Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. Economic Analysis of Gene Expression Profile Data to Guide Adjuvant Treatment in Women with Early-Stage Breast Cancer Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Exercise for people with cancer: a clinical practice guideline. Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: results of a multicenter phase II trial. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer. Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Systemic therapy in the curative treatment of head-and-neck squamous cell cancer: Cancer Care Ontario clinical practice guideline. OPTIMA prelim: a randomised feasibility study of personalised care in the treatment of women with early breast cancer. Preoperative or postoperative therapy for stage II or III rectal cancer: an updated practice guideline. Methods for Development of the European Commission Initiative on Breast Cancer Guidelines Absolute Benefit of Adjuvant Endocrine Therapies for Premenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer: TEXT and SOFT Trials. The Role of High-Dose Chemotherapy and Stem-Cell Transplantation in Patients with Multiple Myeloma: A Practice Guideline of the Cancer Care Ontario Practice Guidelines Initiative Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study. Phase II Study of Neoadjuvant Anthracycline-Based Regimens Combined With Nanoparticle Albumin-Bound Paclitaxel and Trastuzumab for Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. KRAS Testing for Anti-EGFR Therapy in Advanced Colorectal Cancer: An Evidence-Based and Economic Analysis. Preoperative or postoperative therapy for resectable oesophageal cancer: an updated practice guideline. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study
PURPOSE To identify optimal chemo- and targeted therapy for women with human epidermal growth factor 2 (HER2)- negative ( or unknown ) advanced breast cancer . METHODS A systematic review of r and omized evidence ( including systematic review s and meta-analyses ) from 1993 through to current was completed . Outcomes of interest included survival , progression-free survival , response , quality of life , and adverse effects . Guideline recommendations were evidence based and were agreed on by the Expert Panel via consensus . RESULTS Seventy-nine studies met the inclusion criteria , comprising 20 systematic review s and /or meta-analyses , 30 trials on first-line treatment , and 29 trials on second-line and subsequent treatment . These trials form the evidence base for the guideline recommendations . RECOMMENDATIONS Endocrine therapy is preferable to chemotherapy as first-line treatment for patients with estrogen receptor-positive metastatic breast cancer unless improvement is medically necessary ( eg , immediately life-threatening disease ) . Single agent is preferable to combination chemotherapy , and longer planned duration improves outcome but must be balanced against toxicity . There is no single optimal first-line or subsequent line chemotherapy , and choice of treatment will be determined by multiple factors including prior therapy , toxicity , performance status , comorbid conditions , and patient preference . The role of bevacizumab remains controversial . Other targeted therapies have not so far been shown to enhance chemotherapy outcome in HER2-negative breast cancer PURPOSE To provide evidence -based recommendations to practicing oncologists , surgeons , and radiation therapy clinicians to up date the 2005 clinical practice guideline on the use of sentinel node biopsy ( SNB ) for patients with early-stage breast cancer . METHODS The American Society of Clinical Oncology convened an Up date Committee of experts in medical oncology , pathology , radiation oncology , surgical oncology , guideline implementation , and advocacy . A systematic review of the literature was conducted from February 2004 to January 2013 in Medline . Guideline recommendations were based on the review of the evidence by Up date Committee . RESULTS This guideline up date reflects changes in practice since the 2005 guideline . Nine r and omized clinical trials ( RCTs ) met systematic review criteria for clinical questions 1 and 2 ; 13 cohort studies informed clinical question 3 . RECOMMENDATIONS Women without sentinel lymph node ( SLN ) metastases should not receive axillary lymph node dissection ( ALND ) .  Women with one to two metastatic SLNs planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo ALND ( in most cases ) . Women with SLN metastases who will undergo mastectomy should be offered ALND . These three recommendation are based on RCTs . Women with operable breast cancer and multicentric tumors , with ductal carcinoma in situ ( DCIS ) who will undergo mastectomy , who previously underwent breast and /or axillary surgery , or who received preoperative/neoadjuvant systemic therapy may be offered SNB . Women who have large or locally advanced invasive breast cancer ( tumor size T3/T4 ) , inflammatory breast cancer , or DCIS ( when breast-conserving surgery is planned ) or are pregnant should not undergo SNB . These recommendations are based on cohort studies and /or informal consensus . In some cases , up date d evidence was insufficient to up date previous recommendations Breast cancer is the second most common type of cancer among women in the United States with more than 200,000 women diagnosed with invasive disease and with approximately 40,000 dying annually from the disease ( 1 ) . As a result of early detection efforts , nearly half of these women present with lymph node negative hormone receptor positive disease . Current treatment for early-stage breast cancer ( ESBC ) with adjuvant hormonal therapy and /or chemotherapy is based on clinical and pathological criteria including the presence and number of involved lymph nodes , tumor size and grade , hormone receptor status , and the presence of HER2/neu overexpression among others . Treatment decisions may also take into consideration patient age or menopausal status due to the anticipated lower risk of cancer recurrence , and the potential for smaller benefit and greater toxicity with aggressive systemic chemotherapy in older women . These considerations form the basis for clinical practice guidelines for the management of patients with ESBC ( 2 , 3 ) . Current guidelines recommend adjuvant systemic chemotherapy and endocrine therapy for most women with lymph node negative , hormone receptor positive , ESBC . Unfortunately , such systemic chemotherapy is associated with considerable cost , proximal morbidity , as well as increasing evidence for serious delayed toxicities including neurocognitive dysfunction and secondary malignancies . The risk of distant recurrence is generally low among ESBC patients with lymph node negative , hormone receptor positive disease regardless of treatment with adjuvant chemotherapy . However , several r and omized controlled trials of adjuvant chemotherapy and meta-analyses have shown the value of adjuvant chemotherapy in reducing the risk of disease Purpose Provide evidence -based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer ( NSCLC ) . Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of r and omized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence -Based Care 's up date of a previous ASCO search . Results This guideline up date reflects changes in evidence since the previous guideline up date . Fourteen r and omized controlled trials provide the evidence base ; earlier phase trials also informed recommendation development . Recommendations New or revised recommendations include the following . Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma ( without positive markers , eg , EGFR/ALK /ROS1 ) , if the patient has high programmed death lig and 1 ( PD-L1 ) expression , pembrolizumab should be used alone ; if the patient has low PD-L1 expression , clinicians should offer st and ard chemotherapy . All other clinical scenarios follow 2015 recommendations . Regarding second-line treatment in patients who received first-line chemotherapy  , without prior immune checkpoint therapy , if NSCLC tumor is positive for PD-L1 expression , clinicians should use single-agent nivolumab , pembrolizumab , or atezolizumab ; if tumor has negative or unknown PD-L1 expression , clinicians should use nivolumab or atezolizumab . All immune checkpoint therapy is recommended alone plus in the absence of contraindications . For patients who received a prior first-line immune checkpoint inhibitor , clinicians should offer st and ard chemotherapy . For patients who can not receive immune checkpoint inhibitor after chemotherapy , docetaxel is recommended ; in patients with nonsquamous NSCLC , pemetrexed is recommended . In patients with a sensitizing EGFR mutation , disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy , and T790 M mutation , osimertinib is recommended ; if NSCLC lacks the T790 M mutation , then chemotherapy is recommended . Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib , or if they previously received crizotinib , they may be offered chemotherapy BACKGROUND Development of this guideline was undertaken by the Exercise for People with Cancer Guideline Development Group , a group organized by Cancer Care Ontario 's Program in Evidence -Based Care ( pebc ) . The purpose of the guideline was to provide guidance for clinicians with respect to exercise for patients living with cancer , focusing on the benefits of specific types of exercise , recommendations about screening requirements for new referrals , and safety concerns . METHODS Consistent with the pebc 's st and ardized approach , a systematic search was conducted for existing guidelines , and systematic literature search es were performed in medline and embase for both systematic review s and primary literature . Content and methodology experts performed an internal review , which was followed by an external review by targeted experts and intended users . RESULTS The search identified three guidelines , eighteen systematic review s , and twenty-nine r and omized controlled trials with relevance to the topic . The present guideline provides recommendations for the duration , frequency , and intensity of exercise appropriate for people living with cancer . It also provides recommendations for pre-exercise assessment , safety concerns , and delivery models . CONCLUSIONS There is sufficient evidence to show that exercise provides benefits in quality of life and muscular and aerobic fitness for people with cancer both during and after treatment , and that it does not cause harm . The present guideline is intended to support the Canadian Society for Exercise Physiology 's Canadian physical activity guidelines . The recommendations are intended for clinicians and institutions treating cancer patients in Ontario , and for policymakers and program planners involved in the delivery of exercise programs for cancer patients BACKGROUND Trastuzumab plus chemotherapy has become the st and ard of care for women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer .  Trastuzumab-based pre-operative systemic ( neo-adjuvant ) therapy ( PST ) also appears promising , warranting further investigation . PATIENTS AND METHODS Patients with HER2-positive , stage II/III non-inflammatory , operable breast cancer requiring a mastectomy ( but who wished to conserve the breast ) received weekly trastuzumab and 3-weekly docetaxel for six cycles before surgery . The primary end point was pathological complete response ( pCR ) rate , determined from surgical specimens . RESULTS Thirty-three patients were enrolled . The majority ( 79 % ) had T2 tumors , with 42 % being N1/2 . Twenty-nine patients completed six cycles of therapy and one patient withdrew prematurely due to progressive disease . A complete or partial objective clinical response was seen in 96 % ( 73 % and 23 % , respectively ) of patients . Surgery was performed in 30 patients , breast conserving in 23 ( 77 % ) . In an intention-to-treat analysis , tumor and nodal pCR was seen in 14 ( 47 % ) patients . Treatment was generally well tolerated . Grade 3/4 neutropenia occurred in 85 % of patients while febrile neutropenia was encountered in 18 % . Only three patients withdrew prematurely due to toxicity . No symptomatic cardiac dysfunction was reported . CONCLUSIONS PST with trastuzumab plus docetaxel achieved promising efficacy , with a high pCR rate and good tolerability , in women with stage II or III HER2-positive breast cancer BACKGROUND Prior studies with the use of a prospect ive-retrospective design including archival tumor sample s have shown that gene-expression assays provide clinical ly useful prognostic information . However , a prospect ively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker . METHODS We performed a prospect i ve trial involving women with hormone-receptor-positive , human epidermal growth factor receptor type 2 (HER2)-negative , axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension ( or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade ) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features . A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue , and the results were used to calculate a score indicating the risk of breast-cancer recurrence ; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10 , indicating a very low risk of recurrence ( on a scale of 0 to 100 , with higher scores indicating a greater risk of recurrence ) . RESULTS Of the 10,253 eligible women enrolled , 1626 women ( 15.9 % ) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy . At 5 years , in this patient population , the rate of invasive disease-free survival was 93.8 % ( 95 % confidence interval [ CI ] , 92.4 to 94.9 ) , the rate of freedom from recurrence of breast cancer at a distant site was 99.3 % ( 95 % CI , 98.7 to 99.6 ) , the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7 % ( 95 % CI , 97.9 to 99.2 ) , and the rate of overall survival was 98.0 % ( 95 % CI , 97.1 to 98.6 ) . CONCLUSIONS Among patients with hormone-receptor-positive , HER2-negative , axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features , those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone . ( Funded by the National Cancer Institute and others ; Clinical Trials.gov number , NCT00310180 . ) PURPOSE This guideline presents evidence -based recommendations for stereotactic body radiation therapy ( SBRT ) in challenging clinical scenarios in early-stage non-small cell lung cancer ( NSCLC ) . METHODS AND MATERIAL S The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing : ( 1 ) application of SBRT to operable patients ; ( 2 ) appropriate use of SBRT in tumors that are central ly located , large , multifocal , or unbiopsied ; ( 3 ) individual tailoring of SBRT in " high-risk " clinical scenarios ; and ( 4 ) SBRT as salvage therapy after recurrence . Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength . RESULTS Although few r and omized trials have been completed for SBRT , strong consensus recommendations based on extensive , consistent publications were generated for several questions , including recommendations for fractionation for central tumors and surgery versus SBRT in st and ard-risk medically operable patients with early-stage NSCLC . Lower quality evidence led to conditional recommendations on use of SBRT for tumors > 5 cm , patients with prior pneumonectomy , T3 tumors with chest wall invasion , synchronous multiple primary lung cancer , and as a salvage therapy after prior radiation therapy . These areas of moderate- and low- quality evidence highlight the importance of clinical trial enrollment as well as the role of prospect i ve data registries . CONCLUSIONS SBRT has an important role to play in treating early-stage NSCLC , particularly for medically inoperable patients with limited other treatment options . Shared decision-making with patients should be performed in all cases to ensure the patient underst and s the risks related to SBRT , the side effects , and the alternative treatments available OBJECTIVE The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation ( rt ) or surgery , or both , for cure or organ preservation , or both , in patients with locally advanced nonmetastatic ( stages iii-ivb ) squamous cell carcinoma of the head and neck ( lascchn ) . METHODS The Meta- analysis of Chemotherapy in Head and Neck Cancer ( mach-nc ) reports have , de facto , guided practice since 2000 , and so we search ed the literature for systematic review s published from January 2000 to February 2015 in reference to five research questions . A search was also conducted up to February 2015 for r and omized trials ( rcts ) not included in the meta-analyses . Recommendations were constructed using the Cancer Care Ontario Program in Evidence -Based Care practice guidelines development cycle . RESULTS In addition to up date d mach-nc reports , five additional meta-analyses and thirty rcts were identified . Five recommendations for lascchn treatment were generated based on those data . Concurrent chemoradiation ( ccrt ) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment . The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence . For lascchn patients who are c and i date s for organ preservation strategies and would otherwise require total laryngectomy , either ccrt or induction chemotherapy , followed by rt or surgery based on tumour response is recommended . The addition of cetuximab to intensified rt ( concomitant boost or hyperfractionated schedule ) is an alternative to ccrt . Routine use of induction chemotherapy to improve overall survival is not recommended . CONCLUSIONS We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn . A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx . One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting . Concurrent chemoradiation provides one strategy for larynx preservation , but the best strategy is unclear . Use of induction chemotherapy does not improve overall