Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene.

PURPOSE: The prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. METHODS: An observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. RESULTS: 2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2=0.8%, BRIP1=1.1%, RAD51C=0.4% and RAD51D=0.4%. In 940 unselected cases, BRIP1 (OR=8.7, 95% CI 4.6-15.8) was the third commonest OC predisposition gene followed by RAD51C (OR=8.3, 95% CI 3.1-23.1), RAD51D (OR=6.5, 95% CI 2.1-19.7) and PALB2 (OR=3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. CONCLUSIONS: Panel testing in OC resulted in a detection rate of 2-3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

BRCA1/2 in non-mucinous epithelial ovarian cancer: tumour with or without germline testing?

National guidelines recommend testing all cases of non-mucinous epithelial ovarian cancer (NMEOC) for germline (blood) and somatic (tumour) BRCA1/2 pathogenic variants (PVs). We performed paired germline and somatic BRCA1/2 testing in consecutive cases of NMEOC (n = 388) to validate guidelines. Thirty-four somatic BRCA1/2 (sBRCA) PVs (9.7%) were detected in 350 cases with germline BRCA1/2 (gBRCA) wild-type. All sBRCA PVs were detected in non-familial cases. By analysing our regional germline BRCA1/2 database there were 92/1114 (8.3%) gBRCA PVs detected in non-familial cases (only 3% ≥70 years old) and 245/641 (38.2%) in familial cases. Germline non-familial cases were dominated by BRCA2 in older women (8/271 ≥ 70 years old, all BRCA2). The ratio of sBRCA-to-gBRCA was ≤1.0 in women aged <70 years old, compared to 5.2 in women aged ≥70 years old (P = 0.005). The likelihood of missed germline BRCA1/2 PVs (copy-number variants missed on most somatic assays) by testing only tumour DNA was 0.4% in women aged ≥70 years old. We recommend reflex tumour BRCA1/2 testing in all NMEOC cases, and that gBRCA testing is not required for women aged ≥70 years old with no identifiable tumour BRCA1/2 PV and/or family history of breast, ovarian, prostate and/or pancreatic cancer.

Randomised Controlled Trial Evidence Questions the Assumption that Pulmonary Metastasectomy Benefits Patients with Colorectal Cancer.

Pulmonary metastasectomy for sarcoma is surgery without proven benefit, and in the light of a randomized controlled trial examining pulmonary metastasectomy in colorectal cancer, it should be questioned.

Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial.

OBJECTIVE: Vascular co-option is a resistance mechanism to anti-angiogenic agents, but combinations of anti-vascular agents may overcome this resistance. We report a phase 1b and randomised phase 2 trial to determine the safety and efficacy of pazopanib with fosbretabulin. METHODS: Eligible patients had recurrent, epithelial ovarian cancer with a platinum-free interval (PFI) of 3 to 12 months. Patients were stratified according to PFI (>6 versus ≤6 months) and prior bevacizumab use. RESULTS: Twelve patients were treated in the phase 1b. Commonest grade ≥ 2 adverse events (AEs) were hypertension (100%), neutropenia (50%), fatigue (50%), vomiting (50%). There was one DLT (grade 3 fatigue). The recommended phase 2 dose level was fosbretabulin 54 mg/m2 on days 1, 8 and 15 and pazopanib 600 mg once daily (od), every 28 days, which was then compared to pazopanib 800 mg od in a randomised phase 2 trial. Twenty-one patients were randomised (1:1) in the phase 2 trial. In phase 1b and phase 2, four patients treated with pazopanib and fosbretabulin developed reversible, treatment-related cardiac AEs, leading to premature discontinuation of the study. In the phase 2 trial, the median PFS was 7.6 months (95% CI 4.1-not estimated) versus 3.7 months (95% CI 1.0-8.1) in favour of the experimental arm (HR 0.30, 95% CI 0.09-1.03, P = .06). CONCLUSIONS: It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials.

