Rachel N. Grisham

BRAF mutation is associated with early stage disease and improved outcome in patients with low-grade serous ovarian cancer.

Low‐grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer.

Improved survival for BRCA2‐associated serous ovarian cancer compared with both BRCA‐negative and BRCA1‐associated serous ovarian cancer

Multiple observational studies have suggested that breast cancer gene (BRCA)‐associated ovarian cancers have improved survival compared with BRCA‐negative ovarian cancers. However, most of those studies combined BRCA1 and BRCA2 patients or evaluated only BRCA1 patients. The objective of the current study was to examine whether BRCA1‐associated and BRCA2‐associated ovarian cancers were associated with different outcomes.

Extreme Outlier Analysis Identifies Occult Mitogen-Activated Protein Kinase Pathway Mutations in Patients With Low-Grade Serous Ovarian Cancer

PURPOSE No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor. PATIENTS AND METHODS Next-generation sequencing was used to analyze this patients tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed. RESULTS Analysis of the extraordinary responders tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy. CONCLUSION Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease.

Placental site trophoblastic tumor: Analysis of presentation, treatment, and outcome

OBJECTIVE Placental-site trophoblastic tumor (PSTT) is the rarest form of gestational trophoblastic disease (GTD). A risk-adapted treatment approach has been advocated, but controversy exists as to the most important prognostic markers for this disease. Our goal was to determine the prognostic markers for patients with PSTT seen at our center. METHODS We conducted a retrospective analysis of patients with PSTT seen at a single tertiary care center between 1996 and 2011. The association of FIGO stage, interval from antecedent pregnancy, antecedent pregnancy outcome, human chorionic gonadotropin (hCG) level, and age to overall survival was examined using univariate log-rank tests. Presentation, treatment, and outcome were summarized using descriptive statistics. RESULTS Data from 17 patients were analyzed. Eight (47%) had Stage I/II disease and 9 (53%) had Stage III/IV disease. Median overall survival for the entire cohort was 86 months (range, 2-101 months). Median duration of follow-up for surviving patients was 56 months. Increasing FIGO stage (I-III versus IV) was associated with a worse overall survival (p=0.009). Interval from antecedent pregnancy (≥12months), antecedent pregnancy outcome (full-term), hCG (≥1000 IU/L), and age (≥40) were not associated with worse survival. CONCLUSION FIGO stage, specifically Stage IV disease, was the most important predictor of overall survival in our cohort of PSTT patients.

Bevacizumab shows activity in patients with low-grade serous ovarian and primary peritoneal cancer.

Objective Low-grade serous (LGS) ovarian and primary peritoneal cancer is a rare disease with limited therapeutic options. Low response rates are observed with cytotoxic chemotherapy. However, significant responses have been reported in patients treated with bevacizumab. The objective of this study was to determine the response rate to bevacizumab with or without concurrent chemotherapy in patients with recurrent serous borderline or LGS ovarian or primary peritoneal cancer. Methods This single-institution retrospective study examined the response rate to treatment with bevacizumab in patients with serous borderline or LGS cancer. Patients were treated at the Memorial Sloan Kettering Cancer Center between 2005 and 2012. The best overall response was determined with the use of the Response Evaluation Criteria in Solid Tumors. Results A total of 17 patients were identified, 15 of whom were evaluable for the primary end point of best overall response. Two patients were treated with bevacizumab as a single agent, and the remainder received bevacizumab in conjunction with chemotherapy (paclitaxel, topotecan, oral cyclophosphamide, gemcitabine, or gemcitabine and carboplatin). The median duration of bevacizumab administration in evaluable patients was 23 weeks (mean, 32.2 weeks; range, 6–79.4 weeks). There were no complete responses. Partial responses were observed in 6 patients (5 patients received concurrent paclitaxel, and 1 patient received concurrent gemcitabine). The overall response rate was 40%, with a response rate of 55% among the subgroup of patients with LGS cancer. Conclusions These results indicate that bevacizumab in combination with chemotherapy is an active treatment for recurrent LGS ovarian cancer. A prospective trial of bevacizumab in combination with paclitaxel for the treatment of LGS ovarian cancer should be considered.

