J.J. Mueller

Recurrent SMARCA4 mutations in small cell carcinoma of the ovary

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, highly aggressive form of ovarian cancer primarily diagnosed in young women. We identified inactivating biallelic SMARCA4 mutations in 100% of the 12 SCCOHT tumors examined. Protein studies confirmed loss of SMARCA4 expression, suggesting a key role for the SWI/SNF chromatin-remodeling complex in SCCOHT.

Neoadjuvant chemotherapy and primary debulking surgery utilization for advanced-stage ovarian cancer at a comprehensive cancer center

OBJECTIVE The aim of this study was to evaluate the use of neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) before and after results from a randomized trial were published and showed non-inferiority between NACT and PDS in the management of advanced-stage ovarian carcinoma. METHODS We evaluated consecutive patients with advanced-stage ovarian cancer treated at our institution from 1/1/08-5/1/13, which encompassed 32 months before and 32 months after the randomized trial results were published. We included all newly diagnosed patients with high-grade histology and stage III/IV disease. Associations between the use of NACT and clinical variables over time were evaluated. RESULTS Our study included 586 patients. Median age was 62 years (range, 30-90); 406 patients (69%) had stage III disease, and 570 (97%) had disease of serous histology. Twenty-six percent (154/586) were treated with NACT and 74% (432/586) with PDS. NACT use increased significantly from 22% (56/256) before 2010 (at which point the results of the randomized trial were published) to 30% (98/330) after 2010 (p=0.037). Although patients who underwent PDS were more likely to experience grade 3/4 surgical complications than those who underwent NACT, those selected for PDS had a median OS of 71.7 months (CI, 59.8-not reached) compared with 42.9 months (CI 37.1-56.3) for those selected for NACT. CONCLUSIONS In this single-institution analysis, the best survival outcomes were observed in patients who were deemed eligible for PDS followed by platinum-based chemotherapy. Selection criteria for NACT require further definition and should take institutional surgical strategy into account.

Loss of SMARCA4 Expression Is Both Sensitive and Specific for the Diagnosis of Small Cell Carcinoma of Ovary, Hypercalcemic Type.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare ovarian neoplasm that occurs in young women and has a poor prognosis. The histologic diagnosis of SCCOHT can be challenging due to its rarity and relatively nonspecific histologic features, which range from the classic, first-described small cell morphology to a pattern in which there are large cells with abundant eosinophilic cytoplasm. Many entities can be in the differential diagnosis and to date, immunohistochemical stains have shown no distinctive profile and have been of limited aid. SMARCA4 (also known as BRG1) mutations have recently been reported at high frequency in these tumors. SMARCA4 is an important component of the SWI/SNF complex that regulates gene expression through alteration of nucleosome conformation. Studies to date have suggested that immunohistochemical loss of expression of SMARCA4 is associated with the presence of a SMARCA4 mutation in most cases. In this study, the sensitivity and specificity of the immunohistochemical loss of SMARCA4 expression for the diagnosis of SCCOHT is examined in the context of the differential diagnosis with other primary or metastatic ovarian tumors. All but one of the SCCOHT showed loss of SMARCA4 expression (16/17; 94%), while of 279 other tumors tested, only two tumors (one clear cell carcinoma and one ovarian melanoma) showed loss of SMARCA4 expression. We conclude that SMARCA4 immunohistochemistry is highly sensitive and specific for a diagnosis of SCCOHT and is of clinical utility in the differential diagnosis of poorly differentiated ovarian tumors.

Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type.

