NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors.

XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE in vitro and in vivo Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.

Tumor characteristics and outcome of uterine carcinosarcoma in women aged ≥80 years.

OBJECTIVE: To examine clinico-pathological characteristics and outcomes of uterine carcinosarcoma (UCS) in women aged ≥80 years. METHODS: This is a secondary analysis of a previous multicenter retrospective study examining 906 women with stage I-IV UCS who underwent primary hysterectomy. Patient demographics, treatment types, tumor characteristics, and survival were examined across aged ≥80 (n = 82 [9.1%]), aged 60-79, (n = 526 [58.1%]), and aged <60 (n = 298 [32.9%]). RESULTS: Women in the aged ≥80 group were more likely to be Caucasian, undergo simple hysterectomy without lymphadenectomy, and receive no postoperative therapy (all, P < 0.05). Tumors in the aged ≥80 group were more likely to have high-grade carcinoma, heterologous sarcoma, and sarcoma dominance but less likely to have lympho-vascular space invasion (all, P < 0.05). Lymphadenectomy did not improve survival in the aged ≥80 group (P > 0.05), whereas lymphadenectomy was protective for survival in the younger groups (both, P < 0.05). Postoperative chemotherapy was associated with improved progression-free survival (PFS) in the aged ≥80 group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22-0.89, P = 0.021). With chemotherapy treatment, women in the aged ≥80 group had PFS similar to those in the aged 60-79 group (HR 0.97, 95%CI 0.51-1.83, P = 0.92). In contrast, without chemotherapy treatment, women in the aged ≥80 group had significantly decreased PFS compared to the aged 60-79 group (HR 1.62, 95%CI 1.09-2.40, P = 0.016). Similar associations were observed for postoperative radiotherapy. CONCLUSION: Nearly 10% of women with UCS are aged ≥80 that are characterized by aggressive tumor factors. Postoperative therapy but not extensive surgery may improve survival in this age group.

Race and nodal disease status are prognostic factors in patients with stage IVB cervical cancer.

BACKGROUND: Patients presenting with stage IVB cervical cancer pose a significant clinical challenge. While previous studies described several poor prognostic factors, they were limited by small sample sizes. The aim of this study was to identify clinicopathological prognostic factors in a large sample of patients with stage IVB cervical cancer at a single institution. METHODS: Patients with primary stage IVB cervical cancer diagnosed between 1992 and 2011 were extracted from a search of the MD Anderson Cancer Center registry. Clinicopathological data retrieved from their medical records included demographics (age and race), tumor characteristics (primary lesion size, grade, and histology), TNM classification, and metastatic site (nodal/organ). Treatment approach (radiation, chemotherapy, or both) and intent (palliation or curative) were recorded. Survival rates were evaluated using the Kaplan-Meier method. Cox proportional hazards regression was used to model the association between key variables and overall survival (OS). RESULTS: Two hundred sixty-six patients with stage IVB cervical cancer were identified. Their median OS was 12.7 months. The hazard ratio for African-Americans vs. patients with other ethnicities was 1.76 (95% confidence interval [CI], 1.18-2.54, P = 0.0063), and that for patients with para-aortic nodes alone vs. more extensive metastases was 0.37 (95% CI, 0.26-0.51, P < 0.0001). Other clinicopathological factors were not significantly associated with survival. CONCLUSIONS: African-American race was an independent adverse prognostic factor in this cohort. On the other hand, nodal disease in the para-aortic chain alone predicted a favorable prognosis.

Characterizing sarcoma dominance pattern in uterine carcinosarcoma: Homologous versus heterologous element.

OBJECTIVE: To examine significance of sarcoma dominance (SD) patterns in uterine carcinosarcoma (UCS). METHODS: This is a secondary analysis of multicenter retrospective study examining women with stages I-IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. RESULTS: SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P < 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35-1.69, and hetero/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homo/non-dominance (all, P < 0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P > 0.05). CONCLUSION: In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy.

Proposal for a Risk-Based Categorization of Uterine Carcinosarcoma.

PURPOSE: To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. METHODS: This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. RESULTS: Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). CONCLUSION: Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.

Significance of Lymphovascular Space Invasion by the Sarcomatous Component in Uterine Carcinosarcoma.

OBJECTIVE: The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS: This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I-IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS: Tumors in the LVSI-sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression-free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36-2.50, p < 0.001), and cause-specific survival (5-year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39-2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI-sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI-carcinoma (26% reduction, p = 0.08). CONCLUSION: In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS.

Significance of venous thromboembolism in women with uterine carcinosarcoma.

OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P=0.012), non-Asian race (HR 6.28, P<0.001), large body habitus (HR per kg/m2 1.04, P=0.014), residual disease at surgery (HR 3.04, P=0.003), tumor size ≥5cm (HR 2.73, P=0.003), and stage IV disease (HR 2.12, P=0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P<0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P=0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46, 95%CI 1.05-2.04, P=0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population.

Survival outcome of women with stage IV uterine carcinosarcoma who received neoadjuvant chemotherapy followed by surgery.

