Christopher J. Darus

The Use of p16 in enhancing the histologic classification of uterine smooth muscle tumors.

Background Uterine smooth muscle tumors can usually be divided histologically into leiomyoma (L) and leiomyosarcoma (LMS). Occasionally, the histologic features are indeterminate and classified as smooth muscle tumor of uncertain malignant potential (STUMP). Recent gene expression studies have found p16 overexpressed in LMS when compared with normal myometrium. This study evaluated the protein expression of p16 by immunohistochemistry in LMS, L, and normal myometrium. Additionally, 8 tumors originally classified as STUMP were evaluated for p16 expression and correlated to their clinical outcome. Methods A tissue microarray was constructed and composed of 15 LMS, 8 STUMPs, 22 L, and 10 samples of normal myometrium. p16 expression was correlated with clinical outcome and histologic features. Results Twelve of the 15 LMS strongly and diffusely expressed p16, 3 of the L had focal p16 staining, and none of the normal myometria were p16 positive. Three of the tumors originally classified as STUMP developed metastatic disease and 2 of these tumors had strong, diffuse p16 positivity. Histologically, these 2 cases were characterized by coagulative tumor cell necrosis and only mild cytologic atypia. Conclusions p16 is preferentially expressed in LMS with only rare L showing positivity. Histologically, tumors with coagulative tumor cell necrosis alone were clinically LMS. In those cases in which the type of necrosis is uncertain (coagulative tumor cell vs. hyalinized), the addition of p16 may aid in discerning a subset of STUMP that should be classified as LMS.

Growth Hormone Promotes the Association of Transcription Factor STAT5 with the Growth Hormone Receptor

Members of the cytokine/growth hormone (GH)/prolactin receptor superfamily transduce signals by association and activation of JAK tyrosine kinases. For GH receptor (GHR), both JAK2 and the GHR undergo tyrosine phosphorylation upon GH stimulation. Also, GH has recently been shown to activate the transcription factor STAT5 by tyrosine phosphorylation. In the present study, we demonstrate that GH induces rapid tyrosine phosphorylation of different isoforms of STAT5 in mouse L cells stably transfected with a cDNA encoding porcine GHR (pGHR). In this cell system, STAT5 directly interacts with the GHR in a GH-dependent manner. Additionally, GH-induced tyrosine phosphorylation of STAT5 and the interaction of STAT5 with GHR can be observed in mouse 3T3-F442A cells which express endogenous mouse GHR. Interestingly, when cDNAs encoding the two mouse STAT5 homologs (STAT5A and STAT5B) were individually transfected into mouse L cells expressing pGHR, only STAT5A demonstrated the ability to interact with the pGHR and subsequently underwent GH-dependent tyrosine phosphorylation. STAT5B did not. Therefore, the GH-dependent interaction of a particular STAT5 with tyrosine-phosphorylated GHR may play an important role in GH-mediated signal transduction.

Cyclooxygenase-2 in cervical neoplasia: A review

OBJECTIVE Previous data demonstrate an association between cyclooxygenase activity and development of cervical cancer. This review investigates the role of cyclooxygenase-2 (COX-2) in the development of cervical cancer and potential therapeutic options targeting this pathway. METHODS A literature search was conducted using MEDLINE 1997-2007 utilizing the terms inflammation, cervical cancer, cyclooxygenase, COX-2, indomethacin, cervical intraepithelial neoplasia, and squamous cell cancer. Articles were included based on the quality of the study and pertinence to the topic. Other sources were culled from the references of the articles identified. RESULTS Over 150 abstracts were reviewed for inclusion. Studies in vivo and in vitro confirm the role of COX-2 in the development of cervical cancer. In addition, COX-2 overexpression is associated with an increase in angiogenesis markers. Clinical correlation found that COX-2 overexpression in cervical cancer patients is a poor prognostic marker associated with increased risk for recurrent or metastatic disease. Despite early promise, two phase II trials in use of specific COX-2 inhibitors as radio-sensitizers in locally advanced cervical cancer demonstrated increased toxicity with no change in therapeutic effect. Results of studies using COX-2 inhibitors in pre-invasive cervical disease are encouraging. CONCLUSIONS Treatment of cervical intraepithelial neoplasia with cyclooxygenase inhibitors may provide a medical alternative to surgical therapy.

