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In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08–0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34–0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13–0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35–0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination–deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18–0.61) and in patients with homologous recombination–proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36–0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS.Significance:We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo.

PURPOSE ATHENA (ClinicalTrials.gov identifier: NCT03522246 ) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo. METHODS Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

Background Toxicity during chemoradiotherapy (CRT) in cervical cancer patients might limit the chances of receiving an optimal treatment and to be cured. Few studies have shown relationships between side effects and patient’s age. Here, the association between age and side effects such as nausea/vomiting, diarrhea and weight loss during CRT was analysed in cervical cancer patients. Methods This study included 93 patients with primary cervical cancer stage IBI to IVA who received CRT from 2013 to 2019. The frequency of symptoms/toxicity grade was analysed by using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results Patients ≥52 years had a significantly higher frequency of nausea/vomiting and increased grade ≥3 toxicity during CRT compared to younger patients (p < 0.001, p = 0.001). Toxicity grade ≥3 of nausea/vomiting was associated with increased frequency of weight loss (p = 0.001), reduced ADL (p = 0.001) and dose modifications of both radiotherapy (RT) (p = 0.020) and chemotherapy (CT) (p = 0.030) compared to toxicity grade 2. The frequency of diarrhea (p = 0.015) and weight loss (p = 0.020) was higher in older patients compared to younger. Conclusions Older patients have an increased risk of side effects as nausea/vomiting, diarrhea and weight loss. Age could be useful in predicting side effects in primary cervical cancer patients with CRT.

In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08–0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34–0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13–0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35–0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination–deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18–0.61) and in patients with homologous recombination–proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36–0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS.Significance:We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo. UNLABELLED: In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08-0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34-0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13-0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35-0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination-deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18-0.61) and in patients with homologous recombination-proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36-0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS.SIGNIFICANCE: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo.

Objective To assess the impact of lymphadenectomy and lymphoedema of the lower limbs (LLL) on health-related quality of life (HRQoL) 1 year after surgery for endometrial cancer (EC). Design Prospective longitudinal cohort multicentre study. Setting Departments of obstetrics and gynaecology at four university hospitals, six central hospitals and four county hospitals in Sweden. Population Two-hundred-and-thirty-five women with early stage EC were included; 116 with high-risk EC underwent surgery including lymphadenectomy (+LA), and 119 with low-risk EC had surgery without lymphadenectomy (-LA). Methods The generic SF-36 and EQ-5D-3L and the lymphoedema-specific LYMQOL questionnaire were used to assess HRQoL. LLL was assessed by systematic circumferential measurements of the legs enabling volume estimation, clinical evaluation and patient-reported perception of leg swelling. All assessments were carried out on four occasions; preoperatively, and 4-6 weeks, 6 months and 1 year postoperatively. Main outcome measure HRQoL scores. Results No significant differences were seen in HRQoL between the +LA and -LA groups 1 year postoperatively. Irrespective of method of determining LLL, women with LLL were significantly more affected in the LYMQOL domains Function, Appearance/body image and Physical symptoms, but not in the domain Emotion/mood, than women without LLL. No such differences were seen in the generic HRQoL or in the LYMQOL global score between the groups with and without LLL. Conclusions Lymphadenectomy did not seem to affect generic HRQoL adversely. Irrespective of the method of measuring, LLL affected the lymphoedema-specific HRQoL negatively, mainly in physical domains, but had no impact on the generic HRQoL. Tweetable abstract Lymphoedema has impact on lymphoedema-specific, but not on generic, HRQoL, 1 year after surgery for EC. Funding Agencies|Swedish Cancer Society (Cancerfonden)Swedish Cancer Society [CAN2013/620]; Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [FORSS-308611, FORSS-391311, FORSS-662141, FORSS-858611]; Uppsala-Orebro Regional Research Council [LUL-349271]; Scientific Council of the Region Halland; County Council of Ostergotland; Linkoping University