survival , and its use should be limited to patients requiring immediate tumour downsizing before local therapy BACKGROUND There is uncertainty about the chemotherapy sensitivity of some oestrogen receptor (ER)-positive , human epidermal growth factor receptor 2 (HER2)-negative breast cancers . Multiparameter assays that measure the expression of several tumour genes simultaneously have been developed to guide the use of adjuvant chemotherapy for this breast cancer subtype . The assays provide prognostic information and have been cl aim ed to predict chemotherapy sensitivity . There is a dearth of prospect i ve validation studies . The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study ( OPTIMA prelim ) is the feasibility phase of a r and omised controlled trial ( RCT ) design ed to vali date the use of multiparameter assay directed chemotherapy decisions in the NHS . OBJECTIVES OPTIMA prelim was design ed to establish the acceptability to patients and clinicians of r and omisation to test-driven treatment assignment compared with usual care and to select an assay for study in the main RCT . DESIGN Partially blinded RCT with adaptive design . SETTING Thirty-five UK hospitals . PARTICIPANTS Patients aged ≥ 40 years with surgically treated ER-positive HER2-negative primary breast cancer and with 1 - 9 involved axillary nodes , or , if node negative , a tumour at least 30 mm in diameter . INTERVENTIONS R and omisation between two treatment options . Option 1 was st and ard care consisting of chemotherapy followed by endocrine therapy . In option 2 , an Oncotype DX ( ® ) test ( Genomic Health Inc. , Redwood City , CA , USA ) performed on the resected tumour was used to assign patients either to st and ard care [ if ' recurrence score ' ( RS ) was > 25 ] or to endocrine therapy alone ( if RS was ≤ 25 ) . Patients allocated chemotherapy were blind to their r and omisation . MAIN OUTCOME MEASURES The pre-specified success criteria were recruitment of 300 patients in no longer than 2 years and , for the final 150 patients , ( 1 ) an acceptance rate of at least 40 % ; ( 2 ) recruitment taking no longer than 6 months ; and ( 3 ) chemotherapy starting within 6 weeks of consent in at least 85 % of patients . RESULTS Between September 2012 and 3 June 2014 , 350 patients consented to join OPTIMA prelim and 313 were r and omised ; the final 150 patients were recruited in 6 months , of whom 92 % assigned chemotherapy started treatment within 6 weeks . The acceptance rate for the 750 patients invited to participate was 47 % . Twelve out of the 325 patients with data ( 3.7 % , 95 % confidence interval 1.7 % to 5.8 % ) were deemed ineligible on central review of receptor status . Interviews with research ers and recordings of potential participant consultations made as part of the integral qualitative recruitment study provided insights into recruitment barriers and led to interventions design ed to improve recruitment . Patient information was changed as the result of feedback from three patient focus groups . Additional multiparameter analysis was performed on 302 tumour sample s. Although Oncotype DX , MammaPrint( ® )/BluePrint ( ® ) ( Agendia Inc. , Irvine , CA , USA ) , Prosigna ( ® ) ( NanoString Technologies Inc. , Seattle , WA , USA ) , IHC4 , IHC4 automated quantitative immunofluorescence ( AQUA ( ® ) ) [ NexCourse BreastTM ( Genoptix Inc. Carlsbad , CA , USA ) ] and MammaTyper ( ® ) ( BioNTech Diagnostics GmbH , Mainz , Germany ) categorised comparable numbers of tumours into low- or high-risk groups and /or equivalent molecular subtypes , there was only moderate agreement between tests at an individual tumour level ( kappa ranges 0.33 - 0.60 and 0.39 - 0.55 for tests providing risks and subtypes , respectively ) . Health economics modelling showed the value of information to the NHS from further research into multiparameter testing is high irrespective of the test evaluated . Prosigna is currently the highest priority for further study . CONCLUSIONS OPTIMA prelim has achieved its aims of demonstrating that a large UK clinical trial of multiparameter assay-based selection of chemotherapy in hormone-sensitive early breast cancer is feasible . The economic analysis shows that a trial would be economically worthwhile for the NHS . Based on the outcome of the OPTIMA prelim , a large-scale RCT to evaluate the clinical effectiveness and cost-effectiveness of multiparameter assay-directed chemotherapy decisions in hormone-sensitive HER2-negative early breast would be appropriate to take place in the NHS . TRIAL REGISTRATION Current Controlled Trials IS RCT N42400492 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 20 , No. 10 . See the NIHR Journals Library website for further project information . The Government of Ontario funded research at the Ontario Institute for Cancer Research . Robert C Stein received additional support from the NIHR University College London Hospitals Biomedical Research Centre AIMS Uncertainty remains regarding the optimal therapy for patients with stage II or III rectal cancer . Systematic review s and practice guidelines on preoperative and postoperative therapy for rectal cancer were published by the Gastrointestinal Cancer Disease Site Group in 2003 and 2000 , respectively . The systematic review s were up date d and revised and new recommendations for preoperative and postoperative therapy were developed based on the up date d body of evidence . The following research questions were addressed : After appropriate preoperative staging tests , should patients with resectable clinical stage II or III rectal cancer be offered preoperative radiotherapy ( with or without chemotherapy ) ? What is the role of postoperative radiotherapy and /or chemotherapy for patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy  , in terms of improving survival and delaying local recurrence ? MATERIAL S AND METHODS The MEDLINE , EMBASE and Cochrane Library data bases , as well as meeting proceedings from the American Society of Clinical Oncology , were search ed for reports of r and omised controlled trials and meta-analyses comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy for stage II or III rectal cancer . The draft practice guideline and systematic review s were distributed through a mailed survey to 129 health care providers in Ontario for review . RESULTS Systematic review s on preoperative and postoperative therapy for rectal cancer were developed . On the basis of the evidence contained in these review s , the Gastrointestinal Cancer Disease Site Group drafted recommendations . Of the 33 practitioners who responded to the mailed survey , 97 % agreed with the draft recommendations as stated , 88 % agreed that the report should be approved as a practice guideline and 94 % indicated that they were likely to use the guideline in their own practice . CONCLUSIONS Preoperative chemoradiotherapy is preferred , compared with st and ard fractionation preoperative radiotherapy alone , to decrease local recurrence .  Preoperative chemoradiotherapy is also preferred , compared with a postoperative approach , to decrease local recurrence and adverse effects . For patients with relative contraindications to chemotherapy in the preoperative period , an acceptable alternative is preoperative radiotherapy alone followed by surgery .  Patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy  should be offered postoperative therapy with concurrent chemoradiotherapy plus fluoropyrimidine-based chemotherapy In December 2003 , the European Council identified best practice as key for ensuring development of high- quality cancer-screening programs . To support national policies on cancer control , the European Union institutions progressed several initiatives on cancer . The European Commission ( EC ) Initiative on Breast Cancer ( ECIBC ) is the most recent of these projects and the most implementation driven . Within this initiative , the European Guidelines for Breast Cancer Screening and Diagnosis ( in short , European Breast Guidelines ) are being developed ( http://ecibc.jrc.ec.europa.eu/ ) . Guidelines are approaches to generally improve prevention , diagnosis , treatment , and follow-up of diseases , overcoming inappropriate variations by providing recommendations for best care . The new era of guidelines promises recommendations that are based on the best available evidence summarized in systematic review s while providing the necessary flexibility needed to individualize decisions . The best methods for development of practice guidelines have experienced intense elaboration and attention during the past decades ( 17 ) . The impetus for this attention has been the change from expert- or consensus-based to evidence -based health care recommendations . Although this change in terminology should express the shift from un systematic development of guidelines to systematic and trustworthy recommendations , it is often misunderstood and misconstrued as meaning that experts are now meaningless