TP53 mutants and non-HPV16/18 genotypes are poor prognostic factors for concurrent chemoradiotherapy in locally advanced cervical cancer.

Targeted sequencing for somatic mutations across the hotspots of 50 cancer-related genes was performed using biopsy specimens to investigate whether clinicopathological factors and genomic alterations correlated with prognosis in locally advanced cervical cancer. Seventy patients diagnosed with International Federation of Obstetrics and Gynecology (FIGO) stage III to IVA cervical cancer underwent radiotherapy or concurrent chemoradiotherapy at the National Cancer Center Hospital between January 2008 and December 2017. Mutations were detected in 47 of 70 [67% of cases; frequency of genetic alterations was as follows: PIK3CA (51%), FBXW7 (10%), PTEN (7.1%), and TP53 (5.7%)]. The Cancer Genome Atlas (TCGA) datasets showed a similar distribution of somatic mutations, but PIK3CA mutation frequency was significantly higher in our cohort than in TCGA datasets (P = 0.028). Patients with TP53 mutation were significantly related to poor progression-free survival (PFS) (hazard ratio [HR] = 3.53, P = 0.042). Patients with tumor diameters > 70 mm were associated with poor prognosis (HR = 2.96, P = 0.0048). Patients with non-HPV16/18 genotypes had worse prognosis than those with HPV16/18 genotypes (HR = 2.15, P = 0.030). Hence, patients with locally advanced cervical cancer, TP53 mutation, large tumor diameter, and non-HPV16/18 genotype were independently correlated with poor PFS, despite concurrent chemoradiotherapy.

Distribution of genetic alterations in high-risk early-stage cervical cancer patients treated with postoperative radiation therapy.

Somatic genetic alteration analysis was performed for post-hysterectomy high-risk early-stage uterine cervical cancer patients who underwent post-operative radiation therapy. Post-operative radiation therapy was performed for patients with pathological features of pelvic lymph node metastasis, parametrium invasion, or positive vaginal margin, which corresponded to the post-operative high-risk category. DNA was extracted from paraffin-embedded surgical specimens, and 50 somatic hotspot genetic alternations were detected using Ion AmpliSeq Cancer Hotspot Panel. The existence of actionable mutation was assessed based on OncoKB evidence level > 3A. Between January 2008 and November 2019, 89 patients who underwent abdominal radical hysterectomy followed by post-operative radiation therapy were identified. The follow-up period for living patients was 82.3 months (range 9.3-153.9), and the 5-year relapse-free survival and overall survival rates were 72.6% and 85.9%, respectively. The most frequently detected somatic mutation was PIK3CA (26 [29.2%] patients); however, no prognostic somatic genetic alterations were identified. Actionable mutations were detected in 30 (33.7%) patients. Actionable mutations were detected in approximately one-third of patients, suggesting that precision medicine can be offered to patients with post-operative high-risk uterine cervical cancer in the near future.

Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix.

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.

Analysis of risk factors for patients with early-stage cervical cancer: A study of 374 patients.

AIM: This study aimed to identify the postoperative histological features affecting the prognosis of patients with early-stage cervical cancer who underwent open radical hysterectomy. METHODS: This retrospective study enrolled 374 patients with pT1a, 1b1 and 2a1 early-stage cervical cancer who underwent open radical hysterectomy between 2001 and 2018. Survival outcomes were analyzed by Kaplan-Meier method and compared with log-rank test. Using the Cox proportional hazards regression test, we conducted a multivariate analysis for disease-free survival and overall survival. RESULTS: Others histology, including other epithelial tumors and neuroendocrine tumors, had a significantly worse prognosis in both disease-free survival and overall survival than those of squamous cell carcinoma and adenocarcinoma (hazard ratio, 4.37 and 11.76; P = 0.006 and P = 0.002, respectively), along with lymph node metastasis (hazard ratio, 2.99 and 7.03; P = 0.009 and P = 0.001, respectively). CONCLUSION: Others histology including adenosquamous carcinoma had a poor prognosis in early-stage cervical cancer as with high-risk factors.

Genomic alterations in STK11 can predict clinical outcomes in cervical cancer patients.

OBJECTIVE: Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.

Retrospective analysis of sites of recurrence in stage I epithelial ovarian cancer.

