Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer
Introduction
Although the incidence of cervical cancer has steadily decreased in developed countries because of effective screening and human papillomavirus (HPV) vaccination, cervical cancer remains the second most prevalent cancer among women worldwide [1]. The vast majority (> 95%) of cervical cancers are of the HPV-associated histologic subtypes of squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma [2]. Fewer than 1% of women with cervical cancer have a neuroendocrine tumor, which translates to approximately 100 to 200 cases of neuroendocrine cervical cancer diagnosed each year in the United States.
Neuroendocrine carcinoma of the cervix encompasses several histologic subtypes, including small cell, large cell, and carcinoid (low- and high-grade) tumors. Unlike the more common squamous and adenocarcinoma subtypes, which spread primarily by local extension, small and large cell neuroendocrine cervical cancers have a propensity to spread both locally and hematogenously, and affected patients frequently present with extrapelvic disease (e.g., liver and lung parenchymal metastases) at initial diagnosis [3]. In addition, even among patients with disease clinically limited to the cervix, the prevalence of regional nodal disease is substantially higher among patients with neuroendocrine cervical cancer than among patient with the more common histologic subtypes: up to 40% of newly diagnosed patients with stage IB1 small cell cervical cancer have nodal metastases [3], [4], [5]. Stage for stage, the survival of women with small cell carcinoma of the cervix compares poorly against the survival of women with the more common cervical cancer subtypes.
Because of the rarity of small cell carcinoma of the cervix, no prospective trials have been performed to determine optimal therapy for women with the disease. These tumors do, however, have pathologic appearances and clinical behaviors similar to those of small cell lung cancer. Therefore, almost all patients with small cell cervical cancer receive cisplatin and etoposide as part of their primary therapy, according to guidelines developed by professional societies and largely extrapolated from treatment protocols for small cell lung cancer [6], [7]. In addition, because of the aggressiveness of small cell cervical cancer, most patients undergo multimodal therapy with consideration of surgery, radiation therapy, and/or chemotherapy. Fifty-eight percent of patients receive dual-modality treatment, and 9% receive all 3 treatment modalities [8]. Nevertheless, overall survival remains poor, despite multimodal treatment plans, with 5-year survival rates ranging from 13% to 25% for all patients and as low as 0% for women with advanced-stage disease (stages II–IV) [9].
Improving outcomes for women with small cell carcinoma of the cervix has proven difficult because of the rarity of this disease. For patients with recurrent disease, there are no standard treatment protocols, and both the Society of Gynecologic Oncology and Gynecologic Cancer InterGroup recommend individualized treatment because of the acknowledged lack of any clinical trials to guide therapy for these women [6], [7]. As outcomes are poor and therapeutic regimens are uncertain, we sought to determine whether there were common somatic mutations that might inform targeted therapy or potential clinical trials for women with recurrent small cell cancer of the cervix. Specifically, we reviewed the results in a cohort of 44 patients with small cell carcinoma of the cervix who had next generation sequencing at our institution to identify mutations in a panel of 50 genes that are commonly altered and/or targetable with existing drug inhibitors.
Section snippets
Methods
Data presented in this manuscript were abstracted from the Neuroendocrine Cervical Tumor Registry (NeCTuR) of The University of Texas MD Anderson Cancer Center. This Institutional Review Board–approved registry collects a wide range of data on women with small and large cell cervical cancers. Women who have been diagnosed with this disease or family members of deceased patients consent to participate in the registry and then provide their medical records for entry. Participants are recruited
Results
Forty-four patients with small cell cervical cancer had molecular testing for genomic alterations. Demographics for the entire cohort are shown in Table 2. The median age was 37.5 years (range, 24.7–63.6). Thirty-eight patients (84%) had pure small cell cervical cancer and 6 (14%) had mixed small and large cell cervical cancer. Twenty-six patients (59%) had clinical stage I disease.
Tumor for molecular evaluation was obtained from the cervix in 37 patients (84%), from a lymph node in 3 patients
Discussion
In this study of 44 patients with small cell cervical cancer, a rare disease, the most commonly mutated gene was PIK3CA, which was mutated in more than 18% of patients. Other mutations found in more than 10% of patients were KRAS (14% of patients) and TP53 (11%). Fifty-five percent of all patients in the series had at least 1 mutation, and many of these mutations were targetable by a drug in the emerging portfolio of novel targeted agents (Table 3).
The pattern of mutations in this series of
Conflict of interest statement
The authors have no conflicts of interest to disclose.
Acknowledgments
Supported by the NIH/NCI under award number P30CA016672.
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