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Welcome
RANDOMIZED TRIAL OF PELVIC RADIATION WITH AND WITHOUT CONCURRENT CISPLATIN IN PATIENTS WITH A PELVIC ONLY RECURRENCE OF ENDOMETRIAL CANCER
Abstract
Objectives
The pelvis is a common site of recurrence for patients with endometrial cancers. A randomized trial was conducted to compare progression-free survival in patients treated with radiation therapy alone as compared to radiation therapy with concurrent cisplatin-based chemotherapy.
Methods
165 Patients were accrued between February 2009 and August 2020. Women with recurrent endometrial carcinoma limited to the pelvis were eligible. The median time for follow up for vital status was 60 months.
Results
Most patients had grade 1 or 2 endometroid endometrial cancer (81%) and most recurrences were vaginal (86%). Radiation therapy was delivered to the pelvis with 3D or IMRT techniques followed by HDR or LDR interstitial or intracavitary brachytherapy. Chemotherapy was delivered with weekly cisplatin. Grade 4 or higher acute adverse event were reported in 8 participants in the chemotherapy and radiation arm as compared to 1 treated with radiation only. 68% of patients treated with radiation therapy were alive and progression-free as compared to 59.8% of those that received chemotherapy and radiation. Overall, patients treated with weekly cisplatin had a lower rate of PFS as compared to patients treated with radiation alone (stratified HR=1.40, 95% CI: 0.82-2.39, p=0.8919).
Conclusions
Results of this randomized trial suggest that the addition of chemotherapy does not improve, and may worsen, outcomes for patients treated with definitive radiation therapy for recurrent endometrial cancer. Those with low grade and vaginal apex recurrences may be best treated with radiation therapy alone.
Distillation & Q&A
POST-HOC ANALYSIS OF OBJECTIVE RESPONSE RATE BY MISMATCH REPAIR PROTEIN DIMER LOSS/MUTATION STATUS IN PATIENTS WITH MISMATCH REPAIR DEFICIENT ENDOMETRIAL CANCER TREATED WITH DOSTARLIMAB
Abstract
Objectives
Mismatch repair (MMR) deficiency is caused by loss of expression of MMR proteins, MLH1, PMS2, MSH2, and/or MSH6, that function as heterodimers (MLH1/PMS2 and MSH2/MSH6) to mediate DNA repair. Loss of function caused by mutation or epigenetic methylation leads to defective MMR and genomic instability. MMR deficient (dMMR) tumors can respond to anti-programmed death 1 (PD-1) therapy. We report on a post-hoc analysis of ORR with loss of MMR dimers and mutation status of MMR genes in patients with dMMR endometrial cancer (EC) treated with dostarlimab.
Methods
GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort A1 enrolled patients with dMMR advanced/recurrent EC. Patients received 500 mg dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. MMR protein status (presence or loss) was determined by local IHC. MMR gene mutation was determined by Foundation One. MLH1 loss without MMR gene mutation was a surrogate indicator for epigenetic methylation.
Results
Cohort A1 included 143 patients; MMR gene mutation data was available for 101 (Table). Cohort A1 ORR was 45.5%. 66% of patients had loss of MLH1/PMS2; ORR was 48.9%. 11.2% of patients had loss of MSH2/MSH6; ORR was 56.2%. ORR was 41.7% for MLH1 loss with MMR gene mutation and 39.4% for MLH1 loss without MMR gene mutation.
Conclusions
Patients with dMMR advanced/recurrent EC benefitted from dostarlimab, with no noticeable difference by dimer-pair loss or MMR gene methylation/mutation status. These data suggest route to MMR deficiency does not influence response to dostarlimab.