Small cell carcinoma of the ovary, hypercalcemic type is an aggressive tumor generally affecting young women with limited treatment options. Mutations in SMARCA4, a catalytic subunit of the SWI/SNF chromatin remodeling complex, have recently been identified in nearly all small cell carcinoma of the ovary, hypercalcemic type cases and represent a signature molecular feature for this disease. Additional biological dependencies associated with small cell carcinoma of the ovary, hypercalcemic type have not been identified. SMARCA2, another catalytic subunit of the SWI/SNF complex mutually exclusive with SMARCA4, is thought to be post-translationally silenced in various cancer types. We analyzed 10 archival small cell carcinoma of the ovary, hypercalcemic type cases for SMARCA2 protein expression by immunohistochemistry and found that SMARCA2 expression was lost in all but one case. None of the 50 other tumors that primarily or secondarily involved the ovary demonstrated concomitant loss of SMARCA2 and SMARCA4. Deep sequencing revealed that this loss of SMARCA2 expression is not the result of mutational inactivation. In addition, we established a small cell carcinoma of the ovary, hypercalcemic type patient-derived xenograft and confirmed the loss of SMARCA2 in this in vitro model. This patient-derived xenograft model, established from a recurrent tumor, also had unexpected mutational features for this disease, including functional mutations in TP53 and POLE. Taken together, our data suggest that concomitant loss of SMARCA2 and SMARCA4 is another hallmark of small cell carcinoma of the ovary, hypercalcemic type—a finding that offers new opportunities for therapeutic interventions.

Staging Lymphadenectomy in Patients with Clear Cell Carcinoma of the Ovary

Objective The purpose of this study was to assess the rate of lymph node (LN) metastasis in comprehensively staged ovarian clear cell carcinoma (OCCC) clinically confined to the ovary and determine factors associated with LN metastasis. Methods We identified all cases of OCCC treated at 4 institutions from January 1994 through December 2011. We included cases with disease grossly confined to the ovary that had surgical staging performed, including at least 10 LNs sampled. Clinical and pathologic data were abstracted from electronic medical records, and a deidentified data set was compiled and processed at a single institution. Factors potentially associated with LN metastasis were tested. Appropriate statistical tests were performed. Results We identified 145 eligible cases that met the criteria for this analysis. Median age was 52.9 years (range, 30–81 years), and median total LN count was 19 (range, 10–74). Seven (4.8%) of 145 comprehensively staged cases had LN metastasis; 6 of these cases (4.1%) were isolated metastasis. Cytologic washings, peritoneal, omental, and fallopian tube involvement were not associated with nodal metastasis. Cases with ovarian surface involvement and positive cytology had a 37.5% incidence of LN positivity, which was statistically meaningful when compared with all other cases (P = 0.003). Conclusions Women who underwent comprehensive staging for clinical stage I OCCC had an LN metastasis rate of 4.8%. The subgroup of cases with both ovarian surface involvement and positive cytology had the highest incidence of LN metastasis. This may influence clinical decision making on whether to perform lymphadenectomy in patients with incidental OCCC found after salpingo-oophorectomy.

Intraperitoneal chemotherapy after interval debulking surgery for advanced-stage ovarian cancer: Feasibility and outcomes at a comprehensive cancer center

OBJECTIVES Intraperitoneal (IP)-based chemotherapy following primary debulking surgery (PDS), although associated with substantial toxicity, is supported by a strong evidence base. We sought to determine feasibility and outcomes of IP chemotherapy after interval debulking surgery (IDS) among patients deemed ineligible for PDS. METHODS We identified all patients with high-grade, stage III/IV ovarian cancer treated at our institution with neoadjuvant chemotherapy (NACT) followed by IDS and postoperative chemotherapy from 1/2008-5/2013. IP and intravenous (IV) regimens were defined; demographic and clinical data were analyzed using appropriate statistics. RESULTS Of 128 evaluable patients, 118 (92%) achieved ≤1cm residual disease at IDS and 74 (58%) achieved a complete gross resection (CGR). An IP port was placed in 54/128 patients (42%), with 89% port utilization. Forty-eight (38%) of 128 patients received IP chemotherapy, 17 (13%) weekly IV paclitaxel/q3week carboplatin, and 63 (49%) q3week IV carboplatin/paclitaxel. Patients completed a median of 3 IP cycles (range, 2-6), with 3 (5.5%) of 54 ports removed due to complications. Overall survival (OS) for patients with a CGR treated with IP and weekly IV chemotherapy was 53.2months (range, 24.7-NE), and 44.2months (range, 30.2-NE) with any visible residual disease (p<0.001). Median OS was 53.2months (range, 44.5-NE) for IP-, not reached for weekly IV-, and 34.2months (range, 27.5-49.8) for q3week IV-treated patients (p=0.1). CONCLUSIONS Patients administered IP after IDS had a high rate of successful port utilization, with few regimen switches. Oncologic outcomes were optimal in patients with a CGR at IDS, regardless of chemotherapy used.

