Background In the SOLO2 trial (ENGOT Ov-21; NCT01874353), maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS). Following disease progression on olaparib, efficacy of subsequent chemotherapy remains unknown. Patients and methods We conducted a post-hoc hypothesis-generating analysis of SOLO2 data to determine the efficacy of different chemotherapy regimens following RECIST disease progression in patients who received olaparib or placebo. We evaluated time to second progression (TTSP) calculated from the date of RECIST progression to the next progression/death. Results The study population comprised 147 patients who received chemotherapy as their first subsequent treatment after RECIST progression. Of these, 69 (47%) and 78 (53%) were originally randomized to placebo and olaparib arms, respectively. In the placebo-treated cohort, 27/69 and 42/69 received non-platinum and platinum-based chemotherapy, respectively, compared with 24/78 and 54/78, respectively, in the olaparib-treated cohort. Among patients treated with chemotherapy (N = 147), TTSP was significantly longer in the placebo than in the olaparib arm: 12.1 versus 6.9 months [hazard ratio (HR) 2.17, 95% confidence interval (CI) 1.47-3.19]. Similar result was obtained on multivariable analysis adjusting for prognostic factors at RECIST progression (HR 2.13, 95% CI 1.41-3.22). Among patients treated with platinum-based chemotherapy (n = 96), TTSP was significantly longer in the placebo arm: 14.3 versus 7.0 months (HR 2.89, 95% CI 1.73-4.82). Conversely, among patients treated with non-platinum-based chemotherapy (n = 51), the TTSP was comparable in the placebo and olaparib arms: 8.3 versus 6.0 months (HR 1.58, 95% CI 0.86-2.90). Conclusions Following progression from maintenance olaparib in the recurrent setting, the efficacy of platinum-based subsequent chemotherapy seems to be reduced in BRCA1/2-mutated patients with PSROC compared to patients not previously receiving poly (ADP-ribose) polymerase inhibitors (PARPi). The optimal strategy for patients who relapse after PARPi is an area of ongoing research.

OBJECTIVE:Immediate facial nerve reconstruction is the standard of care following radical parotidectomy; however, quality of life comparisons with those undergoing limited superficial parotidectomy without facial nerve sacrifice is lacking.METHOD:Patients who underwent parotidectomy were contacted to determine quality of life using the University of Washington Quality of Life and Parotidectomy Specific Quality of Life questionnaires. A total of 29 patients (15 in the radical parotidectomy and 14 in the limited superficial parotidectomy groups) completed and returned questionnaires.RESULTS:Using the University of Washington Quality of Life Questionnaire, similar quality of life was noted in both groups, with the radical parotidectomy group having significantly worse speech and taste scores. Using the Parotidectomy Specific Quality of Life Questionnaire, the radical parotidectomy group reported significantly worse speech, eye symptoms and eating issues.CONCLUSION:Those undergoing radical parotidectomy with reconstruction had comparable overall quality of life with the limited superficial parotidectomy group. The Parotidectomy Specific Quality of Life Questionnaire better identified subtle quality of life complaints. Eye and oral symptoms remain problematic, necessitating better rehabilitation and more focused reconstructive efforts.

Background: In postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)negative early breast cancer, the risk for distant recurrence can extend beyond 5 years of adjuvant endocrine therapy. This study aims to identify genomic driver alterations associated with late distant recurrence. Patients and methods: Next generation sequencing was used to characterize driver alterations in primary tumors from a subset of 764 postmenopausal estrogen receptor-positive/HER2-negative patients from the BIG 1-98 randomized trial. Late distant recurrence events were defined as >= 5 years from time of randomization). The association of driver alterations with distant recurrence-free interval in early and late time periods was assessed using Cox regression models. Multivariable analyses were carried out to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences. Results: A total of 538 of 764 (70%) samples were successfully sequenced including 88 (63%) early and 52 (37%) late distant recurrence events after a median follow up of 8.1 years. In univariable analysis for late distant recurrence, PIK3CA mutations (58.8%) were significantly associated with reduced risk [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.20-0.82, P = 0.012], whereas amplifications on chromosome 8p11 (10.9%) (HR 4.79, 95% CI 2.30-9.97, P < 0.001) and BRCA2 mutations (2.3%) (HR 5.39, 95% CI 1.51-19.29, P = 0.010) were significantly associated with an increased risk. In multivariable analysis, only amplifications on 8p11 (P = 0.002) and BRCA2 mutations (P = 0.013) remained significant predictors. Conclusions: In estrogen receptor-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. The characterization of oncogenic driver alterations may aid in refining treatment choices in the late disease setting, and help identify potential drug targets for testing in future trials.

