Background Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence. Methods In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life. Results Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group. Conclusions Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.)

5589 Background: Protocol GOG-258 randomized Cis-RT+CP or CP for 6 cycles to patients (pts) with stage III/IVA endometrial carcinoma (Matei et al, ASCO 2017). Recurrence-free survival was the primary endpoint and was not increased by addition of RT. PRO analyses evaluated the impact of treatment (tx) on quality of life (QOL) during tx and up to 1 year. Methods: PROs were assessed at baseline prior to tx, 6 weeks (wks) after starting tx (corresponding to 1-wk post completion of RT (Cis-RT+CP) or prior to cycle 3 (CP)), and 18 and 70 wks after tx start. The analysis used FACT-En TOI, FACT/GOG-neuropathy (Ntx) subscale, and FACT-C items C3, C5 combined with En1, O1, O3, Cx6 in TOI of FACT-En for gastrointestinal (GI) symptoms (exploratory). Results: Questionnaire compliance was 95% at baseline, 90% at 6 wks, 87% at 18 wks, and 78% at 70 wks after tx start. Pts (332 on Cis-RT+CP and 349 on CP) with valid baseline and ≥ 1 follow-up PRO assessments were evaluable for analysis. After adjusting age and baseline scores, pts receiving Cis-RT+CP reported 5.2 points (97.5% CI: 2.7~7.8; adjusted p < 0.001) lower TOI scores on average at 18 wks (end of tx) compared to CP. The tx difference remained statistically significant at 70 wks (3.4 points lower on Cis-RT+CP group; 97.5% CI: 0.7~6.2; adjusted p = 0.022); none exceeded the 6 point difference pre-set as “clinically meaningful.” Pts in both groups reported increased chemo-induced Ntx symptoms since tx start, but pts on CP reported 2.0 points lower (worse Ntx symptoms) (97.5% CI: 1.4~2.6; adjusted p-value < 0.001) in the Ntx subscale score at 6 wks (post 2 cycles of chemo) than those receiving RT. Pts on Cis-RT+CP reported significantly worse GI symptoms compared to CP arm pts at all assessments. Conclusions: The Cis-RT+CP group experienced overall worse QOL and GI toxicity; both groups reported neuropathy which did not return to baseline by 1 year. PRO differences observed with Cis-RT+CP and CP may influence choice of treatment for locally advanced endometrial cancer. Clinical trial information: NCT00942357.

Morphological variants of lobular carcinoma in situ (LCIS) include classical (CLCIS), pleomorphic (PLCIS) and florid type (FLCIS). Treatment guidelines suggest managing PLCIS and FLCIS like ductal carcinoma in situ (DCIS); therefore accurate identification of LCIS subtypes is critical. However, the significance of separating PLCIS from FLCIS is not clear. Also, interobserver agreement in identifying LCIS subtypes, using contemporary criteria, is not known. We aimed to evaluate interobserver agreement amongst breast pathologists in diagnosing LCIS subtypes and use the agreement data to justify LCIS classification for management purposes. Six breast pathologists independently reviewed 50 hematoxylin and eosin stained slides comprised of a mix of LCIS subtypes. After reviewing published criteria, participants diagnosed PLCIS, CLCIS and apocrine change in a marked region of interest and FLCIS based on entire section. PLCIS was identified in 8 to 37 slides with overall moderate agreement (Fleiss' kappa = 0.565) and pair wise kappa (Cohen's) ranging from-.008 to 0.492. FLCIS was diagnosed in 15-26 slides with overall substantial agreement (Fleiss' kappa = 0.687) and pairwise kappa ranging from-.068 to 0.706. Both FLCIS and PLCIS coexisted in 45% of slides with consensus on non-classical LCIS. Comedo-type necrosis (odds ratio = 5.5) and apoptosis (odds ratio = 1.8) predicted FLCIS. We found moderate and substantial agreement in diagnosing PLCIS and FLCIS respectively. Objective histological features linked with aggressive behavior were more frequent with FLCIS. PLCIS and FLCIS patterns frequently coexist, contain similar molecular aberrations, and are managed similarly (like DCIS); therefore, combining FLCIS and PLCIS into one category (non-classical LCIS) should be considered. Published by Elsevier Inc.