Distillation & Q&A
COMBINATION THERAPY WITH TOPOTECAN, PACLITAXEL, AND BEVACIZUMAB IMPROVES PROGRESSION-FREE SURVIVAL IN PATIENTS WITH RECURRENT HIGH-GRADE NEUROENDOCRINE CARCINOMA OF THE CERVIX: A NECTUR STUDY
Abstract
Objectives
The objective of this study was to evaluate the efficacy of the three-drug regimen topotecan, paclitaxel, and bevacizumab (TPB) in women with recurrent high-grade neuroendocrine cervical cancer (HGNECC).
Methods
This retrospective cohort study used data from the Neuroendocrine Cervical Tumor Registry (NeCTuR). The study compared women with recurrent HGNECC who received TPB as first- or second-line therapy for recurrence and women with recurrent HGNECC who received chemotherapy but not TPB. Progression-free survival from the start of treatment for recurrence to the next recurrence or death, overall survival from first recurrence, and response rates were evaluated.
Results
The study included 57 patients who received TPB as first- or second-line treatment for recurrence and 48 patients who received chemotherapy but not TPB for recurrence. Median progression-free survival was 8.2 months in the TPBgroup compared to 3.1 months in the non-TPBgroup, with a hazard ratio for progression of 0.23 (95% CI 0.14-0.40; P < 0.0001). In the TPB group, 16% had stable disease, 38% had a partial response, and 16% had a complete response. Significantly more patients in the TPB group than in the non-TPB group remained on treatment at 6 months (67% vs. 25%, P = 0.0002) and 1 year (24% vs. 6%, P = 0.03). Median overall survival was 16.9 months in the TPBgroup compared to 14.0 months in the non-TPB group, with a hazard ratio for death of 0.89 (95% CI 0.55-1.45).
Conclusions
TPB is an active regimen in women with recurrent HGNECC and improves progression-free survival while decreasing the hazard ratio for progression.
NEXT GENERATION SEQUENCING REVEALS A HIGH PREVALENCE OF PATHOGENIC MUTATIONS IN HOMOLOGOUS RECOMBINATION DNA DAMAGE REPAIR GENES AMONG PATIENTS WITH UTERINE SARCOMA.
Abstract
Objectives
Evaluate the prevalence of alterations in homologous recombination DNA damage repair genes (HR-DDR) among patients with uterine sarcomas.
Methods
The AACR GENIE v12.0 database was accessed and patients with uterine leiomyosarcoma, adenosarcoma and endometrial stromal sarcoma were identified. We examined the incidence of pathogenic alterations of genes involved in HR-DDR: ATM, ARID1A, ATRX, BAP1, BARD1, BLM, BRCA2, BRCA1, BRIP1, CHEK2, CHEK1, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN.
Results
A total of 433 patients contributing to 450 samples were identified; 298 patients with leiomyosarcoma (LMS), 53 patients with adenosarcoma (AS), 30 patients with low-grade endometrial stromal sarcoma (ESS), 19 patients with high-grade, and 34 patients with ESS not specified (34 samples). The overall incidence of pathogenic HR-DDR gene alterations was 30% (135/450). The most prevalent gene alteration was ATRX (20%, 84/419) followed by BRCA2 (5%, 20/416), RAD51B (4%, 10/271), ATM (2.2%, 10/446) and ARID1A (1.9%, 8/419). The highest incidence of HR-DDR gene alterations was observed in leiomyosarcoma (36.5%) followed by adenosarcoma (29.8%), and HG-ESS (26.3%) while HR-DDR gene alterations were less common in ESS NOS (17.7%) and LG-ESS (13.3%). In the present cohort, incidence of TP53 mutations was 49% (213/432), while other common pathogenic gene alterations included the RB1 (29%, 128/449), PTEN (13%, 58/449) and MED12 (11%, 42/375) genes.
Conclusions
Approximately 1 in 3 patients with uterine sarcoma, harbor a pathogenic alteration in HR-DDR genes. These results provide further rationale for the design of molecularly driven clinical trials exploring agents targeting DNA damage repair.
Distillation & Q&A
Closing Comments