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In advanced cancers, biomarker research has focused on discovery with a lag in validation and implementation. Clinical biomarkers available from routine investigations represent an untapped source of research opportunities. In this thesis, chapter 2 reviews the evidence to support the role of biomarkers for personalising treatment. Using data from two large RCTs (N=1512) in advanced lung cancer, chapter 3 evaluates the clinical utility of lactate dehydrogenase (LDH). Elevated LDH was associated with a 49% increased risk of death in patients treated with immunotherapy but did not predict greater benefit with immunotherapy over chemotherapy, demonstrating the importance of RCT data to definitively assess candidate predictive markers. Chapters 4-6 focuses on ovarian cancer patients treated with maintenance poly(adenosine diphosphate–ribose) polymerase inhibitor (PARPi) therapy. Using three landmark RCTs (N=1412), approximately 1 in 2 women on maintenance PARPi therapy with progression (PD) on routine CT scans did not have CA-125 PD (Ch 4 & 5); underscoring the need to re-evaluate pre-existing biomarkers within the contemporary treatment context. In chapter 6, a nomogram was developed and validated that allowed for simultaneous evaluation of four prognostic factors. It is also essential to evaluate whether newer biomarkers provide value beyond existing knowledge. Using data from a RCT of targeted therapies (n=1110) in kidney cancer, baseline neutrophil-to-lymphocyte ratio (NLR) was confirmed as an independent and significant prognostic factor. However, NLR did not substantially reclassify patients beyond the pre-existing prognostic grouping, and hence did not justify its use in routine practice (Ch 7). The findings from this work supports oncologists in treating patients and trialists to better design trials with personalised therapies. This thesis will stimulate future research in biomarker evaluation as an increasing number of novel therapies become available.

Background The impact of maintenance therapy with PARP inhibitors (PARPi) on progression-free survival (PFS) in patients with BRCA mutations and platinum-sensitive recurrent ovarian cancer (PSROC) varies widely. Individual prognostic factors do not reliably distinguish patients who progress early from those who have durable benefit. We developed and validated a prognostic nomogram to predict PFS in these patients. Methods The nomogram was developed using data from a training patient cohort with BRCA mutations and high-grade serous PSROC on the placebo arm of two maintenance therapy trials, Study 19 and SOLO2/ENGOT-ov21. We performed multivariable Cox regression analysis based on pre-treatment characteristics to develop a nomogram that predicts PFS. We assessed the discrimination and validation of the nomogram in independent validation patient cohorts treated with maintenance olaparib. Results The nomogram includes four PFS predictors: CA-125 at randomisation, platinum-free interval, presence of measurable disease and number of prior lines of platinum therapy. In the training (placebo) cohort (internal validation C-index 0.64), median PFS in the model-predicted good, intermediate and poor-risk groups was: 7.7 (95% CI 5.3–11.3), 5.4 (4.8–5.8) and 2.9 (2.8–4.4) months, respectively. In the validation (olaparib) cohort (C-index 0.71), median PFS in the model-predicted good, intermediate and poor-risk groups was: not reached, 16.6 (13.1–22.4) and 8.3 (7.1–10.8) months, respectively. The nomogram showed good calibration in the validation cohort (calibration plot). Conclusions This nomogram can be used to predict PFS and counsel patients with BRCA mutations and PSROC prior to maintenance olaparib and for stratification of patients in trials of maintenance therapies.

AIM The American Joint Committee on Cancer (AJCC) melanoma staging system eighth edition (AJCC-8) was recently released to provide accurate staging reflecting advances in the treatment of melanoma. Using population registry data, this study independently validates and compares the prognostic performance of AJCC-8 to the seventh edition (AJCC-7). METHODS We extracted patient-, tumor-related, and survival data from the SEER-18 registry between 2010 and 2015. To assess overall survival (OS) and cancer-specific survival (CSS) for AJCC-7 and AJCC-8, we performed Kaplan-Meier analysis and computed cumulative hazard functions using Nelson-Aalen function. RESULTS Of 126,408 individuals, 59,989 (47%) and 60,411 (48%) had available data for pathological and clinical-stage OS analysis, respectively. The 3-year OS for AJCC-7 among pathologically staged patients was: stage IA 97%, stage IB 95%, stage IIA 87%, stage IIB 76%, stage IIC 57%, stage IIIA 86%, stage IIIB 69%, stage IIIC 50%, and stage IV 24%. The 3-year OS for AJCC-8 patients was similar but was 56% for stage IIIC and 30% for stage IIID. Stage IV individuals with an elevated LDH had worse OS and CSS at all measured time-points up to 60 months compared to those with a normal LDH. CONCLUSION The discriminatory ability of AJCC-8 and AJCC-7 appear comparable. Changes in AJCC-8 identified stage IIID as a poor prognostic subgroup among stage III patients and elevated LDH in stage IV. However, patients with advanced T-stage, node-negative tumors experienced worse survival compared to those with earlier T-stage, node-positive tumors, and the results of ongoing trials should inform adjuvant therapy in this subset of patients.