Phase II Evaluation of Dalantercept, a Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK1) Receptor Fusion Protein, for the Treatment of Recurrent or Persistent Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study 0229N

OBJECTIVE This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). METHODS Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. RESULTS All 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively. CONCLUSIONS Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.

A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer

PURPOSE Cediranib is a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This phase II study was conducted to assess activity and tolerability of single-agent cediranib in recurrent/persistent endometrial cancer. PATIENTS AND METHODS Eligible patients had recurrent or persistent endometrial cancer after receiving one or two prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group (GOG) performance status of ≤2 (≤1 if two prior cytotoxic regimens given). Cediranib 30mg orally daily for a 28daycycle was administered until disease progression or prohibitive toxicity. Microvessel density (MVD) was measured in tumor tissue from initial hysterectomy specimens and correlated with clinical outcome. Primary endpoints were tumor response and surviving progression-free for six months without subsequent therapy (6-month event-free survival [EFS]). RESULTS Of 53 patients enrolled, 48 were evaluable for cediranib efficacy and toxicity. Median age was 65.5 years, 52% of patients had received prior radiation, and 73% of patients received only one prior chemotherapy regimen. A partial response was observed in 12.5%. Fourteen patients (29%) had six-month EFS. Median progression-free survival (PFS) was 3.65 months and median overall survival (OS) 12.5 months. No grade 4 or 5 toxicities were observed. A trend towards improved PFS was found in patients whose tumors expressed high MVD. CONCLUSION Cediranib as a monotherapy treatment for recurrent or persistent endometrial cancer is well tolerated and met protocol set objectives for sufficient activity to warrant further investigation. MVD may be a useful biomarker for activity.

Randomized Phase II Evaluation of Bevacizumab Versus Bevacizumab Plus Fosbretabulin in Recurrent Ovarian, Tubal, or Peritoneal Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study

PURPOSE The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. PATIENTS AND METHODS Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. RESULTS The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. CONCLUSION On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension.

A phase II trial of trebananib (AMG 386; IND#111071), a selective angiopoietin 1/2 neutralizing peptibody, in patients with persistent/recurrent carcinoma of the endometrium: An NRG/Gynecologic Oncology Group trial

OBJECTIVES Ang1 & 2 (angiopoietin-1; -2) interact with Tie2 receptors on endothelial cells to mediate vascular remodeling in an angiogenesis signaling pathway distinct from the VEGF axis. Trebananib is a peptide Fc fusion protein that binds Ang1 and 2 and prevents interaction with Tie2. The efficacy of trebananib in recurrent/persistent endometrial cancer (EC) was studied. METHODS The primary objective was to determine the frequency of patients with objective tumor responses (ORR) and event-free survival for ≥6months (6-month EFS) and determine toxicity of trebananib at a dose and schedule of 15mg/kg, IV QW. Recurrent/persistent EC, measurable disease, and ≤2 prior chemotherapy lines were required. RESULTS Thirty-two patients were eligible and treated. The most common histologies were G1/2 endometrioid (31%), G3 endometrioid (28%) and serous (31.3%). 78% of patients had 1 prior regimen. Patients received 1-9+ cycles of trebananib; 24 patients (75%) received ≤2cycles. One patient had a partial response (3.1%); 8 patients had stable disease (25%) and 5 patients (15.6%) had 6 month EFS. Median progression-free survival and overall-survival were 1.97 months (90% CI 1.77-2.1) and 6.6 months (90% CI 4.01-14.75), respectively. Most common adverse events (AEs) were fatigue, anemia, and GI issues. Grade 3 and 4 AEs were: GI 31 and 0%; vascular 22 and 0%; metabolism/nutrition 19 and 3%; and general (including edema) 16 and 0%. CONCLUSIONS Trebananib has insufficient single agent activity in recurrent EC to warrant further investigation at this dose/schedule.

