Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. PATIENTS AND METHODS: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSIONS: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. RESULTS: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.

Assessment of structural chromosomal instability phenotypes as biomarkers of carboplatin response in triple negative breast cancer: the TNT trial.

BACKGROUND: In the TNT trial of triple negative breast cancer (NCT00532727), germline BRCA1/2 mutations were present in 28% of carboplatin responders. We assessed quantitative measures of structural chromosomal instability (CIN) to identify a wider patient subgroup within TNT with preferential benefit from carboplatin over docetaxel. PATIENTS AND METHODS: Copy number aberrations (CNAs) were established from 135 formalin-fixed paraffin-embedded primary carcinomas using Illumina OmniExpress SNP-arrays. Seven published [allelic imbalanced CNA (AiCNA); allelic balanced CNA (AbCNA); copy number neutral loss of heterozygosity (CnLOH); number of telomeric allelic imbalances (NtAI); BRCA1-like status; percentage of genome altered (PGA); homologous recombination deficiency (HRD) scores] and two novel [Shannon diversity index (SI); high-level amplifications (HLAMP)] CIN-measurements were derived. HLAMP was defined based on the presence of at least one of the top 5% amplified cytobands located on 1q, 8q and 10p. Continuous CIN-measurements were divided into tertiles. All nine CIN-measurements were used to analyse objective response rate (ORR) and progression-free survival (PFS). RESULTS: Patients with tumours without HLAMP had a numerically higher ORR and significantly longer PFS in the carboplatin (C) than in the docetaxel (D) arm [56% (C) versus 29% (D), PHLAMP,quiet = 0.085; PFS 6.1 months (C) versus 4.1 months (D), Pinteraction/HLAMP = 0.047]. In the carboplatin arm, patients with tumours showing intermediate telomeric NtAI and AiCNA had higher ORR [54% (C) versus 20% (D), PNtAI,intermediate = 0.03; 62% (C) versus 33% (D), PAiCNA,intermediate = 0.076]. Patients with high AiCNA and PGA had shorter PFS in the carboplatin arm [3.4 months (high) versus 5.7 months (low/intermediate); and 3.8 months (high) versus 5.6 months (low/intermediate), respectively; Pinteraction/AiCNA = 0.027, Padj.interaction/AiCNA = 0.125 and Pinteraction/PGA = 0.053, Padj.interaction/PGA = 0.176], whilst no difference was observed in the docetaxel arm. CONCLUSIONS: Patients with tumours lacking HLAMP and demonstrating intermediate CIN-measurements formed a subgroup benefitting from carboplatin relative to docetaxel treatment within the TNT trial. This suggests a complex and paradoxical relationship between the extent of genomic instability in primary tumours and treatment response in the metastatic setting.

Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES.

BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane. PATIENTS AND METHODS: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated. RESULTS: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4. CONCLUSION: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years.

Bone marrow micrometastases in early breast cancer-30-year outcome.

BACKGROUND: Micrometastases in bone marrow of women with early breast cancer were first identified immunocytochemically in the 1980s. We report on the original cohort of women with a median follow-up of 30 years. PATIENTS AND METHODS: In total, 350 women with primary breast cancer had eight bone marrow aspirates examined with antibody to epithelial membrane antigen. Data on long-term mortality were obtained via record linkage to death certification. RESULTS: At a 30-year median follow-up, 79 out of 89 (89%) patients with micrometastases have died compared with 202 out of 261 (77%) without (hazard ratio=1.46 (95% CI 1.12-1.90), P=0.0043). Most marked effect of micrometastases on overall survival (OS) was seen in patients aged ⩽ 50 at surgery (N=97, P=0.012), and on all patients within 10 years of diagnosis. In multivariable analyses, the presence of micrometastases was no longer a statistically significant prognostic factor. CONCLUSIONS: Bone marrow micrometastases are predictive for OS, particularly in the first decade and in younger patients.

Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial.