Role of front-line bevacizumab in advanced ovarian cancer: the OSCAR study.

OBJECTIVE: Two randomized phase III trials demonstrated the efficacy and safety of combining bevacizumab with front-line carboplatin/paclitaxel for advanced ovarian cancer. The OSCAR (NCT01863693) study assessed the impact of front-line bevacizumab-containing therapy on safety and oncologic outcomes in patients with advanced ovarian cancer in the UK. METHODS: Between May 2013 and April 2015, patients with high-risk stage IIIB-IV advanced ovarian cancer received bevacizumab (7.5 or 15 mg/kg every 3 weeks, typically for ≤12 months, per UK clinical practice) combined with front-line chemotherapy, with bevacizumab continued as maintenance therapy. Co-primary endpoints were progression-free survival and safety (NCI-CTCAE v4.0). Patients were evaluated per standard practice/physician's discretion. RESULTS: A total of 299 patients received bevacizumab-containing therapy. The median age was 64 years (range 31-83); 80 patients (27%) were aged ≥70 years. Surgical interventions were primary debulking in 21%, interval debulking in 36%, and none in 43%. Most patients (93%) received bevacizumab 7.5 mg/kg with carboplatin/paclitaxel. Median duration of bevacizumab was 10.5 months(range <0.1-41.4); bevacizumab and chemotherapy were given in combination for a median of three cycles (range 1-10). Median progression-free survival was 15.4 (95% CI 14.5 to 16.9) months. Subgroup analyses according to prior surgery showed median progression-free survival of 20.8, 16.1, and 13.6 months in patients with primary debulking, interval debulking, and no surgery, respectively. Median progression-free survival was 16.1 vs 14.8 months in patients aged <70 versus ≥70 years, respectively. The 1-year overall survival rate was 94%. Grade 3/4 adverse events occurred in 54% of patients, the most common being hypertension (16%) and neutropenia (5%). Thirty-five patients (12%) discontinued bevacizumab for toxicity (most often for proteinuria (2%)). CONCLUSIONS: Median progression-free survival in this study was similar to that in the high-risk subgroup of the ICON7 phase III trial. Median progression-free survival was shortest in patients who did not undergo surgery.

Prevalence of germline pathogenic BRCA1/2 variants in sequential epithelial ovarian cancer cases.

INTRODUCTION: Poly(ADP-ribose) polymerase inhibitors significantly improve progression-free survival in platinum-sensitive high-grade serous and endometrioid ovarian carcinoma, with greatest benefits observed in women with a pathogenic BRCA1/2 variant. Consequently, the demand for germline BRCA1/2 testing in ovarian cancer has increased substantially, leading to the screening of unselected populations of patients. We aimed to determine the prevalence of pathogenic germline BRCA1/2 variants in women diagnosed with epithelial ovarian cancer, categorised according to the established risk factors for hereditary breast and ovarian cancer syndrome and the Manchester BRCA Score, to inform risk stratification. METHODS: A cohort of sequential epithelial ovarian cancer cases recruited between June 2013 and September 2018 underwent germline BRCA1/2 testing by next-generation sequencing and multiplex ligation-dependent probe amplification. RESULTS: Five hundred and fifty-seven patients were screened. Of these, 18% had inherited a pathogenic BRCA1/2 variant. The prevalence of pathogenic BRCA1/2 variants was >10% in women diagnosed with ovarian cancer earlier than 60 years of age (21%) and those diagnosed later than 60 years of age with a family history of breast and/or ovarian cancer (17%) or a medical history of breast cancer (34%). The prevalence of pathogenic BRCA1/2 variants was also >10% in women with a Manchester BRCA Score of ≥15 points (14%). DISCUSSION: Our study suggests that age at diagnosis, family history of breast and/or ovarian cancer, medical history of breast cancer or a Manchester BRCA Score of ≥15 points are associated with a >10% prevalence of germline pathogenic BRCA1/2 variants in epithelial ovarian cancer.