Clinically relevant histological categorization of fibroepithelial lesions can be a daunting task, especially in a core needle biopsy. Assessment of stromal nuclear atypia, including nuclear pleomorphism and mitotic activity, is a key morphological feature employed to classify fibroepithelial lesions. We describe a case of fibroadenoma with markedly atypical nuclear features in the stromal cells that led to misclassification as phyllodes tumor in the core needle biopsy. Excision showed a fibroadenoma containing pleomorphic stromal giant cells, with occasional mitotic figures, including atypical forms. Aforementioned nuclear findings in a fibroepithelial lesion raise a legitimate question of phyllodes tumor. Knowledge of this pitfall may help avoid overtreatment of an otherwise benign fibroepithelial lesion.

Objective: The 2014 Bethesda System recommends that benign-appearing endometrial cells (BECs) in routine Pap tests should be reported in patients aged ≥45 years. This is a change from previous guidelines to report BECs in women ≥40 years of age. BECs are reported to have 1% chance of endometrial lesion on follow-up. This study tests whether the new threshold may increase the specificity of the test for the detection of clinically significant endometrial lesions. Study Design: After institutional review board approval, 1,177 BECs, reported during an 8-year study period in patients aged ≥40 years, were retrieved from 672,000 routine ThinPrep Pap tests. The results of subsequent workup were collected by chart review, and the Fisher exact test was used to compare results in patients aged <50 and ≥50 years. Results: No endometrial carcinoma and only 2 cases of endometrial hyperplasia were detected in women aged <50 years, whereas 5.5% of women aged ≥50 years with BECs had carcinoma and/or endometrial hyperplasia (p = 0.000169). Conclusion: Investigation of BECs on routine Pap test are useful in patients aged ≥50 years as 5.5% of cases were confirmed to have significant endometrial disease. Our data as well as other studies support raising the BEC-reporting age threshold from ≥45 to ≥50 years, as the new threshold may improve the specificity of the test.

There is no consensus regarding biomarker testing on the ipsilateral breast carcinomas present in separate biopsies, irrespective of whether the biopsies are performed concurrently or consecutively. We aimed to investigate estrogen receptor (ER), progesterone receptor (PR) and HER2 concordance in ipsilateral concurrent biopsies with invasive breast tumors. Consecutive ipsilateral concurrent biopsies with invasive breast tumors were identified retrospectively. Biomarker results, histologic grade and histologic subtype among the tumors in concurrent samples were compared. ER, PR, and HER2 expression was different in 3 (2.5%), 11 (9.2%) and 7 (5.9%) cases, respectively. All ER-discordant cases were sets of ER-negative (ER−) and weak-low ER-positive (ER+), ductal subtype and histologic grade 2 or 3 tumors. All PR-discordant cases were ER+, and comprised of histologic grades 1 to 3 ductal as well as lobular tumors. All HER2 discordant cases were histologic grade 2 to 3 ductal tumors. Biomarker discordance was independent of grade and subtype discordance. We found very low biomarker discordance among tumors in concurrent samples from ipsilateral breast. Our results suggest that ER and HER2 discordance in concurrent samples is predictable. ER discordance is present only in a setting of low ER+ tumors. Low-grade ductal and/or lobular tumors are ER and HER2 concordant. HER2 discordance is noted in grade 2 to 3 ductal tumors only. Histologic subtype and grade may guide extent of biomarker testing in concurrent ipsilateral breast biopsies.

Objective: Sentinel node biopsy is the standard of care for the assessment of nodal status in breast and skin cancers. The National Comprehensive Cancer Network guidelines now include sentinel lymph node dissection (SLND) as an option for nodal evaluation in women with endometrial cancer. The objective of this study was to evaluate the surgical learning curve, describe our experience with high-grade tumors, and examine the performance characteristics of SLND.

