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Tailored recommendation for adjuvant chemotherapy in breast cancer patients is of great importance. This survey assessed agreement among oncologists on risk assessment and chemotherapy recommendation, the impact of adding the 70-gene signature to clinical-pathological characteristics, and changes over time. A survey consisting of 37 discordant patient cases from the MINDACT trial (T1-3N0-1M0) was sent to European breast cancer specialists for assessment of risk (high or low) and chemotherapy administration (yes or no). In 2015 the survey was sent twice (survey 1 and 2), several weeks apart, and in 2021 a third time (survey 3). Only the second and third surveys included the 70-gene signature result. 41 breast cancer specialists participated in all three surveys. Overall agreement between respondents decreased slightly between survey 1 and 2, but increased again in survey 3. Over time there was an increase in agreement with the 70-gene signature result on risk assessment, 23% in survey 2 versus 1 and 11% in survey 3 versus 2. With information available indicating a low risk 70-gene signature (n = 25 cases), 20% of risk assessments changed from high to low and 19% of recommendations changed from yes to no chemotherapy in survey 2 versus 1, further increasing with 18% and 21%, respectively, in survey 3 versus 2. There is a variability in risk assessment of early breast cancer patients among breast cancer specialists. The 70-gene signature provided valuable information, resulting in fewer patients being assessed as high risk and fewer recommendations for chemotherapy, increasing over time. • Risk assessment of early breast cancer patients varies among breast specialists. • The 70-gene signature provides valuable information for risk assessment. • Information on the 70-gene signature resulted in fewer high risk assessments. • Information on the 70-gene signature resulted in fewer chemotherapy recommendations. • Agreement with the 70-gene signature result increased over time. [ABSTRACT FROM AUTHOR]

The meta-analytic approach is the gold standard for validation of surrogate markers, but has the drawback of requiring data from several trials. We refine modern mediation analysis techniques for time-to-event endpoints and apply them to investigate whether pathological complete response can be used as a surrogate marker for disease-free survival in the EORTC 10994/BIG 1-00 randomised phase 3 trial in which locally advanced breast cancer patients were randomised to either taxane or anthracycline based neoadjuvant chemotherapy. In the mediation analysis, the treatment effect is decomposed into an indirect effect via pathological complete response and the remaining direct effect. It shows that only 4.2% of the treatment effect on disease-free survival after five years is mediated by the treatment effect on pathological complete response. There is thus no evidence from our analysis that pathological complete response is a valuable surrogate marker to evaluate the effect of taxane versus anthracycline based chemotherapies on progression free survival of locally advanced breast cancer patients. The proposed analysis strategy is broadly applicable to mediation analyses of time-to-event endpoints, is easy to apply and outperforms existing strategies in terms of precision as well as robustness against model misspecification. [ABSTRACT FROM AUTHOR]

Objective Infertility due to anticancer treatments is a major source of distress for young patients with cancer. A survey was performed among breast cancer patients younger than 35 years, to evaluate the acceptance of chemotherapy in the context of infertility risk. Methods After obtaining written informed consent, we asked 400 premenopausal, early stage breast cancer patients aged ≤35 years to complete a short, previously pilot-tested questionnaire. Three hundred and eighty-nine patients were evaluable. The association between the explanatory variables and the outcome variables was assessed using logistic regression. Results Two hundred and twenty-eight (59%) participants wanted to have (more) children in the future, whereas 158 (41%) did not. Fifty-seven (36%) of the latter did not want additional children because of fear of cancer recurrence. Thirty-two women (8%) stated they would not accept chemotherapy should it reduce their fertility. This was dependent upon already having children, the wish to have (further) children, geographical area, disease stage, and already planned chemotherapy. One hundred and seventy-one women who would agree to chemotherapy (48%) would accept a risk of infertility of 76-100%. This acceptance was dependent on already having children and the wish to have (more) children. Of the 355 participants (91%) accepting chemotherapy, 48 would accept it only for ≥20% gain in cure. Conclusion For the majority of young patients with breast cancer, cure remains their first priority; for this, they are willing to accept a considerable decrease in future fertility, and only less than 10% will forego chances of cure to preserve fertility. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies. [ABSTRACT FROM AUTHOR]