Background Limited evidence exists to support CA-125 as a valid surrogate biomarker for progression in patients with ovarian cancer on maintenance PARP inhibitor (PARPi) therapy. We aimed to assess the concordance between CA-125 and Response Evaluation Criteria in Solid Tumours (RECIST) criteria for progression in patients with BRCA mutations on maintenance PARPi or placebo. Methods We extracted data on progression as defined by Gynecologic Cancer InterGroup CA-125, investigator- and independent central-assessed RECIST from the SOLO2/ENGOT-ov21(NCT01874353) trial. We excluded those with progression other than by RECIST, progression on date of randomisation, and no repeat CA-125 beyond baseline. We evaluated the concordance between CA-125 progression and RECIST progression, and assessed the negative (NPV) and positive predictive value (PPV). Results Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included. 171 patients had investigator-assessed RECIST progression. Of 80 patients with CA-125 progression, 77 had concordant RECIST progression (PPV 96%, 95% confidence interval 90–99%). Of 195 patients without CA-125 progression, 94 had RECIST progression (NPV 52%, 45–59%). Within treatment arms, PPV was similar (olaparib: 95% [84–99%], placebo: 97% [87–100%]) but NPV was lower in patients on placebo (olaparib: 60% [52–68%], placebo: 30% [20–44%]). Of 94 patients with RECIST but without CA-125 progression, 64 (68%) had CA-125 that remained within normal range. We observed similar findings using independent-assessed RECIST. Conclusions Almost half the patients without CA-125 progression had RECIST progression, and most of these had CA-125 within the normal range. Regular computed tomography imaging should be considered as part of surveillance in patients treated with or without maintenance olaparib rather than relying on CA-125 alone.

BACKGROUND: The authors performed a meta‐analysis to better quantify the benefit of maintenance poly(ADP‐ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum‐sensitive, recurrent, high‐grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild‐type BRCA but homologous recombinant‐deficient (HRD), homologous recombinant‐proficient (HRP), and baseline clinical prognostic characteristics. METHODS: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression‐free survival were pooled across trials using the inverse variance weighted method. RESULTS: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23‐0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17‐0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12‐0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild‐type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31‐0.56); and, in those who had wild‐type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49‐0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab. CONCLUSIONS: In platinum‐sensitive, recurrent, high‐grade ovarian cancer, maintenance PARPi improves progression‐free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy.

BACKGROUND: An elevated neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis in advanced renal cell carcinoma (RCC). We examined whether the addition of NLR improves the risk reclassification of advanced RCC using current prognostic tools from the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). METHODS: Using randomised data from the COMPARZ trial of first-line pazopanib vs sunitinib in advanced RCC, we constructed multivariable models containing MSKCC and IMDC predictor variables with and without NLR. We evaluated model discrimination using the concordance index (C-index). We computed net reclassification improvement (NRI) to quantify patient reclassification into low/intermediate/poor risk groups with the addition of NLR. RESULTS: Of 1102 patients, NLR≥5 (16%) was associated with shorter survival adjusting for MSKCC variables (adjusted HR 1.89, P

Background There is limited information on the risk of metastatic breast cancer (MBC) to inform younger women, particularly those under 40 years. Aims We conducted a retrospective analysis of a population-based cohort study to describe the risk, site and prognosis of MBC in young women under 40 years with an initial diagnosis of non-metastatic breast cancer and compared with older women. Methods Data were extracted from the New South Wales Central Cancer Registry and the Admitted Patient Data Collection database between 2001–2007. Main outcome measures were 5-year cumulative incidence of MBC, prognostic factors for MBC and overall survival (OS) from the date of MBC diagnosis. Results Three hundred and ninety-five (6%) of 6640 women with non-metastatic BC were