BACKGROUND: Chromosomal instability (CIN) has been shown to be associated with drug resistance and poor clinical outcome in several cancer types. However, in oestrogen receptor (ER)-negative breast cancer we have previously demonstrated that extreme CIN is associated with improved clinical outcome, consistent with a negative impact of CIN on tumour fitness and growth. The aim of this current study was to validate this finding using previously defined CIN thresholds in a much larger prospective cohort from a randomised, controlled, clinical trial. PATIENTS AND METHODS: As a surrogate measurement of CIN, dual centromeric fluorescence in situ hybridisation was performed for both chromosomes 2 and 15 on 1173 tumours from the breast cancer TACT trial (CRUK01/001). Each tumour was scored manually and the mean percentage of cells deviating from the modal centromere number was used to define four CIN groups (MCD1-4), where tumours in the MCD4 group were defined as having extreme CIN. RESULTS: In a multivariate analysis of disease-free survival, with a median follow-up of 91 months, increasing CIN was associated with improved outcome in patients with ER-negative cancer (P trend = 0.03). A similar pattern was seen in ER-negative/HER2-negative cancers (Ptrend = 0.007). CONCLUSIONS: This prospective validation cohort study further substantiated the association between extreme CIN and improved outcome in ER-negative breast cancers. Identifying such patients with extreme CIN may help distinguish good from poor prognostic groups, and therefore support treatment and risk stratification in this aggressive breast cancer subtype.

Prognostic and predictive value of ERß1 and ERß2 in the Intergroup Exemestane Study (IES)-first results from PathIES†.

BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERß1 and ERß2 expression in primary tumours in order to determine benefit in the two treatment arms. PATIENTS AND METHODS: Primary tumour samples were available for 1256 patients (27% IES population). ERß1 and ERß2 expression was dichotomised at the median IHC score (high if ERß1 ≥ 191, ERß2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs. RESULTS: Neither ERß1 nor ERß2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERß1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERß1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERß2 expression in either DFS or OS. CONCLUSION: In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERß1 expression but not in those with high ERß1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.

Learning from the QUEST multicentre feasibility randomization trials in breast reconstruction after mastectomy.

BACKGROUND: Breast reconstruction aims to improve health-related quality of life after mastectomy. However, evidence guiding patients and surgeons in shared decision-making concerning the optimal type or timing of surgery is lacking. METHODS: QUEST comprised two parallel feasibility phase III randomized multicentre trials to assess the impact of the type and timing of latissimus dorsi breast reconstruction on health-related quality of life when postmastectomy radiotherapy is unlikely (QUEST A) or highly probable (QUEST B). The primary endpoint for the feasibility phase was the proportion of women who accepted randomization, and it would be considered feasible if patient acceptability rates exceeded 25 per cent of women approached. A companion QUEST Perspectives Study (QPS) of patients (both accepting and declining trial participation) and healthcare professionals assessed trial acceptability. RESULTS: The QUEST trials opened in 15 UK centres. After 18 months of recruitment, 17 patients were randomized to QUEST A and eight to QUEST B, with overall acceptance rates of 19 per cent (17 of 88) and 22 per cent (8 of 36) respectively. The QPS recruited 56 patients and 51 healthcare professionals. Patient preference was the predominant reason for declining trial entry, given by 47 (53 per cent) of the 88 patients approached for QUEST A and 22 (61 per cent) of the 36 approached for QUEST B. Both trials closed to recruitment in December 2012, acknowledging the challenges of achieving satisfactory patient accrual. CONCLUSION: Despite extensive efforts to overcome recruitment barriers, it was not feasible to reach timely recruitment targets within a feasibility study. Patient preferences for breast reconstruction types and timings were common, rendering patients unwilling to enter the trial.

Second cancer risk and mortality in men treated with radiotherapy for stage I seminoma.

BACKGROUND: Patients with stage I testicular seminoma are typically diagnosed at a young age and treatment is associated with low relapse and mortality rates. The long-term risks of adjuvant radiotherapy in this patient group are therefore particularly relevant. METHODS: We identified patients and obtained treatment details from 12 cancer centres (11 United Kingdom, 1 Norway) and ascertained second cancers and mortality through national registries. Data from 2629 seminoma patients treated with radiotherapy between 1960 and 1992 were available, contributing 51,151 person-years of follow-up. RESULTS: Four hundred and sixty-eight second cancers (excluding non-melanoma skin cancers) were identified. The standardised incidence ratio (SIR) was 1.61 (95% confidence interval (CI): 1.47-1.76, P<0.0001). The SIR was 1.53 (95% CI: 1.39-1.68, P<0.0001) when the 32 second testicular cancers were also excluded. This increase was largely due to an excess risk to organs in the radiation field; for pelvic-abdominal sites the SIR was 1.62 (95% CI: 1.43-1.83), with no significant elevated risk of cancers in organs elsewhere. There was no overall increase in mortality with a standardised mortality ratio (SMR) of 1.06 (95% CI: 0.98-1.14), despite an increase in the cancer-specific mortality (excluding testicular cancer deaths) SMR of 1.46 (95% CI: 1.30-1.65, P<0.0001). CONCLUSION: The prognosis of stage I seminoma is excellent and it is important to avoid conferring long-term increased risk of iatrogenic disease such as radiation-associated second cancers.