Introduction/Background* Risk factors for lymphoedema of the lower limbs (LLL) after treatment of endometrial cancer (EC) is disputed. Body mass index (BMI) is strongly associated with LLL. The aim of this study was to determine the impact of BMI on risk factors for LLL, assessed as crude volume increase ≥10% or as BMI-standardised volume increase (BMI-SV) ≥10%, one year after surgery for early-stage EC . Methodology An observational prospective multicentre study was conducted in 14 Swedish hospitals enrolling 234 women with EC; 116 underwent surgery including pelvic and para-aortic lymphadenectomy (LA) and 119 had surgery without LA. LLL was assessed at baseline preoperatively and one year postoperatively by systematic circumferential measurements of the legs, enabling estimation of leg volume. Leg volume was determined as the de facto volume, i.e. crude volume and as the leg volume to a standardised BMI, i.e. BMI-SV. Risk factors were analysed using multiple logistic forward stepwise regression models. Result(s)* Lower BMI and medication with diuretics were independent risk factors for LLL determined by crude leg volume ≥10% (aOR 0.88, 95%CI 0.80-0.97 and aOR 2.67, 95%CI 1.04-6.89, respectively) whereas LA was not a risk factor. The BMI and change in BMI from baseline to one year outweighed the effect of LA as a risk factor. Neither number of lymph nodes removed, location, nor extent of LA were independent risk factors for LLL determined by crude volume increase ≥10%. By using BMI-SV volume increase ≥10% as LLL independent risk factors were adjuvant radiation therapy (aOR 15.02, 95%CI 2.34–96.57), LA (aOR 14.42, 95%CI 3.49–59.62), diabetes mellitus (aOR 5.44, 95%CI 1.67–17.66), and age (aOR 1.07, 95%CI 1.00–1.15). Simultaneously, the number of lymph nodes removed, location and extent of LA were strongly predictive for development of LLL. Conclusion* BMI was a strong risk factor for LLL that outweighed the effect of obvious risk factors and therefore should be adjusted for when assessing LLL. Adjuvant radiation therapy and LA were strong independent risk factors for LLL together with age and diabetes mellitus. There is a need for a `gold standard` for determining LLL when addressing risk factors.

OBJECTIVE: The aim of the study was to determine risk factors for lymphedema of the lower limbs, assessed by four methods, 1 year after surgery for endometrial cancer. METHODS: A prospective longitudinal multicenter study was conducted in 14 Swedish hospitals. 235 women with endometrial cancer were included; 116 underwent surgery including lymphadenectomy, and 119 had surgery without lymphadenectomy. Lymphedema was assessed preoperatively and 1 year postoperatively objectively by systematic circumferential measurements of the legs, enabling volume estimation addressed as (1) crude volume and (2) body mass index-standardized volume, or (3) clinical grading, and (4) subjectively by patient-reported perception of leg swelling. In volume estimation, lymphedema was defined as a volume increase ≥10%. Risk factors were analyzed using forward stepwise logistic regression models and presented as adjusted odds ratio (aOR) and 95% confidence interval (95% CI). RESULTS: Risk factors varied substantially, depending on the method of determining lymphedema. Lymphadenectomy was a risk factor for lymphedema when assessed by body mass index-standardized volume (aOR 14.42, 95% CI 3.49 to 59.62), clinical grading (aOR 2.11, 95% CI 1.04 to 4.29), and patient-perceived swelling (aOR 2.51, 95% CI 1.33 to 4.73), but not when evaluated by crude volume. Adjuvant radiotherapy was only a risk factor for lymphedema when assessed by body mass index-standardized volume (aOR 15.02, 95% CI 2.34 to 96.57). Aging was a risk factor for lymphedema when assessed by body mass index-standardized volume (aOR 1.07, 95% CI 1.00 to 1.15) and patient-perceived swelling (aOR 1.06, 95% CI 1.02 to 1.10), but not when assessed by crude volume or clinical grading. Increase in body mass index was a risk factor for lymphedema when estimated by crude volume (aOR 1.92, 95% CI 1.36 to 2.71) and patient-perceived swelling (aOR 1.36, 95% CI 1.11 to 1.66), but not by body mass index-standardized volume or clinical grading. The extent of lymphadenectomy was strongly predictive for the development of lymphedema when assessed by body mass index-standardized volume and patient-perceived swelling, but not by crude volume or clinical grading. CONCLUSION: Apparent risk factors for lymphedema differed considerably depending on the method used to determine lymphedema. This highlights the need for a 'gold standard' method when addressing lymphedema for determining risk factors. Funding: Swedish Cancer Society (Cancerfonden)Swedish Cancer Society [CAN2013/620]; Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [FORSS-308611, FORSS-391311, FORSS-662141, FORSS-858611]; Uppsala-Orebro Regional Research Council [LUL-349271]; Scientific Council of the Region Halland; County Council of Ostergotland; Linkoping University