5505 Background: Patients with stage III/IVA uterine cancer (UC) carry high risk of systemic and local recurrence. Chemotherapy was shown to reduce systemic recurrence, however the risk of local failure remains high. Methods: The primary endpoint of this open label, randomized phase III trial was to determine if treatment with cisplatin and volume-directed radiation followed by carboplatin and paclitaxel for 4 cycles (C-RT, experimental arm) reduces the rate of recurrence or death (i.e., increases recurrence-free survival, RFS) when compared to carboplatin and paclitaxel for 6 cycles (CT, control arm) in patients with stages III-IVA (<2 cm residual disease) or FIGO 2009 stage I/II serous or clear cell UC and positive cytology. Secondary objectives were assessment of overall survival (OS), acute and late toxicities, and quality of life. A 28.5% reduction in the rate of recurrence or death was considered significant. Treatment randomization and analysis were stratified by gross residual tumor and age. Results: Between 6/2009 and 7/2014, 813 patients were enrolled and randomized (407 C-RT and 406-CT). Of those, 733 were eligible (344 C-RT and 360 CT), and 680 received the trial intervention (333 C-RT and 347 CT). Median follow up is 47 months. Patients characteristics were balanced between arms. There were 201 (58%) > grd 3 toxicity events in the C-RT arm and 227 (63%) in the CT arm. The most common > grd 3 events were myelosupression (40% vs. 52%), gastrointestinal (13% vs. 4%), metabolic (15% vs. 19%), neurological (7% vs. 6%), infectious (4% vs. 5%). Treatment hazard ratio for RFS was 0.9 (C-RT vs. CT; CI 0.74 to 1.10). C-RT reduced the incidence of vaginal (3% vs. 7%, HR = 0.36, CI 0.16 to 0.82), pelvic and paraaortic recurrences (10% vs. 21%, HR=0.43, CI 02.8 to 0.66) compared to CT, but distant recurrences were more common with C-RT vs. CT (28% vs. 21%, HR 1.36, CI 1 to 1.86). The analysis is premature for OS comparison. Conclusions: Although C-RT reduced the rate of local recurrence compared to CT; the combined modality regimen did not increase RFS in optimally debulked, stage III/IVA UC. Clinical trial information: NCT00942357.

For dual probe HER2 FISH assay, the 2013 CAP/ASCO guideline recommendations lowered the HER2/CEP17 ratio cut off for HER2 amplification to ≥2.0 and introduced an average HER2 copy number criterion for HER2 amplification (≥6.0/cell) and HER2 equivocal categories (≥4 and <6/cell). The HER2/CEP17 equivocal category is eliminated. The aim of this study is to assess the impact of 2013 HER2 FISH testing guideline recommendations update on the assignment of HER2 status with dual probe HER2 FISH assay. Dual probe HER2 FISH assay results on breast cancers from 09/2009 to 07/2015 that underwent reflex HER2 FISH testing after equivocal HER2 (2+) immunohistochemistry (IHC) were reviewed. HER2 copy number, CEP17 signals, and HER2/CEP ratios were noted. HER2 status was assigned as HER2 negative (HER2−), HER2 equivocal (HER2e), and HER2 amplified (HER2+) by applying both 2007 and 2013 CAP/ASCO HER2 FISH guideline recommendations and results were compared. New guidelines reclassified HER2 FISH status in a significant proportion of cases (8.3 %, 69/836; p = .021). There were 22 (2.6 %) more HER2+, 17 (2.1 %) more HER2e, and 39 (4.1 %) fewer HER2− tumors. Change of HER2 status correlated significantly with ≥3 CEP17 signals (38 vs. 2 %; p < .001). The 2013 CAP/ASCO guideline recommendations for HER2 FISH testing by dual probe assay increased the HER2 amplified and HER2 equivocal tumors. Increase in HER2 equivocal tumors would potentially increase the frequency of repeat HER2 testing. Tumors with ≥3 CEP17 signals, so-called chromosome 17 polysomy, are more likely to be impacted and classified as HER2 equivocal.

e17037 Background: Treatment of early stage ovarian cancers (EOCs) is oophorectomy with “complete” surgical staging (bilateral lymphadenectomy, peritoneal/pelvic washings, and omental sampling), but recent research has revealed variable adherence with these standards despite the fact that up to 30% of EOC cases have occult metastases. Inadequate staging has significant treatment implications given that more aggressive treatment is indicated for those with high-risk EOCs and more conservative management should be considered for those with true lower-risk EOCs. Methods: A retrospective IRB-approved review of women diagnosed with early-stage ovarian cancers at Women and Infants’ Hospital from 1995-2009 was performed. 608 cases were identified of which 369 met inclusion criteria. All available records were reviewed and coded for patient characteristics, surgical and staging information, and outcome and recurrence. Data was analyzed with STATA. Results: Staging was considered complete in 222 patients (60.3%), partial in 98 (26.6%), absent in 43 (11.7%) and unknown in 5. Adequacy of staging was significantly associated with 10-year recurrence-free survival (RFS), with 80.4%, 67.9% and 67% respectively for completely, partially and unstaged patients (p = 0.03). Additionally, adequacy of staging was significantly associated with overall (all-cause) survival (OS) (p = 0.04), with a 10-year OS rate of 76.0% among fully staged patients as opposed to 62.8% of partially staged women. When stratified into “high risk” (stages IC, II, and all grade III cancers) versus “low risk” cases, significance persisted in the low risk population for 10-year RFS and OS (p = 0.009 and p = 0.01, respectively). Similarly, younger age ( < 48 years) was the only significant factor associated with completion of staging (p = 0.02). Conclusions: Adherence to surgical staging guidelines for presumed early stage ovarian cancer yields a statistically significant improvement in 10-year recurrence-free survival as well as overall survival. Notably, older patients were significantly less likely to be fully staged. Adequacy of surgical staging has significant implications for post-surgical treatment recommendations in women with early stage ovarian cancer.