Dose-dense cisplatin with gemcitabine for relapsed platinum-resistant ovarian cancer.

INTRODUCTION: Standard of care treatment for women who develop relapsed ovarian cancer includes sequential platinum- and/or paclitaxel-based chemotherapy, with reducing disease-free intervals. Once platinum resistance develops, treatment options become limited and dose-dense regimens may be offered. We report the efficacy and safety of dose-dense cisplatin with gemcitabine chemotherapy for relapsed platinum-resistant ovarian cancer. METHODS: A retrospective analysis of all patients with relapsed, platinum-resistant ovarian, primary peritoneal or fallopian tube cancer treated with cisplatin 35 mg/m2 of body surface area by intravenous infusion with gemcitabine 1000 mg/m2 of body surface area by intravenous infusion on days 1 and 8 of every 21-day treatment cycle between 1 January 2009 and 1 June 2017. RESULTS: Ninety-four eligible patients had received a median of three (range one-eight) prior lines of cytotoxic therapy for relapsed ovarian cancer. Sixty patients (64%) had received ≥ 1 prior dose-dense chemotherapy regimen. Dose-dense cisplatin with gemcitabine was associated with a median progression-free survival (PFS) of 4.4 months (95% CI 3.6 to 5.3) and overall survival of 7.6 months (95% CI 5.6 to 9.6). The median PFS for dose-dense cisplatin with gemcitabine as first- (n = 34), second- (n = 42), and third-line or later (n = 18) dose-dense therapy was 4.2 (95% CI 3.2 to 5.2), 5.0 (95% CI 3.5 to 6.5), and 4.2 (95% CI 3.3 to 5.1) months respectively. The RECIST objective response rate for first-, second-, and third-line dose-dense cisplatin with gemcitabine was 23%, 14 %, and 7 % respectively. The most common grade 3 - 4 adverse events were thrombocytopenia (20%), anemia (18%), and neutropenia (14%). DISCUSSION: Dose-dense cisplatin with gemcitabine provides modest efficacy whether it is used as a first- or subsequent line of dose-dense chemotherapy to treat relapsed platinum-resistant ovarian cancer and the toxicity is manageable with supportive measures.

An Outpatient, Dose-Intense, Intravenous Cisplatin and Oral Etoposide Regimen for the Treatment of Advanced, Platinum-Resistant Ovarian Cancer.

OBJECTIVES: Advanced-stage, platinum-resistant, ovarian cancer can be treated with dose-intense chemotherapy; one such regimen includes intravenous cisplatin and oral etoposide. To minimize the toxicity associated with weekly cisplatin, pretreatment and posttreatment hydration is required, often necessitating inpatient, overnight admission. We report a shorter, within-day regimen for delivering weekly cisplatin. METHODS: This was a retrospective study to assess the use of standard (inpatient; treatment time of 12 hours) versus modified (outpatient; treatment time of 4 hours) regimens. The primary outcome included all-grade and grade 3/4 adverse events. Secondary outcomes included clinical benefit response and, median progression-free survival and overall survival. RESULTS: Between January 2012 and December 2014, 66 women with metastatic ovarian cancer received dose-intense weekly cisplatin and oral etoposide (n = 45 standard, n = 21 modified). The commonest all-grade adverse events were anemia (96% vs 90%, standard and modified, respectively), fatigue (73% vs 67%), neutropenia (71% vs 76%), hypocalcemia (51% vs 43%), and thrombocytopenia (49% vs 57%). There were no statistically significant differences in the incidence or grades of adverse events. The clinical benefit response was 53% in the standard group and 62% in the modified group (P = 0.9). The median progression-free survival was 4.2 and 6.5 months (incidence rate ratio, 1.22; 95% confidence interval, 0.71-2.15; P = 0.29), and median overall survival was 6.6 and 8.4 months (incidence rate ratio, 1.83; 95% confidence interval, 1.04-3.35; P = 0.03), in favor of the modified regimen. CONCLUSIONS: Our shorter, within-day regimen for delivering dose-intense weekly cisplatin and oral etoposide to treat platinum-resistant metastatic ovarian cancer is safe and efficacious.

