INSR gene polymorphisms correlate with sensitivity to platinum-based chemotherapy and prognosis in patients with epithelial ovarian cancer

ObjectiveTo investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy.MethodsThis single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics.ResultsTwenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6–13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%).ConclusionsHu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy.Trial registrationNCT01137071.

Download Full-text

Clinical Practice of Adjuvant Chemotherapy in Patients with Early-Stage Epithelial Ovarian Cancer

Chemotherapy ◽

10.1159/000445024 ◽

2016 ◽

Vol 61 (6) ◽

pp. 287-294

Author(s):

Lindy M.J. Frielink ◽

Brenda M. Pijlman ◽

Nicole P.M. Ezendam ◽

Johanna M.A. Pijnenborg

Keyword(s):

Ovarian Cancer ◽

Clinical Practice ◽

Adjuvant Chemotherapy ◽

Epithelial Ovarian Cancer ◽

Early Stage ◽

Figo Stage ◽

Selective Treatment ◽

Platinum Based Chemotherapy ◽

Grade 3 ◽

Practice Methods

Background: Adjuvant platinum-based chemotherapy improves survival in women with early-stage epithelial ovarian cancer (EOC). Yet, there is a wide variety in clinical practice. Methods: All patients diagnosed with FIGO I and IIa EOC (2006-2010) in the south of the Netherlands were analyzed. The percentage of patients that received adjuvant chemotherapy was determined as well as the comprehensiveness of staging and outcome. Results: Forty percent (54/135) of the patients with early-stage EOC received adjuvant chemotherapy. Treatment with adjuvant chemotherapy was associated with FIGO stage, clear-cell histology and nonoptimal staging. Optimal staging was achieved in 50%, and nonoptimal staging was associated with advanced age, comorbidity and treatment in a non-referral hospital. Overall, there was no difference in outcome between patients with and without adjuvant chemotherapy. Yet, in grade 3 tumors, adjuvant chemotherapy seems beneficial. Conclusions: Selective treatment of patients with early-stage EOC might reduce adjuvant chemotherapy without compromising outcome.

Download Full-text

Oral Topotecan as Single-Agent Second-Line Chemotherapy in Patients With Advanced Ovarian Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.19.3967 ◽

2001 ◽

Vol 19 (19) ◽

pp. 3967-3975 ◽

Cited By ~ 36

Author(s):

D. L. Clarke-Pearson ◽

L. Van Le ◽

T. Iveson ◽

C. W. Whitney ◽

P. Hanjani ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Median Time ◽

Single Agent ◽

Advanced Ovarian Cancer ◽

Prolonged Treatment ◽

Second Line ◽

Gynecology And Obstetrics ◽

Platinum Based Chemotherapy ◽

Oral Topotecan

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age ≥ 18 years, performance status ≤ 2, and life expectancy ≥ 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

Download Full-text

Genetic Association of Interleukin-31 Gene Polymorphisms with Epithelial Ovarian Cancer in Chinese Population

Disease Markers ◽

10.1155/2018/3503858 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Chenlu Liu ◽

Yanyun Wang ◽

Huizi Song ◽

Qin Li ◽

Yan Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Therapeutic Target ◽

Gene Polymorphisms ◽

Chinese Population ◽

Clinical Characteristics ◽

Chinese Women ◽

Healthy Individuals ◽

Potential Therapeutic Target ◽

Kaplan Meier

Roles of interleukin-31 (IL-31) in the development and progression of human epithelial ovarian cancer are largely unknown. Studies report that the polymorphisms, rs7977932 C>G and rs4758680 C>A in IL-31, affect the expression level of IL-31. In the present study, we examined 412 patients with epithelial ovarian cancer and 428 healthy individuals to explore whether these polymorphisms are associated with the epithelial ovarian cancer in Chinese women. The genotype of the polymorphisms in each individual was identified. The associations of the polymorphisms with patients’ clinical characteristics and outcomes were evaluated. For rs7977932, the frequency of the CG/GG was significantly decreased in patients with epithelial ovarian cancer. However, the frequency of the rs4758680 CA/AA was significantly increased in those patients. Moreover, the frequency of rs7977932 CG/GG genotype was significantly higher in patients with less advanced FIGO stages. Kaplan-Meier curve showed that patients with CG/GG genotypes of rs7977932 had a decreased risk for recurrence compared to those with CC genotype. Our findings suggested that rs7977932 and rs4758680 of IL-31 may be associated with the development and progression of the epithelial ovarian cancer in the Chinese population. IL-31, therefore, may be a potential therapeutic target for the development of drugs to treat the disease.