SOLO2 (ENGOT Ov-21; NCT01874353) demonstrated that maintenance olaparib (O) in patients (pts) with platinum-sensitive relapsed EOC and a BRCA1/2 mutation led to clinically significant survival benefit. We report on the efficacy of subsequent chemotherapy at the time of disease progression. First subsequent treatment was analysed in pts who progressed according to RECIST1.1 in the O and placebo (P) arms. We conducted a post-hoc analysis of time to second progression (TTSP) calculated from the date of RECIST progression after O maintenance to next progression or death as a surrogate of first post-olaparib treatment progression-free survival. 106/195 (54%) and 80/99 (81%) pts had a RECIST progression in the O and P arms respectively. Pt baseline demographics were balanced between both arms. Overall, 161/186 (87%) pts received a first subsequent therapy, including a chemotherapy in 150/161 (93%) and a PARP inhibitor in 29/161 (18%, all in the P arm). In the P arm, 33/75 (44%) and 42/75 (56%) pts received a non-platinum and a platinum-based chemotherapy respectively vs 32/86 (37%) and 54/86 (63%) in the O arm. Overall, in pts receiving subsequent treatment, TTSP was longer in the placebo compared to the O arm: 11.1 vs 7 months (HR 1.93; 95% CI [1.35-2.76]). TTSP was 14.3 vs 7m with platinum-based chemotherapy and 8.3 vs 5.5m with non-platinum chemotherapy in the P and O arm respectively. In this SOLO2 post-hoc comparison, some degree of resistance to standard subsequent platinum and non-platinum chemotherapy is noted in the O arm. However, the TTSP reduction being not at the expense of overall survival, it suggests that the earlier use of O remains optimal in this population. The best post O management should be studied in prospective manner.

Objective: To investigate whether baseline cartilage thickness and its longitudinal change are associated with incident widespread full-thickness cartilage loss (wsFTCL) in knee osteoarthritis, and whether there are optimal cut-off values for predicting wsFTCL. Methods: Central medial tibial (cMT) and femoral (cMF) cartilage were assessed using quantitative magnetic resonance imaging data from the Osteoarthritis Initiative cohort (N = 600 knees). Cartilage thickness was measured at baseline and 12 months. wsFTCL was defined semi-quantitatively (scores 2 and 3 from the MRI Osteoarthritis Knee Score) and its incidence at 24 months recorded. Logistic regression was used to determine the odds of developing wsFTCL for baseline and for each 0.1 mm decrease in cartilage thickness. Cut-off values were investigated using the minimal-p method and area under the Receiver Operating Characteristic curves (AUC). Results: Incident wsFTCL was observed in 66 (12%) and 73 (14%) knees in cMT and cMF, respectively. Lower baseline cMT and cMF cartilage thickness values were associated with wsFTCL (OR = 1.20; 95% CI: 1.11, 1.28 and OR = 1.15; 95% CI: 1.06 to 1.24, respectively). Optimal cut-off AUCs for the tibia and femur were 0.64 (0.57-0.70) and 0.63 (0.57-0.69), respectively. Longitudinal decrease in femoral, but not tibial, cartilage thickness was associated with incident wsFTCL (OR = 1.77; 95% CI: 1.30 to 2.40); optimal cut-off AUC 0.65 (95% CI: 0.58-0.72). Conclusion: Lower baseline cMT and baseline/change (decrease) over 12 months in cMF cartilage thickness were associated with incident, location-specific, wsFTCL at 24 months. Optimal cut-off values were relatively low and of uncertain utility for predicting incident wsFTCL. (C) 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