Three versus six cycles of adjuvant platinum-based chemotherapy in early stage clear cell ovarian carcinoma – A multi-institutional cohort

OBJECTIVES To determine if 6 versus 3cycles of adjuvant platinum-based chemotherapy with or without taxane impacts survival in early stage ovarian clear cell carcinoma (OCCC). METHODS We retrospectively identified all cases of stage I and II OCCC treated at 5 institutions from January 1994 through December 2011. Patients were divided into 2 groups: those who received 3 versus 6cycles of adjuvant chemotherapy. Our cohort consisted of 210 patients with stage IA-II disease, 116 of whom underwent full surgical staging. Cox proportional hazards regression and Kaplan-Meier analyses were performed to evaluate progression-free (PFS) and overall survival (OS) between groups. RESULTS Among 210 eligible patients, the median age was 53years (range 30-88). The majority of patients were Caucasian (83.8%). All patients received adjuvant chemotherapy with 90% receiving carboplatin and paclitaxel. Thirty-eight (18.1%) patients received 3cycles, and 172 (81.9%) patients received 6cycles of adjuvant treatment. Recurrence rate was comparable between groups (18.4% vs. 27.3% for 3 vs. 6cycles, p=0.4). There was no impact of 3 versus 6cycles of chemotherapy on PFS (hazard ratio [HR] 1.4; 95% confidence interval [CI] 0.63-3.12, p=0.4) or OS (HR 1.65; 95% CI 0.59-4.65, p=0.3) on univariate analysis. There was no benefit to more chemotherapy in stratified analysis by stage nor on multivariate analysis adjusting for the impact of stage. Subgroup analysis of surgically staged patients also showed no difference in survival between 3 versus 6cycles of chemotherapy. CONCLUSIONS Three cycles of platinum with or without taxane adjuvant chemotherapy were comparable to 6cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort. CONDENSATION Three cycles of platinum with or without taxane adjuvant chemotherapy are comparable to 6 cycles with respect to recurrence and survival in patients diagnosed with early stage ovarian clear cell carcinoma in this retrospective multi-institutional cohort.

Massively parallel sequencing analysis of mucinous ovarian carcinomas: genomic profiling and differential diagnoses

OBJECTIVE Mucinous ovarian cancer (MOC) is a rare type of epithelial ovarian cancer resistant to standard chemotherapy regimens. We sought to characterize the repertoire of somatic mutations in MOCs and to define the contribution of massively parallel sequencing to the classification of tumors diagnosed as primary MOCs. METHODS Following gynecologic pathology and chart review, DNA samples obtained from primary MOCs and matched normal tissues/blood were subjected to whole-exome (n = 9) or massively parallel sequencing targeting 341 cancer genes (n = 15). Immunohistochemical analysis of estrogen receptor, progesterone receptor, PTEN, ARID1A/BAF250a, and the DNA mismatch (MMR) proteins MSH6 and PMS2 was performed for all cases. Mutational frequencies of MOCs were compared to those of high-grade serous ovarian cancers (HGSOCs) and mucinous tumors from other sites. RESULTS MOCs were heterogeneous at the genetic level, frequently harboring TP53 (75%) mutations, KRAS (71%) mutations and/or CDKN2A/B homozygous deletions/mutations (33%). Although established criteria for diagnosis were employed, four cases harbored mutational and immunohistochemical profiles similar to those of endometrioid carcinomas, and one case for colorectal or endometrioid carcinoma. Significant differences in the frequencies of KRAS, TP53, CDKN2A, FBXW7, PIK3CA and/or APC mutations between the confirmed primary MOCs (n = 19) and HGSOCs, mucinous gastric and/or mucinous colorectal carcinomas were found, whereas no differences in the 341 genes studied between MOCs and mucinous pancreatic carcinomas were identified. CONCLUSIONS Our findings suggest that the assessment of mutations affecting TP53, KRAS, PIK3CA, ARID1A and POLE, and DNA MMR protein expression may be used to further aid the diagnosis and treatment decision-making of primary MOC.