OBJECTIVE: The aim of the study is to investigate recurrence of stage I epithelial ovarian cancer. METHODS: Six hundred two patients diagnosed with stage I epithelial ovarian cancer at 4 hospitals between 2000 and 2013 were retrospectively analyzed. Age, surgical procedure, substage, histologic type, adjuvant chemotherapy, recurrence, initial recurrence site (peritoneal dissemination [P], hematogenous recurrence [H], lymphogenous recurrence [L], and others [O]), and frequency of recurrence at each site were investigated retrospectively. RESULTS: Median age was 54 years and median follow-up was 60 months. The stage was IA in 180 cases (30%), IB in 8 (1%), IC1 in 247 (41%), IC2 in 63 (10%), and IC3 in 104 (17%). Systematic lymph node dissection including both pelvic and para-aortic lymph nodes was performed in 224 patients (37%), and 412 patients (68%) received adjuvant chemotherapy. Recurrence occurred in 70 patients (11.6%). The median time to recurrence was 18 months, and the stage was IA in 13 (19%), IB in 1 (1%), IC1 in 24 (34%), IC2 in 9 (13%), and IC3 in 23 (33%) cases. The numbers of recurrence at the P, H, L, and O sites, including overlapping cases, were 49 (70%), 18 (26%), 9 (13%), and 6 (9%), respectively, and recurrence by peritoneal dissemination in the pelvis occurred in 43 cases (61%). CONCLUSION: Recurrence of stage I epithelial ovarian cancer by peritoneal dissemination was frequent, especially in the pelvis. There is a need to elucidate the pathogenesis of peritoneal recurrence and to prepare a treatment strategy to prevent pelvic peritoneal recurrence.

Gene aberration profile of tumors of adolescent and young adult females.

There has been little improvement in the prognosis for adolescent and young adult (AYA) tumor patients. Hence, there is an urgent need to understand the etiology of tumor development and identify actionable gene aberrations to improve prevention and therapy. Here, 76 sporadic tumors (48 breast, 22 ovarian, and six uterine) from 76 AYA females (age range, 25-39 years) were subjected to whole exome and RNA sequencing to determine their mutational signatures and actionable gene profiles. Two individuals with breast cancer (4.2% of cases) and one with ovarian cancer (5.3% of cases) carried germline BRCA2 mutations. The two cases with breast tumors also each carried an additional deleterious germline mutation: one in TP53 and the other in CHEK2. Mutational signature analysis of the 76 tumors indicated that spontaneous deamination of 5-methylcytosine and activity of the APOBEC cytidine deaminase protein family are major causes of mutagenesis. In addition, 18 breast or ovarian tumors (18/70, 26%), including the three cases with germline BRCA2 mutations, exhibited a predominant "BRCAness" mutational signature, an indicator of functional BRCA1/BRCA2 deficiency. Actionable aberrations and high tumor mutation burdens were detected in 24 breast (50%), 17 ovarian (77%), and five uterine (83%) tumor cases. Thus, mutational processes and aberrant genes in AYA tumors are largely shared with those identified in non-AYA tumors. The efficacy of molecular targeting and immune checkpoint inhibitory therapies should be explored for both AYA and non-AYA patients.

[A Case of Abdominal Wall Hernia Rupture during Bevacizumab Treatment].

A 78 -year-old man with rectal cancer underwent abdominoperineal resection of the rectum. In the postoperative period, the patient experienced wound infection, leading to an abdominal wall hernia. Two years following surgery, a rise in the serum CEA level was seen. A metastatic tumor was detected in the right lung on chest CT. VATS right lung inferior lobe segmental resection was performed. After lobectomy, the serum CEA level continued to increase. Another metastatic tumor was detected in the right lung on chest CT. Chemotherapy with capecitabine, oxaliplatin, and bevacizumab was commenced. The erosive part of the abdominal wall scar hernia extended during the nine weeks of chemotherapy. The chemotherapy was then discontinued. In the follow-up CT scan, a right pleural recurrence, local recurrence in the pelvis, and a liver metastasis were detected. Chemotherapy was re-introduced 3 years after surgery. The erosive part of the abdominal wall hernia again began to spread with chemotherapy recommencement. Four months after restarting chemotherapy, the hernia ruptured, with a loop of the small intestine protruding out of it. The patient covered this with a sheet of vinyl and was taken by the ambulance to our hospital. The erosive part of the abdominal wall hernia had split by 10 cm, and a loop of the small intestine was protruding. As ischemia of the small intestine was not observed, we replaced it into the abdominal cavity, and performed a temporary suture repair of the hernia sac. Following this, bevacizumab was discontinued, and the erosive part reduced. We performed a radical operation for abdominal wall scar hernia repair 11 weeks after the discontinuation of bevacizumab.