Malignant bowel obstruction in advanced ovarian cancer.

AIM: Malignant bowel obstruction (MBO) in ovarian cancer is poorly understood. METHODS: This retrospective cohort study analyzed 129 patients with ovarian cancer and MBO. RESULTS: At presentation, 69 (53%) had platinum-resistant, 37 (29%) platinum-sensitive and 23 (18%) chemotherapy-naive disease. In patients receiving chemotherapy following the MBO episode, median overall survival (OS) was 107 days for chemotherapy-naive patients compared with 83 and 86 for platinum-sensitive or platinum-resistant patients (p = 0.98). OS was inferior for best supportive care (45 days) compared with chemotherapy (152 days) or surgery (124 days; p < 0.001). The Manchester Bowel Obstruction Score using Eastern Cooperative Oncology Group and obstruction level discriminated patients by median OS of 181 days (neither) versus 98 days (one) versus 42 days (both; p < 0.01). CONCLUSION: The Manchester Bowel Obstruction Score may aide treatment stratification.

Evaluation of hypertension and proteinuria as markers of efficacy in antiangiogenic therapy for metastatic colorectal cancer.

BACKGROUND: The vascular endothelial growth factor pathway is strongly implicated in cancer-related angiogenesis. Antiangiogenic agents such as bevacizumab commonly cause hypertension (HTN) and proteinuria (PTN), which may be biomarkers of response and clinical outcome. STUDY: We conducted a retrospective analysis of patients with histologically proven metastatic colorectal cancer (mCRC) treated with either bevacizumab or a tyrosine kinase inhibitor in combination with chemotherapy at The Christie Hospital from January 2006 to September 2009. RESULTS: Of 90 patients evaluated, 50 were eligible. Seventeen (34%), 4 (8%), and 3 (6%) patients developed Common Toxicity Criteria (v 3.0) grades 1, 2, and 3 HTN, respectively. Response rates were 42% for patients with grades 0 to 1 HTN compared with 86% for patients with ≥grade 2 HTN (P=0.043). Median overall survival was 21.6 months for patients with grades 0 to 1 HTN and 25.2 months for patients with ≥grade 2 HTN (P=0.270). Twelve patients (24%) developed grade 1 PTN and 4 patients (8%) developed ≥grade 2 PTN. Median overall survival was 23.9 months for patients with grades 0 to 1 PTN and 4.2 months for those with ≥grade 2 PTN (P=0.028). CONCLUSIONS: To our knowledge, this is the first study to demonstrate the utility of PTN as a surrogate marker of outcome in antiangiogenic therapy for metastatic colorectal cancer. Although HTN is predictive of a significantly higher response rate, the development of PTN during treatment with bevacizumab or tyrosine kinase inhibitor portends poorer survival and should be evaluated prospectively.

Real-World Concordance between Germline and Tumour BRCA1/2 Status in Epithelial Ovarian Cancer.

