Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare.

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study.

BACKGROUND: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis. METHODS: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing. FINDINGS: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy. INTERPRETATION: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP. FUNDING: F Hoffmann-La Roche.

Clinical research in endometrial cancer: consensus recommendations from the Gynecologic Cancer InterGroup.

The Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Consensus Conference on Clinical Research (ECCC) was held in Incheon, South Korea, Nov 2-3, 2023. The aims were to develop consensus statements for future trials in endometrial cancer to achieve harmonisation on design elements, select important questions, and identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and finalisation of 18 statements within four topic groups, addressing adjuvant treatment in high-risk disease; treatment for metastatic and recurrent disease; trial designs for rare endometrial cancer subgroups and special circumstances; and specific methodology and adaptation for trials in low-resource settings. In addition, eight areas of unmet need were identified. This was the first GCIG Consensus Conference to include patient advocates and an expert on inclusion, diversity, equity, and access to take part in all aspects of the process and output. Four early-career investigators were also selected for participation, ensuring that they represented different GCIG member groups and regions. Unanimous consensus was obtained for 16 of the 18 statements, with 97% concordance for the remaining two. Using the described methodology from previous Ovarian Cancer Consensus Conferences, this conference did not require even one minority statement. The high acceptance rate following active involvement in the preparation, discussion, and refinement of the statements by all representatives confirmed the consensus progress within a global academic setting, and the expectation that the ECCC will lead to greater harmonisation, actualisation, inclusion, and resolution of unmet needs in clinical research for individuals living with and beyond endometrial cancer worldwide.

Prognostic impact and causality of age on oncological outcomes in women with endometrial cancer: a multimethod analysis of the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials.

BACKGROUND: Numerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal prognostic factor, or whether other risk factors become increasingly common with age. We aimed to address this question with a unique multimethod study design using state-of-the-art statistical and causal inference techniques on datasets of three large, randomised trials. METHODS: In this multimethod analysis, data from 1801 women participating in the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk endometrial cancer, 427 patients with high-intermediate risk endometrial cancer, and 660 patients with high-risk endometrial cancer. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable, a deep learning causal inference model called AutoCI was used. FINDINGS: Median follow-up as estimated using the reversed Kaplan-Meier method was 12·3 years (95% CI 11·9-12·6) for PORTEC-1, 10·5 years (10·2-10·7) for PORTEC-2, and 6·1 years (5·9-6·3) for PORTEC-3. Both overall recurrence and endometrial cancer-specific death significantly increased with age. Moreover, older women had a higher frequency of deep myometrial invasion, serous tumour histology, and p53-abnormal tumours. Age was an independent risk factor for both overall recurrence (hazard ratio [HR] 1·02 per year, 95% CI 1·01-1·04; p=0·0012) and endometrial cancer-specific death (HR 1·03 per year, 1·01-1·05; p=0·0012) and was identified as a significant causal variable. INTERPRETATION: This study showed that advanced age was associated with more aggressive tumour features in women with endometrial cancer, and was independently and causally related to worse oncological outcomes. Therefore, our findings suggest that older women with endometrial cancer should not be excluded from diagnostic assessments, molecular testing, and adjuvant therapy based on their age alone. FUNDING: None.

PARP inhibition with rucaparib alone followed by combination with atezolizumab: Phase Ib COUPLET clinical study in advanced gynaecological and triple-negative breast cancers.

BACKGROUND: Combining PARP inhibitors (PARPis) with immune checkpoint inhibitors may improve clinical outcomes in selected cancers. We evaluated rucaparib and atezolizumab in advanced gynaecological or triple-negative breast cancer (TNBC). METHODS: After identifying the recommended dose, patients with PARPi-naive BRCA-mutated or homologous recombination-deficient/loss-of-heterozygosity-high platinum-sensitive ovarian cancer or TNBC received rucaparib plus atezolizumab. Tumour biopsies were collected pre-treatment, during single-agent rucaparib run-in, and after starting combination therapy. RESULTS: The most common adverse events with rucaparib 600 mg twice daily and atezolizumab 1200 mg on Day 1 every 3 weeks were gastrointestinal effects, fatigue, liver enzyme elevations, and anaemia. Responding patients typically had BRCA-mutated tumours and higher pre-treatment tumour levels of PD-L1 and CD8 + T cells. Markers of DNA damage repair decreased during rucaparib run-in and combination treatment in responders, but typically increased in non-responders. Apoptosis signature expression showed the reverse. CD8 + T-cell activity and STING pathway activation increased during rucaparib run-in, increasing further with atezolizumab. CONCLUSIONS: In this small study, rucaparib plus atezolizumab demonstrated acceptable safety and activity in BRCA-mutated tumours. Increasing anti-tumour immunity and inflammation might be a key mechanism of action for clinical benefit from the combination, potentially guiding more targeted development of such regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03101280).