Objectives: In the ENGOT-OV16/NOVA study, maintenance therapy with niraparib significantly prolonged progression-free survival (PFS) in patients (pts) with platinum-sensitive recurrent ovarian cancer (PSROC) regardless of germline BRCA mutation (gBRCAm) or homologous recombination deficiency (HRd) biomarker status. This analysis updates long-term safety and available data on secondary efficacy outcomes. Methods: In this randomized, double-blind, placebo-controlled, phase III trial, pts with PSROC were enrolled into 1 of 2 independent cohorts by gBRCAm status (gBRCAm or non-gBRCAm). Stratification factors were PFS after the penultimate platinum therapy (6 to Results: A total of 553 pts were randomized in the NOVA study. Median follow-up was 66 months at the time of the current analysis. Hematologic treatment-emergent adverse effects (TEAEs) primarily occurred in the first year of niraparib treatment: incidence of grade ≥3 thrombocytopenia decreased from 33.8% to 2.8%, anemia decreased from 25.6% to 0.7%, and neutropenia decreased from 19.3% to 2.1% from year 1 to year 2–3, respectively. A total of 13 (3.5%; 9 gBRCAm, 4 non-gBRCAm) pts who received niraparib developed MDS/AML vs 3 (1.7%) placebo pts. Survival status could not be obtained for ~15% of pts. Data on post-progression therapy, including PARP inhibitors, were not available for 25% of the study pts. Based on data cut-off on October 2020, 127 and 238 deaths occurred in the gBRCAm and non-gBRCAm cohorts, respectively. For pts with available data, placebo pts received subsequent PARP inhibitor therapy (crossover) after disease progression: 46% (30/65) in the gBRCAm cohort and 13% (15/116) in the non-gBRCAm cohort. Hazard ratios for PFS2 were 0.67 (95% CI: 0.48, 0.95) in the gBRCAm cohort and 0.81 (95% CI: 0.62, 1.05) in the non-gBRCAm cohort. Restricted mean survival time analyses for OS up to 72 months were 43.2 months in placebo vs 45.9 months in niraparib (Δ of 2.7m, 95% CI: -4.1, 9.5) in the gBRCAm cohort and 39.1 months in placebo vs 38.5 months in niraparib (Δ of -0.6m, 95% CI: -6.0, 4.7) in the non-gBRCAm cohort. Conclusions: These final data support the safe long-term use of niraparib for maintenance treatment in pts with PSROC. PFS2 analysis indicates that the benefit of niraparib maintenance therapy extends beyond first progression. No difference in survival was observed. The NOVA study was not powered for OS, and analysis is confounded by a high rate of crossover and missing data thus limiting its interpretation. Sponsor: GlaxoSmithKline. Clinical Trial Registration: NCT01847274.

Objective. The study aimed to determine the incidence of lower limb lymphedema (LLL) after surgery for endometrial cancer (EC) by means of three methods, and to determine the incidence of lymphocysts after one year. Methods. A prospective longitudinal multicenter study was conducted in 14 hospitals in Sweden. Two-hundred-and-thirty-five women with EC were included; 116 underwent surgery that included lymphadenectomy (+LA) and 119 were without lymphadenectomy ( -LA). Lymphedema was assessed objectively on four occasions; preoperatively, at 4-6 weeks, six months and one year postoperatively using systematic measurement of leg circumferences, enabling calculation of leg volumes, and a clinical grading of LLL, and subjectively by the patients perception of lymphedema measured by a lymphedema-specific quality-of-life instrument. Lymphocyst was evaluated by vaginal ultrasonography. Results. After one year the incidence of LLL after increase in leg volume adjusted for body mass index was 15.8% in +LA women and 3.4% in -IA women. The corresponding figures for clinical grading were 24.1% and 11.8%, and for patient-reported perceived LLL 10.7% and 5.1%. The agreement between the modalities revealed fair to moderate correlation between patient-reported LLL and clinical grading, but poor agreement between volume increase and patient-reported LLL or clinical grading. Lymphocysts were found in 43% after one year. Conclusions. Although the incidence of ILL and lymphocysts after surgery for EC including LA seemed to be relatively high the study demonstrated significant variations in incidence depending on the measurement modality. This emphasizes the need for a gold standard of measurement of LLL in clinical practice and research. (C) 2020 Elsevier Inc. All rights reserved. Funding Agencies|Swedish Cancer Society [Cancerfonden]Swedish Cancer Society [CAN2013/620]; Medical Research Council of Southeast Sweden [FORSS-308611, FORSS-391311, FORSS-662141, FORSS-858611]; Uppsala-Orebro Regional Research Council [LUL-349271]; Scientific Council of the Region Halland; County Council of Ostergotland; Linkoping University