Patients diagnosed with epithelial ovarian cancer may undergo reflex tumour BRCA1/2 testing followed by germline BRCA1/2 testing in patients with a positive tumour test result. This testing model relies on tumour BRCA1/2 tests being able to detect all types of pathogenic variant. We analysed germline and tumour BRCA1/2 test results from patients treated for epithelial ovarian cancer at our specialist oncological referral centre. Tumour BRCA1/2 testing was performed using the next-generation sequencing (NGS)-based myChoice® companion diagnostic (CDx; Myriad Genetics, Inc.). Germline BRCA1/2 testing was performed in the North West Genomic Laboratory Hub using NGS and multiplex ligation-dependent probe amplification. Between 11 April 2021 and 11 October 2023, 382 patients were successfully tested for tumour BRCA1 and BRCA2 variants. Of these, 367 (96.1%) patients were tested for germline BRCA1/2 variants. In those patients who underwent tumour and germline testing, 15.3% (56/367) had a BRCA1/2 pathogenic variant (36 germline and 20 somatic). All germline BRCA1/2 pathogenic small sequencing variants were detected in tumour DNA. By contrast, 3 out of 8 germline BRCA1/2 pathogenic large rearrangements were not reported in tumour DNA. The overall concordance of germline BRCA1/2 pathogenic variants detected in germline and tumour DNA was clinically acceptable at 91.7% (33/36). The myChoice® CDx was able to detect most germline BRCA1/2 pathogenic variants in tumour DNA, although a proportion of pathogenic large rearrangements were not reported. If Myriad's myChoice® CDx is used for tumour BRCA1/2 testing, our data supports a testing strategy of germline and tumour BRCA1/2 testing in all patients diagnosed with epithelial ovarian cancer aged < 79 years old, with germline BRCA1/2 testing only necessary for patients aged ≥ 80 years old with a tumour BRCA1/2 pathogenic variant.

The Mental Health Burden of Patients with Colorectal Cancer Receiving Care during the COVID-19 Pandemic: Results of the PICO-SM Study.

The COVID-19 pandemic has resulted in unprecedented changes to the lives of patients with cancer. To evaluate the impact of the COVID-19 pandemic on the mental health and well-being of patients with colorectal cancer, we conducted a prospective longitudinal questionnaire study at a UK tertiary cancer centre. In total, 216 participants were included: mean age 65 years, 57% (n = 122) male, 92% (n = 198) of white ethnicity. Amongst participants who completed the screening psychometric questionnaire, 24% (n = 48/203) reported anxiety (GAD-7 ≥ 5), 15% (n = 31/204) depressive symptoms (PHQ-9 ≥ 10), 3% (n = 5/190) probable post-traumatic stress disorder (PC-PTSD-5 ≥ 4), and 31% (n = 66/213) poor well-being (WHO-5 < 50). In the subgroup (n = 95/216, 44%) who consented to and completed a follow-up survey 6 months later, there was a significant increase in the number of participants at risk of depression (4% vs. 13%, p = 0.021). Self-reported concern about the COVID-19 pandemic impacting one's mental health is associated with increased likelihood of anxiety, depression, and poor well-being, in respective multivariate analyses. In conclusion, screening for the mental health impact of the COVID-19 pandemic is essential to ensure timely action from all key stakeholders and to avoid potentially longer-term detrimental consequences.

Is Reflex Germline BRCA1/2 Testing Necessary in Women Diagnosed with Non-Mucinous High-Grade Epithelial Ovarian Cancer Aged 80 Years or Older?

Women diagnosed with non-mucinous high-grade epithelial ovarian cancer (EOC) in England are often reflex-tested for germline and tumour BRCA1/2 variants. The value of germline BRCA1/2 testing in women diagnosed aged ≥80 is questionable. We performed an observational study of all women diagnosed with non-mucinous high-grade EOC who underwent germline and tumour BRCA1/2 testing by the North West of England Genomic Laboratory Hub. A subgroup of women also underwent germline testing using a panel of homologous recombination repair (HRR) genes and/or tumour testing for homologous recombination deficiency (HRD) using Myriad's myChoice® companion diagnostic. Seven-hundred-two patients successfully underwent both germline and tumour BRCA1/2 testing. Of these, 48 were diagnosed with non-mucinous high-grade EOC aged ≥80. In this age group, somatic BRCA1/2 pathogenic/likely pathogenic variants (PV/LPVs) were detected nine times more often than germline BRCA1/2 PV/LPVs. The only germline PV reported in a patient aged ≥80 was detected in germline and tumour DNA (BRCA2 c.4478_4481del). No patient aged ≥80 had a germline PV/LPVs in a non-BRCA1/2 HRR gene. Thirty-eight percent of patients aged ≥80 had a tumour positive for HRD. Our data suggest that tumour BRCA1/2 and HRD testing is adequate for patients diagnosed with non-mucinous high-grade EOC aged ≥80, with germline BRCA1/2 testing reserved for women with a tumour BRCA1/2 PV/LPVs.

