impacted mechanisms of tumour biology are highly complex. Additionally, given that only 25% of the altered genes in this series of SCLC cases are currently considered to be actionable, it is critical that the sequencing test used to assess the tumours for potential therapy targets be sensitive enough not to miss any of these important alterations. This finding necessitates that a broad diagnostic assay that can detect these genomic changes at a high degree of sensitivity from limited biopsy material be used to maximise targeted therapeutic options in an individual patient.

Of the seven most frequently altered genes in SCLC, the only potentially actionable gene in this group of alterations is RICTOR amplification which was found in 10 (10%) of SCLC cases (figure 1A,B). All 10 (100%) of the alterations of RICTOR in this study of SCLC were amplifications. An example of RICTOR amplification in SCLC is seen in case 45 (figure 2). RICTOR encodes the protein, RICTOR (rapamycin-insensitive companion of mTOR), an mTOR binding protein that interacts with mTOR in the complex mTORC2.12 When all types of NSCLC are included, amplification of RICTOR has been found in 8–10% of cases, but there is no data for the frequency of RICTOR amplification in SCLC currently available (cBioPortal for Cancer Genomics, Oct 2013). Tumours with RICTOR amplification may be sensitive to inhibitors of mTORC2, the RICTOR-containing complex.13 Numerous inhibitors that target both mTORC1 and mTORC2 complexes, as well as dual PI3K/mTOR inhibitors, are under preclinical and clinical investigation in multiple tumour types.14 ,15

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Figure 2

Bronchial biopsy from a 78-year-old man demonstrating classic histology for small cell undifferentiated carcinoma (case number 45). The low magnification image (1×) of the tumour is at the upper left and the high magnification image (20×) at upper right. The tumour was stage IV at the time of diagnosis with extensive bone metastases. The tumour was sequenced to a mean coverage depth of 610× and NGS revealed an amplification of the RICTOR gene at 13 copies shown in the lower portion of the figure. There were also lower level amplifications of FGFR3, FGF10 and MYST3. The tumour also had base substitutions in TP53 (G266*) and MSH6 (V509A) along with a loss (homozygous deletion) in RB1. The chromosomal location is provided in the X axis below and the gene copy number on the Y axis to the right of the gene copy number plot.

Additional potentially actionable alterations in this series of SCLC involved the KIT (multiple types of alterations in 7% of SCLC) and EGFR (base substitutions in 5% of SLCL) genes. KIT mutations in SCLC are rare and have been reported only in 2.1% in the COSMIC database (COSMIC, January 2014). KIT protein expression has been reported in 36.4–83.3% of SCLC samples.16 ,17 A number of tyrosine kinase inhibitors that target KIT have been successful for patients with various KIT-mutated solid tumours. Additionally, PI3K inhibitors and mTOR inhibitors, may have potential for treatment of a tumour with either a KIT amplification or activating mutation. The combination of first-line kinase inhibitors with MEK, PI3K, or mTOR inhibitors, or new therapies such as switch kinase inhibitors, may be a useful strategy to target kinase inhibitor-resistant tumours. EGFR mutations have been reported in 2–5% of SCLC (COSMIC, February 2014).18 ,19 Although activating mutations in EGFR have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib and afatinib in NSCLC,20–23 studies showing responsiveness to gefitinib or erlotinib in EGFR-mutated SCLC have been limited.24 ,25

SOX2 amplification was detected in 4% of SCLC in the current study. SOX2 encodes SOX2, a transcription factor described as a ‘lineage survival’ oncogene and SOX2 expression may be associated with resistance to cytotoxic chemotherapy.26 This result is in contrast with the previously reported frequency of high-level SOX2 amplification which has previously been found in 27% (15/56) SCLC.27 The presence of SOX2 expression does not appear to relate to prognosis or survival in patients with SCLC.28 There are currently no therapies available to directly target SOX2 amplification in cancer. However, preclinical research suggests that SOX2 expression may predict sensitivity to inhibitors of Cdk4 and Cdk6.29

In summary, high-sensitivity genomic profiling can discover potential new routes to targeted therapies in patients with SCLC who have relapsed after primary chemotherapy. Given the well-known poor prognosis for relapsed SCLC, further study of the detection of genomic alterations and the potential for targeted therapies to help these patients appears warranted.