The incorporation of molecular profiling into routine clinical practice has already been adopted in some tumor types, such as human epidermal growth factor receptor 2 (HER2) testing in breast cancer ...and KRAS genotyping in colorectal cancer, providing a guide to treatment selection that is not afforded by histopathologic diagnosis alone. It is inevitable that over time, with rapid advances in scientific knowledge, bioinformatics, and technology to identify oncogenic drivers, molecular profiling will complement histopathologic data to influence management decisions. Emerging technologies such as multiplexed somatic mutation genotyping and massive parallel genomic sequencing have become increasingly feasible at point-of-care locations to classify cancers into molecular subsets. Because these molecular subsets may differ substantially between each other in terms of sensitivity or resistance to systemic agents, there is consensus that clinical trials should be more stratified for or be performed only in such molecularly defined subsets. This approach, however, poses challenges for clinical trial designs because smaller numbers of patients would be eligible for such trials, while the number of novel anticancer drugs warranting further clinical exploration is rapidly increasing. This article provides an overview of the emerging methodologic challenges in the cancer genome era and offers some potential solutions for transforming clinical trial designs so they can identify new active anticancer regimens in molecularly defined subgroups as efficiently as possible.
The hydraulic performance of woody species during drought is currently of high interest in the context of climate change. It is known that woody species have the capacity to mitigate water shortage ...by using internally stored water. Elastic shrinkage of living cells and also water release during cavitation contribute to the so-called 'hydraulic capacitance' (C) of the plant, which adds water to the transpiration stream and buffers fluctuations in water potential. Although sap-conducting conduits may ultimately serve as a water pool, cavitation will hamper the conduction of sap. Both hydraulic conductivity and C are thus inextricably linked and the interaction between both should be studied to better understand hydraulic functioning of woody species during drought. However, measurements of C are scarce and no distinction is usually made between C from elastic storage and C supplied by cavitation. In this paper, we propose a new method to assess both the decrease in hydraulic conductivity and the change in C during bench dehydration of a whole-branch segment using continuous measurements of acoustic emissions, radial diameter shrinkage and gravimetrical water loss. With this method we could establish proper vulnerability curves for grapevine (Vitis vinifera L. 'Johanniter') and quantify C during dehydration. Our results showed that loss in hydraulic conductivity during the cavitation phase was accompanied by 22-92% gain in hydraulic capacitance; therefore, a certain degree of cavitation may be tolerated in grapevine during periods of drought stress.
Summary 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 The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, ...revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.
Summary 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. Funding US Food and Drug Administration.
Summary Background If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary ...lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. Methods Patients with T1–2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov , number NCT00014612. Findings Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1–8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00–0·92) after axillary lymph node dissection versus 1·19% (0·31–2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00–5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. Interpretation Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1–2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. Funding EORTC Charitable Trust.
Twenty years after its initial introduction, Response Evaluation Criteria in Solid Tumors (RECIST) remains today a unique standardized tool allowing uniform objective evaluation of response in solid ...tumors in clinical trials across different treatment indications. Several attempts have been made to update or replace RECIST, but none have realized the general traction or uptake seen with RECIST. This communication provides an overview of some challenges faced by RECIST in the rapidly changing oncology landscape, including the incorporation of PET with 18F-fluorodeoxyglucose tracer as a tool for response assessment and the validation of criteria for use in trials involving immunotherapeutics. The latter has mainly been slow due to lack of data sharing. Work is ongoing to try to address this.We also aim to share our view as statistician representatives on the RECIST Working Group on what would be needed to validate new imaging endpoints for clinical trial use, with a specific focus on RECIST. Whether this could lead to an update of RECIST or replace RECIST altogether, depends on the changes being proposed. The ultimate goal remains to have a well defined, repeatable, confirmable and objective standard as provided by RECIST today.
Summary Background The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or ...positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. Methods The EORTC 10801 trial was open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. Findings After a median follow-up of 22·1 years (IQR 18·5–23·8), 175 patients (42%) had distant metastases in the MRM group versus 207 (46%) in the BCT group. Furthermore, 506 patients (58%) died (232 55% in the MRM group and 274 61% in the BCT group). No significant difference was observed between BCT and MRM for time to distant metastases (hazard ratio 1·13, 95% CI 0·92–1·38; p=0·23) or for time to death (1·11, 0·94–1·33; 0·23). Cumulative incidence of distant metastases at 20 years was 42·6% (95% CI 37·8–47·5) in the MRM group and 46·9% (42·2–51·6) in the BCT group. 20-year overall survival was estimated to be 44·5% (95% CI 39·3–49·5) in the MRM group and 39·1% (34·4–43·9) in the BCT group. There was no difference between the groups in time to distant metastases or overall survival by age (time to distant metastases: <50 years 1·09 95% CI 0·79–1·51 vs ≥50 years 1·16 0·90–1·50; overall survival <50 years 1·17 0·86–1·59 vs ≥50 years 1·10 0·89–1·37). Interpretation BCT, including radiotherapy, offered as standard care to patients with early breast cancer seems to be justified, since long-term follow-up in this trial showed similar survival to that after mastectomy. Funding European Organisation for Research and Treatment of Cancer (EORTC).
Response Evaluation Criteria In Solid Tumours (RECIST) remain an integral part of the assessment of tumour burden in many clinical trials in oncology; these criteria are used to evaluate the activity ...and efficacy of new cancer therapeutics in solid tumours. We aim to define the purpose of RECIST, and reflect on the level of documentation needed to enable changes for these criteria to develop a new RECIST. Maintaining the applicability of RECIST as a standard evaluation approach is associated with many challenges, in particular with maintaining a balance between the specificity and generalizability, continued validation and innovation, and use of RECIST in early phase versus late-phase drug development, as well as its relevance in clinical trials versus clinical practice. Key questions relate to different modes of actions of new classes of treatments and new imaging modalities; thus, the RECIST Working Group remains committed to maintain RECIST as a standard for the oncology community.
To better understand the relationship between tumor-host interactions and the efficacy of chemotherapy, we have developed an analytical approach to quantify several biological processes observed in ...gene expression data sets. We tested the approach on tumor biopsies from individuals with estrogen receptor-negative breast cancer treated with chemotherapy. We report that increased stromal gene expression predicts resistance to preoperative chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) in subjects in the EORTC 10994/BIG 00-01 trial. The predictive value of the stromal signature was successfully validated in two independent cohorts of subjects who received chemotherapy but not in an untreated control group, indicating that the signature is predictive rather than prognostic. The genes in the signature are expressed in reactive stroma, according to reanalysis of data from microdissected breast tumor samples. These findings identify a previously undescribed resistance mechanism to FEC treatment and suggest that antistromal agents may offer new ways to overcome resistance to chemotherapy.
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