BACKGROUND:Standard treatment of early cervical cancer involves a radical hysterectomy and retroperitoneal lymph node dissection. The existing evidence on the incidence of adverse events after minimally invasive vs open radical hysterectomy for early cervical cancer is either nonrandomized or retrospective. OBJECTIVE:The purpose of this study was to compare the incidence of adverse events after minimally invasive vs open radical hysterectomy for early cervical cancer. STUDY DESIGN:The Laparoscopic Approach to Carcinoma of the Cervix trial was a multinational, randomized noninferiority trial that was conducted between 2008 and 2017, in which surgeons from 33 tertiary gynecologic cancer centers in 24 countries randomly assigned 631 women with International Federation of Gynecology and Obstetrics 2009 stage IA1 with lymph-vascular invasion to IB1 cervical cancer to undergo minimally invasive (n = 319) or open radical hysterectomy (n = 312). The Laparoscopic Approach to Carcinoma of the Cervix trial was suspended for enrolment in September 2017 because of an increased risk of recurrence and death in the minimally invasive surgery group. Here we report on a secondary outcome measure: the incidence of intra- and postoperative adverse events within 6 months after surgery. RESULTS:Of 631 randomly assigned patients, 536 (85%; mean age, 46.0 years) met inclusion criteria for this analysis; 279 (52%) underwent minimally invasive radical hysterectomy, and 257 (48%) underwent open radical hysterectomy. Of those, 300 (56%), 91 (16.9%), and 69 (12.8%) experienced at least 1 grade ≥2 or ≥3 or a serious adverse event, respectively. The incidence of intraoperative grade ≥2 adverse events was 12% (34/279 patients) in the minimally invasive group vs 10% (26/257) in the open group (difference, 2.1%; 95% confidence interval, -3.3 to 7.4%; P=.45). The overall incidence of postoperative grade ≥2 adverse events was 54% (152/279 patients) in the minimally invasive group vs 48% (124/257) in the open group (difference, 6.2%; 95% confidence interval, -2.2 to 14.7%; P=.14). CONCLUSION:For early cervical cancer, the use of minimally invasive compared with open radical hysterectomy resulted in a similar overall incidence of intraoperative or postoperative adverse events.

Background: The PARP inhibitor olaparib (Lynparza®) has shown significant efficacy as maintenance therapy for patients (pts) with PSR OC, especially pts with BRCA mutations, as capsules (Ledermann et al Lancet Oncol 2014) and tablets (Pujade-Lauraine et al Lancet Oncol 2017). Olaparib capsules have shown long-term benefit, with pts staying on treatment for ≥5 years (yrs; Gourley et al ASCO 2017). We analysed the long-term tolerability of olaparib tablets in the SOLO2 trial (ENGOT-Ov21; NCT01874353). Methods: In SOLO2, pts with BRCA-mutated PSR OC in response to platinum received maintenance olaparib tablets (300 mg bid) or placebo until disease progression. Adverse events (AEs) were graded by CTCAE v4.0. Results: At the primary data cut-off (DCO; 19 Sep 2016), of 195 pts treated with olaparib, 62 (32%) had received olaparib for ≥1–<2 yrs (Group 1) and 59 (30%) for ≥2 yrs (Group 2), vs 12/99 (12%) and 9/99 (9%), respectively, who received placebo. Most AEs that began after ≥1 yr (Group 1) or ≥ 2 yrs (Group 2) were grade 1–2, with few serious AEs (Table). The most common AEs with onset during the second yr of olaparib treatment were anaemia (19%), nausea (18%), and vomiting (15%). The most common AEs with onset after ≥2 yrs were diarrhoea (8%), abdominal pain (5%), and upper abdominal pain (5%). Four pts in Group 1 discontinued olaparib because of AEs (acute myeloid leukaemia, decreased neutrophil count, muscular weakness, disturbance in attention and depression; all n = 1) vs no pts in Group 2.Table: 952PLong-term AE data for olaparib tablets as maintenance therapyGroup 1 (n = 62)Group 2 (n = 59)AEs with onset reported during the second yr (≥1–<2 yrs) of olaparib treatmentAEs with onset reported after ≥2 yrs of olaparib treatmentAE (any grade), n (%)54 (87)23 (39)AE (grade ≥3), n (%)11 (18)1 (2)Serious AE, n (%)7 (11)1 (2)Dose interruption caused by AE, n (%)14 (23)4 (7)Dose reduction caused by AE, n (%)4 (6)0Treatment discontinuation caused by AE, n (%)4 (6)0 Open table in a new tab Conclusions: AEs reported during long-term olaparib maintenance therapy were mostly low grade, non-serious and associated with a low rate of treatment discontinuation. Common AEs were consistent with the known safety profile. Olaparib tablets are suitable for long-term maintenance therapy for PSR OC pts, without cumulative toxicity and with few late-onset AEs. Clinical trial identification: NCT01874353, January 2017. Editorial acknowledgement: Editorial assistance was provided by Rachel Patel, Mudskipper Business Limited, funded by AstraZeneca. Legal entity responsible for the study: AstraZeneca. Funding: AstraZeneca. Disclosure: J. Korach: Advisory board member: AstraZeneca Israel. G. Freyer: Board and speaker fees: AstraZeneca, Pfizer, Lilly, Novartis, Biogaran, Clovis, Amgen; Speaker fees: Roche; Research funding: AstraZeneca, BMS, Amgen; Consultant honoraria: Amgen. S. Banerjee: Honoraria: AstraZeneca, Tesaro, Clovis, PharmaMar, and Gamamabs; Research funding to institution: AstraZeneca. J. Cosin: Consultant for Medtronic. A.M. Oza: Steering committees (non-compensated) for trials: AstraZeneca, Clovis, Tesaro; Honoraria: Intas Pharma. A.M. Poveda: Advisor: AstraZeneca, Roche, Tesaro, Clovis, PharmaMar. C. Scott: Personal fees and non-financial support: AstraZeneca; Grants, personal fees, non-financial support, and others: Clovis Oncology, Roche; Others: Eisai Australia, Beigene. M. Lapresa: Fees: AstraZeneca, PharmaMar. G.S. Sonke: Institutional research support: AstraZeneca, Merck, Novartis, Roche. S. Tjulandin: Honoraria: AstraZeneca, Pfizer, Eli Lilly, MSD, Hoffmann La Roche. I.B. Vergote: Advisory board fees: Roche, Genmab, Advaxis, Morphotek, Hoffmann La Roche, Cerulean Pharma, Novocure, AstraZeneca, Mateon Therapeutics, Immunogen, Eli Lilly Benelux, Amgen, Theradex Europe, Pfizer, Debiopharma International, Vifor Pharma, Novartis, MSD, Janssen-Cilag, Bayer, Clovis Oncology, Takeda, PharmaMar, Oncoinvent; Research grants: Amgen, Roche; Accommodation and travel expenses: Tesaro, Clovis Oncology, Takeda, PharmaMar, Roche, Genmab, Oncoinvent; Institutional research grants: Morphotek. S. Turner: Employee of AstraZeneca and owns stock. E. Pujade-Lauraine: Honoraria, advisory board member: AstraZeneca, Roche, Tesaro, Clovis, Pfizer. All other authors have declared no conflicts of interest.