Predicting the likelihood of a BRCA1/2 pathogenic variant being somatic by testing only tumour DNA in non-mucinous high-grade epithelial ovarian cancer.

AIMS: Clinical guidelines recommend testing both germline and tumour DNA for BRCA1/2 pathogenic variants (PVs) in non-mucinous high-grade epithelial ovarian cancer (NMEOC). In this study, we show that some tumour BRCA1/2 PVs are highly likely to be somatic based on certain clinical and variant characteristics, meaning it may not be necessary to test all NMEOC cases for germline BRCA1/2 PVs. METHODS: An observational study that included all tumour BRCA1/2 PVs detected in cases of NMEOC in the Northwest of England between July 2017 and February 2022. All tumour BRCA1/2 PVs were compared with PVs recorded in a prospectively gathered pan-cancer germline BRCA1/2 (gBRCA) testing database for the same geographical region (gBRCA1 PVs=910 and gBRCA2 PVs=922). Tumour BRCA1/2 PVs were categorised as common (≥1%), uncommon (<1%) or absent from the germline database. RESULTS: One hundred and thirteen tumour BRCA1/2 PVs were detected in 111 NMEOC cases. There were 69 germline and 44 somatic variants. The mean age at diagnosis for gBRCA and somatic BRCA1/2 (sBRCA) PVs was 56.9 and 68.5 years, respectively (Student's t-test p<0.0001). All sBRCA PVs were detected in non-familial cases. All tumour BRCA1/2 PVs with a variant allele frequency (VAF) <35% in non-familial cases were somatic variants. Eighty-one per cent of germline-tumour BRCA1/2 PVs were present (common=31, uncommon=25) in the gBRCA testing database, while 89% of somatic-tumour BRCA1/2 PVs were absent (n=39). CONCLUSIONS: We predict the likelihood of a tumour BRCA1/2 PV being somatic is 99.8% in non-familial cases of NMEOC diagnosed aged ≥75, where the VAF is ≤30% and there is no regional germline commonality.

Multi-Maintenance Olaparib Therapy in Relapsed, Germline BRCA1/2-Mutant High-Grade Serous Ovarian Cancer (MOLTO): A Phase II Trial.

PURPOSE: A single maintenance course of a PARP inhibitor (PARPi) improves progression-free survival (PFS) in germline BRCA1/2-mutant high-grade serous ovarian cancer (gBRCAm-HGSOC). The feasibility of a second maintenance course of PARPi was unknown. PATIENTS AND METHODS: Phase II trial with two entry points (EP1, EP2). Patients were recruited prior to rechallenge platinum. Patients with relapsed, gBRCAm-HGSOC were enrolled at EP1 if they were PARPi-naïve. Patients enrolled at EP2 had received their first course of olaparib prior to trial entry. EP1 patients were retreated with olaparib after RECIST complete/partial response (CR/PR) to platinum. EP2 patients were retreated with olaparib ± cediranib after RECIST CR/PR/stable disease to platinum and according to the platinum-free interval. Co-primary outcomes were the proportion of patients who received a second course of olaparib and the proportion who received olaparib retreatment for ≥6 months. Functional homologous recombination deficiency (HRD), somatic copy-number alteration (SCNA), and BRCAm reversions were investigated in tumor and liquid biopsies. RESULTS: Twenty-seven patients were treated (EP1 = 17, EP2 = 10), and 19 were evaluable. Twelve patients (63%) received a second course of olaparib and 4 received olaparib retreatment for ≥6 months. Common grade ≥2 adverse events during olaparib retreatment were anemia, nausea, and fatigue. No cases of MDS/AML occurred. Mean duration of olaparib treatment and retreatment differed (12.1 months vs. 4.4 months; P < 0.001). Functional HRD and SCNA did not predict PFS. A BRCA2 reversion mutation was detected in a post-olaparib liquid biopsy. CONCLUSIONS: A second course of olaparib can be safely administered to women with gBRCAm-HGSOC but is only modestly efficacious. See related commentary by Gonzalez-Ochoa and Oza, p. 2563.

