PARP inhibitors represent a major breakthrough in ovarian cancer care. Almost half of all ovarian cancers have deficiencies in the homologous recombination (HR) DNA repair pathway, namely BRCA1/2 ...mutations. Given the limited therapeutic options for recurrent ovarian cancer patients there has been a significant effort to develop novel therapies to exploit DNA repair deficiencies. In 2005 and 2006, inhibiting PARP enzymes was first observed to be highly effective against cancers with HR deficiencies. PARP inhibitors are being utilized in the clinic to manage recurrent ovarian cancers that display defects in the HR repair pathway. However, PARP inhibitors also show significant clinical benefit in patients without HR deficiencies. There are currently three FDA-approved PARP inhibitors for recurrent ovarian cancer and an additional two PARP inhibitors being evaluated in late stage clinical trials. Given the expanding clinical use of PARP inhibitors and the high likelihood of acquired resistance, there is a significant need for clinical strategies to manage PARP inhibitor resistant disease. This review will examine PARP inhibitors in the context of: indications and toxicities, novel biomarkers to predict response, targeted-therapy resistance, and potential approaches to manage resistant disease.
•Indications and toxicities of clinically applicable PARP inhibitors•Novel biomarkers to predict PARP inhibitor response•Molecular mechanisms of PARP inhibitor resistance•Managing PARP inhibitor resistant ovarian cancer
Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy. Roughly 80% of patients are diagnosed with late-stage disease, which is defined by wide-spread ...cancer dissemination throughout the pelvic and peritoneal cavities. HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis (apoptosis triggered by cell detachment). Epithelial cell detachment from the underlying basement membrane or extracellular matrix leads to cellular stress, including nutrient deprivation. In this report, we examined the contribution of fatty acid oxidation (FAO) in supporting anoikis resistance. We examined expression Carnitine Palmitoyltransferase 1A (CPT1A) in a panel of HGSOC cell lines cultured in adherent and suspension conditions. With CPT1A knockdown cells, we evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 immunofluorescence, flow cytometry, and colony formation. We assessed CPT1A-dependent mitochondrial activity and tested the effect of exogenous oleic acid on anoikis and mitochondrial activity. In a patient-derived xenograft model, we administered etomoxir, an FAO inhibitor, and/or platinum-based chemotherapy. CPT1A is overexpressed in HGSOC, correlates with poor overall survival, and is upregulated in HGSOC cells cultured in suspension. CPT1A knockdown promoted anoikis and reduced viability of cells cultured in suspension. HGSOC cells in suspension culture are dependent on CPT1A for mitochondrial activity. In a patient-derived xenograft model of HGSOC, etomoxir significantly inhibited tumor progression. IMPLICATIONS: Targeting FAO in HGSOC to promote anoikis and attenuate dissemination is a potential approach to promote a more durable antitumor response and improve patient outcomes.
Abstract Purpose Standard of care (SOC) treatment for locally advanced cervical cancer includes pelvic external beam radiation (EBRT) with chemotherapy and interdigitated brachytherapy. We evaluated ...national utilization trends and factors associated with receiving SOC therapy. Materials and methods We utilized the National Cancer Database (NCDB) to identify women with locally advanced cervical cancer treated with definitive radiation or chemoradiation therapy and stratified these patients by treatment received. Results We identified 15,194 patients. Only 44.3% of patients received SOC treatment and this group had significantly improved OS. High volume centers, academic centers, comprehensive community cancer centers, private insurance, and higher income, were all associated with an increased likelihood of receiving SOC, whereas Black patients were less likely to receive SOC. We found 26.8% of patients received no radiation boost, 23.8% received an EBRT boost only, and 49.5% of patients received EBRT with brachytherapy. Although an EBRT boost was advantageous over no boost at all (HR 0.720, p < 0.001), OS was superior in patients who received brachytherapy (HR 0.554, p < 0.001). Patients were more likely to receive no radiotherapy boost if they had lower incomes, Medicaid, were treated at low volume centers, or were treated at non-comprehensive community cancer centers. Conclusions SOC for locally advanced cervical cancer offers superior outcomes, yet less than half of patients receive SOC and there are disparities in which patients receive SOC treatment. No additional treatment, including sophisticated EBRT techniques including IMRT or SBRT, can make up for the survival decrement from lack of brachytherapy as a component of definitive care.
Fixed-dose rate gemcitabine plus docetaxel achieves objective response in 35% of patients with uterine leiomyosarcoma (uLMS). This study aimed to determine whether the addition of bevacizumab to ...gemcitabine-docetaxel increases progression-free survival (PFS) in uLMS.