6012 Background: We previously reported significantly improved progression-free survival (PFS) with the chemotherapy-free regimen of niraparib and bevacizumab compared to niraparib alone, in women with platinum-sensitive relapsed ovarian cancer (PSROC), regardless of homologous recombination deficiency (HRD) status (MyChoice HRD), duration of chemotherapy-free interval (CFI) and number of previous lines of therapy (Mirza MR et al, Lancet Oncol 2019). We now present the updated PFS, overall survival (OS) and other efficacy and safety endpoints. Methods: In this randomized, open-label, phase 2 study, women with measurable/evaluable, high-grade serous or endometrioid PSROC were randomized to niraparib 300mg once daily or the combination of niraparib 300mg once daily and bevacizumab 15mg/kg IV every 3 weeks until disease progression (1:1 randomization). The primary endpoint was PFS. Stratification was according to HRD status and CFI (6-12months (mo) vs. > 12mo). First-line maintenance bevacizumab was permitted. Results: Of 97 enrolled patients, 48 were randomized to niraparib monotherapy and 49 to the chemotherapy-free combination. The combined treatment significantly improved PFS compared to niraparib alone: updated median PFS 12.5 mo vs. 5.5 mo; hazard ratio (HR) adjusted for stratification factors 0.34; 95% confidence interval (CI) [0.21 to 0.55]; P < 0.0001. Preplanned exploratory subgroup analyses: patients with HRD-positive tumors (n = 54) HR 0.41 (CI, 0.23-0.76); HRD-negative disease (n = 43) HR, 0.40 (CI, 0.20-0.79); Time to First Subsequent Therapy (TFST) (n=97) HR, 0.4 (CI, 0.25-0.64); PFS2 (n=97) HR 0.55 (CI, 0.35-0.88); Time to Second Subsequent Therapy (TSST) (n=97) HR, 0.56 (CI, 0.35-0.90); OS (49 events only) HR, 0.77 (CI, 0.42-1.41). There was no difference in treatment-emergent grade 3-4 adverse events except for the rate of hypertension (22.9% vs. 0%) and neutropenia (8.3% vs. 2.0%). Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms. Conclusions: Updated PFS consistently demonstrates that the niraparib-bevacizumab combination had clinically and statistically meaningful activity in PSROC. This phase 2 study was not powered to detect differences in OS or any other efficacy endpoints however TFST, PFS2 & TSST are significantly improved while there is a trend towards OS improvement with niraparib-bevacizumab combination. Clinical trial information: NCT02354131.

