David G. Mutch

Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup

PURPOSE To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. PATIENTS AND METHODS Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. RESULTS Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. CONCLUSION Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.

Randomized Phase III Trial of Gemcitabine Compared With Pegylated Liposomal Doxorubicin in Patients With Platinum-Resistant Ovarian Cancer

PURPOSE Ovarian cancer (OC) patients experiencing progressive disease (PD) within 6 months of platinum-based therapy in the primary setting are considered platinum resistant (Pt-R). Currently, pegylated liposomal doxorubicin (PLD) is a standard of care for treatment of recurrent Pt-R disease. On the basis of promising phase II results, gemcitabine was compared with PLD for efficacy and safety in taxane-pretreated Pt-R OC patients. PATIENTS AND METHODS Patients (n = 195) with Pt-R OC were randomly assigned to either gemcitabine 1,000 mg/m2 (days 1 and 8; every 21 days) or PLD 50 mg/m2 (day 1; every 28 days) until PD or undue toxicity. Optional cross-over therapy was allowed at PD or at withdrawal because of toxicity. Primary end point was progression-free survival (PFS). Additional end points included tumor response, time to treatment failure, survival, and quality of life. RESULTS In the gemcitabine and PLD groups, median PFS was 3.6 v 3.1 months; median overall survival was 12.7 v 13.5 months; overall response rate (ORR) was 6.1% v 8.3%; and in the subset of patients with measurable disease, ORR was 9.2% v 11.7%, respectively. None of the efficacy end points showed a statistically significant difference between treatment groups. The PLD group experienced significantly more hand-foot syndrome and mucositis; the gemcitabine group experienced significantly more constipation, nausea/vomiting, fatigue, and neutropenia but not febrile neutropenia. CONCLUSION Although this was not designed as an equivalency study, gemcitabine and PLD seem to have a comparable therapeutic index in this population of Pt-R taxane-pretreated OC patients. Single-agent gemcitabine may be an acceptable alternative to PLD for patients with Pt-R OC.

Epigenetic Repression of microRNA-129-2 Leads to Overexpression of SOX4 Oncogene in Endometrial Cancer

Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the SRY-related high mobility group box family, was found to be overexpressed (P < 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P < 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P < 0.001) and poor overall survival (P < 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells.

A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer

OBJECTIVE Ovarian cancer is one of the most deadly human cancers, resulting in over 15,000 deaths in the US each year. A reliable method that could predict disease outcome would improve care of patients with this disease. The main aim of this study is to identify novel prognostic biomarkers for advanced ovarian cancer. METHODS We hypothesized that microRNAs (miRNAs) may predict outcome and have examined the prognostic value of these small RNA molecules on disease outcome prediction. miRNAs are a newly identified family of non-coding RNA genes, and recent studies have shown that miRNAs are extensively involved in the tumor development process. We have profiled the expression of miRNAs in advanced ovarian cancer using a novel PCR-based platform and correlated miRNA expression profiles with disease outcome. RESULTS By performing miRNA expression profiling analysis of 55 advanced ovarian tumors, we have shown that three miR-200 miRNAs (miR-200a, miR-200b and miR-429) in the miR-200b-429 cluster are significantly associated with cancer recurrence and overall survival. Further target analysis indicates that these miR-200 miRNAs target multiple genes that are involved in cancer development. In addition, we have also shown that overexpression of this miR-200 cluster inhibits ovarian cancer cell migration. CONCLUSIONS miR-200b-429 may be used as a prognostic marker for ovarian cancer outcome, and low-level expression of miR-200 miRNAs in this cluster predicts poor survival. In addition, our study suggests that miR-200 miRNAs could play an important regulatory role in ovarian cancer.