Download Full-text

“BRCAness” Syndrome in Ovarian Cancer: A Case-Control Study Describing the Clinical Features and Outcome of Patients With Epithelial Ovarian Cancer Associated WithBRCA1andBRCA2Mutations

Journal of Clinical Oncology ◽

10.1200/jco.2008.16.1703 ◽

2008 ◽

Vol 26 (34) ◽

pp. 5530-5536 ◽

Cited By ~ 291

Author(s):

David S.P. Tan ◽

Christian Rothermundt ◽

Karen Thomas ◽

Elizabeth Bancroft ◽

Rosalind Eeles ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Germ Line ◽

Response Rates ◽

Line Treatment ◽

Histologic Subtype ◽

Platinum Based Chemotherapy ◽

History Of ◽

First Relapse ◽

Third Line

PurposeWe evaluated the clinical impact of germ-line BRCA1/2 mutations in patients with epithelial ovarian cancer (EOC) on responses to first and subsequent lines of chemotherapy, treatment-free interval (TFI) between each line of therapy, and overall survival (OS).Patients and MethodsTwenty-two EOC patients with germ-line BRCA1 or BRCA2 mutations (BRCA-positive) were selected from our database and matched (1:2) with 44 nonhereditary EOC controls (defined by no associated personal history of breast cancer and no family history of breast and ovarian cancer or an uninformative BRCA mutation test) for stage, histologic subtype, age, and year of diagnosis. All patients received primary platinum-based chemotherapy. Statistical comparisons included responses after first-, second-, and third-line treatment (χ2/Fisher's exact test) and median OS (Kaplan-Meier method/log-rank test).ResultsCompared with controls, BRCA-positive patients had higher overall (95.5% v 59.1%; P = .002) and complete response rates (81.8% v 43.2%; P = .004) to first line treatment, higher responses to second and third line platinum-based chemotherapy (second line, 91.7% v 40.9% [P = .004]; third line, 100% v 14.3% [P = .005]) and longer TFIs. A significant improvement in median OS in BRCA-positive patients compared with controls was observed from both time of diagnosis (8.4 v 2.9 years; P < .002) and time of first relapse (5 v 1.6 years; P < .001). BRCA status, stage, and length of first response were independent prognostic factors from time of first relapse.ConclusionBRCA-positive EOC patients have better outcomes than nonhereditary EOC patients. There exists a clinical syndrome of BRCAness that includes serous histology, high response rates to first and subsequent lines of platinum-based treatment, longer TFIs between relapses, and improved OS.

Download Full-text

ERCC-1 gene expression as a predictor of outcome following platinum-based chemotherapy in epithelial ovarian cancer (EOC)

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.5564 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 5564-5564

Author(s):

C. O. Michie ◽

J. S. Clark ◽

A. C. Hoffman ◽

K. D. Danenberg ◽

M. E. Stewart ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Platinum Based Chemotherapy

Download Full-text

Toxicity related to first line, platinum-based chemotherapy in BRCA1-associated epithelial ovarian cancer: Is DNA repairing impairment associated with more adverse events?

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.e17092 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. e17092-e17092

Author(s):

Agnieszka Badora-Rybicka ◽

Magdalena Budryk ◽

Danuta Starzyczny-Słota ◽

Elzbieta Nowara

Keyword(s):

Ovarian Cancer ◽

Adverse Events ◽

Epithelial Ovarian Cancer ◽

First Line ◽

Platinum Based Chemotherapy

Download Full-text

DUETTE: A randomized phase II study to assess a second maintenance treatment with olaparib (ola) or ola+ceralasertib (cer), in patients (pts) with platinum-sensitive relapsed (PSR) epithelial ovarian cancer who have previously received PARP inhibitor maintenance treatment (NCT04239014).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps6104 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS6104-TPS6104 ◽

Cited By ~ 1

Author(s):