BACKGROUND AND OBJECTIVES: To examine survival of women with stage IV uterine carcinosarcoma (UCS) who received neoadjuvant chemotherapy followed by hysterectomy. METHODS: This is a nested case-control study within a retrospective cohort of 1192 UCS cases. Women who received neoadjuvant chemotherapy followed by hysterectomy based-surgery for stage IV UCS (n = 26) were compared to those who had primary hysterectomy-based surgery without neoadjuvant chemotherapy for stage IV UCS (n = 120). Progression-free survival (PFS) and cause-specific survival (CSS) were examined. RESULTS: The most common regimen for neoadjuvant chemotherapy was carboplatin/paclitaxel (53.8%). Median number of neoadjuvant chemotherapy cycles was 4. PFS was similar between the neoadjuvant chemotherapy group and the primary surgery group (unadjusted-hazard ratio [HR] 1.19, 95% confidence interval [CI] 0.75-1.89, P = 0.45). Similarly, CSS was comparable between the two groups (unadjusted-HR 1.13, 95%CI 0.68-1.90, P = 0.64). When the types of neoadjuvant chemotherapy regimens were compared, women who received a carboplatin/paclitaxel regimen had better survival outcomes compared to those who received other regimens: PFS, unadjusted-HR 0.38, 95%CI 0.15-0.93, P = 0.027; and CSS, unadjusted-HR 0.21, 95%CI 0.07-0.61, P = 0.002. CONCLUSION: Our study found that there is no statistically significant difference in survival between women with stage IV UCS who are tolerated neoadjuvant chemotherapy and those who undergo primary surgery.

Salvage chemotherapy with taxane and platinum for women with recurrent uterine carcinosarcoma.

OBJECTIVE: To examine survival after recurrence (SAR) among women with recurrent uterine carcinosarcoma who received a taxane/platinum doublet as the first-line salvage chemotherapy. METHODS: We retrospectively examined 148 women with recurrent uterine carcinosarcoma who received salvage chemotherapy within a cohort of 906 uterine carcinosarcomas. An independent association of salvage chemotherapy type and SAR was examined with multivariate analysis. RESULTS: There were 71 (48.0%) women who received a taxane/platinum regimen. On univariate analysis, women who received a taxane/platinum doublet had a higher 2-year SAR rate compared to women who received non-taxane/platinum regimens (55.5% versus 34.8%, P<0.001). On multivariate analysis, use of taxane/platinum regimen was independently associated with improved SAR compared to the non-taxane/platinum regimens (adjusted-hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35 to 0.91, P=0.02). When stratified by disease-free interval, women with a disease-free interval ≥6months who received a taxane/platinum doublet had a higher 2-year SAR rate compared to those who received non-taxane/platinum regimens (61.9% versus 40.0%, HR 0.46, 95% CI 0.28 to 0.75, P=0.002); conversely, in women with a disease-free interval <6months, 2-year SAR rates were similar between the two groups (20.5% versus 18.4%, HR 0.80, 95% CI 0.33 to 1.90, P=0.61). Among women who received a taxane/platinum doublet as adjuvant chemotherapy, re-treatment with taxane/platinum doublet as salvage chemotherapy remained beneficial (2-year SAR rate, 62.1% versus 39.7%, HR 0.40, 95% CI 0.18 to 0.86, P=0.019). CONCLUSION: Our study suggests that taxane/platinum doublet may be a more effective chemotherapy regimen compared to other regimens among women with recurrent uterine carcinosarcoma, especially for those who had a disease-free interval of ≥6months.

Impact of adjuvant therapy on recurrence patterns in stage I uterine carcinosarcoma.

BACKGROUND: To examine recurrence patterns in women with stage I uterine carcinosarcoma (UCS) stratified by adjuvant therapy pattern. METHODS: We examined 443 cases of stage I UCS derived from a retrospective cohort of 1192 UCS cases from 26 institutions. Adjuvant therapy patterns after primary hysterectomy-based surgery were correlated to recurrence patterns. RESULTS: The most common adjuvant therapy was chemotherapy alone (41.5%) followed by chemotherapy/radiotherapy (15.8%) and radiotherapy alone (8.4%). Distant-recurrence was the most common recurrence pattern (5-year cumulative rate, 28.1%) followed by local-recurrence (13.3%). On multivariate analysis, chemotherapy but not radiotherapy remained an independent prognostic factor for decreased risk of local-recurrence (5-year cumulative rates 8.7% versus 19.8%, adjusted-hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25-0.83, P=0.01) and distant-recurrence (21.2% versus 38.0%, adjusted-HR 0.41, 95%CI 0.27-0.62, P<0.001). The chemotherapy/radiotherapy group had a lower 5-year cumulative local-recurrence rate compared to the chemotherapy alone group but it did not reach statistical significance (5.1% versus 10.1%, adjusted-HR 0.46, 95%CI 0.13-1.58, P=0.22). Radiotherapy significantly decreased local-recurrence when tumors had high-grade carcinoma, sarcoma component dominance, and deep myometrial tumor invasion (all, P<0.05); and combining radiotherapy with chemotherapy was significantly associated with decreased local-recurrence compared to chemotherapy alone in the presence of multiple risk factors (5-year cumulative rates, 2.5% versus 21.8%, HR 0.12, 95%CI 0.02-0.90; P=0.013) but not in none/single factor (P=0.36). CONCLUSION: Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.

Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma.

OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.

2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity.

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2'-O-Methyl (2'-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2'-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.

Contemporary use of bevacizumab in ovarian cancer.

INTRODUCTION: Ovarian cancer remains the most lethal gynecologic malignancy. Although standard platinum-based chemotherapy results in high response rates, more than 70% of patients with advanced disease will experience recurrence within 5 years. Therefore, novel treatment strategies to increase primary efficacy, decrease recurrence after primary treatment and improve the response rate for recurrent disease are needed. AREAS COVERED: This review covers antiangiogenesis therapy and the efficacy of bevacizumab as primary treatment and in platinum-sensitive and resistant recurrent disease. EXPERT OPINION: The evidence provided from Phase III trials has supported the efficacy of bevacizumab in primary and recurrent ovarian cancer management. Future investigation is needed to improve clinical performance (via biomarkers of efficacy, early discontinuation, additional agents, etc.), as well as, more sensitive tools to assess direct patient impact.