Tumor Size, Irradiation Dose, and Long-Term Outcome of Carcinoma of Uterine Cervix

PURPOSE To assess the impact of tumor size and extent, and dose of irradiation on pelvic tumor control, incidence of distant metastases, and disease-free survival in carcinoma of the uterine cervix. METHODS AND MATERIALS Records were reviewed of 1499 patients (Stages IA-IVA) treated with definitive irradiation (combination of external beam plus two intracavitary insertions to deliver doses of 65-95 Gy to point A, depending on stage and tumor volume). Follow-up was obtained in 98% of patients (median 11 years, minimum 3 years, maximum 30 years). The relationship between outcome and tumor size was analyzed in each stage. Pelvic tumor control was correlated with total doses to point A and to the lateral pelvic wall. RESULTS The 10-year actuarial pelvic failure rate in Stage IB was 5% for tumors <2 cm, 15% for 2.1-5 cm, and 35% for tumors >5 cm (p = 0.01); in Stage IIA, the rates were 0%, 28%, and 25%, respectively (p = 0.12). Stage IIB unilateral or bilateral nonbulky tumors <5 cm had a 23% pelvic failure rate compared with 34% for unilateral or bilateral bulky tumors >5 cm (p = 0.13). In Stage IIB, pelvic failures were 18% with medial parametrial involvement only, compared with 28% when tumor extended into the lateral parametrium (p = 0.05). In Stage III, unilateral parametrial involvement was associated with a 32% pelvic failure rate versus 50% for bilateral extension (p < 0.01). Ten-year disease-free survival rates were 90% for IB tumors <2 cm, 76% for 2.1-4 cm, 61% for 4.1-5 cm, and 47% for >5 cm (p = 0.01); in Stage IIA, the rates were 93%, 63%, 39%, and 59%, respectively (p < or = 0.01). Patients with Stage IIB medial parametrial involvement had better 10-year disease-free survival (67%) than those with lateral parametrial extension (56%) (p = 0.02). Stage III patients with unilateral tumor extension had a 48% 10-year disease-free survival rate compared with 32% for bilateral parametrial involvement (p < or = 0.01). The presence of endometrial extension or tumor only in the endometrial curettings had no significant impact on pelvic failure. However, in patients with Stage IB disease, the incidence of distant metastases was 31% with positive curettings, 15% with negative curettings, and 22% with admixture (p < or = 0.01). In Stage IIA, the corresponding values were 51%, 33%, and 18% (p = 0.05). The 10-year disease-free survival rates in Stage IB were 67% with positive curettings, 81% for negative curettings, and 77% for admixture (p = 0.02); in Stage IIA, the rates were 45%, 66%, and 67%, respectively (p = 0.14). Because this is not a prospective Phase II dose-escalation study, the correlation of doses of irradiation with pelvic tumor control in the various stages and tumor size groups is not consistent. Nevertheless, with Stage IB and IIA tumors <2 cm in diameter, the pelvic failure rate was under 10% with doses of 70-80 Gy to point A, whereas for larger lesions even doses of 85-90 Gy resulted in 25% to 37% pelvic failure rates. In Stage IIB with doses of 70 Gy to point A, the pelvic failure rate was about 50% compared with about 20% in nonbulky and 30% in bulky tumors with doses > 80 Gy. In Stage III unilateral lesions, the pelvic failure rate was about 50% with < or =70 Gy to point A versus 35% with higher doses, and in bilateral or bulky tumors it was 60% with doses <70 Gy and 50% with higher doses. CONCLUSIONS Clinical stage and size of tumor are critical factors in prognosis, therapy efficacy, and evaluation of results in carcinoma of the uterine cervix. The doses to point A suggest that for lesions <2 cm, doses of 75 Gy result in < or =10% pelvic failures, whereas in more extensive lesions, even with doses of 85 Gy, the pelvic failure rate is about 30%; and in Stage IIB-III tumors, doses of 85 Gy result in 35-50% pelvic failures. Refinements in brachytherapy techniques and/or use of agents to selectively sensitize the tumors to irradiation will be necessary to improve the present results in invasive carcinoma of t

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.

ASCO/SSO Review of Current Role of Risk-Reducing Surgery in Common Hereditary Cancer Syndromes