The evolution of molecular management of carcinoma of unknown primary.

PURPOSE OF REVIEW: There is significant need to improve diagnostic and therapeutic options for patients with cancer of unknown primary (CUP). In this review, we discuss the evolving landscape of molecular profiling in CUP. RECENT FINDINGS: Molecular profiling is becoming accepted into the diagnostic work-up of CUP patients with tumour mutation profiling now described in international CUP guidelines. Although tissue-of-origin (ToO) molecular tests utilising gene-expression and DNA methylation have existed some time, their clinical benefit remains unclear. Novel technologies utilising whole genome sequencing and machine learning algorithms are showing promise in determining ToO, however further research is required prior to clinical application. A recent international clinical trial found patients treated with molecularly-guided therapy based on comprehensive-panel DNA sequencing had improved progression-free survival compared to chemotherapy alone, confirming utility of performing genomic profiling early in the patient journey. Small phase 2 trials have demonstrated that some CUP patients are responsive to immunotherapy, but the best way to select patients for treatment is not clear. SUMMARY: Management of CUP requires a multifaceted approach incorporating clinical, histopathological, radiological and molecular sequencing results to assist with identifying the likely ToO and clinically actionable genomic alternations. Rapidly identifying a subset of CUP patients who are likely to benefit from site specific therapy, targeted therapy and/or immunotherapy will improve patient outcomes.

Molecular and Clinicopathologic Characterization of Mismatch Repair-Deficient Endometrial Carcinoma Not Related to MLH1 Promoter Hypermethylation.

Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.

A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary.

Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-expansion stage of a multicentre, open-label, phase I trial.

BACKGROUND: The aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours. METHODS: In this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability. RESULTS: Overall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0-47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients. CONCLUSIONS: Pamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT02660034.

Six-year experience of Australia's first dedicated cancer of unknown primary clinic.

BACKGROUND: Diagnosis and management of cancers of unknown primary (CUP) remain challenging. This study examines the referral patterns, management and outcomes of patients referred to Australia's first dedicated CUP clinic. METHODS: Retrospective medical record review was conducted for patients seen at the Peter MacCallum Cancer Centre CUP clinic between July 2014 and August 2020. Overall survival (OS) was analysed for patients with a CUP diagnosis where treatment information was available. RESULTS: Of 361 patients referred, fewer than half had completed diagnostic work-up at the time of referral. A diagnosis of CUP was established in 137 (38%), malignancy other than CUP in 177 (49%) and benign pathology in 36 (10%) patients. Genomic testing was successfully completed in 62% of patients with initial provisional CUP and impacted management in 32% by identifying a tissue of origin or actionable genomic alteration. The use of site-specific, targeted therapy or immunotherapy was independently associated with longer OS compared to empirical chemotherapy. CONCLUSION: Our specialised CUP clinic facilitated diagnostic work-up among patients with suspected malignancy and provided access to genomic testing and clinical trials for patients with a CUP diagnosis, all of which are important to improve outcomes in this patient population.

Prognostic refinement of NSMP high-risk endometrial cancers using oestrogen receptor immunohistochemistry.

BACKGROUND: Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement. METHODS: Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n = 424), and a Dutch prospective clinical cohort called MST (n = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan-Meier method, log-rank tests and Cox's proportional hazard models were used for survival analysis. RESULTS: In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15-0.75). CONCLUSIONS: We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Prognostic significance of FIGO 2018 staging of loco-regionally advanced cervical cancer (LRACC) with the use of MRI and PET and implications for treatment selection.