Amit M. Oza ◽

Andrew Pierce ◽

Alan Lau ◽

Nisha Kurian ◽

Graeme Parr ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Phase Ii ◽

Maintenance Treatment ◽

Phase Ii Study ◽

Brca Mutation ◽

Unmet Need ◽

Advanced Ovarian Cancer ◽

Resistance Mechanisms ◽

Platinum Based Chemotherapy

TPS6104 Background: Ovarian cancer is the leading cause of death from gynecological cancers in the USA, and the fifth most common cause of cancer death in women. Ola is a PARPi approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer in women who achieve a complete or partial response to platinum-based chemotherapy. Ola is also efficacious in combination with bevacizumab in the same population, independent of BRCA mutation status. Cer is a potent, oral, selective inhibitor of ATR. ATR is a critical DDR kinase that is activated in response to replication stress and stalled replication forks. There is no second maintenance standard of care for patients with PSR ovarian cancer who have previously received a PARPi in the maintenance setting. Pre-clinical models have shown that several mechanisms of PARPi resistance may be overcome by ATR inhibition, such as BRCA reversion, replication fork protection and DDR rewiring. DUETTE will select pts with tumor response or stable disease after second or third-line platinum-based treatment, with the expectation to enrich for non-BRCA reversion PARPi resistance mechanisms. The study will address the role of a second maintenance treatment following prior 1L or 2L maintenance, an emerging population of unmet need, and includes translational studies that aim to further our knowledge of clinical PARPi resistance mechanisms and predictors of treatment response. Methods: DUETTE is a global, multi-center, phase II study. 192 pts with PSR epithelial ovarian cancer who have previously received PARPi maintenance treatment, will be retreated with platinum and those who have not progressed after ≥ 4 cycles will be randomized (1:1:1) to 3 treatment arms: Arm 1, open-label: cer 160 mg once daily (qd) days 1 to 7 plus ola 300 mg twice daily (bd); Arm 2, blinded: ola monotherapy 300 mg bd and Arm 3, blinded: ola-placebo. Treatment is administered in 28-day cycles. All pts will be stratified by BRCA status (mutation or wildtype) and response to most recent line of platinum-based chemotherapy (CR/PR or SD). The primary endpoint is to assess the efficacy of maintenance ola monotherapy and cer+ola combination therapy compared with placebo by PFS using blinded, independent central review. Secondary endpoints are overall survival, PFS2, ORR, DoR, safety and tolerability. Enrolment is planned to start in April 2020.

Download Full-text

Association of Vascular Endothelial Growth Factor Gene Polymorphisms With Susceptibility to Epithelial Ovarian Cancer

International Journal of Gynecological Cancer ◽

10.1111/igc.0b013e3181dbd32b ◽

2010 ◽

Vol 20 (5) ◽

pp. 717-723 ◽

Cited By ~ 10

Author(s):

Yan Li ◽

Yan Wang ◽

Shan Kang ◽

Na Wang ◽

Rong-Miao Zhou ◽

...

Keyword(s):

Ovarian Cancer ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Confidence Interval ◽

Epithelial Ovarian Cancer ◽

Odds Ratio ◽

Gene Polymorphisms ◽

Angiogenic Factor ◽

Vascular Endothelial ◽

Endothelial Growth Factor

Background:Vascular endothelial growth factor (VEGF) is a major angiogenic factor involved in a number of pathological processes, including neovascularization, a crucial step in the development of solid malignancies. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with susceptibility to epithelial ovarian cancer (EOC).Methods:This case-control study included 303 EOC patients and 303 healthy controls. Genotyping of the VEGF gene polymorphisms at −460C/T, −1154G/A, −2578C/A, and +936C/T were performed by polymerase chain reaction and restriction fragment length polymorphism analysis.Results:No significant difference was found in allele and genotype distributions of the −460C/T, +936C/T, and −2578C/A polymorphisms between patients and controls. However, the frequencies of −1154G/A genotype and allele were significantly different between the two groups (P = 0.037, P = 0.013). Compared with the G/A + A/A genotype, the G/G genotype could significantly increase the risk of developing EOC (odds ratio, 1.64; 95% confidence interval, 1.12-2.39). The haplotype analysis suggested that the −460T/−1154A/−2578C haplotype exhibited a decrease in the risk of developing EOC compared with the −460T/−1154G/−2578C haplotype (odds ratio, 0.644; 95% confidence interval, 0.415-0.999).Conclusions:The study suggested a possible association between the VEGF −1154G/A polymorphism with susceptibility to EOC, but there is no support for an association of the VEGF −460C/T, +936C/T, and −2578C/A polymorphisms with the risk for EOC.

Download Full-text