Background Changes to the AJCC melanoma staging system eighth edition (AJCC-8) should be independently validated to assess its prognostic performance compared with the seventh edition (AJCC-7) in accurately staging melanoma. Methods We used the SEER-18 registry from 2010 to 2015 to extract patient-, tumour-related and survival data. Kaplan-Meier analysis was used for overall survival (OS) and cancer-specific survival (CSS) for AJCC-7 and AJCC-8. Cumulative hazard functions were computed using Nelson-Aalen function. Results Of 126,408 individuals, 59,989 (47%) and 60,411 (48%) had available data for pathological and clinical stage OS analysis, respectively. The 12-month OS for AJCC-7 among pathologically staged patients were: stage IA 99%, stage IB 99%, stage IIA 96%, stage IIB 94%, stage IIC 87%, stage IIIA 98%, stage IIIB 94%, stage IIIC 82% and stage IV 41%. The 12-month OS for AJCC-8 patients was similar to AJCC-7 but was 88% for stage IIIC and 65% for stage IIID. The 12-month risk of dying for pathological stage IIIC was 13% compared to 41% for pathological stage IIID (p Conclusions The discriminatory ability of the AJCC-7 and AJCC-8 melanoma staging system appear comparable. Changes in AJCC-8 identifies individuals with a poorer prognostic within new subgroups. These include the subgroups of stage IIID and M1d within stage IV individuals, and the addition of elevated LDH as a prognostic marker in stage IV disease. However, advanced T stage, node-negative tumours experienced worse survival compared with earlier T stage, node-positive tumours requiring further research to evaluate the underlying biology of these tumour subgroups. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Treatments for autoimmune blistering diseases have significant risk of medical complications and quality of life impacts during treatment, and it is difficult to differentiate these impacts from disease burden or the effects of treatment. Objectives To develop a quality of life instrument specific to the effects of treatments used in patients with autoimmune bullous disease (AIBD). Methods A comprehensive item generation process was used to build a 45-item pilot Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire, distributed to 70 patients with AIBD. Experts in bullous disease refined the pilot ABQOL, selecting only those questions pertaining to the treatment effects. This pilot Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) questionnaire was administered to 70 patients, before factor analysis was performed to yield the final questionnaire of 17 questions. Validity and reliability were evaluated across a range of indices. Results Face and content validity were established through a comprehensive patient interview process, expert review and summaries of treatments used. The questionnaire was found to have appropriate correlation with the Dermatology Life Quality Index (r = 0·64) and the level of treatments used (P < 0·01), and was found to be responsive to overall variations in treatment burden. The TABQOL was also found to be a reliable instrument as evaluated by internal consistency (Cronbach α = 0·892) and test-retest reliability (r = 0·99). Conclusions We have shown that the TABQOL questionnaire is a valid and reliable instrument that may to be used to measure treatment burden in AIBD and serve as an end point in clinical trials. What's already known about this topic? Treatments for autoimmune bullous disease (AIBD) have a significant risk of medical complications and quality of life impacts during treatment. It is difficult to differentiate quality of life impacts from disease burden or the effects of treatment. What does this study add? The Treatment of Autoimmune Bullous Disease Quality of Life questionnaire allows quantitative measurement of treatment-based quality of life impacts in AIBDs. Longitudinal measurements allow consideration of optimal balance between disease control and treatment burden.

BACKGROUND: This study defined the risk of serious toxicity in phase I trials of molecularly targeted agents (MTA). PATIENTS AND METHODS: A retrospective analysis of toxicity data from patients treated in phase I trials of MTAs was carried out to define the rate of treatment-related grade 3/4 toxic effects, deaths and risk factors associated with grade 3 or more toxicity. RESULTS: Data from 687 patients [median age, 59.1 years (range 12.5-85.5)] treated in 36 trials were analysed. Two hundred and eleven patients were of Eastern Cooperative Oncology Group performance status (PS) zero, 432 of PS one, 38 of PS two and 6 unknown. The rate of grade 3 and 4 events was 14.1% (n=97) and 1.9% (n=13), respectively. Twenty-four percent of events were gastrointestinal, 22% constitutional and 20% metabolic. PS two was associated with a higher risk of toxicity [odds ratio (OR), 2.6; 95% confidence interval (CI) 1.1-6.1; P=0.032] as was receiving >100% of maximum tolerated dose or maximum administered dose (OR 2.5; CI 1.6-3.9; P