Psychosexual Morbidity in Women With Ovarian Cancer: Evaluation by Germline BRCA Gene Mutational Status.

INTRODUCTION: Up to 75% of women with ovarian cancer experience psychosexual morbidity and approximately 15-20% of women with ovarian cancer have a germline BRCA1/2 mutation (gBRCAm). However, psychosexual morbidity remains unexplored in women with gBRCAm ovarian cancer. AIM: Given their younger age, genetic diagnosis, breast cancer risk, and increased prevalence of surgically-induced menopause, we aim to assess whether women with gBRCAm ovarian cancer experience distinct psychosexual morbidity. METHODS: Psychosexual morbidity was investigated in 2 cohorts of women with ovarian cancer: women with gBRCAm ovarian cancer vs women with gBRCA wildtype (gBRCAwt) ovarian cancer. Between August 2019 and March 2020, women with high-grade serous carcinoma of the ovary, Fallopian tube or primary peritoneum were approached in clinic or telephoned and invited to take part. Exclusion criteria included: women with alternative histology; women admitted from clinic; and women who lacked capacity to independently complete the questionnaire. The Female Sexual Function Index (FSFI) and background information were collected at a single time-point per patient. Scores below 26.55 were interpreted to suggest psychosexual dysfunction. MAIN OUTCOME MEASURE: Responses including total and domain FSFI scores, self-reported psychosexual problems and interest in psychosexual support were compared. RESULTS: Of 103 women approached, 53% returned questionnaires. In this exploratory analysis, women with gBRCAm ovarian cancer were significantly younger (51-60 years vs 61-70 years, gBRCAwt, P = .010). There was a trend towards increased prevalence of surgical menopause (57% vs 27%, P = .097) and breast surgery (53% vs 22%, P = .132, gBRCAm vs gBRCAwt, respectively). Women with gBRCAm ovarian cancer scored higher in the FSFI questionnaire, particularly women under 60 years (15.1 vs 2.7, P = .070), approaching significance. Women with gBRCAm ovarian cancer expressed more interest for face-to-face services (P = .018), especially psychosexual therapy (65% vs 30%) and more often felt the service was insufficient, approaching significance (71% vs 44%, gBRCAm vs gBRCAwt, respectively, P = .076). CONCLUSION: Women with gBRCAm ovarian cancer are younger, express more interest for specialist psychosexual support and potentially different psychosexual problems, warranting further exploration. Logue C, Pugh J, Foden P, et al., Psychosexual Morbidity in Women With Ovarian Cancer: Evaluation by Germline BRCA Gene Mutational Status. Sex Med 2022;10:100465.

Modification to Systemic Anticancer Therapy at the Start of the COVID-19 Pandemic and its Overall Impact on Survival Outcomes in Patients with Colorectal Cancer.

BACKGROUND: Since the beginning of the COVID-19 pandemic, multiple changes to the provision of cancer care has been introduced to maximize patient safety and protect staff. We aimed to identify factors influencing clinicians' decision on treatment modification during the initial phase of the pandemic, and to assess its impact on outcomes in patients with colorectal cancer. PATIENTS AND METHODS: Electronic records of patients seen in a large United Kingdom tertiary cancer center was reviewed. The frequency and type of changes to systemic anticancer therapy , as well as the factors predicting clinicians' decision were assessed. RESULTS: A total of 418 patients; mean age 63 ± 12 years and 57% male were included. More than half of the patients had modification to their treatment; with treatment delay (21%) or cancellation (10%), being the most common. Majority of patients on neoadjuvant treatment (97%) proceeded with treatment, with some form of treatment modification in 20%. Half of patients on adjuvant treatment had their treatment plan modified. Overall, a change in treatment was more likely in older patients (OR 1.028 [95% CI 1.010-1.047]; P = .002), and in patients who had already received higher number of cycles of systemic anticancer therapy (OR 1.040 [95% CI 1.016-1.065]; P = .001). A change in treatment was less likely further out of the first national lockdown (OR 0.837 [95% CI 0.758-0.925]; P < .001). Patients on third-line treatment were most likely to have alterations to their treatment plan (69%, n=33/48). CONCLUSION: During the first wave of COVID-19 in the United Kingdom, clinicians adapted clinical practice in accordance to local and national guidance, especially amongst older patients and those on third-line treatment. Further real-world data are needed to document the important impact of changes to treatment on outcomes in patients with cancer.