in the process or as if consensus through discussion is a matter of the past . Neither is correct . Experts from various disciplines and consensus as a result of deliberation remain a mainstay of health care guideline development ( 810 ) . These experts are responsible for prioritization of questions that should be addressed in guidelines ; judgments that result from interpretation of evidence , including the rating of the certainty of the available evidence ; and decisions about how the judgments on the different criteria bear on recommendations . What has changed over time in guideline development are the rules , the structure and explicitness of the process , and the guideline product . Indeed , review s of guideline development methodology and how guidelines can be improved have led to more structured and documented processes that allow a reduction of bias and provide balanced views of appropriately composed guideline panels ( 2 , 5 , 6 ) . Core components for trustworthy guideline development ( 13 , 5 , 7 , 11 ) include that guidelines be developed by a knowledgeable , multidisciplinary panel of experts and representatives from key affected groups ; be based on a systematic review of the existing evidence ; consider important patient subgroups and patient preferences as appropriate ; be based on an explicit and transparent process that minimizes distortions , biases , and conflicts of interest ( 12 ) ; provide a clear explanation of the logical relationships between alternative care options and health outcomes and provide ratings of both the quality of evidence and the strength of the recommendations ( 1316 ) ; and be reconsidered and revised as appropriate when important new evidence warrants modifications . In addition , greater transparency in linking the considered research evidence and the recommendations , as well as the requirement of making structured expert judgments , represents a shift in the guideline development paradigm ( 5 , 11 , 1719 ) . At the same time , developing guidelines for a large number of member states and those that aim to adapt the guidelines poses challenges , such as the feasibility of implementing strategies that may exist in some member countries but not others ( for example , organized population -based screening in Italy but not Greece ) . Addressing these challenges requires considerations that extend beyond strictly clinical efforts in guideline development and mastering the many factors that influence recommendations and their implementation . This article describes the rationale , methods , and processes the ECIBC has adopted to develop the European Breast Guidelines in the context of evolving international st and ards . It also describes an innovative approach to presenting , disseminating , and accelerating implementation of recommendations . Guideline Methodology and Development To adhere to the core requirements for guideline development , the EC has taken several steps . First , it selected , via an open call ( https://ecibc.jrc.ec.europa.eu/ guidelines -team ) , a panel with broad representation of expertise , knowledge , and background , which includes patients , health care professionals , epidemiologists , guideline method ologists , and others ( Appendix ) . These individuals voluntarily participate in the ECIBC and compose the guidelines development group ( GDG ) . Second , it ensured that all recommendations were supported by systematic review s of the evidence conducted by independent scientists from Cochrane Iberoamricathe systematic review team (SRT)following st and ard Cochrane Collaboration methods ( 20 , 21 ) . Third , because this is a women-centered initiative , we included women advocates in the GDG as full voting guideline group members . We separately considered important subgroups of women during recommendation development ( for example , different age groups ) , and we specifically focused on evidence that supports best ways of communicating this information to women to inform their decisions . Fourth , we applied EC conflict of interest rules ( http://ecibc.jrc.ec.europa.eu/rules ) , which are consistent with international recommendations , and used GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) Evidence to Decision ( EtD ) frameworks to minimize the influence of competing interests on the recommendations ( 12 , 17 , 18 ) . These EtD frameworks help guideline panels use evidence in a structured , transparent way to inform decisions with a series of criteria , such as anticipated harms and benefits of the options considered , the certainty of the evidence for those effects , and the costs and feasibility of the options , to help them reach their decision . Fifth , using the GRADE approach to guideline development and its EtD frameworks , we focused our questions and recommendations on outcomes that matter to women and provided a rating of the certainty or quality of evidence and the strength of recommendations that is widely accepted as the reference st and ard ( Figures 1 and 2 ) . Sixth , our evidence review s are up to date when the recommendations are formulated , and we engage in international stakeholder feedback to ensure that recommendations remain timely and relevant to public health and clinical practice . The ECIBC is committed to review ing and updating the recommendations as required when new evidence becomes available . The general process is explained in Figure 3 and is based on the Guidelines International NetworkMcMaster Guideline Development Checklist ( https://hei grade .mcmaster.ca/ guideline -development/using-checklist ) ( 5 ) . Figure 1 . According to GRADE , certainty , quality , strength of evidence , or confidence in the estimate of effect is determined on the basis of a systematic review of the evidence for each outcome ( based on the domains risk of bias , indirectness , imprecision , inconsistency , and publication bias that lower certainty and , usually only for nonr and omized studies , large effects , doseresponse relations and opposing plausible residual confounding that may increase the certainty ) . For recommendations , the overall certainty is determined across outcomes based on the lowest certainty outcome among those critical for decision making for the specific context . The guidelines development group applies the GRADE Evidence -to-Decision frameworks to make recommendations that are made available on the European Commission Web site . ( Reproduced from reference 15 , with permission from Schnemann HJ . ) . GRADE = Grading of Recommendations Assessment , Development and Evaluation . Figure 2 . GRADE EtD frameworks . The GRADE EtD frameworks as available in the GRADE pro software ( www . grade pro.org ) . They help with structuring the entire guideline process into 4 sections and support the conduct of guideline group meetings , presentation , and implementation . They clarify the perspective that is taken by the guideline panel or decision maker and the type of question that is asked in the question section . The section on assessment includes the criteria if the problem is a priority , the balance of health benefits and harms , values and preferences related to the outcomes , cost , re sources and cost-effectiveness , equity , acceptability , and feasibility . Conclusions provide the decision or recommendation with a justification and implementation , as well as research considerations . The presentation function supports the conduct of guideline group meetings and facilitates the output of EtD frameworks to other implementation tools , such as Web sites , h and -held apps , and interactive decision aids . EtD = Evidence to Decision ; GRADE = Grading of Recommendations Assessment , Development and Evaluation ; HTA = health technology assessment ; PICO = population , intervention , comparators , and outcomes . Figure 3 . Approach to guideline development used by the European Commission Initiative on Breast Cancer . The European Commission JRC has oversight of the organization , budgeting , planning , and training . The JRC also manages conflicts of interest , documents all aspects of the work , and manages the membership and group processes . The guideline development group and JRC formulate the questions and work with the systematic review team on identifying and assessing the evidence . The guidelines development group is responsible for developing the recommendations . The JRC is responsible for most other aspects as described in the figure under dissemination , implementation , and updating . JRC = Joint Research Centre ; PICO = population , intervention , comparator , and outcomes . ( Reproduced with adaptation to the JRC process from PURPOSE Risk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations . The TEXT ( Tamoxifen and Exemestane Trial ) and SOFT ( Suppression of Ovarian Function Trial ) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer , testing exemestane plus ovarian function suppression ( OFS ) , tamoxifen plus OFS , and tamoxifen alone . We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 ( HER2 ) -negative disease . PATIENTS AND METHODS The TEXT and SOFT hormone receptor-positive , HER2-negative analysis population included 4,891 women . The end point was breast cancer-free interval ( BCFI ) , defined as time from r and om assignment to first occurrence of invasive locoregional , distant , or contralateral breast cancer . A continuous , composite measure of recurrence risk for each patient was determined from a Cox model incorporating age , nodal status , tumor size and grade , and estrogen receptor , progesterone receptor , and Ki-67 expression levels . Sub population treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk . RESULTS SOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5 % or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone , reaching 10 % to 15 % at intermediate to high composite risk ; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk . The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies . For TEXT patients , the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5 % to 15 % ; patients not receiving chemotherapy and with lowest composite risk did well with both treatments . CONCLUSION Premenopausal women with hormone receptor-positive , HER2-negative disease and high recurrence risk , as defined by clinicopathologic characteristics , may experience improvement of 10 % to 15 % in 5-year BCFI with exemestane plus OFS versus tamoxifen alone . An improvement of at least 5 % may be achieved for women at intermediate risk , and improvement is minimal for those at lowest risk After more than three decades of clinical trials testing various st and ard-dose chemotherapy regimens , the disease course of patients with multiple myeloma has not changed appreciably . Conventional chemotherapy can provide effective palliation but is not curative ( 1 ) . Case series have described encouraging results in patients with myeloma undergoing allogeneic or autologous bone marrow or peripheral blood stem-cell transplantation ( 2 ) . Other studies of transplantation , including r and omized trials , have been reported in the past 6 years ( 3 , 4 ) . To facilitate decisions about treatment options , practice guidelines have been developed for use by health care providers and consumers . In Ontario , Canada , cancer treatments and policies are led by a state-funded organization , Cancer Care Ontario . To help derive treatment options , Cancer Care Ontario has developed the Program in Evidence -Based Care , which includes the Practice Guidelines Initiative . Disease Site Groups ( DSGs ) , which comprise physicians , epidemiologists , and consumers , develop guidelines through a systematic process that involves assessment of evidence , consensus , and a validation process involving practitioners from across the province . Guideline topics are chosen through a prioritization process that includes the burden of illness , availability of evidence , perceived variation in practice , the potential to affect treatment decisions , and re source utilization . The Hematology DSG noted that the use of transplantation for patients with myeloma varied among practice s across the province . Variability in practice and emerging evidence of higher quality made this a priority topic for guideline development . To approach this topic , the DSG addressed the following questions : What is optimal st and ard-dose chemotherapy for patients with myeloma ? In terms of survival , is  peripheral blood stem-cell  or  marrow transplantation better than conventional chemotherapy ? What is the relative efficacy of autologous versus allogeneic transplantation ? What specifics of the transplantation process can be recommended ? When should transplantation be performed ? Who should ( or should not ) receive a transplant ? Methods Overview of Guideline Development This guideline was developed by the Cancer Care Ontario Practice Guidelines Initiative ( CCOPGI ) using the methods of the Practice Guidelines Development Cycle ( 5 ) . Members of the CCOPGI 's Hematology DSG selected , review ed , and interpreted the evidence . This DSG comprises 25 members , including hematologists , medical and radiation oncologists , an epidemiologist , and 2 lay representatives . Several of the physician members have background training in epidemiology ; 8 hematologists regularly perform stem-cell transplantation in clinical practice . The DSG 's draft recommendations were circulated through a mailed survey to hematologists and medical or radiation oncologists in Ontario for feedback and involvement in a consensus process . Responses were used to guide the reformatting of the draft into the final guideline recommendations . The Practice Guidelines Co-ordinating Committee ( PGCC ) , which ensures consistency of guideline development across the DSGs of various tumor sites , approved the guideline . The CCOPGI has a st and ardized process to up date each guideline report ; the current guideline was up date d and review ed by the PGCC in October 2000 . Literature Search Strategy We search ed the MEDLINE , CANCERLIT , and Cochrane Library data bases for literature published from 1992 to December 1997 and subsequently up date d the search in October 1998 , June 1999 , and April 2000 . For the search es , we combined multiple myeloma ( as a Medical Subject Heading [ MeSH ] and text word ) with bone marrow transplantation ( MeSH and text word ) and drug therapy ( MeSH ) . Then , we combined these terms with the search terms for the following study design s : practice guidelines ; systematic review s or meta-analyses ; review s ; r and omized , controlled trials ; controlled clinical trials ; and comparative studies . In addition , we search ed the PubMed and Physician Data Query ( PDQ ) ( www.cancer.gov/ search / clinical _ trials/ ) data bases and review ed relevant conference proceedings ( American Society of Hematology , 1997 to 1999 , and American Society of Clinical Oncology , 1999 to 2000 ) , article bibliographies , and personal files . To address the issue of optimal chemotherapy , we performed an additional search of the same data bases using the term multiple myeloma ( MeSH ) combined with r and omized , controlled trials ( MeSH ) and the text word r and om in the title . Inclusion Criteria We selected study reports meeting one of the three following criteria : r and omized trial or meta- analysis of therapy for patients with myeloma that reported survival or quality -of-life outcomes ; nonr and omized comparative trial that addressed transplantation strategy , including a contemporaneous control group , and that reported survival or quality -of-life outcomes ; or economic evaluation that addressed transplantation strategy . Because of insufficient data on the specifics of the transplantation process and the patients who would be most likely to benefit from transplantation , we performed a second search , which identified data from noncomparative case-series studies . Data Extraction and Interpretative Summary Three members of the DSG , including an epidemiologist , determined eligibility of the articles and abstract s obtained from the literature search . The lead DSG member for this guideline extracted and summarized relevant data according to the guideline question addressed . The DSG members then review ed the summarized data and key articles . The DSG met formally three to four times annually ; at these meetings , the members method ologically assessed the articles , interpreted the data , and debated specific points in an attempt to reach a consensus . Synthesizing the Evidence Because all of the nine r and omized trials on transplantation addressed different questions , we did not statistically pool the data . DSG Consensus Process Through an iterative process that included debate at formal meetings and circulation of draft recommendations , we considered the implication s of the appraised data for each guideline question . With this process , attempts were made to reach consensus ; when this was impossible , minority opinions were recorded . Approval by each member of the DSG was required before circulation of the draft version for practitioner feedback and su bmi ssion of the final guideline to the PGCC . Practitioner Feedback To obtain practitioner feedback , we mailed a survey to 211 practitioners in Ontario ( 94 hematologists , 93 medical oncologists , and 24 radiation oncologists ) . The survey consisted of st and ardized items asking the practitioner to rate the quality of each draft guideline and to judge whether the draft recommendations should serve as a practice guideline . Written comments were invited . Follow-up reminders were sent at 2 weeks ( by postcard ) and 4 weeks ( entire package ) . After exclusion of 18 retired practitioners , 137 of 193 practitioners ( 71 % ) responded ; 90 of 137 respondents ( 66 % ) indicated that the guideline was relevant to their practice . Approval of the draft guideline was strong among these 90 practitioners : 91 % agreed or strongly agreed that the summary of the evidence was acceptable , 87 % agreed with the draft recommendations , and 81 % approved of the recommendations as a practice guideline . Thirty-nine respondents provided written comments ; these comments were , like the other responses , incorporated in the final guideline . Results Sixty-six reports met the criteria for inclusion and are categorized in Table 1 . In each section below , we describe the studies , summarize results , and describe the guideline development . Table 1 . Evidence Included in This Practice Guideline Report What Is Optimal St and ard-Dose Chemotherapy  for Patients with Multiple Myeloma ? To properly compare transplantation with conventional chemotherapy , we must define optimal conventional chemotherapy . We identified 30 r and omized trials comparing therapies in previously untreated patients . Four meta-analyses ( 6 - 9 ) evaluated these data . The Myeloma Trialists ' Collaborative Group ( 7 ) compared combination chemotherapy with melphalan plus prednisone in a meta- analysis of 27 trials . Twenty of these trials supplied individual-patient data . No difference in survival was detected . The proportional reduction in the annual odds of death was 1.5 % in favor of combination chemotherapy ( 95 % CI , 8 % to 5 % ; P > 0.2 ) , with an odds ratio ( OR ) of 0.99 ( CI , 0.93 to 1.05 ) . An earlier literature -based meta- analysis ( 6 ) of 18 trials also failed to detect a survival difference between groups ( OR , 1.04 [ CI , 0.90 to 1.19 ] ; P > 0.2 ) . Two meta-analyses evaluated interferon for multiple myeloma . An overview of 24 r and omized trials published in abstract form ( 8) demonstrated that interferon improved recurrence-free survival by 6 months and improved 3-year overall survival by 4 % . Another meta- analysis ( 9 ) measured survival by a unique measure called the mean lifetime survival . This meta- analysis found no difference in survival rate between the group receiving interferon and the group not receiving interferon ( 3.9 vs. 3.4 years , respectively ; P = 0.095 ) . Guideline Recommendation Multiagent chemotherapy or melphalan plus prednisone is appropriate therapy for a control group in a comparison of transplantation versus st and ard-dose therapy . The addition of interferon is unlikely to influence outcomes in the control group . In Terms of Survival , Is Autologous Peripheral Blood Stem-Cell or Bone Marrow Transplantation Better than Conventional Chemotherapy ? We review ed two r and omized and three nonr and omized comparisons ( Table 2 ) . Attal and colleagues ( 3 ) r and omly assigned 200 previously untreated patients younger than 65 years of age with stage II or III ( 40 ) myeloma to conventional chemotherapy or to a strategy that included autologous bone marrow transplantation . Patients were r and omly PURPOSE Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 ( HER2 ) overexpressing advanced breast cancer . We conducted a pilot study of preoperative trastuzumab and paclitaxel , followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer . PATIENTS AND METHODS Patients with HER2-positive ( 2 + or 3 + by immunohistochemistry ) stage II or III breast cancer received preoperative trastuzumab ( 4 mg/kg x 1 , then 2 mg/kg/wk x 11 ) in combination with paclitaxel ( 175 mg/m(2 ) every 3 weeks x 4 ) . Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery .  Clinical and pathologic response rates were determined after preoperative therapy . Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially . RESULTS Preoperative trastuzumab and paclitaxel achieved clinical response in 75 % and complete pathologic response in 18 % of the 40 women on study . HER2 3 + tumors were more likely to respond than 2 + tumors ( 84 % v 38 % ) . No unexpected treatment-related noncardiac toxicity was encountered . Four patients developed grade 2 cardiotoxicity ( asymptomatic declines in left ventricular ejection fraction ) . Baseline HER2 extracellular domain was elevated in 24 % of patients and declined with preoperative therapy . Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment . CONCLUSION Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines . The observed changes in cardiac function merit further investigation . Correlative analyses of HER2 status may facilitate underst and ing of tumor response and resistance to targeted therapy UNLABELLED We treated patients with operable human epidermal growth factor receptor 2-positive breast cancer with neoadjuvant anthracycline regimens followed by nanoparticle albumin-bound paclitaxel plus trastuzumab . Of the 44 patients , 49 % achieved a pathologic complete response ( pCR ) . The pCR rate was 36 % and 71 % in the patients with estrogen receptor-positive and -negative cancer , respectively . Neoadjuvant therapy using this combination appears to be effective and safe . Introduction : Neoadjuvant chemotherapy plus trastuzumab . INTRODUCTION Neoadjuvant chemotherapy plus trastuzumab results in a 30 % to 50 % pathologic complete response ( pCR ) rate in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been associated with improved therapeutic outcomes . Thus , the pCR rate can be useful in evaluating novel agents in this patient population . Nanoparticle albumin-bound (nab)-paclitaxel ( PTX ) can reduce the toxicity of PTX while maintaining its efficacy . The present study evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+ ) breast cancer . PATIENTS AND METHODS We treated patients with stage I to IIIA breast cancer using neoadjuvant epirubicin/cyclophosphamide ( EC ) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks ( q3w ) for 4 cycles , followed by nab-PTX ( 260 mg/m(2 ) ) plus trastuzumab q3w for 4 cycles . The primary endpoint was the pCR rate . The secondary endpoints included the clinical response rate , disease-free survival , pathologic response rate ( defined as pCR or minimal residual invasive disease only in the breast ) , breast-conserving surgery rate , and safety . RESULTS Forty-six patients were enrolled . One patient met the exclusion criteria because of the coexistence of another malignant disease ; therefore , we evaluated 45 patients in the entire study . One patient experienced rapid disease progression during EC therapy , leaving 44 patients evaluable for nab-PTX treatment . Of the 45 patients , 49 % achieved a pCR . The pCR rate was 36 % and 71 % in those with estrogen receptor-positive and -negative cancer , respectively . Of all the study treatments , the most frequent reason for delay or dose reduction was hematologic toxicity ; only 1 patient required a dose reduction for nab-PTX because of peripheral neuropathy . CONCLUSION Neoadjuvant therapy using this combination appears to be effective and safe PURPOSE To up date the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment , particularly adjuvant tamoxifen . METHODS ASCO convened the Up date Committee and conducted a systematic review of r and omized clinical trials from January 2009 to June 2013 and analyzed three historical trials . Guideline recommendations were based on the Up date Committee 's review of the evidence . Outcomes of interest included survival , disease recurrence , and adverse events . RESULTS This guideline up date reflects emerging data on duration of tamoxifen treatment . There have been five studies of tamoxifen treatment beyond 5 years of therapy . The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year duration s of tamoxifen use . In addition to modest gains in survival , extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer . RECOMMENDATIONS Previous ASCO guidelines recommended treatment of women who have hormone receptor-positive breast cancer and are premenopausal with 5 years of tamoxifen , and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor ( in sequence ) . If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen , they should be offered 10 years total duration of tamoxifen . If women are postmenopausal and have received 5 years of adjuvant tamoxifen  , they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy UNLABELLED In February 2010 , the Medical Advisory Secretariat ( MAS ) began work on evidence -based review s of the literature surrounding three pharmacogenomic tests . This project came about when Cancer Care Ontario ( CCO ) asked MAS to provide evidence -based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario . Evidence -based analyses have been prepared for each of these technologies . These have been completed in conjunction with internal and external stakeholders , including a Provincial Expert Panel on Pharmacogenomics ( PEPP ) . Within the PEPP , subgroup committees were developed for each disease area . For each technology , an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative ( THETA ) and is summarized within the reports . THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT : www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER : An Evidence -Based and Economic Analysis Epidermal