Summary: Background: TP53 has a crucial role in the DNA damage response. We therefore tested the hypothesis that taxanes confer a greater advantage than do anthracyclines on breast cancers with mutated TP53 than in those with wild-type TP53. Methods: In an open-label, phase 3 study, women (age <71 years) with locally advanced, inflammatory, or large operable breast cancers were randomly assigned in a 1:1 ratio to either a standard anthracycline regimen (six cycles of intravenous fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days [FEC100], or fluorouracil 600 mg/m2, epirubicin 75 mg/m2, cyclophosphamide 900 mg/m2 [tailored FEC] starting on day 1 and then every 21 days) or a taxane-based regimen (three cycles of docetaxel 100 mg/m2, intravenously infused over 1 h on day 1 every 21 days, followed by three cycles of intravenous epirubicin 90 mg/m2 and docetaxel 75 mg/m2 on day 1 every 21 days [T-ET]) at 42 centres in Europe. Randomisation was by use of a minimisation method that stratified patients by institution and initial tumour stage. The primary endpoint was progression-free survival (PFS) according to TP53 status. Analysis was by intention to treat. This is the final analysis of this trial. The study is registered with ClinicalTrials.gov, number NCT00017095. Findings: 928 patients were enrolled in the FEC group and 928 in the T-ET group. TP53 status was not assessable for 183 (20%) patients in the FEC group and 204 (22%) patients in the T-ET group mainly because of low tumour-cell content in the biopsy. 361 primary endpoint events were recorded in the FEC group and 314 in the T-ET group. In patients with TP53-mutated tumours, 5-year PFS was 59·5% (95% CI 53·4–65·1) in the T-ET group (n=326) and 55·3% (49·2–60·9) in the FEC group (n=318; hazard ratio 0·84, 98% CI 0·63–1·14; p=0·17). In patients with TP53 wild-type tumours, 5-year PFS was 66·8% (95% CI 61·4–71·6) in the T-ET group (n=398) and 64·7% (59·6–69·4) in the FEC group (n=427; 0·89, 98% CI 0·68–1·18; p=0·35). For all patients, irrespective of TP53 status, 5-year PFS was 65·1% (95% CI 61·6–68·3) in the T-ET group and 60·8% (57·3–64·2) in the FEC group (0·85, 98% CI 0·71–1·02; p=0·035). At the sites using FEC100 versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (75 [9%] of 803 vs 173 [21%] of 809, respectively), and neutropenia (653 [81%] vs 730 [90%], respectively). At the sites using tailored FEC versus T-ET, the most common grade 3 or 4 adverse events were febrile neutropenia (ten [8%] of 118 vs 26 [22%] of 116, respectively), and neutropenia (100 [85%] vs 115 [99%], respectively). Two patients died of toxicity during or within 30 days of chemotherapy completion and without disease relapse (one in each group). Interpretation: Although TP53 status was prognostic for overall survival, it was not predictive of preferential sensitivity to taxanes. TP53 status tested by use of the yeast assay in this patient population cannot be used to select patients for an anthracycline-based chemotherapy versus a taxane-based chemotherapy. Funding: US National Cancer Institute, La Ligue Nationale Contre le Cancer, European Union, Pharmacia, and Sanofi-Aventis. [Copyright &y& Elsevier]

Background: Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS. Methods: We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response—ypT0 ypN0, ypT0/is ypN0, and ypT0/is—for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS. Findings: We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0•44, 95% CI 0•39—0•51; ypT0/is ypN0: 0•48, 0•43—0•54) and OS (0•36, 0•30—0•44; 0•36, 0•31—0•42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0•60, 95% CI 0•55—0•66; OS 0•51, 0•45—0•58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0•24, 95% CI 0•18—0•33; OS: 0•16, 0•11—0•25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0•15, 0•09—0•27; OS: 0•08, 0•03, 0•22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R2=0•03, 95% CI 0•00—0•25) and OS (R2=0•24, 0•00—0•70). Interpretation: Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS. [ABSTRACT FROM AUTHOR]

Summary: Background: The gold standard endpoint in randomised trials of locally advanced head and neck squamous-cell carcinoma (HNSCC) is overall survival. Our objective was to study whether duration of locoregional control or event-free survival (EFS) could be considered as surrogate endpoints to estimate the effect of radiotherapy and chemotherapy on overall survival. This would allow a reduction in the duration and cost of the development of new treatments. Methods: Individual patient data from 104 trials (22 744 patients), with 116 treatment–control comparisons, from four meta-analyses on hyperfractionated or accelerated radiotherapy and concomitant, induction, or adjuvant chemotherapy were analysed. Duration of locoregional control was defined as the time from randomisation to the first locoregional event and EFS as the time to any first event (ie, locoregional relapse, distant recurrence, or death). At the individual level, a rank correlation coefficient between the surrogate endpoint and overall survival was used to assess surrogacy; at the trial level, a correlation coefficient R between treatment effects was used. Findings: At the individual level, overall survival was more strongly correlated with EFS (range of correlations 0·82–0·90) than with locoregional control (0·65–0·76). For radiotherapy, treatment effects on both locoregional control and EFS were strongly correlated with those on overall survival (R=0·94 and 0·98, respectively). For chemotherapy, the correlations between treatment effects on EFS and overall survival were stronger than those between locoregional control and overall survival (range of R 0·79–0·93 vs 0·53–0·84, respectively). Interpretation: EFS is a better correlate with overall survival than locoregional control and could be used as a surrogate for overall survival to assess the treatment effect of radiotherapy and chemotherapy in randomised trials of locally advanced HNSCC. Funding: Programme Hospitalier de Recherche Clinique, the Association pour la Recherche sur le Cancer, the Ligue Nationale Contre le Cancer, and Sanofi-Aventis. [Copyright &y& Elsevier]

Abstract: Background: In this phase I/II study, the addition of lapatinib (LAP) was investigated in combination with the sequential use of both approaches TPF induction chemotherapy (ICT) followed by chemoradiation (CRT) in locally advanced larynx or hypopharynx squamous cell carcinoma. Patients and methods: Objectives were to assess maximum tolerated dose, dose-limiting toxicity (DLT) and to recommend a safe dose of LAP when administered with 4 cycles of TPF followed by CRT. Results: Seven male patients were included. Three patients were included in the first cohort, at dose level 1 (LAP 500mg daily plus TPF). Renal toxicity was observed among these three patients (grade 3 [n =1], grade 2 [n =1] and grade 1 [n =1]), with 1 DLT, leading to treatment interruption in this group. Nephrotoxicity was reversible after stopping LAP and hydration of the patients. In a second cohort of four patients administering docetaxel from the second cycle, 3 more DLTs were observed (grade 2 renal toxicity and grade 3 diarrhea, grade 3 anorexia and grade 3 stomatitis, and grade 4 neutropenia). Based on the occurrence of 4 DLTs at the first dose level of LAP, patient recruitment was closed. Conclusion: These data indicate that LAP cannot be combined safely with full dose TPF. [Copyright &y& Elsevier]