Purpose: The purpose of this study is to evaluate the association between sleep quality, fatigue and hip pain exacerbations in persons with symptomatic hip OA. Methods: We conducted an internet-based case-crossover study to assess potential risk factors, including sleep and fatigue, for hip pain exacerbation. Eligible participants with symptomatic hip OA were followed for 90 days and asked to complete online questionnaires at 10-day intervals (control periods). They also logged on to the study website to complete questionnaires in the episode of a hip pain exacerbation (case periods) defined as an increase of two points in pain intensity compared with baseline on the numeric rating scale (0-10). Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) (global PSQI score range: 0–21), and fatigue was measured by Multi-Dimensional Assessment of Fatigue (MAF) (global fatigue index (GFI) range: 0–51). The relationship of sleep quality and fatigue to the risk of pain exacerbation was analysed using conditional logistic regression. Results: Of 252 participants recruited, 130 (52%) had both case (average: 2.3) and control (average: 8.5) periods and were included in the final analysis. Two case periods in PSQI questionnaires and one control period in MAF questionnaires were lost during follow-up. Poor sleep quality during the last seven days was significantly associated with increased odds of pain exacerbations (global PSQI score >5 vs ≤5: odds ratio [OR] 1.72, 95% CI 1.04, 2.86). Greater fatigue (GFI > 21) during the last seven days was also associated with an increased risk of hip pain exacerbation (OR 1.92, 95% CI 1.21, 3.05). There was no significant interaction between sleep quality and fatigue (P = 0.236). Conclusions: Poor sleep quality and fatigue were significantly related to pain exacerbation in persons with symptomatic hip OA. Interventions improving sleep quality and avoiding fatigue may decrease the risk of hip pain exacerbations in persons with hip OA.Table 1Association of sleep quality, fatigue and hip pain exacerbation (130 participants).Independent variablesCase periodsControl periodsDependent variable (Pain exacerbations)OR (95% CI)P-valueSleep quality* Good91 (31%)276 (34%)–– Poor205 (69%)532 (66%)1.72 (1.04, 2.86)0.036Fatigue** No125 (42%)446 (55%)–– Yes173 (58%)361 (45%)1.92 (1.21, 3.05)0.006*A global PSQI score ≤ 5 is indicative of good sleep quality and poor sleep quality is greater than 5. Two missing case periods were lost during follow-up.**A cut-off score of 21 on the global fatigue index (GFI) was used to detect significant fatigue. One control period was lost during the follow-up. Open table in a new tab *A global PSQI score ≤ 5 is indicative of good sleep quality and poor sleep quality is greater than 5. Two missing case periods were lost during follow-up. **A cut-off score of 21 on the global fatigue index (GFI) was used to detect significant fatigue. One control period was lost during the follow-up.