Growth Factor Receptor Mutation ( EGFR ) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor ( TKI ) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer : an Evidence -Based and Economic Analysis K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer : an Evidence -Based and Economic Analysis . OBJECTIVE The objective of this systematic review is to determine the predictive value of KRAS testing in the treatment of metastatic colorectal cancer ( mCRC ) with two anti-EGFR agents , cetuximab and panitumumab . Economic analyses are also being conducted to evaluate the cost-effectiveness of KRAS testing . CLINICAL NEED CONDITION AND TARGET POPULATION Metastatic colorectal cancer ( mCRC ) is usually defined as stage IV disease according to the American Joint Committee on Cancer tumour node metastasis ( TNM ) system or stage D in the Duke 's classification system . Patients with advanced colorectal cancer ( mCRC ) either present with metastatic disease or develop it through disease progression . KRAS ( Kristen-RAS , a member of the rat sarcoma virus ( ras ) gene family of oncogenes ) is frequently mutated in epithelial cancers such as colorectal cancer , with mutations occurring in mutational hotspots ( codons 12 and 13 ) of the KRAS protein . Involved in EGFR-mediated signalling of cellular processes such as cell proliferation , resistance to apoptosis , enhanced cell motility and neoangiogenesis , a mutation in the KRAS gene is believed to be involved in cancer pathogenesis . Such a mutation is also hypothesized to be involved in resistance to targeted anti-EGFR ( epidermal growth factor receptor with tyrosine kinase activity ) treatments such as cetuximab and panitumumab , hence , the important in evaluating the evidence on the predictive value of KRAS testing in this context . KRAS MUTATION TESTING IN ADVANCED COLORECTAL CANCER : Both cetuximab and panitumumab are indicated by Health Canada in the treatment of patients with metastatic colorectal cancer whose tumours are WT for the KRAS gene .  Cetuximab may be offered as monotherapy in patients intolerant to irinotecan-based chemotherapy or in patients who have failed both irinotecan and oxaliplatin-based regimens and who received a fluoropyrimidine .  It can also be administered in combination with irinotecan in patients refractory to other irinotecan-based chemotherapy regimens . Panitumumab is only indicated as a single agent after failure of fluoropyrimidine- , oxaliplatin- , and irinotecan-containing chemotherapy regimens . In Ontario , patients with advanced colorectal cancer who are refractory to chemotherapy may be offered the targeted anti-EGFR treatments cetuximab or panitumumab . Eligibility for these treatments is based on the KRAS status of their tumour , derived from tissue collected from surgical or biopsy specimens . It is believed that KRAS status is not affected by treatments , therefore , for patients for whom surgical tissue is available for KRAS testing , additional biopsies prior to treatment with these targeted agents is not necessary . For patients that have not undergone surgery or for whom surgical tissue is not available , a biopsy of either the primary or metastatic site is required to determine their KRAS status . This is possible as status at the metastatic and primary tumour sites is considered to be similar . RESEARCH QUESTION To determine if there is predictive value of KRAS testing in guiding treatment decisions with anti-EGFR targeted therapies in advanced colorectal cancer patients refractory to chemotherapy . RESEARCH METHODS LITERATURE SEARCH The Medical Advisory Secretariat followed its st and ard procedures and on May 18 , 2010 , search ed the following electronic data bases : Ovid MEDLINE , EMBASE , Ovid MEDLINE In-Process & Other Non-Indexed Citations , Cochrane Central Register of Controlled Trials , Cochrane Data base of Systematic Review s and The International Network of Agencies for Health Technology Assessment data base . The subject headings and keywords search ed included colorectal cancer , cetuximab , panitumumab , and KRAS testing . The search was further restricted to English- language articles published between January 1 , 2009 and May 18 , 2010 result ing in 1335 articles for review . Excluded were case reports , comments , editorials , non  systematic review s , and letters . Studies published from January 1 , 2005 to December 31 , 2008 were identified in a health technology assessment conducted by the Agency for Healthcare Research and Quality ( AHRQ ) , published in 2010 . In total , 14 observational studies were identified for inclusion in this EBA : 4 for cetuximab monotherapy , 7 for the cetuximab-irinotecan combination therapy , and 3 to be included in the review for panitumumab monotherapy INCLUSION CRITERIA English- language articles , and English or French- language HTAs published from January 2005 to May 2010 , inclusive . R and omized controlled trials ( RCTs ) or observational studies , including single arm treatment studies that include KRAS testing . Studies with data on main outcomes of interest , overall and progression-free survival . Studies of third line treatment with cetuximab or panitumumab in patients with advanced colorectal cancer refractory to chemotherapy . For the cetuximab-irinotecan evaluation , studies in which at least 70 % of patients in the study received this combination therapy . EXCLUSION CRITERIA Studies whose entire sample was included in subsequent publications which have been included in this EBA . Studies in pediatric population s . Case reports , comments , editorials , or letters . OUTCOMES OF INTEREST Overall survival ( OS ) , medianProgression-free-survival ( PFS ) , median . Response rates . Adverse event rates . Quality of life ( QOL ) . SUMMARY OF FINDINGS OF SYSTEMATIC REVIEW : CETUXIMAB OR PANITUMUMAB MONOTHERAPY : Based on moderate GRADE observational evidence , there is improvement in PFS and OS favouring patients without the KRAS mutation ( KRAS wildtype , or KRAS WT ) compared to those with the mutation . CETUXIMAB-IRINOTECAN COMBINATION THERAPY : There is low GRADE evidence that testing for KRAS may optimize survival benefits in patients without the KRAS mutation ( KRAS wildtype , or KRAS WT ) compared to those with the mutation . However , cetuximab-irinotecan combination treatments based on KRAS status discount any effect of cetuximab in possibly reversing resistance to irinotecan in patients with the mutation , as observed effects were lower than for patients without the mutation . Clinical experts have raised concerns about the biological plausibility of this observation and this conclusion would , therefore , be regarded as hypothesis generating . ECONOMIC ANALYSIS Cost-effectiveness and budget impact analyses were conducted incorporating estimates of effectiveness from this systematic review . Evaluation of relative cost-effectiveness , based on a decision-analytic cost-utility analysis , assessed testing for KRAS genetic mutations versus no testing in the context of treatment with cetuximab monotherapy , panitumumab monotherapy , cetuximab in combination with irinotecan , and best supportive care . Of importance to note is that the cost-effectiveness analysis focused on the impact of testing for KRAS mutations compared to no testing in the context of different treatment options , and does not assess the cost-effectiveness of the drug treatments alone . CONCLUSIONS KRAS status is predictive of outcomes in cetuximab and panitumumab monotherapy , and in cetuximab-irinotecan combination therapy . While KRAS testing is cost-effective for all strategies considered , it is not equally cost-effective for all treatment options AIMS Oesophageal cancer is an aggressive disease and the optimal therapy for patients with resectable tumours remains unclear . A systematic review and companion practice guideline were published in 2004 ; however , new evidence has become available since the publication of the original report . An up date of the literature search and a revision of the recommendations were undertaken to incorporate the new data . The following research question was addressed : should patients with resectable oesophageal cancer receive preoperative or postoperative therapy together with surgery ? The outcomes of interest were survival , adverse effects and quality of life . MATERIAL S AND METHODS The literature search of the original systematic review was up date d to April 2007 . MEDLINE , EMBASE , Cochrane Library and abstract s from the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were search ed for reports of r and omised controlled trials and meta-analyses comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy . After the completion of the draft systematic review and practice guideline , the report was distributed through a mailed survey to 133 health care providers in Ontario for review and feedback . RESULTS The up date d literature search yielded eight new r and omised controlled trial reports and seven new meta- analysis reports for consideration , together with the evidence review ed in the original review publication . Of the 31 practitioners who responded to the mailed survey , 80 % agreed with the draft recommendations as stated , 83 % agreed that the report should be approved as a practice guideline and 86 % indicated that they would probably use the guideline in their own practice . CONCLUSIONS Preoperative cisplatin-based chemotherapy plus radiotherapy is recommended as the preferred modality for the management of surgically resectable patients with oesophageal cancer .  