Development and impact of human papillomavirus vaccines.

Cervical cancer is a global health crisis that disproportionately affects developing nations and underserved populations. Two vaccines targeting HPV-16 and 18, which account for 70% of invasive cervical carcinomas, are licensed in the United States and numerous countries worldwide. Both vaccine formulations have shown excellent efficacy with minimal toxicity. Numerous questions remain, including cost-effectiveness, vaccination of males, societal acceptance of HPV vaccination, and cervical dysplasia screening in the HPV-immunized population. Access to vaccination for underserved populations both in developed and resource-poor nations remains an issue. Multivalent vaccines that encompass additional oncogenic HPV strains are under development.

Association of Primary Breast Cancer of the Vulva With Hereditary Breast and Ovarian Cancer

Case Report A 59-year-old woman of French-Canadian ancestry, with a family history of breast cancer and a documented BRCA2 mutation in a first-degree relative, sought care for a 5-month history of a 1-cm, raised, and erythematous mass lateral to the left labium majus. Excisional biopsy results revealed infiltrating mammary adenocarcinoma with mucinous differentiation (Fig 1A). The tumor cells were positive for cytokeratin 7 (CK7), mammoglobin (Fig 1B), estrogen receptor (90%; Fig 1C), and progesterone receptor (30%), and were negative for CK20, Wilms tumor 1, gross cystic disease fluid protein 15, and human epidermal growth factor receptor 2 (HER2)/neu (1 ). The tumor infiltrated through the epithelium, and specimen biopsy margins were focally positive. She had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy at age 51 years because of abnormal vaginal bleeding. Pathology was nondiagnostic. She was without a history of breast problems and had regular mammograms in the past. On referral to gynecologic oncology, a minimal scar without underlying mass was noted at the biopsy site. Otherwise, physical examination, including examination of the breasts and the remainder of the external genitalia, anus, and inguinal regions was negative for clinical evidence of malignancy.Breastmagneticresonanceimaging,bodycomputedtomography, and bone scan were nondiagnostic. She underwent a radical local vulvar excision of the scar with left inguinofemoral lymphadenectomy. There was no residual tumor noted in the vulva, and left groin lymph nodes were negative. Following an uneventful postoperative course, she was started on tamoxifen, 20 mg daily. Her family history was significant for breast cancer in her sister at age 59 years, and her mother’s history of bilateral breast cancer at ages 39 and 49 years (Fig 2). A close relative had previously undergone comprehensive BRCA analysis. This result returned with a BRCA2 mutation (8765delAG) that is a founder mutation in breast and ovarian cancer families of French-Canadian descent. Following her final surgery, the patient underwent single-site testing for this BRCA2 mutation and was found to be positive.

A cost comparison of two strategies for treating stage IB2 cervical cancer

Patients with stage IB2 cervical cancer at our institution are treated primarily with definitive chemoradiation, or chemoradiation followed by adjuvant hysterectomy. We sought to compare the cost differences associated with these two strategies. We identified all patients with stage IB2 cervical cancer who received their entire treatment regimen at our institution between 1995 and 2004. All patients received a combination of chemotherapy, external beam radiation, and one brachytherapy procedure, followed by either a second brachytherapy procedure or a simple hysterectomy. We retrieved cost data associated with hospitalization for the completion of respective treatment, including pharmacy, laboratory and pathology, radiation, and operating room services, as well as the costs of supplies and room and board. We identified 46 patients with stage IB2 cervical cancer, 23 who received a second brachytherapy procedure and 23 who underwent simple hysterectomy. Patients displayed similar demographics and similar disease characteristics including initial tumor diameter and histology. The cost of care for adjuvant hysterectomy group was greater (