The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)+/- mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively. This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. This is a molecular sub-study of MAX clinical trial (NCT00294359).

Abstract Background Next generation sequencing (NGS) has revealed that ER+/HER2- BCs have diverse somatic copy number and mutation profiles but thus far the clinical relevance of such findings is unknown. We characterized the molecular alterations in post-menopausal primary BC patients treated in the BIG 1-98 adjuvant letrozole and tamoxifen study and evaluated their associations with prognosis. Materials and Methods NGS was used to genotype DNA from archival primary tumor blocks for 286 cancer-related genes. From 2706 available eligible samples (confirmed ER+, excluding HER2-positivity or neoadjuvant treatment, adequate DNA quality/quantity), a case-cohort design selected 764 samples: all distant relapses and a stratified sampling of non-relapses after 8yr median follow-up. Mutation prevalence and associations with clinicopathological factors (CP) as well as distant recurrence-free interval (DRFS) were analyzed using weighted tests and Cox regression models, with sampling weights to represent the ER+/HER2-negative trial population. Multivariable analyses were adjusted for tumor size, nodal status, grade and age. Results NGS data was available from 538/764 samples (70%), there were 140 (26%) distant relapses. Median sequencing depth was 483x. There was a mean of 11 mutations (1-46) per sample, with 25% having 13 or more mutations and no tumors without a mutation. Overall 28 genes were altered at a frequency of >10%. The most commonly mutated genes were PIK3CA (49.3%), NCOR1 (27.2%), MAP3K1 (23.8%) TP53 (16.6%), CCND1 (17.8%) and GATA3 (17.1%). Alterations that were significantly associated with both Luminal B (Ki67 >14%) and grade 3 included TP53 mutations (p<0.001), FGFR1 (p=0.001) and MYC amplifications (p=0.004). Gene alterations that were significantly associated with shorter DRFS included TP53 (HR:2.16), ARID1A (HR:2.43), CHEK2 (HR:2.54), BRCA2 (HR:1.93), PTEN (HR:2.03), CCND1 (HR:1.82) and FGFR1 (HR:1.78). PIK3CA was significantly associated with lower risk of distant relapse (HR:0.64; 0.43-0.97). Increasing number of total mutations was significantly associated with shorter DRFS (HR:1.04; 95% CI 1.01-1.07; p=0.006). In the multivariable model adjusted for CP factors, ARID1A, BRCA2, CCND1, CHEK2 and PTEN remained independent for shorter DRFS. Greater than 90% of PIK3CA mutations co-existed with another alteration, most common being NCOR1 (29%), MAP3K1 (24%), CDH1 (16%), GATA3 (16%), TP53 (14%) and CCND1 (13%). Patients with a PIK3CA mutation had greater benefit with letrozole over tamoxifen monotherapy (HR 0.32; 0.13-0.8) than those without (HR:0.70; 0.33-1.48) (Pint=0.06). This effect was strongest in the subgroup of PIK3CA mutant patients who were CCND1 and TP53 wild-type (HR:0.24, 0.12-0.48; Pint=0.02) with only 1% relapsing at 5 years. Conclusion: For the first time, we report the prognostic relevance of oncogenic mutations in ER+/HER2- postmenopausal early-stage BCs from a clinical trial. Tumors with PIK3CA mutations derived greater benefit from letrozole over tamoxifen monotherapy, especially if wild-type for CCND1 and TP53. These findings could significantly improve prognostic risk classification and guide future clinical trials of targeted therapies in ER+/HER2- BCs. Citation Format: Loi S, Asher R, Lee CK, Luen S, Savas P, Kammler R, Dell'Orto P, Blasi OM, Demanse D, JeBailley L, Dolan S, Hackl W, Thuerlimann B, Viale G, Regan M, Colleoni MA. Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-10.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. Patients and methods Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. Results Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (κ = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. Conclusions There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

BACKGROUND:Women with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic. PATIENTS AND METHODS:Data from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic. RESULTS:In AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67-93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13-44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively. CONCLUSIONS:Physical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient-doctor communication about prognosis, and clinical decision-making. CLINICAL TRIAL REGISTRATION:NCT00976911.