Background: The aim of this study was to validate a translated Swedish version of the lymphoedema-specific quality of life questionnaire (LYMQOL) in a cohort of Swedish cancer patients with secondary lymphoedema of the limbs after cancer treatment. Material and methods: We recruited 102 patients with lymphoedema of the arms or legs after cancer treatment who were visiting lymphoedema therapists at the departments of oncology at the university hospitals in Linköping and Umeå. The LYMQOL questionnaires were translated forward and backward from English to Swedish. Content and face validity were evaluated. The construct validity was assessed by comparing the LYMQOL with the Short Form Health Survey (SF-36) and the perceived degree of lymphoedema of the limbs, respectively. Reliability was determined through test-retest. The internal consistency was assessed by determining Cronbach’s alpha and by factor analysis. Results: The content and face validity assessments showed that LYMQOL was an easy, clear and not too long questionnaire to use for patients with lymphoedema. Construct validity was high in both versions when compared with the SF-36. The association between the degrees of perceived lymphoedema and the LYMQOL was only significant in the domains Function and Body Image in the arm version, whereas all domains in the leg version were significant. The reliability was good for the arm version (intra-class-correlation coefficients 0.53–0.87) and very good for the leg version (intra-class-correlation coefficients 0.78–0.90). The internal consistency was acceptable to excellent, with Cronbach’s alpha values between 0.79–0.93 (arm-version) and 0.87–0.94 (leg-version). The factor analysis confirmed the usefulness of the four domains in the LYMQOL versions. Conclusions: This study confirmed the validity of the Swedish version of LYMQOL and demonstrated that LYMQOL may be a simple and useful tool for use in clinical practice and scientific contexts for evaluating QoL in patients with lymphoedema of the limbs. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [CAN 2013/620]; Linkoping University; County Council of Ostergotland

Breast cancer is the most common cancer among women worldwide today. Nearly 9000 women are diagnosed with breast cancer in Sweden yearly and despite advantages in diagnostics and treatments approxi ...

Introduction/Background Rucaparib has clinical activity in patients with recurrent OC with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genomic loss of heterozygosity [LOH]) and is hypothesised to provide clinical benefit following frontline treatment. ATHENA is evaluating rucaparib + nivolumab as maintenance treatment following frontline platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for this combination includes: tumours with BRCA mutations express tumour-specific proteins (neoantigens), which attract PD-L1-expressing, tumour-infiltrating lymphocytes; ovarian tumours with HRD have more neoantigens relative to HR-proficient tumours and may respond to immune checkpoint inhibitors; rucaparib combined with anti-PD-1 demonstrated improved antitumour activity in an OC model; it is hypothesised that PARP inhibitor-induced DNA damage may increase neoantigens, regardless of HRD status. Methodology Eligible patients must have completed frontline platinum-doublet chemotherapy and surgery and achieved an investigator-assessed response without disease progression or rising CA-125 at any time during frontline treatment. Cytoreductive surgery (R0 permitted) could have been completed prior to chemotherapy or following neoadjuvant chemotherapy. Patients will be randomised 4:4:1:1 to receive maintenance treatment in Arm A (oral rucaparib 600 mg BID + intravenous nivolumab 480 mg Q4W), Arm B (oral rucaparib + intravenous placebo), Arm C (oral placebo + intravenous nivolumab), or Arm D (oral placebo + intravenous placebo). Stratification factors include centrally determined tumour HRD status (BRCA mutant, non-BRCA mutant/LOH high, non-BRCA mutant/LOH low, or non-BRCA mutant/LOH indeterminate), posttreatment disease status, and timing of surgery. Investigator-assessed progression-free survival (RECIST v1.1; primary endpoint) will be compared between arms. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, objective response rate, and safety. Results Patients (n≈1000) will be enrolled at >270 sites worldwide. Conclusion ATHENA is evaluating rucaparib + nivolumab as frontline maintenance treatment in patients with OC. Disclosure AO: Clovis, AstraZeneca, Genmab/Seattle Genetics, ImmunoGen, PharmaMar, Roche, Tesaro DL: Clovis, AstraZeneca, ImmunoGen, Merck, PharmaMar, Roche, Tesaro DC: AstraZeneca, Genmab, Pfizer, Seattle Genetics, BMS, MSD, Roche RLC: Clovis, AbbVie, AstraZeneca, Esperance, Janssen, Millennium, Merck, OncoMed, Roche/Genentech, Bayer, GamaMabs, Genmab, Gradalis, Pfizer, Tesaro KF: Advanced Oncotherapy, AstraZeneca, Chugai-Roche, Daiichi-Sankyo, Eisai, GSK, ImmunoGen, Kaken-Seiyaku, Lilly, Merck, Ono Pharmaceutical, Pfizer, Shionogi, Taiho, Zeria Pharmaceutical AMO: Clovis, Amgen, Immunovaccine, Verastem, AstraZeneca, WebRx SNW: Clovis, AstraZeneca, Bio Ascend, Genentech, Gynecologic Oncology Group, Medivation/Pfizer, Merck, Ovation, Roche, Takeda, Tesaro, Vermillion, ArQule, Bayer, Cotinga Pharmaceuticals, Novartis DMO’M: Clovis, AstraZeneca, Gynecologic Oncology Group, Janssen, Myriad, Tesaro, Amgen, ImmunoGen, AbbVie, Health Analytics, Ambry, Agenus, Ajinomoto, Array BioPharma, BMS, ERGOMED Clinical Research, Exelixis, Genentech, GSK, INC Research, inVentiv Health Clinical, Ludwig Institute for Cancer Research, Novartis, PRA International, Regeneron, Serono, Stemcentrx, TRACON TJH: Clovis, AstraZeneca, Caris, Johnson & Johnson, Roche, Tesaro RE: Clovis, AstraZeneca, Roche/Genentech, Merck, Pfizer, Tesaro MW: AstraZeneca, MSD, Roche SA, NG: Clovis IAM: Clovis, AstraZeneca, Tesaro BJM: Clovis, AstraZeneca, Janssen/Johnson & Johnson, Myriad, Roche/Genentech, Tesaro, Amgen, Bayer, Biodesix, Cerulean, GSK, Gradalis, ImmunoGen, Insys, Mateon, Merck, NuCana, Perthera, Pfizer, Precision Oncology, Verastem, Vermillion RSK: Clovis, Tesaro, Roche All other authors have nothing to disclose.