Abagovomab: an anti-idiotypic CA-125 targeted immunotherapeutic agent for ovarian cancer

Ovarian cancer remains the leading cause of death due to gynecologic malignancies. Most patients present with advanced disease at the time of diagnosis. Although many have a good initial response to surgical debulking and platinum-based chemotherapy, relapse is common, with the eventual development of chemotherapy resistance. Innovative treatments are needed in the remission setting to prolong the disease-free interval or prevent recurrence. Abagovomab is a murine monoclonal anti-idiotypic antibody (molecular weight: 165-175 kDa) that functionally imitates the tumor-associated antigen, CA-125. It has been shown to be well tolerated and to induce a sustained immune response in initial Phase I and II clinical trials. An ongoing, double-blind, placebo-controlled, multicenter, Phase III trial (MIMOSA) completed its double-blind period in December 2010 and will compare abagovomab maintenance therapy to placebo, which will definitively determine the efficacy of this immunotherapeutic approach in patients with ovarian cancer.

Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma

OBJECTIVE BRCA-associated and sporadic ovarian cancers have different pathologic and clinical features. Our goal was to determine if BRCA mutation status is an independent predictor of residual tumor volume following primary surgical cytoreduction. METHODS We conducted a retrospective analysis of patients with FIGO stage IIIC-IV high-grade serous ovarian cancer classified for the presence or absence of germline BRCA mutations. The primary outcome was tumor-debulking status categorized as complete gross resection (0mm), optimal but visible disease (1-10 mm), or suboptimal debulking (>10 mm) following primary surgical cytoreduction. Overall survival by residual tumor size and BRCA status was also assessed as a secondary endpoint. RESULTS Data from 367 patients (69 BRCA mutated, 298 BRCA wild-type) were analyzed. Rate of optimal tumor debulking (0-10 mm) in BRCA wild-type and BRCA-mutated patients were 70.1% and 84.1%, respectively (P=0.02). On univariate analysis, increasing age (10-year OR, 1.33; 95% CI, 1.07-1.65; P=0.01) and wild-type BRCA status (OR, 0.47; 95% CI, 0.23-0.94, P=0.03) were both significantly associated with suboptimal surgical outcome. On multivariate analysis, BRCA mutation status was no longer associated with residual tumor volume (OR, 0.63; 95% CI, 0.31-1.29; P=0.21) while age remained a borderline significant predictor (10-year OR, 1.25; 95% CI, 1.01-1.56; P=0.05). Both smaller residual tumor volume and mutant BRCA status were significantly associated with improved overall survival. CONCLUSION BRCA mutation status is not associated with the rate of optimal tumor debulking at primary surgery after accounting for differences in patient age. Improved survival of BRCA carriers is unlikely the result of better surgical outcomes but instead intrinsic tumor biology.

The Performance of BRCA1 Immunohistochemistry for Detecting Germline, Somatic, and Epigenetic BRCA1 Loss in High-Grade Serous Ovarian Cancer

BACKGROUND BRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in high-grade serous ovarian cancer, we sought to evaluate the utility of BRCA1 immunohistochemistry (IHC) in screening for BRCA1 loss by germline, somatic, and epigenetic mechanisms. PATIENTS AND METHODS Patients with advanced high-grade serous ovarian cancer who had previously undergone germline BRCA1 testing were identified. Samples from each tumor were stained for BRCA1 and reviewed independently by two pathologists blinded to BRCA status. Tumors with abnormal BRCA1 IHC and wild-type germline testing underwent further evaluation for somatic BRCA1 mutations and promoter hypermethylation. McNemars test was used to determine the association of BRCA1 IHC with germline BRCA1 mutations and BRCA1 loss through any mechanism. Kaplan-Meier methods were used to estimate overall survival (OS), and the log-rank test was used to assess differences between groups. RESULTS Inter-rater reliability between the two pathologists on BRCA IHC interpretation was very good (kappa coefficient 0.865, P = 0.16; McNemars test). BRCA1 IHC was abnormal in 36% (48/135) of cases. When compared with germline BRCA1 status, BRCA1 IHC had a high negative predictive value (95.4%) but a low positive predictive value (PPV, 52.1%). When accounting for promoter hypermethylation and somatic mutations as alternative methods of BRCA1 loss, the PPV rose to 87.5%. Five-year OS rate was 49.6% [95% confidence interval (CI) 26.3% to 69.3%] for patients with germline BRCA1 mutations, 50.4% (95% CI 27.5% to 69.5%) for germline wild-type BRCA1 and abnormal IHC, and 52.1% (95% CI 38.4% to 64.2%) for germline wild-type BRCA1 and normal IHC (P = 0.92). CONCLUSIONS BRCA1 IHC interpretation was a highly reproducible and accurate modality for detecting germline, somatic, or epigenetic mechanisms of BRCA1 loss. These results support further development of BRCA1 IHC as a potential biomarker for BRCA1 loss in high-grade serous ovarian cancer.