Although the etiology of solid cancers is multifactorial, with environmental and genetic factors playing a variable role, a significant portion of the burden of cancer is accounted for by a heritable component. Increasingly, the heritable component of cancer predispositions has been linked to mutations in specific genes, and clinical interventions have been formulated for mutation carriers within affected families. The primary interventions for mutations carriers for highly penetrant syndromes such as multiple endocrine neoplasias, familial adenomatous polyposis, hereditary nonpolyposis colon cancer, and hereditary breast and ovarian cancer syndromes are primarily surgical. For that reason, the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO) have undertaken an educational effort within the oncology community. A joint ASCO/SSO Task Force was charged with presenting an educational symposium on the surgical management of hereditary cancer syndromes at the annual ASCO and SSO meetings, resulting in an educational position article on this topic. Both the content of the symposium and the article were developed as a consensus statement by the Task Force, with the intent of summarizing the current standard of care. This article is divided into four sections addressing breast, colorectal, ovarian and endometrial cancers, and multiple endocrine neoplasia. For each, a brief introduction on the genetics and natural history of the disease is provided, followed by a detailed description of modern surgical approaches, including a description of the clinical and genetic indications and timing of prophylactic surgery, and the efficacy of prophylactic surgery when known. Although a number of recent reviews have addressed the role of genetic testing for cancer susceptibility, including the richly illustrated Cancer Genetics and Cancer Predisposition Testing curriculum by the ASCO Cancer Genetics Working Group (available through http://www.asco.org), this article focuses on the issues surrounding the why, how, and when of surgical prophylaxis for inherited forms of cancer. This is a complex process, which requires a clear understanding of the natural history of the disease and variance of penetrance, a realistic appreciation of the potential benefit and risk of a risk-reducing procedure in a potentially otherwise healthy individual, the long-term sequelae of such surgical intervention, as well as the individual patient and familys perception of surgical risk and anticipated benefit.

Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study.

BACKGROUND Low-grade serous carcinoma of the ovary is chemoresistant but mutations in the MAPK pathway could be targeted to control tumour growth. We therefore assessed the safety and activity of selumetinib, an inhibitor of MEK1/2, for patients with this cancer. METHODS In this open-label, single-arm phase 2 study, women (aged ≥18 years) with recurrent low-grade serous ovarian or peritoneal carcinoma were given selumetinib (50 mg twice daily, orally) until progression. The primary endpoint was the proportion of patients who had an objective tumour response according to RECIST version 1.1, assessed for all the treated patients. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00551070. FINDINGS 52 patients were enrolled between Dec 17, 2007, and Nov 23, 2009. All were eligible for analyses. Eight (15%) patients had an objective response to treatment-one patient had a complete response and seven had partial responses. 34 (65%) patients had stable disease. There were no treatment-related deaths. Grade 4 toxicities were cardiac (one), pain (one), and pulmonary events (one). Grade 3 toxicities that occurred in more than one patient were gastrointestinal (13), dermatological (nine), metabolic (seven), fatigue (six), anaemia (four), pain (four), constitutional (three), and cardiac events (two). INTERPRETATION Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma of the ovary or peritoneum. The findings suggest that inhibitors of the MAPK pathway warrant further investigation in these patients. FUNDING National Cancer Institute.

Lymph Node Staging by Positron Emission Tomography in Cervical Cancer: Relationship to Prognosis

PURPOSE A previous retrospective study demonstrated that positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) was more sensitive than computed tomography for lymph node staging in patients with cervical cancer; the findings on FDG-PET were strongly associated with progression-free survival. Therefore, a prospective cohort study was initiated to evaluate FDG-PET lymph node staging in a larger patient population. PATIENTS AND METHODS The study was conducted between July 2000 and March 2009. All 560 patients with cervical cancer underwent pretreatment FDG-PET lymph node staging. Treatment included surgery alone, surgery and postoperative radiation therapy, and definitive radiation or combination radiation and chemotherapy. PET findings were correlated with the risk of disease progression and with survival. Results Overall, 47% of patients had lymph node involvement by FDG-PET at diagnosis. The frequency of lymph node metastasis increased with clinical stage and was similar to that in historical surgical series. Within a stage, patients with PET-positive lymph nodes had significantly worse disease-specific survival than those with PET-negative lymph nodes (P < .001). Disease-specific survival was stratified into distinct groups based on the most distant level of PET-detected nodal disease (none, pelvic, para-aortic, or supraclavicular; P < .001). The hazard ratios for disease recurrence increased incrementally based on the most distant level of nodal disease: pelvic 2.40 (95% CI, 1.63 to 3.52), para-aortic 5.88 (95% CI, 3.80 to 9.09), and supraclavicular 30.27 (95% CI 16.56 to 55.34). CONCLUSION Nodal involvement detected by FDG-PET in cervical cancer relates to clinical stage, is comparable to historical data, and stratifies patient recurrence and survival outcomes.

Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial

PURPOSE Sorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS This open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment. Results Seventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS. CONCLUSION Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.