INTRODUCTION: The FIGO 2018 staging of cervix cancer recognizes a total of 11 categories of loco-regionally advanced cervix cancer (LRACC). Whilst incorporating imaging is an improvement over clinical staging (FIGO 2009), this had led to more categories of disease which are not prognostically discrete groups. We aimed to analyze survival according to 2018 FIGO stages of cervix cancer and identify isoprognostic groups of patients based on primary tumor volume and nodal status. METHODS: Patients referred for radiotherapy with curative intent between 1996 and 2014 were eligible. Baseline clinico-pathological and follow up information was retrieved from an ethics-approved institutional prospective database. Patients were classified according to FIGO 2018 staging based on histo-pathology, MRI (tumor volume and local compartmental spread assessment) and PET results (nodal spread). Kaplan-Meier method was used to estimate survival at five years. Following survival analysis using recognized prognostic factors, isoprognostic categories were identified and merged to form 5 isoprognostic groups. RESULTS: Seven hundred and forty-four LRACC patients were included. The median (IQR) follow-up was 5.1 (2.6-8.4) yrs. Stage migration occurred in most patients, showing heterogeneous 5 years survival according to 2018 FIGO stages. In contrast progressively worsening prognosis could be demonstrated in the 5 observed isoprognostic clusters (p < 0.002). CONCLUSION/IMPLICATIONS: Prognosis in LRACC depends on the interplay between primary tumor characteristics, type of local spread and nodal disease. A prospective study of survival and patterns of failure according to isoprognostic clusters would be useful to determine the most appropriate treatment modality and estimate survival as well as better patient selection for clinical trials.

Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours.

BACKGROUND: Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. METHODS: This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. RESULTS: Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%). CONCLUSIONS: Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS. GOV IDENTIFIER: NCT02361723.

Women with gynaecological cancer awaiting radiotherapy: Self-reported wellbeing, general psychological distress, symptom distress, sexual function, and supportive care needs.

OBJECTIVE: To better serve women with gynaecological cancers, we need a sound understanding of their health, wellbeing and needs. This study sought to explore these issues in a sample of Australian women before commencing curative radiotherapy. METHODS: We undertook a secondary analysis of baseline data from a supportive care trial (n = 311). Descriptive statistics were used to summarise responses to measures of wellbeing, general psychological distress, symptom distress, sexual function and vaginal changes, and supportive care needs. Pre-specified regression models were used to examine sources of variation in wellbeing and sexual function. RESULTS: Women reported lower emotional, functional and physical wellbeing than population norms (all p < 0.001). The prevalence of general psychological distress was 31% (95% CI 26-36%). Distress caused by physical symptoms was typically low. Health system and information needs comprised eight of the top ten moderate-to-high supportive care needs. Most women reported no change in interest for physical contact or sex compared to pre-diagnosis, but some sexually active women (16-24%) reported smaller vaginal size, increased dryness, and more pain on intercourse. General psychological distress was a robust marker of poorer wellbeing and sexual function. CONCLUSIONS: Before radiotherapy, a substantial minority of women with gynaecological cancers experience general psychological distress, reduced wellbeing and moderate-to-high health system and information needs. A model of comprehensive care incorporating assessment of unmet needs, general psychological distress, and sexual issues is recommended. Healthcare providers may require training to elicit and respond to a constellation of interrelated issues and access relevant services for women requiring additional support.

Efficacy and safety of pembrolizumab for patients with previously treated advanced vulvar squamous cell carcinoma: Results from the phase 2 KEYNOTE-158 study.

OBJECTIVE: Treatment options for advanced vulvar cancer are limited. We evaluated pembrolizumab monotherapy in patients with advanced vulvar squamous cell carcinoma (SCC) enrolled in the phase 2 multicohort, open-label KEYNOTE-158 study (NCT02628067). METHODS: Eligible patients had histologically or cytologically documented advanced vulvar SCC with prior treatment failure, measurable disease per RECIST v1.1, ECOG performance status 0-1, and a tumor sample available for biomarker analysis. Pembrolizumab 200 mg was administered intravenously Q3W for up to 35 cycles (approximately 2 years). The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent central radiologic review in all patients and subgroups based on PD-L1 combined positive score (≥1 [PD-L1-positive] versus <1 [PD-L1-negative]). RESULTS: 101 patients were enrolled. Median time from first dose to data cutoff was 36.0 months. The ORR (95% CI) was 10.9% (5.6%-18.7%) among all patients, 9.5% (4.2%-17.9%) among the 84 patients with PD-L1-positive tumors, and 28.6% (3.7%-71.0%) among the 7 patients with PD-L1-negative tumors. Among patients with a response, median DOR was 20.4 (range, 2.1+ to 28.0) months. Median (95% CI) PFS and OS were 2.1 (2.0-2.1) and 6.2 (4.9-9.4) months, respectively. Treatment-related AEs occurred in 50.5% of patients (grade 3-5, 11.9%) and led to discontinuation of treatment in 5.0% of patients. Two deaths were considered treatment-related (hepatitis, n = 2). CONCLUSIONS: Pembrolizumab monotherapy was associated with durable responses in a subset of patients with vulvar SCC. Responses occurred regardless of tumor PD-L1 status. No new safety signals emerged; overall, pembrolizumab was well tolerated.