Home Parenteral Nutrition in Patients with Advanced Cancer: Quality Outcomes from a Centralized Model of Care Delivery.

Lack of expertise in home parenteral nutrition (HPN) management has been reported as a barrier to its initiation in patients with advanced cancer (AC), and there are limited data describing hospital readmissions and HPN-related complications. We aimed to assess a centralized approach for managing HPN in AC and evaluate associated outcomes, including hospital readmissions and HPN-related complications. This was a cohort study of adults with AC requiring palliative HPN between 2010-2018 at a tertiary intestinal failure (IF) center, primarily utilizing a centralized model of HPN oversight to discharge patients remotely from an oncology center to their homes over a wide geographic area. A total of 126 patients were included, with a median distance between the patient's home and the IF center of 17.5 km (IQR 10.9-39.1; maximum 317.4 km). A total of 28 (22%) patients experienced at least one HPN-related complication, the most common being a central venous catheter (CVC) occlusion and electrolyte abnormalities. The catheter-related bloodstream infection (CRBSI) rate was 0.49/1000 catheter days. The CVC type, administration of concomitant chemotherapy via a distinct CVC lumen separate from PN, venting gastrostomy and distance between the patient's home and the IF center were not associated with CRBSI or mechanical CVC complications. A total of 82 (65.1%) patients were readmitted while on HPN, but only 7 (8.5%) of these readmissions were HPN-related. A total of 44 (34.9%) patients died at home, 41 (32.5%) at a hospice and 41 (32.5%) in a hospital. In conclusion, this study demonstrates that a centralized approach to IF care can provide HPN to patients over a large geographical area while maintaining low HPN-related complications that are comparable to patients requiring HPN for benign conditions and low hospital readmission rates.

Outcomes after multiple lines of chemotherapy for platinum-resistant epithelial cancers of the ovary, peritoneum, and fallopian tube.

BACKGROUND: Platinum-resistant and refractory cancers of the ovary, fallopian tube, and peritoneum have a poor prognosis, yet in some cases, they can respond to multiple lines of chemotherapy. Uncertainty remains over optimal drug choice and when therapeutic focus should be switched from active therapy to supportive care. METHODS: A retrospective case note review was performed on 274 women treated for platinum-resistant/refractory ovarian, fallopian tube, or peritoneal carcinoma at the Christie Hospital between 2004 and 2008. Baseline data at onset of platinum resistance and outcomes from subsequent lines of therapy were recorded. RESULTS: A total of 689 lines of therapy were administered with a median overall survival from initiation of first-line therapy for platinum-resistant disease of 61 weeks. Twenty-eight percent of women commenced cytotoxic therapy in the last 3 months of life. Treatment efficacy declined rapidly with successive lines of therapy particularly if disease progression occurred during first-line therapy. Factors independently associated with worse overall survival at recognition of platinum resistance were performance status, presence of stage IV disease, elevated cancer antigen 125, and platinum-refractory disease. CONCLUSIONS: A significant proportion of women who were treated received therapy within the last few months of life with little clinical benefit. Disease progression on 2 consecutive lines of therapy should be used as a guide to discontinue cytotoxic treatment. A subset of patients with poor prognosis at the onset of platinum resistance, who may have little gain from anticancer treatment, can be identified.