e17066 Background: Past analyses have demonstrated that adjuvant chemotherapy is indicated for high-risk early stage ovarian cancers (EOCs) (stages IC and II, grade III cancers) only, though prospective trials are limited in this disease setting. Identifying low-risk patients minimizes chemotherapy toxicities in those with tumors least likely to recur. Methods: A retrospective IRB-approved review of women diagnosed with EOCs at Women and Infants’ Hospital from 1995-2009 was performed. 608 cases were found and 369 met inclusion criteria. Records were reviewed and coded for patient characteristics, surgical information, and outcomes. Data was analyzed with STATA. Results: Adjuvant post-operative chemotherapy was given to 67.1% of EOC patients; it was administered to 92.8% classified as “high risk” vs. 52.2% for “low risk” patients. Additionally, age, stage, grade, and histology were associated with likelihood of chemotherapy administration (p = 0.004, p < 0.0001, p < 0.0001, p < 0.0001, respectively). Chemotherapy use was not significantly associated with 10-year recurrence-free survival (RFS) or overall survival (OS) among all patients (p = 0.4, p = 0.2). When stratified by risk, high-risk patients had significantly lower RFS and OS (p = 0.04, p = 0.05). Among high-risk patients, those who received chemotherapy had higher 10-year RFS than those who did not (71.2% vs. 46.7%), but this did not reach significance (p = 0.07), and there were no significant differences in OS (p = 0.3). In the low-risk cohort, RFS did not reach significance, but those who received chemotherapy had a 10-year OS benefit (p = 0.03). Conclusions: Patient factors predictive of chemotherapy administration were identified, but the overall cohort did not demonstrate a chemotherapy survival benefit. When stratified by risk, different patterns emerged. Although the standard recommendation for low risk EOC is observation, a majority were given chemotherapy, yielding a statistically significant OS benefit contrary to past reports. Conversely, we could not demonstrate a significant RFS or OS benefit for chemotherapy administration in the high-risk group. The survival impact of chemotherapy for EOC patients remains ill-defined and requires further research.

Products of conception (POC) are encountered daily in general pathology practice. The molar workup is an important part of POC examination. Ploidy analysis, expressed as DNA index (DI), is part of the pathologic workup of molar pregnancy. For the past decade, chromogenic in situ hybridization (CISH) has become a popular way to detect HER2 gene amplification. Current study aims to determine whether HER2 CISH dual-color assay can be used to determine DI in POCs. Twenty-two POC cases were chosen from the departmental archives, including 6 complete hydatidiform mole (CM), 10 partial mole (PM), and 6 hydropic POC (HP). CISH assay was performed using the HER2 CISH PharmDx Kit (SK109; Dako). This kit generates red (HER2) and blue (CEN-17) chromogenic signals on the same tissue section. In the 10 triploid PM cases, CISH generated HER2 signal value of 2.925±0.19. Nine cases (90%) had values within this range, except 1 case (2.5). In diploid cases, CISH generated HER2 signal value of 2.063±0.19. Results from 11 (91.7%) cases fell within this range, except 1 HP case (2.35). Sensitivity is 90%, specificity 91.6%, and overall accuracy 90.9%. The current study is the first one that demonstrates HER2/CEN-17 dual-color CISH can be used for microscopic analysis of cell ploidy. This technique provides a relatively easy and straight way to access DI using regular bright-field microscope. Concurrent CEN-17 signal and ploidy in both placental and maternal tissue can be used as internal control. This assay can be performed in any laboratory that can perform immunohistochemistry.