Assessment of microtubule-associated protein (MAP)-Tau expression as a predictive and prognostic marker in TACT; a trial assessing substitution of sequential docetaxel for FEC as adjuvant chemotherapy for early breast cancer.

The TACT trial is the largest study assessing the benefit of taxanes as part of adjuvant therapy for early breast cancer. The goal of this translational study was to clarify the predictive and prognostic value of Tau within the TACT trial. Tissue microarrays (TMA) were available from 3,610 patients. ER, PR, HER2 from the TACT trial and Tau protein expression was determined by immunohistochemistry on duplicate TMAs. Two parallel scoring systems were generated for Tau expression ('dichotomised' vs. 'combined' score). The positivity rate of Tau expression was 50 % in the trial population (n = 2,483). Tau expression correlated positively with ER (p < 0.001) and PR status (p < 0.001); but negatively with histological grade (p < 0.001) and HER2 status (p < 0.001). Analyses with either scoring systems for Tau expression demonstrated no significant interaction between Tau expression and efficacy of docetaxel. Contrary to the hypothesis that taxane benefit would be enriched in Tau negative/low patients, the only groups with a suggestion of a reduced event rate in the taxane group were the HER2-positive, Tau positive subgroups. Tau expression was seen to be a prognostic factor on univariate analysis associated with an improved DFS, independent of the treatment group (p < 0.001). It had no prognostic value in ER-negative tumours and the weak prognostic effect of Tau in ER-positive tumours (p = 0.02) diminished, when considering ER as an ordinal variable. On multivariable analyses, Tau had no prognostic value in either group. In addition, no significant interaction between Tau expression and benefit from docetaxel in patients within the PR-positive and negative subsets was seen. This is now the second large adjuvant study, and the first with quantitative analysis of ER and Tau expression, failing to show an association between Tau and taxane benefit with limited utility as a prognostic marker for Tau in ER-positive early breast cancer patients.

NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE100C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Accrual and statistical power failure in published adjuvant phase III oncology trials: a comprehensive analysis from 2013 to 2023.

BACKGROUND: In a competitive landscape with many ongoing adjuvant randomised controlled trials (RCTs), the prevalence of trials that failed to recruit their targeted sample size and were inadequately powered is unclear. The aims of the study are (i) to determine the percentage of trials with accrual and statistical power failure and (ii) to evaluate their potential impact on the drug development process. MATERIALS AND METHODS: A systematic review was carried out to identify adjuvant phase III oncology RCTs reported between 2013 and 2023 across all solid tumours. No restrictions were applied regarding the type of intervention or journal of publication. The percentage of trials with accrual failure and power failure was estimated as well as their association with the efficacy endpoints. Logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI). RESULTS: A total of 282 RCTs met the inclusion criteria with a median sample size of 661 patients and a median accrual period of 4.3 years. Most of these studies were superiority trials (83.0%). Accrual failure was observed in 22.0% of the studies, finishing recruitment without achieving the targeted sample size. Overall, 39.7% of the studies experienced power failure, having less power than specified in the protocol at the date of the read-out. Among superiority RCTs evaluating intermediate survival endpoints, only 31.1% presented statistically significant results. Trials with power failure were less likely to present statistically significant results (37.9% versus 21.9%, P = 0.04). The association was consistent across all cancer types. In the subset of non-inferiority trials, 35.0% formally demonstrated non-inferiority of the experimental arm. CONCLUSIONS: Nearly 40% of adjuvant phase III RCTs experienced power failure, and the reduction in power significantly impacted the final study results. There is a need for procedural refinements in the design and implementation of future adjuvant RCTs to mitigate these fallacies.

Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Singlet Oxygen Quenching by Resveratrol Derivatives.

We investigated the singlet oxygen quenching ability of several derivatives of trans-resveratrol which have been reported to have significant antioxidant ability, including photoprotective activity. We measured the total rate constants of singlet oxygen removal (kT ) by the methylated resveratrol derivative 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene, and the partially methylated resveratrol derivatives 4-((E)-2-(3,5-dimethoxyphenyl)ethenyl)phenol (pterostilbene), 5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene-1,3-diol and (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one (dihydromyricetin). A protic solvent system results in higher kT values, except for the completely methylated derivative. We also investigated the ability of trans-resveratrol to directly act as a photosensitizer (rather than via secondary photoproducts resulting from other primary photochemical reactions) for the production of singlet oxygen but found that neither resveratrol nor any of its derivatives are able to do so. We then studied the chemical reactions of the methylated derivative with singlet oxygen. The main pathway consists of a [4 + 2] cycloaddition reaction involving the trans-double bond and the para-substituted benzene ring similar to what has been observed for trans-resveratrol. Unlike trans-resveratrol, the primary singlet oxygen product undergoes a second [4 + 2] cycloaddition with singlet oxygen leading to the formation of diendoperoxides. A second reactivity pathway for both trans-resveratrol and the methylated derivative leads to the formation of aldehydes via cleavage of a transient dioxetane.

Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomisation.

BACKGROUND: The Intergroup Exemestane Study (IES) (ISRCTN11883920) demonstrated improved survival for postmenopausal women with ER-positive/unknown primary breast cancer who switched to exemestane after 2-3 years tamoxifen, compared with those continuing on tamoxifen to complete 5 years therapy. This was achieved without detriment to on-treatment quality-of-life (QoL). We report on- and post-treatment QoL impact in IES. METHODS: A total of 582 patients from 8 countries participated in the QoL substudy. Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine symptom subscale (ES) were completed at baseline, 3, 6, 9, 12, 18, 24, 30, 36, 48 and 60 months. The primary endpoint was FACT-B Trial Outcome Index (TOI); secondary endpoints included severity of individual endocrine symptoms. RESULTS: Both the groups showed gradual improvement in overall QoL and lessening of total endocrine symptoms post treatment compared with baseline (P<0.002). There was no evidence of any between-group differences in TOI. Vasomotor complaints remained high on treatment. Vaginal discharge was more frequent (P<0.01) with tamoxifen up to 24 months from baseline. In both the groups, post-treatment libido did not recover to baseline levels. CONCLUSION: Clinical benefits of switching to exemestane are accompanied by good overall QoL. Although some symptoms persist, the majority of endocrine symptoms improve after treatment completion.

Adjuvant chemotherapy in older women (ACTION) study - what did we learn from the pilot phase?

BACKGROUND: The ACTION trial was initiated to provide evidence from a randomised trial on the effects of chemotherapy in women aged over 70 years where evidence for risk and benefit are lacking. METHODS: This was a randomised, phase III clinical trial for high risk, oestrogen receptor (ER) negative/ER weakly positive early breast cancer. The trial planned to recruit 1000 women aged 70 years and older, randomised to receive 4 cycles of anthracycline chemotherapy or observation. The primary endpoint was relapse-free interval. The trial included a pilot phase to assess the acceptability and feasibility of recruitment. RESULTS: The trial opened at 43 UK centres. Information on number of patients approached was available from 38 centres. Of the 43 eligible patients that were approached, 39 were not randomised due to patients declining entry. After 10 months only 4 patients had been randomised and after discussion with the research funder, the trial was closed and funding terminated. CONCLUSION: Despite widespread support at several public meetings, input from patient groups including representation on the Trial Management Group, the trial failed to recruit due to the inability to convince patients to accept randomisation. It would therefore seem that randomising the patients to receive chemotherapy vs observation is not a viable design in the current era for this patient population.

Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to Implementation.

INTRODUCTION: The phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule. IPSILATERAL BREAST TUMOUR RELAPSE (IBTR): Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4-3.1), 1.7% (1.2-1.6) after 27 Gy and 1.4% (0.2-2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-mastectomy. NORMAL TISSUE EFFECTS: The 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or adjuvant chemotherapy. RADIOBIOLOGICAL CONSIDERATIONS: The design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in α/ß estimate for the late normal tissue effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation. CONCLUSION: The 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.

Singlet Oxygen Generation, Quenching and Reactivity with Metal Thiolates.

Metal thiolate complexes can act as photosensitizers for the generation of singlet oxygen, quenchers of singlet oxygen, and they may undergo chemical reactions with singlet oxygen leading to oxidized thiolate ligands. This review covers all of the chemical reactions of thiolate ligands with singlet oxygen (through early 2021). Since some of these reactions are self-sensitized photooxidations, singlet oxygen generation by metal complexes is also discussed. Mechanistic features such as the effects of protic vs. aprotic conditions are presented and compared with the comparatively well-understood photooxidation of organic sulfides. In general, the total rate of singlet oxygen removal correlates with the nucleophilicity of the thiolate ligand which in turn can be influenced by the metal. Some interesting patterns of reactivity have been noted as a result of this survey: Metal thiolate complexes bearing arylthiolate ligands appear to exclusively produce sulfinate (metal-bound sulfone) products upon reaction with singlet oxygen. In contrast, metal thiolate complexes bearing alkylthiolate ligands may produce sulfinate and/or sulfenate (metal-bound sulfoxide) products. Several mechanistic pathways have been proposed for these reactions, but the exact nature of any intermediates remains unknown at this time.