MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of BRCA-mutated breast cancer (BC), including triple-negative BC (TNBC) and ovarian cancer (OvCa). A key challenge is to identify the factors associated with PARPi resistance; although, previous studies suggest that platinum-based agents and PARPi share similar resistance mechanisms. METHODS: Olaparib-resistant (OlaR) cell lines were analyzed using HTG EdgeSeq miRNA Whole Transcriptomic Analysis (WTA). Functional assays were performed in three BRCA-mutated TNBC cell lines. In-silico analysis were performed using multiple databases including The Cancer Genome Atlas, the Genotype-Tissue Expression, The Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, and Gene Omnibus Expression. RESULTS: High miR-181a levels were identified in OlaR TNBC cell lines (p = 0.001) as well as in tumor tissues from TNBC patients (p = 0.001). We hypothesized that miR-181a downregulates the stimulator of interferon genes (STING) and the downstream proinflammatory cytokines to mediate PARPi resistance. BRCA1 mutated TNBC cell lines with miR-181a-overexpression were more resistant to olaparib and showed downregulation in STING and the downstream genes controlled by STING. Extracellular vesicles derived from PARPi-resistant TNBC cell lines horizontally transferred miR-181a to parental cells which conferred PARPi-resistance and targeted STING. In clinical settings, STING levels were positively correlated with interferon gamma (IFNG) response scores (p = 0.01). In addition, low IFNG response scores were associated with worse response to neoadjuvant treatment including PARPi for high-risk HER2 negative BC patients (p = 0.001). OlaR TNBC cell lines showed resistance to platinum-based drugs. OvCa cell lines resistant to platinum showed resistance to olaparib. Knockout of miR-181a significantly improved olaparib sensitivity in OvCa cell lines (p = 0.001). CONCLUSION: miR-181a is a key factor controlling the STING pathway and driving PARPi and platinum-based drug resistance in TNBC and OvCa. The miR-181a-STING axis can be used as a potential marker for predicting PARPi responses in TNBC and OvCa tumors.

Role of adjuvant chemotherapy in patients with early stage uterine papillary serous cancer.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer. We studied survival outcomes in patients with stages I/II UPSC. MATERIALS: A retrospective, multi-institutional study of patients with stages I/II UPSC was conducted. Patients underwent surgical staging followed by observation, adjuvant platinum-based chemotherapy (CT), or radiation therapy (RT). Continuous variables were compared via Wilcoxon rank sum test; Fisher exact test was used for the unordered categorical variables. Kaplan-Meier curves were used to estimate survival. RESULTS: Thirty-nine women were diagnosed with stage I (n = 30) or II (n = 9) UPSC, with a median follow-up of 52 months. Of the 26 patients who did not receive adjuvant CT, 9 developed recurrences and 8 died of their disease. Of the 10 patients with no myometrial invasion who did not receive adjuvant CT, 3 developed recurrences and died. Of the 7 patients who underwent RT, 2 developed distant recurrences and died. Of the 13 patients who underwent CT, 1 developed vaginal recurrence. The 5-year overall (OS) and progression-free survival (PFS) rates for the adjuvant CT group were 100% and 92%, respectively, compared with 69% and 65% for those who did not receive CT (P = 0.002 OS, P = 0.002 PFS). The 5-year OS and PFS rates for RT group were both 71%. CONCLUSIONS: Patients with stages I/II UPSC are at significant risk for distant recurrence and poor survival. Platinum-based adjuvant CT may decrease recurrence rate and improve survival in women with early and well-staged UPSC.

Pelvic radiation improves local control after hysterectomy for uterine leiomyosarcoma: a 20-year experience.

BACKGROUND: Uterine leiomyosarcoma (LMS) is associated with high rate of recurrence after surgical resection. The role of adjuvant radiation therapy in improving survival in women with uterine LMS is unclear. METHODS: All cases of LMS treated from 1985 to 2005 at 11 regional medical centers were identified. Kaplan-Meier survival curves were constructed and compared with log-rank testing. Multivariate analysis was performed to account for the potential influence of confounding factors. RESULTS: One hundred forty-seven patients with LMS were identified. The median age of diagnosis was 51 years with the stage distribution of stage I (n = 87), II (n = 9), III (n = 25), IV (n = 25), and unknown (n = 1). One hundred forty-three underwent total abdominal hysterectomy and bilateral salpingoophorectomy. Twenty-four (17%) of these patients received adjuvant pelvic irradiation, and 63 (44%) received adjuvant and/or palliative chemotherapy. With a median follow-up of 24 months (range, 1-249 months), the median survival for the entire group was 37 months. Cox proportional hazards modeling demonstrated the presence of high tumor grade and advanced stage adversely affected survival. Although the 5-year survival for patients who received adjuvant radiotherapy was significantly higher than those who did not (70% vs 35%), this survival advantage was not sustained as the curves crossed at 90-month follow-up. Pelvic recurrence rate was lower in the radiation group (18% vs 49%; P = 0.02). CONCLUSIONS: Adjuvant radiation therapy was associated with decreased pelvic failure and a modest improvement in 5-year survival, but did not impact overall survival with extended follow-up.

Significance of comprehensive surgical staging in noninvasive papillary serous carcinoma of the endometrium.

OBJECTIVE: To evaluate the biological behavior of noninvasive papillary serous carcinoma of the endometrium. METHODS; From 1990 to 2001, all women with noninvasive uterine papillary serous carcinoma (UPSC) at three Southern California hospitals were identified from tumor registry databases. Data for analysis were collected from hospital charts, office records, and tumor registry files. RESULTS: Of the 100 patients diagnosed with UPSC, 16 had noninvasive lesions. Twelve underwent a comprehensive surgical staging procedure with omental resection. Six of these 12 women were found to have disease beyond the uterine corpus, including 4 with adnexal involvement, 3 with omental disease, 2 with cervical extension, 1 with pelvic lymph node involvement, and 3 with positive washings. Three women were found to have positive cytology and metastases in more than one location. Of the 12 patients, 1 of the 6 with stage IA disease had distant recurrence and 4 of the 6 with stage II-IV disease recurred. Of the remaining 4 patients who underwent a staging procedure without pathologic omental assessment, 1 was found to have cervical extension. In these 4 women, 1 with stage IA disease recurred. CONCLUSION: The typical patterns of spread and prognostic factors for endometrioid carcinoma of the uterus do not apply to UPSC. In our series, omental assessment was necessary to detect the 25% of patients with stage IVB disease due to omental involvement. Thus, women with noninvasive UPSC should undergo a comprehensive staging procedure including omental sampling to determine the extent of disease.

Paying for prevention standardizing the measurement of the value of health care interventions.

It is not clear if spending more on tests that enhance the accuracy of Pap smears would lead to a greater reduction in cancer incidence than if the money were spent to include a greater proportion of women in primary screening. The cost effectiveness of tests beyond the Pap smear has not been clearly demonstrated. There is the question of whether cervical cancer incidence can be decreased more by improving the tests for patients who are already screened or by improving access to the unscreened population. Cervical cancer screening represents only one of many public health issues competing for resources. Given that there are choices to be made, the optimal yardstick against which all resource-competing programs are measured should be marginal benefit versus marginal cost.