Background: Promising therapeutic results of the prostate-specific membrane antigen (PSMA) ligand have been shown when labelling with lutetium-177 ( 177 Lu). We performed a systematic review and meta-analysis to assess the therapeutic response of 177 Lu-PSMA in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Methods: A systematic review was conducted using electronic databases up to December 2016. Two reviewers independently extracted data and assessed methodological quality. The main outcome of interest was antitumour biochemical response of 177 Lu-PSMA, analysing two measures: ‘any PSA decline’ and ‘>50% decline’ from baseline. A random-effects meta-analysis was used to calculate the pooled proportion across studies. The I 2 statistic was calculated in each case to investigate the extent of heterogeneity across the studies. A sensitivity analysis was conducted removing two studies, which were presented as abstracts and proportions were summarised by chemical type ( 177 Lu-J591/DKZ/I&T). All analyses were conducted using Stata v14. Results: A total of 10 studies were included in the analysis giving a total sample size of 369, 220 (of 334 analysable) experienced any PSA decline. The pooled proportion of patients with any PSA decline was 68% (95% confidence interval (CI): 61–74). The I 2 statistic was 39.1% ( P =0.11) suggesting minor heterogeneity between results. The pooled proportion of patients with >50% PSA decline was 37% (95% CI: 22–52). The I 2 statistic was 91.0% ( P <0.001) suggesting substantial heterogeneity between results. On subgroup analysis, a higher proportion of patients in the 177 Lu-DKZ/I&T subgroup had a PSA decline >50%, however, it can be seen that the 177 Lu-DKZ/I&T subgroup had a substantial amount of heterogeneity across studies. Conclusions: This review suggests promising early results for the treatment of mCRPC, especially from patients treated with the more recently developed radioligands. Overall, our meta-analysis showed that approximately two-thirds of patients had a biochemical response. Randomised-controlled trials would be necessary to verify its effectiveness against current systemic therapies and create an ideal treatment protocol.

Background: CMS is a transcriptome-based classification of colorectal cancer (CRC) with prognostic implications, but its association with treatment outcomes, especially in the metastatic setting, remains unknown. We investigated whether CMS classification was predictive of bevacizumab treatment benefit using data from the phase 3 MAX trial. MAX previously reported progression-free survival (PFS) benefit for the addition of bevacizumab (B) to chemotherapy (capecitabine (C) +/- mitomycin (M)) in first line treatment of metastatic CRC. Methods: Archival tumours from 256 patients (54% of trial population) were available for gene expression profiling using Almac Xcel microarray. Tumours were classified into CMS groups 1 to 4 using previously published methods. We correlated CMS groups with PFS in the MAX trial. The predictive value of CMS was demonstrated as the interaction between CMS and bevacizumab treatment, assessed by Cox proportional hazards model. Results: After data quality control, primary tumours from 239 patients (51% of trial population) were suitable for survival analysis. Distribution of CMS groups were CMS1 18%, CMS2 48%, CMS3 12%, CMS4 23%. Hazard ratios (HR)(95% CI) of PFS in C vs CB+CBM arms for CMS 1,2,3 and 4 were 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25) respectively (test for interaction between CMS and treatment, p = 0.03). CMS remained a significant independent predictor of PFS after adjustment for prognostic factors in a multivariate analysis (p = 0.04). Conclusions: In metastatic CRC, CMS 2 and 3 subtypes preferentially benefit from the addition of bevacizumab to chemotherapy, compared to CMS 1 and 4. Validation of these findings in independent cohorts is required. Once validated, CMS classification could be used to guide patient selection for bevacizumab therapy. Legal entity responsible for the study: Olivia Newton-John Cancer Research Institute, Australia Funding: Olivia Newton-John Cancer Research Institute, Australia and Australian Gastrointestinal Trials Group (AGITG) Disclosure: P. Wirapati: Funding: Roche, Bayer and Sanofi for research in predictive biomarker for colorectal cancer. T.J. Price, N. Tebbutt: Advisory boards: Roche All other authors have declared no conflicts of interest.