In this phase III, double-blind, placebo-controlled trial, patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. PFS, overall survival (OS), and objective response rates (ORRs) were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabine-docetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard ratios (HRs), median times to event, and 95% CIs.
In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n = 54) and gemcitabine-docetaxel plus bevacizumab (n = 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; P = .58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; P = .81). Objective responses were observed in 17 (31.5%) of 54 patients randomly assigned to gemcitabine-docetaxel plus placebo and 19 (35.8%) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine-docetaxel plus bevacizumab.
The addition of bevacizumab to gemcitabine-docetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard first-line treatment for uLMS.
Abstract Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors are attractive therapeutic targets in cancer because agents that activate these receptors directly induce tumor cell ...apoptosis and have low toxicity to normal tissues. Consequently, several different drugs that target these receptors (recombinant TRAIL and various agonistic antibodies that activate one of the two TRAIL receptors) have been developed and are being tested in human clinical trials. However, in vitro and in vivo data suggest that resistance to these agents may limit their clinical effectiveness. In this review, we discuss recent findings about some of the ways these resistance mechanisms arise, potential biomarkers to identify TRAIL resistance in patients (Six1, GALNT14, XIAP, certain microRNAs) and potential ways to circumvent resistance and resensitize tumors.
Abstract Objective Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in ...EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers. Methods Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1–3 prior regimens were treated with 25 mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥ 6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall's tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome. Results Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90% CI 14.9%–38.6%) had PFS ≥ 6 months (median 3.1 months), 9.3% (90% CI 3.7%–23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic (8), gastrointestinal (8), pain (6), constitutional (5) and pulmonary (4). Suggested associations were between cyclin D1 and PFS ≥ 6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥ 6 months/longer PFS. Conclusions Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.
OBJECTIVE:To evaluate the efficacy and safety of second uterine curettage in lieu of chemotherapy for patients with low-risk, nonmetastatic gestational trophoblastic neoplasia (GTN) and to evaluate ...whether response to second curettage is independent of patient age, World Health Organization (WHO) risk score, registration human chorionic gonadotropin (hCG) level, lesion size, and depth of myometrial invasion measured on ultrasound examination.
METHODS:This was a cooperative group multicenter prospective phase II study. Prestudy testing included quantitative hCG level, pelvic ultrasonography, and chest radiography. Patients were categorized according to WHO risk scoring criteria (low risk with a score of 0–6).
RESULTS:Sixty-four women with newly diagnosed low-risk, nonmetastatic GTN were enrolled. Four patients were excluded. Twenty-four patients (40%) (lower 95% confidence limit 27.6%) were cured after second curettage. An additional two patients (3%) achieved a complete response but did not complete follow-up. Overall, 26 of 60 patients were able to avoid chemotherapy. Surgical failure was observed in 34 women (59%) and was more common in women 19 years old or younger or 40 years old or older. One case of grade 1 uterine perforation was successfully managed by observation. Four grade 1 and one grade 3 uterine hemorrhages were reported. New metastatic disease (lung) was identified in one of these women after second curettage. In three patients (surgical failures), the second curettage pathology was placental site trophoblastic tumor, and it was placental nodule in one additional patient.
CONCLUSION:Second uterine curettage as initial treatment for low-risk, nonmetastatic GTN cures 40% of patients without significant morbidity.
CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, https://clinicaltrials.gov/, NCT00521118.