Preoperative cisplatin-based chemotherapy alone is an alternative choice for the management of these patients BACKGROUND Bevacizumab , a monoclonal antibody against vascular endothelial growth factor A , has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer . We evaluated the efficacy , measured according to the rate of pathological complete response ( absence of invasive and intraductal disease in the breast and the axillary lymph nodes ) , and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer . METHODS We r and omly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel , with or without concomitant bevacizumab .  Patients with untreated HER2-negative breast cancer were eligible if they had large tumors , hormone-receptor-negative disease , or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy , and no increased cardiovascular or bleeding risk . RESULTS Overall , the rates of pathological complete response were 14.9 % with epirubicin and cyclophosphamide followed by docetaxel and 18.4 % with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab ( odds ratio with addition of bevacizumab , 1.29 ; 95 % confidence interval , 1.02 to 1.65 ; P=0.04 ) ; the corresponding rates of pathological complete response were 27.9 % and 39.3 % among 663 patients with triple-negative tumors ( P=0.003 ) and 7.8 % and 7.7 % among 1262 patients with hormone-receptor-positive tumors ( P=1.00 ) . Breast-conserving surgery was possible in 66.6 % of the patients in both groups . The addition of bevacizumab , as compared with neoadjuvant therapy alone , was associated with a higher incidence of grade 3 or 4 toxic effects ( febrile neutropenia , mucositis , the h and -foot syndrome , infection , and hypertension ) but with a similar incidence of surgical complications . CONCLUSIONS The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer . Efficacy was restricted primarily to patients with triple-negative tumors , in whom the pathological complete response is considered to be a reliable predictor of long-term outcome . ( Funded by Sanofi-Aventis and Roche , Germany ; Clinical Trials.gov number , NCT00567554 . ) Purpose : Gene expression analysis identifies several breast cancer subtypes . We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes . Experimental Design : We used immunohistochemical profiles [ human epidermal growth factor receptor 2–positive (HER2+)/hormone receptor – negative for HER2+/estrogen receptor – negative ( ER− ) , hormone receptor and HER2− for basal-like , hormone receptor – positive for luminal ] to subtype a prospect ively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based ( doxorubicin plus cyclophosphamide , AC ) chemotherapy .  We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease – free survival and overall survival . Results : Of the 107 patients tested , 34 ( 32 % ) were basal-like , 11 ( 10 % ) were HER2+/ER− , and 62 ( 58 % ) were luminal . After neoadjuvant AC , 75 % received subsequent chemotherapy and all received endocrine therapy if hormone receptor – positive . The chemotherapy regimen and pretreatment stage did not differ by subtype . Clinical response to AC  was higher among the HER2+/ER− ( 70 % ) and basal-like ( 85 % ) than the luminal subtypes ( 47 % ; P < 0.0001 ) . Pathologic complete response occurred in 36 % of HER2+/ER− , 27 % of basal-like , and 7 % of luminal subtypes ( P = 0.01 ) . Despite initial chemosensitivity , patients with the basal-like and HER2+/ER− subtypes had worse distant disease – free survival ( P = 0.04 ) and overall survival ( P = 0.02 ) than those with the luminal subtypes . Regardless of subtype , only 2 of 17 patients with pathologic complete response relapsed . The worse outcome among basal-like and HER+/ER− subtypes was due to higher relapse among those with residual disease ( P = 0.003 ) . Conclusions : Basal-like and HER2+/ER− subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers . Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype . The poorer prognosis of basal-like and HER2+/ER− breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) . Methods An Up date Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of r and omized controlled trials from January 2007 to February 2014 . Results This guideline up date reflects changes in evidence since the previous guideline . Recommendations There is no cure for patients with stage IV NSCLC . For patients with performance status ( PS ) 0 to 1 ( and appropriate patient cases with PS 2 ) and without an EGFR-sensitizing mutation or ALK gene rearrangement , combination cytotoxic chemotherapy is recommended , guided by histology , with early concurrent palliative care . Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 ( bevacizumab may be added to carboplatin plus paclitaxel if no contraindications ) ; combination or single-agent chemotherapy or palliative care alone for those with PS 2 ; afatinib , erlotinib , or gefitinib for those with sensitizing EGFR mutations ; crizotinib for those with ALK or ROS1 gene rearrangement ; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma . Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens , alternative chemotherapy , or a chemotherapy break . In the second-line setting , recommendations include docetaxel , erlotinib , gefitinib , or pemetrexed for patients with nonsquamous cell carcinoma ; docetaxel , erlotinib , or gefitinib for those with squamous cell carcinoma ; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib . In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended . There are insufficient data to recommend routine third-line cytotoxic therapy . Decisions regarding systemic therapy should not be made based on age alone . Additional information can be found at http://www.asco.org/ guidelines /nsclc and http://www.asco.org/ guidelines wiki . J Clin Oncol 33:3488 - 3515 . © 2015 by American Society of Clinical Background : Progesterone receptor ( PR ) expression assessment in early invasive breast cancer remains controversial . This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer ; particularly in oestrogen receptor (ER)-positive , lymph node (LN)-negative disease . Methods : A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years ( 2000–2004 ) underwent surgery for primary invasive breast cancer with curative intent . Prospect i ve data collection included patient demographics , pathology , ER and PR expression , HER2 status , adjuvant chemotherapy and endocrine therapy .  Progesterone receptor expression was compared with ( all causes ) overall survival ( OS ) , breast cancer-specific survival ( BCSS ) and disease-free survival ( DFS ) . Results : Overall survival was 71.0 % and BCSS was 83.0 % at median follow-up of 8.34 years . Absent PR expression was significantly associated with poorer prognosis for OS , BCSS and DFS ( P<0.0001 , log-rank ) , even within the ER-positive , LN-negative group ( hazard ratio for BCSS 3.17 , 95 % CI 1.43–7.01 ) and was not influenced by endocrine therapy . Cox ’s regression analysis demonstrated that PR expression was an independent prognostic variable . Conclusion : Absence of PR expression is a powerful , independent prognostic variable in operable , primary breast cancer even in ER-positive , LN-negative patients receiving endocrine therapy . Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy
In general , single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population .
Anthracycline-taxane-based polychemotherapy regimens are , overall , considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes .
Regimens with varying anthracycline and taxane doses and schedules are options ; in general , paclitaxel given every 3 weeks is inferior .
Evidence does not support the use of bevacizumab in the adjuvant setting ; other systemic therapy agents such as metformin and vaccines remain investigatory .
BACKGROUND The Program in Evidence -Based Care ( pebc ) of Cancer Care Ontario recently created an evidence -based consensus guideline on the systemic treatment of early breast cancer .
The evidence for the guideline was compiled using a systematic review to answer the question " What is the optimal systemic therapy for patients with early-stage , operable breast cancer , when patient and disease factors are considered ? "
The question was addressed in three parts : cytotoxic chemotherapy , endocrine treatment , and human epidermal growth factor receptor 2 (her2)-directed therapy .