Objectives: This study aimed to evaluate any correlations between baseline creatinine clearance and the development of grade 3/4 toxicities during treatment within oncology phase I trials of molecularly targeted agents where entry criteria mandate a serum creatinine of ≤1.5 × the upper limit of normal. Methods: Documented toxicity and creatinine clearance (calculated by the Cockcroft-Gault formula) from all patients treated with molecularly targeted agents in the context of phase I trials within our centre over a 5-year period were analyzed. Results: Data from 722 patients were analyzed; 116 (16%) developed at least one episode of grade 3/4 toxicity. Patients who developed a late-onset (>1 cycle) grade 3/4 toxicity had a lower creatinine clearance than those who did not (82.69 ml/min vs. 98.97 ml/min; p = < 0.001). Conclusion: Creatinine clearance (even when within normal limits) should be studied as a potential factor influencing late toxicities in the clinical trials of molecularly targeted anti-cancer drugs.

There is limited information on the risk of metastatic breast cancer (MBC) to inform younger women, particularly those under 40 years.We conducted a retrospective analysis of a population-based cohort study to describe the risk, site and prognosis of MBC in young women under 40 years with an initial diagnosis of non-metastatic breast cancer and compared with older women.Data were extracted from the New South Wales Central Cancer Registry and the Admitted Patient Data Collection database between 2001-2007. Main outcome measures were 5-year cumulative incidence of MBC, prognostic factors for MBC and overall survival (OS) from the date of MBC diagnosis.Three hundred and ninety-five (6%) of 6640 women with non-metastatic BC were40 years. The 5-year cumulative incidence of MBC was 24% (95% CI 20-29%) for women40 years with non-metastatic BC, compared with 9% (95% CI 9-10%) for women ≥40 years. Significant independent risk factors for MBC ≤ 5 years were age40, regional disease at diagnosis, low socioeconomic status and the presence of other non-breast primary. At first record of MBC, visceral sites were more common for women40 years than ≥40 (54% vs 43%; P = 0.03). Median survival for women with MBC within 5 years was not significantly different between young and older women (40 years 18 months vs ≥40 years 14 months; log-rank P = 0.21).Women with non-metastatic BC before age 40 have a higher 5-year risk of developing MBC than older women. There were no significant differences in median survival following MBC between young and older women.

4544 Background: There is strong evidence that neoadjuvant chemotherapy improves survival in MIBC but its uptake in clinical practice is variable. The benefits of adjuvant chemotherapy are controversial, especially with the recent presentation of 3 RCTs not included in previous MA.We sought to summarise the effects of chemotherapy, both neoadjuvant and adjuvant, on survival in MIBC. Methods: We included published summary data from recent MA and RCTs. Eligible RCTs compared the addition of chemotherapy, neoadjuvant or adjuvant, to local treatment versus local treatment alone. We searched CENTRAL, PubMed, MEDLINE, proceedings of ASCO and clinicaltrials.gov from 2004 to August 2012.The primary outcome was overall survival (OS). Disease-free survival (DFS) and adverse events (AE) were secondary outcomes. Pooled hazard ratios (HR), confidence intervals (CI) and p-values (p) were estimated with fixed effects model. Heterogeneity and subgroup effects were assessed with p-values for interaction. Results: We included 21 RCTs (n=3986), 12 of neoadjuvant (n=3047) and 9 adjuvant chemotherapy (n=939).The addition of chemotherapy significantly improved OS (HR 0.86, 95% CI 0.79 to 0.93, p=0.0004). Separate analyses of neoadjuvant therapy and adjuvant therapy yielded significant results in both subgroups (HR 0.89, 95% CI 0.81 to 0.98, p=0.02; HR 0.75, 95% CI 0.63 to 0.90, p=0.002; respectively; p-value for interaction 0.11). There were larger benefits in DFS (HR 0.77, 95% CI 0.71 to 0.84, p