Psychological distress, understanding of cancer and illness uncertainty in patients with Cancer of Unknown Primary.

OBJECTIVE: Patients diagnosed with Cancer of Unknown Primary (CUP) experience high levels of psychological distress and report poor understanding of their cancer. We aimed to investigate: (1) if CUP patients with poorer understanding of their cancer diagnosis and testing experience more symptoms of psychological distress than those with better understanding; (2) if the relationship between patients' understanding of their cancer and psychological distress is mediated by illness uncertainty; and (3) explore whether patients' degree of understanding of their cancer can be predicted by clinical and socio-demographic factors. METHODS: 209 CUP patients completed a questionnaire measuring anxiety, depression, illness uncertainty, fatigue, pain, sleep and understanding of their cancer. Using an apriori theoretical framework, we employed structural equation modelling to investigate predictors of patient's understanding of their cancer and psychological distress and the relationships between understanding, illness uncertainty and distress. RESULTS: The structural equation model displayed good fit indices and supported the hypothesised relationship of patient's understanding of their cancer and the extent of psychological distress, which was mediated via illness uncertainty. Physical symptoms were positively associated with psychological distress and illness uncertainty. Younger age was predictive of lower patient's understanding of their cancer and higher levels of psychological distress. CONCLUSIONS: Patients with CUP, particularly those who are younger and experiencing more physical symptoms, report higher levels of psychological distress and may require additional mental health support. Our findings highlight a need to improve CUP patient's understanding about their illness, which could help reduce their illness uncertainty and alleviate psychological distress.

Uncertainty and the unmet informational needs of patients with cancer of unknown primary (CUP): a cross-sectional multi-site study.

OBJECTIVE: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. METHODS: This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. RESULTS: Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that 'received written information about your cancer…' and asked '…how useful was it?' fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CONCLUSIONS: CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.

Treatment patterns after poly-ADP ribose polymerase (PARP) inhibitors in epithelial ovarian cancer patients.

OBJECTIVES: The primary objective of this study was to describe treatment patterns after poly-ADP ribose polymerase (PARP) inhibitor in patients with epithelial ovarian cancer. Secondary objectives were to evaluate duration of response, time to first subsequent therapy, progression-free survival and overall survival. METHODS: This was a retrospective analysis of patients with epithelial ovarian cancer treated with PARP inhibitor therapy at six Australian gynecological oncology centers. Eligible patients were identified via clinics, trial databases and pharmacy dispensing logs between January 2005 and September 2019. Information regarding clinico-pathological characteristics and treatment outcomes were collated from medical records. RESULTS: A total of 85 patients with epithelial ovarian cancer were identified. Of these, 61% had germline BRCA1/2 mutations, 9% had somatic BRCA1/2 mutations, 5% had confirmed homologous recombination deficiency and 25% were BRCA1/2 wildtype mutations. A total of seventy-seven (91%) patients received chemotherapy after PARP inhibitor, with fifty-six (72.7%) of these patients receiving platinum-based chemotherapy. Four patients (5%) had a complete response, 15 (20%) a partial response, 15 (20%) stable disease and 41 (55%) progressive disease. Median duration of response to chemotherapy was 7.0 months (range 0.2-20.4). Median time to first subsequent therapy was 17.6 and 15.1 months in patients who received a PARP inhibitor as maintenance therapy and treatment, respectively. Median progression-free survival of first line treatment after PARP inhibitor was 9.6, 3.5 and 4.6 months for platinum doublet, single agent platinum and non-platinum chemotherapy, respectively. Adjusting for age and FIGO (Federation of Gynecological Oncologists classification) stage progression-free survival did not differ between treatment groups (p=0.14). Median overall survival for the cohort was 69 months, and patients with platinum sensitive ovarian cancer had improved survival compared with those with platinum refractory or resistant disease. CONCLUSION: Platinum doublet chemotherapy resulted in non-significant improved progression-free survival compared with other regimens, suggesting potential independent mechanisms of resistance between PARP inhibitor and platinum compounds.