BACKGROUND: Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer.METHODS: This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131.FINDINGS: Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], pINTERPRETATION: The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned.FUNDING: Nordic Society of Gynaecological Oncology and Tesaro.

PURPOSE This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. PATIENTS AND METHODS Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation—g BRCAmut and non-g BRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post–random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. RESULTS In the g BRCAmut and non-g BRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the g BRCAmut and non-g BRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. CONCLUSION Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.

IntroductionWomen with cervical cancer in the Nordic countries are increasingly undergoing pretreatment imaging by ultrasound, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT) or computed tomography, or sentinel lymph node procedure. The present survey reports the influence of pretreatment imaging findings on the recorded clinical International Federation of Gynecology and Obstetrics (FIGO) stage in Nordic countries and its impact on treatment planning and preferred surgical approach in cervical cancer.Material and methodsThe Nordic Society of Gynecological Oncology Surgical Subcommittee developed a questionnaire-based survey that was conducted from 1 January to 31 March 2017. All the 22 Nordic Gynecological Oncology Centers (Denmark 5, Finland 5, Iceland 1, Norway 4, and Sweden 7) were invited to participate.ResultsThe questionnaires were returned by 19 of 22 (86.3%) centers. The median number (range) of women with cervical cancer treated at each center annually was 32 (15-120). In 58% (11/19) of the centers, imaging findings were reported to influence the clinical staging. MRI in combination with PET-CT was the preferred imaging method and the results influenced treatment planning. Robotic-assisted radical hysterectomy was the preferred surgical method in 72% (13/18) of the centers. Sentinel lymph node procedure was not routinely implemented in the majority of the Nordic centers.ConclusionMore than half of the Nordic Gynecological Oncology Centers already report a clinical FIGO stage influenced by pretreatment imaging findings. The trend in preferred treatment is robotic-assisted radical hysterectomy and the sentinel lymph node procedure is gradually being introduced.

Anti-oestrogens such as tamoxifen, decrease the risk of breast cancer but are unsuitable for prevention because of their side-effects. Diet modifications may be a breast cancer prevention strategy. Here, we investigated if a diet addition of flaxseed, which can be converted to the phytoestrogen enterolactone by the gut microbiota, exhibited similar effects as tamoxifen on normal human breast tissue in vivo, with special emphasis on inflammatory mediators implicated in cancer progression. A total of 28 postmenopausal women were included. Thirteen women added 25 g of ground flaxseed per day and 15 were treated with tamoxifen as an adjuvant for early breast cancer for 6 weeks. Microdialysis of normal breast tissue and, as a control, in subcutaneous abdominal fat was performed for sampling of extracellular proteins in vivo before and after exposures. Enterolactone levels increased significantly after flaxseed. IL-1Ra and IL-1Ra/IL-1β ratio in the breast increased in a similar fashion after the two different treatments. Flaxseed also increased breast specific levels of IL-1RT2, IL-18 and sST2 and an overall increase of MMP-9. These changes correlated significantly with enterolactone levels. Tamoxifen decreased breast tissue levels of IL-8 and IL-18. None of the treatments induced any changes of IL-1β, IL-1RT1, IL-18BP, IL-33, IL-6, IL-6RA, MMP-1, MMP-2 and MMP-3. We conclude that dietary flaxseed and tamoxifen exert both similar and different effects, as listed above, on normal breast tissue in vivo and that a relatively modest diet change can induce significant effects on the breast microenvironment.

