Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer.

BACKGROUND: Nelfinavir (NFV), an HIV-1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer. METHODS: Two dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse-phase-protein-array analyses. RESULTS: NFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose-limiting toxicity, whereas no dose-limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow-up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT. CONCLUSIONS: NFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.

Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors.

OBJECTIVES: Cancer-testis (CT) antigens have been proposed as potential targets for cancer immunotherapy. Our objective was to evaluate the expression of a panel of CT antigens in epithelial ovarian cancer (EOC) tumor specimens, and to determine if antigen sharing occurs between tumors. METHODS: RNA was isolated from EOC tumor specimens, EOC cell lines and benign ovarian tissue specimens. Real time-PCR analysis was performed to determine the expression level of 20 CT antigens. RESULTS: A total of 62 EOC specimens, 8 ovarian cancer cell lines and 3 benign ovarian tissues were evaluated for CT antigen expression. The majority of the specimens were: high grade (62%), serous (68%) and advanced stage (74%). 58 (95%) of the EOC tumors analyzed expressed at least one of the CT antigens evaluated. The mean number of CT antigen expressed was 4.5 (0-17). The most frequently expressed CT antigen was MAGE A4 (65%). Antigen sharing analysis showed the following: 9 tumors shared only one antigen with 62% of the evaluated specimens, while 37 tumors shared 4 or more antigens with 82%. 5 tumors expressed over 10 CT antigens, which were shared with 90% of the tumor panel. CONCLUSION: CT antigens are expressed in 95% of EOC tumor specimens. However, not a single antigen was universally expressed across all samples. The degree of antigen sharing between tumors increased with the total number of antigens expressed. These data suggest a multi-epitope approach for development of immunotherapy for ovarian cancer treatment.

Does time interval between surgery and intraperitoneal chemotherapy administration in advanced ovarian cancer carry a prognostic impact? An NRG Oncology/Gynecologic Oncology Group study ancillary study.

OBJECTIVES: To determine the relationship of the time from surgery to intraperitoneal (IP) chemotherapy (TSIC) initiation with survival of patients with stage III epithelial ovarian cancer (EOC) patients using ancillary data from cooperative group clinical trials. METHODS: Data from 420 patients with stage III EOC treated with IP chemotherapy under GOG-0114 and 172 were reviewed. The Cox proportional hazards model was used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on PFS and OS. RESULTS: The median TSIC was 62.5days (interquartile range 28-83). The median TSIC was longer for patients in GOG-0114 vs those in GOG-172 (83 vs 26days, p<0.001). TSIC was significantly associated (p=0.049) with PFS: each 10% increase in TSIC (days) decreases the risk of progression by 3%. TSIC was not significantly associated with OS in this model. In a linear regression model, gross residual disease was significantly associated with shorter TSIC (R2 -0.141, 95%CI -0.217, -0.064, p<0.001). When only data from GOG-172 were considered, no statistical significant association was found between TSIC and PFS or OS. CONCLUSIONS: In this ancillary data study, TSIC was not associated with improved OS in patients with stage III epithelial ovarian cancer. TSIC was significantly associated with PFS for the entire cohort, suggesting increase in PFS with longer TSIC. However, this was not found when only data from GOG 172 or GOG 114 were analyzed separately. Hence, the relationship between IP chemotherapy initiation and time from surgery needs to be studied further.

Incidental power morcellation of malignancy: a retrospective cohort study.

OBJECTIVE: Uterine fibroids often require hysterectomy via a laparotomy or utilizing minimally invasive surgical (MIS) approach. Morcellation is a fragmentation of the uterus into smaller pieces. The objective of this study is to determine the incidence of malignancies found in morcellated specimens at our institution. METHODS: Women who had a minimally invasive hysterectomy, for presumptive benign uterine conditions were identified, included and reviewed. Patients were divided into two groups being either benign disease or malignancies. The continuous variables uterine weight and patient age were tested for normalcy with the Shapiro-Wilk test. The exposure of subspecialist vs general gynecology was interrogated via a Chi-Squared analysis. RESULTS: 10 cases of malignancies were identified including endometrioid endometrial carcinomas (3), uterine serous carcinoma (1), endometrial stromal sarcomas (ESS) (3), and leiomyosarcomas (LMS) (3). An overall risk of occult cancer on a morcellated specimen was .73%; leiomyosarcoma was 0.22%, endometrial stromal sarcoma 0.22%, and endometrial cancer 0.29%. The median uterine weight for the 10 morcellated malignancies was 293.5g whereas the median weight for the benign uteri was only 117.5g giving a theta of -106 (95% CI -261,20). There was no difference in patient age or surgeon type between the groups (See Table 1). CONCLUSIONS: Morcellation was associated with substantially higher risk of abdominopelvic recurrence and lower disease-free survival. Morcellated uterine malignancies were significantly heavier than benign uteri. Further research on uterine morcellation should focus on decision and cost-benefit analyses to determine the ideal candidate in whom uterine morcellation during minimally invasive hysterectomy would facilitate more good than harm.

