Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer

Abstract

Objectives Small cell cervical cancer is a rare malignancy with limited treatment options for recurrent disease. We sought to determine if tumor specimens of small cell cervical cancer harbor common somatic mutations and if any of these are actionable. Methods Using a registry of patients with neuroendocrine cervical cancer, we identified 44 patients with pure or mixed small cell cervical cancer who had undergone mutational analysis. Mutations had been detected using next generation sequencing of mutational hotspots in 50 cancer-related genes. Results Thirty-five mutations were identified in 24 patients (55%). Fifteen of these 24 patients (63%) had 1 mutation, 7 patients (29%) had 2 mutations, and 2 patients (8%) had 3 mutations. In all 44 patients, the most commonly seen mutations were mutations in PIK3CA (8 patients; 18%), KRAS (6 patients; 14%), and TP53 (5 patients; 11%). No other mutation was found in >7% of specimens. Of the 24 patients who had a mutation, 21 (88%) had at least 1 alteration for which there currently exists a class of biological agents targeting that mutation. In the entire cohort of 44 patients, 48% had at least 1 actionable mutation. Conclusion Although no single mutation was found in the majority of patients with small cell cervical cancer, almost half had at least 1 actionable mutation. As treatment options for patients with recurrent small cell cervical cancer are currently very limited, molecular testing for targetable mutations, which may suggest potential therapeutic strategies, may be useful for clinicians and patients.

PD‐L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix

“…29 Similarly, mutations in PIK3CA, one of the most frequently mutated genes in HPV-related cancers, were detected in 18% (eight of 44) of SmCC-Cx in a hotspot-based study. 30 In contrast, a study using whole exome sequencing identified recurrent mutations in five cases of SmCC-Cx, including ATRX, ERBB4 and AKT/mTOR pathway genes NF1, PTEN, RICTOR and TSC1/2, which is akin to neuroendocrine tumours arising in sites unrelated to HPV infection. 31 These emerging data have the potential to unveil targets for therapy which, in conjunction with immune modulation treatments, may change the course of the disease.…”

“…A recent study using targeted next‐generation gene sequencing on 10 patients with SmCC‐Cx identified recurrent somatic mutations involving the MAPK , PI3K/AKT/mTOR and TP53/BRCA pathways . Similarly, mutations in PIK3CA , one of the most frequently mutated genes in HPV‐related cancers, were detected in 18% (eight of 44) of SmCC‐Cx in a hot‐spot‐based study . In contrast, a study using whole exome sequencing identified recurrent mutations in five cases of SmCC‐Cx, including ATRX , ERBB4 and AKT/mTOR pathway genes NF1 , PTEN , RICTOR and TSC1/2 , which is akin to neuroendocrine tumours arising in sites unrelated to HPV infection .…”

Updates and management algorithm for neuroendocrine tumors of the uterine cervix

“…Frumovitz et al 29 identified 44 patients with pure or mixed small-cell cervical cancer. All patients underwent mutational analysis using next-generation sequencing of mutational hotspots in 50 cancer-related genes.…”

Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in recurrent small cell neuroendocrine carcinoma of the cervix

“…We found that 48% of patients with small cell cervix cancer had a druggable mutation; these included mutations in PIK3CA (18%), KRAS (14%), and TP53 (11%). [19] On the basis of molecular testing, one patient had a KRAS mutation identified in her tumor and was treated with a MEK inhibitor, and this patient achieved a complete response. [20]…”