Background Older patients are at increased risk of perioperative morbidity and mortality. There are limited data on the safety of a robotic approach in the staging for endometrial cancer. Objective ...We compared outcomes in women undergoing laparotomy or robotic surgical staging for endometrial cancer. Study Design Using the Healthcare Cost and Utilization Project National Inpatient Sample database from 2008 through 2010, we abstracted records for patients who had surgery for endometrial cancer with either a robotic approach or laparotomy. Patients were categorized by age (<65 vs ≥65 years and 5-year increments). Medical comorbidity scores were calculated using the Charlson Comorbidity Index. Outcomes included intraoperative/perioperative/medical complications, death, length of stay (LOS), and discharge disposition. Student t and χ2 tests were used to compare groups and approach. Multiple analysis of variance models were used to compare differences between robotics and laparotomy and age groups. Results We identified 16,980 patients who had surgery for endometrial cancer with either a robotic approach (age ≥65 years, n = 1228; age <65 years, n = 1574) or laparotomy (age ≥65 years, n = 5914; age <65 years, n = 8264). Older patients had a higher Charlson Comorbidity Index score at the time of surgery (2.6 vs 2.5, P < .001). In laparotomy cases, intraoperative complication rates were similar (4.1% vs 3.7%, P = .17). Older patients had higher rates of perioperative surgical (20.5% vs 15.4%, P < .001) and medical (23.3% vs 15.5%, P < .001) complications, longer LOS (5.1 vs 4.2 days, P < .001), and lower rates of discharge to home (71.2% vs 90.1%, P < .001). In robotic cases, rates of intraoperative complications were similar (5.9% vs 6.8%, P = .32). Older patients had higher rates of perioperative surgical (8.3% vs 5.2%, P = .001) and medical (12.3% vs 6.7%, P = .001) complications, longer LOS (2.00 vs 1.67 days, P < .001), and lower rates of discharge to home (88.8% vs 96.8%, P < .001). With both approaches, as age increased, perioperative surgical and medical complications also increased in a linear fashion. In a subanalysis of older patients (n = 7142), there were lower rates of perioperative surgical (8.3% vs 20.5%, P < .001) and medical (12.3% vs 23.3%, P < .001) complications, death (0.0% vs 0.8%, P < .001), shorter LOS (2.00 vs 5.13 days, P < .001) and higher rate of discharge to home (88.8% vs 71.2%, P < .001) in robotic compared to laparotomy cases. Conclusion Although the risks of surgery increase with age, in patients age ≥65 years, a robotic approach for endometrial cancer appears to be safe given current selection criteria utilized in the United States.
A significant factor contributing to poor survival rates for patients with ovarian cancer is the insensitivity of tumors to standard-of-care chemotherapy. In this study, we investigated the effect of ...claudin-4 expression on ovarian tumor cell apoptotic response to cisplatin and paclitaxel. We manipulated claudin-4 gene expression by silencing expression short hairpin RNA (shRNA) in cells with endogenously expressed claudin-4 or overexpressing claudin-4 in cells that natively do not express claudin-4. In addition, we inhibited claudin-4 activity with a claudin mimic peptide (CMP). We monitored apoptotic response by caspase-3 and Annexin V binding. We examined proliferation rate by counting the cell number over time as well as measuring the number of mitotic cells. Proximity ligation assays, immunoprecipitation (IP), and immunofluorescence were performed to examine interactions of claudin-4. Western blot analysis of tubulin in cell fractions was used to determine the changes in tubulin polymerization with changes in claudin-4 expression. Results show that claudin-4 expression reduced epithelial ovarian cancer (EOC) cell apoptotic response to paclitaxel. EOCs without claudin-4 proliferated more slowly with enhanced mitotic arrest compared with the cells expressing claudin-4. Furthermore, our results indicate that claudin-4 interacts with tubulin, having a profound effect on the structure and polymerization of the microtubule network. In conclusion, we demonstrate that claudin-4 reduces the ovarian tumor cell response to microtubule-targeting paclitaxel and disrupting claudin-4 with CMP can restore apoptotic response. IMPLICATIONS: These results suggest that claudin-4 expression may provide a biomarker for paclitaxel response and can be a target for new therapeutic strategies to improve response.
High grade serous ovarian carcinoma (HGSOC) is often diagnosed at an advanced stage. Chromobox 2 (CBX2), a polycomb repressor complex subunit, plays an oncogenic role in other cancers, but little is ...known about its role in HGSOC. We hypothesize that CBX2 upregulation promotes HGSOC via induction of a stem-like transcriptional profile and inhibition of anoikis. Examination of Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) established that increased CBX2 expression conveyed chemoresistance and worse disease-free and overall survival. In primary HGSOC tumors, we observed CBX2 expression was significantly elevated compared to benign counterparts. In HGSOC cell lines, forced suspension promoted CBX2 expression. Subsequently, CBX2 knockdown inhibited anchorage-independent proliferation and potentiated anoikis-dependent apoptosis. Furthermore, CBX2 knockdown re-sensitized cells to platinum-based chemotherapy. Forced suspension promoted increased ALDH activity and ALDH3A1 expression and CBX2 knockdown led to a decrease in both ALDH activity and ALDH3A1 expression. Investigation of CBX2 expression on a HGSOC tissue microarray revealed CBX2 expression was apparent in both primary and metastatic tissues. CBX2 is an important regulator of stem-ness, anoikis escape, HGSOC dissemination, and chemoresistance and potentially serves as a novel therapeutic target.
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