Is comprehensive surgical staging needed for thorough evaluation of early-stage ovarian carcinoma?

OBJECTIVE: Patients with ovarian cancer may have occult metastasis at the time of surgery. Our purpose was to determine the prevalence and sites of occult metastasis in epithelial ovarian cancer grossly confined to the ovary and examine the significance of routine omentectomy and peritoneal biopsies as part of a comprehensive staging procedure. STUDY DESIGN: Data were retrospectively abstracted from patients presenting to University of Texas Southwestern Medical Center Hospitals from 1993 through 2009 with ovarian cancer without gross spread beyond the ovary who underwent comprehensive surgical staging. RESULTS: A total of 86 patients with ovarian cancer grossly confined to the ovary who underwent complete surgical staging were identified. Of patients, 29% were upstaged following comprehensive surgical staging; 6% had metastatic disease in uterus and/or fallopian tubes, 6% in lymph nodes, and 17% in peritoneal, omental, or adhesion biopsies. CONCLUSION: Patients with epithelial ovarian cancer should continue to undergo comprehensive surgical staging, since it identifies occult metastasis in a significant number of patients.

Primary Peritoneal Carcinoma in a BRCA1/2-negative, PALB2-positive patient.

•First reported case of PPC after BSO in a BRCA1/2-negative, PALB2-positive patient•The PALB2 mutation and genetic counseling is discussed•Multi-gene panel testing can benefit prognostic factors and targeted therapy.

New insights on the role of hormonal therapy in ovarian cancer.

Ovarian cancer (OVCA) is the most lethal gynecological malignancy. It is often diagnosed in advanced stages and despite therapy, 70% relapse within 2years with incurable disease. Regimens with clinical benefit and minimal toxicity are urgently needed. More effective hormonal therapies would be appealing in this setting. Estrogens (E2) are implicated in the etiology of OVCA. Estrogens drive proliferation and anti-estrogens inhibit ovarian cancer growth in vitro and in vivo. Despite estrogen receptor (ER) expression in 67% of OVCAs, small anti-estrogen therapy trials have been disappointing and the benefit of hormonal therapy has not been systematically studied in large well-designed trials. OVCAs often manifest de novo anti-estrogen resistance and those that initially respond invariably develop resistance. Estrogens stimulate ovarian cancer progression by transcriptional activation and cross talk between liganded ER and mitogenic pathways, both of which drive cell cycle progression. Estrogen deprivation and estrogen receptor (ER) blockade cause cell cycle arrest in susceptible OVCAs by increasing the cell cycle inhibitor, p27. This review summarizes and discusses scientific and epidemiological evidence supporting estrogen's role in ovarian carcinogenesis, provides an overview of clinical trials of ER blockade and aromatase inhibitors in OVCA and reviews potential causes of antiestrogen resistance. Anti-estrogen resistance was recently shown to be reversed by dual ER and Src signaling blockade. Blocking cross-talk between ER and constitutively activated kinase pathways may improve anti-estrogen therapeutic efficacy in OVCA, as has been demonstrated in other cancers. Novel strategies to improve benefit from anti-estrogens by combining them with targeted therapies are reviewed.

Secreted heat shock protein gp96-Ig: next-generation vaccines for cancer and infectious diseases.

Over the past decade, our laboratory has developed a secreted heat shock protein (HSP), chaperone gp96, cell-based vaccine that generates effective anti-tumor and anti-infectious immunity in vivo. Gp96-peptide complexes were identified as an extremely efficient stimulator of MHC I-mediated antigen cross-presentation, generating CD8 cytotoxic T-lymphocyte responses detectable in blood, spleen, gut and reproductive tract to femto-molar concentrations of antigen. These studies provided the first evidence that cell-based gp96-Ig-secreting vaccines may serve as a potent modality to induce both systemic and mucosal immunity. This approach takes advantage of the combined adjuvant and antigen delivery capacity of gp96 for the generation of cytotoxic immunity against a wide range of antigens in both anti-vial and anti-cancer vaccination. Here, we review the vaccine design that utilizes the unique property/ability of endoplasmic HSP gp96 to bind antigenic peptides and deliver them to antigen-presenting cells.