Management of advanced uterine leiomyosarcoma.

Purpose of review The purpose of this article is to review current evidence-based management strategies for patients with recurrent and metastatic uterine leiomyosarcoma (LMS). We will focus on treatment of advanced multifocal disease as well as new developments in targeted cancer therapies. Recent findings The management of patients with advanced uterine LMS is divided between those with localized and those with disseminated disease. Selected patients with localized or single-organ oligometastatic disease may benefit from surgical resection. For patients with disseminated disease, fixed-dose-rate gemcitabine plus docetaxel is an appropriate first-line chemotherapy regimen. Other active cytotoxic agents include doxorubicin, ifosfamide, and dacarbazine. The role of trabectedin (approved by the European Medicine Agency to be marketed for advanced or metastatic soft tissue sarcoma) is being explored. Trials are also underway for targeted therapy in uterine LMS. Currently, the only approved targeted therapy for advanced soft tissue sarcoma is pazopanib. In patients with small volume and slowly progressive estrogen receptor/progesterone receptor-positive disease, antiestrogen therapy with an aromatase inhibitor is a reasonable alternative to observation alone. Summary Despite recent advances, overall survival for advanced disease remains poor and identification of novel agents with activity in LMS is clearly needed.

Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial sloan-Kettering Cancer Center experience.

Background Gemcitabine is active in several gynecologic malignancies including ovarian cancer, cervical cancer, and uterine leiomyosarcoma. It has been used in an off-label setting for the treatment of advanced endometrial cancer, despite lack of published data showing efficacy. We performed a retrospective study to determine the progression-free survival and response rate of endometrial cancer patients treated with gemcitabine at Memorial Sloan-Kettering Cancer Center. Methods Eligible patients had histologically confirmed advanced (stage IV or recurrent) endometrial cancer that was treated with single-agent gemcitabine at Memorial Sloan-Kettering Cancer Center between 1999 and 2009. Response to therapy was determined by review of computed tomography imaging by Response Evaluation Criteria in Solid Tumors 1.1 criteria. Results Forty-six patients were included in the analysis. Median age was 66 years (range, 52–87 years). All patients were previously treated with chemotherapy. The median number of prior lines of chemotherapy was 2 (range, 1–8). Median dose of gemcitabine administered was 800 mg/m2 infused on days 1 and 8 of a 21-day cycle. Predominant histology was endometrioid (48%, n = 22) followed by serous (35%, n = 16), clear cell (15%, n = 7), and undifferentiated (2%, n = 1). Overall response rate was 10.9% (95% confidence interval, 1.9%–19.9%); 5 patients (11%) achieved a partial response. Thirteen patients (28%) displayed stable disease lasting at least 3 months. Of note, 5 (71%) of the 7 patients with clear cell histology displayed stable disease or partial response (n = 5). The median progression-free survival was 3.0 months (95% confidence interval, 2.1–3.3 months). Nonhematologic grades 3 and 4 toxicities were rare. Ten patients (22%) were treated with granulocyte colony-stimulating factor during treatment. Grade 3 thrombocytopenia was seen in 4 patients (9%). There were no cases of grade 4 thrombocytopenia. Conclusions In a mixed population of patients with previously treated advanced endometrial cancer, gemcitabine was well tolerated and showed modest activity. Patients with clear cell histology appeared to have greater likelihood of benefit.