Brain metastases in patients with low-grade endometrial carcinoma

Objective To report characteristics of patients with low-grade endometrioid endometrial carcinoma (EC) who develop brain metastases. Methods We retrospectively identified all patients treated at our institution for FIGO grades 1/2 EC from 1/2000–12/2016, who developed brain metastases. Electronic medical records were reviewed, data abstracted. Overall survival (OS) was determined from time of brain metastases to death or last follow-up. Appropriate statistical tests were used. Results Of 3052 patients, 23 (9, grade 1; 14, grade 2) developed brain metastases (incidence = 0.75%). Presentation at initial diagnosis: median age = 61.3 years (range, 41–81); median BMI = 29.8 kg/m2 (range, 20.3–42.6 kg/m2); distribution by stage: I, 15/23 (65%); II, 2/23 (8.7%); III, 3/23 (13.0%); IV, 3 (13.0%). None showed clinical evidence of brain metastases at presentation. Median time to diagnosis of brain metastases = 29.7 months (range, 6–145); median age = 64.6 years (range, 47.5–86.5). Brain metastases were the first, isolated site of recurrence in 2/23 (9%). All presented with neurological symptoms. Six (26%) had solitary brain lesions. Seventeen (74%) received treatment; 6 (28%), supportive care only. Median OS for patients receiving any treatment = 5.8 months (95% CI, 1.6–10.0), versus 2.4 months (95% CI, 1.5–3.3; p = .04) for best supportive care. Conclusion Brain metastases in low-grade EC is rare, prognosis generally poor. Compared to supportive care only, any treatment results in more favorable outcomes.

Cited rationale for variance in the use of primary intraperitoneal chemotherapy following optimal cytoreduction for stage III ovarian carcinoma at a high intraperitoneal chemotherapy utilization center

OBJECTIVE Studies have demonstrated improved ovarian cancer survival with the administration of a combination of intravenous (IV) and intraperitoneal (IP) chemotherapy following optimal cytoreduction. Despite this, IV/IP chemotherapy is not uniformly used. In this retrospective cohort study, we assessed the documented reasons for giving IV-only chemotherapy. METHODS All patients who had optimal primary cytoreductive surgery for stage III ovarian, fallopian tube, or primary peritoneal carcinoma, met eligibility criteria for GOG-172, and received primary chemotherapy at our institution between 2006 and 2013 were identified. Patients who received at least one cycle of adjuvant IV/IP therapy were included in the IP group. Patient characteristics, treatment information, and reason cited for not administering IP therapy were collected. RESULTS Of the patients evaluated, 330 met inclusion criteria. The majority (n=261, 79%) received at least one IV/IP cycle (median, 6; range, 1-6), and 62% completed 6cycles. The most common reason for giving IV-only therapy was postoperative status (i.e., delayed wound healing, performance status), accounting for 18 (26%) of the 69 IV-only patients (5% of the entire cohort). Other cited reasons were baseline comorbidities (15%) and IP port complications (12%). Receipt of ≥1cycle of IP chemotherapy (HR 0.51; 95% CI, 0.32-0.80) and no gross residual disease (HR 0.47; 95% CI, 0.31-0.71) were associated with improved overall survival. CONCLUSION Potentially modifiable factors identified as leading to the use of IV-only chemotherapy were postoperative status and IP port complications, which if altered, could potentially lead to increased IP chemotherapy use.