Cervical cancer is the third most common female cancer world wide. In Sweden, some 450 cases are diagnosed annually. One out of three affected Swedish women is under the age of 40. Survival for all stages is 73 % in Sweden. Human papilloma virus (HPV) can be detected in the majority of all cervical cancers. Treatment consists of surgery for early stages, and a combination of chemoradiation and brachytherapy for locally advanced disease. For metastatic disease, the treatment is palliative. Late side effects after treatment may have serious impact on the quality of life. There is a strong need for more efficient treatment of metastatic disease. Current lines of research include surgical strategies, optimised radiotherapy, neoadjuvant therapy, targeted therapy, and immunotherapy including therapeutic vaccines.

The proinflammatory cytokines IL-1α and IL-1β promote tumor angiogenesis that might be counteracted by the IL-1 receptor antagonist (IL-1Ra), anakinra, a clinically approved agent. A diet with high amounts of phytoestrogens, such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL), may affect breast cancer progression in a similar fashion as the antiestrogen tamoxifen. Both cancer cells and tumor stroma may be targets for cancer therapy. By using microdialysis in a model of human breast cancers in nude mice, we could perform species-specific analyses of released proteins in the microenvironment. We show that tumors treated with tamoxifen and fed Flax or ENL exhibited decreased in vivo release of IL-1β derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects. Cancer cell–released IL-1Ra were approximately 5 times higher than stroma-derived IL-1Ra. Tamoxifen, Flax, and ENL increased IL-1Ra levels significantly whereas GEN did not. The tumor stroma contained macrophages, which expressed the estrogen receptor. In vitro, estradiol decreased IL-1Ra released from breast cancer cells and from cultured macrophages. IL-1Ra decreased endothelial cell proliferation significantly in vitro whereas breast cancer cell proliferation was unaffected in presence of estradiol. Finally, IL-1Ra therapy of tumor-bearing mice opposed estrogen-dependent breast cancer growth and decreased angiogenesis. We conclude that the release of IL-1s both by cancer cells and the stroma, where macrophages are a key component, may offer feasible targets for antiestrogen therapy and dietary interventions against breast cancer. Cancer Res; 71(1); 51–60. ©2011 AACR.

The proinflammatory cytokines IL-1α and IL-1β have been shown to promote tumor angiogenesis, which may be counteracted by the IL-1 receptor antagonist (IL-1Ra). A diet with high amounts of phytoestrogens such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL) may affect breast cancer progression possibly in a similar fashion as the anti-estrogen tamoxifen. Both cancer cells and the tumor stroma may be targets for cancer therapy. Therefore, we set up a model with species-specific components of the microenvironment by establishing human breast cancers in nude mice and sampled released proteins by microdialysis. We show that tumors of mice treated with tamoxifen, fed Flax or ENL exhibited decreased in vivo release of IL-1β derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects compared to controls. Cancer cells released IL-1Ra were approximately five times higher compared with stroma derived and tamoxifen, Flax, and ENL increased these levels significantly whereas GEN did not. In vitro, estradiol decreased released IL-1Ra of breast cancer cells. ENL completely reversed this whereas tamoxifen further increased IL-1Ra levels. IL-1Ra had no effect on breast cancer cell proliferation in presence of E2 in vitro whereas endothelial cell proliferation was significantly decreased by IL-1Ra in a dose dependent manner. Finally, IL-1Ra therapy of tumor bearing mice opposed estrogen dependent breast cancer growth and decreased tumor angiogenesis. These data may provide insights into tumor-stroma mechanisms involved in estrogen effects on breast cancer progression and tamoxifen and dietary interventions against this disease. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-02-06.