Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

Ramez N Eskander; Julia Elvin; Laurie Gay; Jeffrey S Ross; Vincent A Miller; Razelle Kurzrock

doi:10.1200/PO.19.00248

Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

JCO Precis Oncol. 2020 Sep 3:4:PO.19.00248. doi: 10.1200/PO.19.00248. eCollection 2020.

Authors

Ramez N Eskander^{1

2}, Julia Elvin³, Laurie Gay³, Jeffrey S Ross^{3

4}, Vincent A Miller³, Razelle Kurzrock^{2

5}

Affiliations

¹ Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of California San Diego, La Jolla, CA.
² Center for Personalized Cancer Therapy, University of California San Diego, La Jolla, CA.
³ Foundation Medicine, Cambridge, MA.
⁴ Upstate Medical University, Syracuse, NY.
⁵ Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, CA.

Abstract

Purpose: High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape.

Patients and methods: Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs.

Results: The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors (P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found.

Conclusion: This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.