PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (1267244)

Clipboard (0)
None

Related Articles

1.  Gene Expression Profiling for Guiding Adjuvant Chemotherapy Decisions in Women with Early Breast Cancer 
Executive Summary
In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of published 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.html
Gene 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 Ecopnomic Analysis
K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis
Objective
To review and synthesize the available evidence regarding the laboratory performance, prognostic value, and predictive value of Oncotype-DX for the target population.
Clinical Need: Condition and Target Population
The target population of this review is women with newly diagnosed early stage (stage I–IIIa) invasive breast cancer that is estrogen-receptor (ER) positive and/or progesterone-receptor (PR) positive. Much of this review, however, is relevant for women with early stage (I and II) invasive breast cancer that is specifically ER positive, lymph node (LN) negative and human epidermal growth factor receptor 2 (HER-2/neu) negative. This refined population represents an estimated incident population of 3,315 new breast cancers in Ontario (according to 2007 data). Currently it is estimated that only 15% of these women will develop a distant metastasis at 10 years; however, a far great proportion currently receive adjuvant chemotherapy, suggesting that more women are being treated with chemotherapy than can benefit. There is therefore a need to develop better prognostic and predictive tools to improve the selection of women that may benefit from adjuvant chemotherapy.
Technology of Concern
The Oncotype-DX Breast Cancer Assay (Genomic Health, Redwood City, CA) quantifies gene expression for 21 genes in breast cancer tissue by performing reverse transcription polymerase chain reaction (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tumour blocks that are obtained during initial surgery (lumpectomy, mastectomy, or core biopsy) of women with early breast cancer that is newly diagnosed. The panel of 21 genes include genes associated with tumour proliferation and invasion, as well as other genes related to HER-2/neu expression, ER expression, and progesterone receptor (PR) expression.
Research Questions
What is the laboratory performance of Oncotype-DX?
How reliable is Oncotype-DX (i.e., how repeatable and reproducible is Oncotype-DX)?
How often does Oncotype-DX fail to give a useable result?
What is the prognostic value of Oncotype-DX?*
Is Oncotype-DX recurrence score associated with the risk of distant recurrence or death due to any cause in women with early breast cancer receiving tamoxifen?
What is the predictive value of Oncotype-DX?*
Does Oncoytpe-DX recurrence score predict significant benefit in terms of improvements in 10-year distant recurrence or death due to any cause for women receiving tamoxifen plus chemotherapy in comparison to women receiving tamoxifen alone?
How does Oncotype-DX compare to other known predictors of risk such as Adjuvant! Online?
How does Oncotype-DX impact patient quality of life and clinical/patient decision-making?
Research Methods
Literature Search
Search Strategy
A literature search was performed on March 19th, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1st, 2006 to March 19th, 2010. A starting search date of January 1st, 2006 was because a comprehensive systematic review of Oncotype-DX was identified in preliminary literature searching. This systematic review, by Marchionni et al. (2008), included literature up to January 1st, 2007. All studies identified in the review by Marchionni et al. as well as those identified in updated literature searching were used to form the evidentiary base of this review. The quality of the overall body of evidence was identified as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Any observational trial, controlled clinical trial, randomized controlled trial (RCT), meta-analysis or systematic review that reported on the laboratory performance, prognostic value and/or predictive value of Oncotype-DX testing, or other outcome relevant to the Key Questions, specific to the target population was included.
Exclusion Criteria
Studies that did not report original data or original data analysis,
Studies published in a language other than English,
Studies reported only in abstract or as poster presentations (such publications were not sought nor included in this review since the MAS does not generally consider evidence that is not subject to peer review nor does the MAS consider evidence that lacks detailed description of methodology).
Outcomes of Interest
Outcomes of interest varied depending on the Key Question. For the Key Questions of prognostic and predictive value (Key Questions #2 and #3), the prospectively defined primary outcome was risk of 10-year distant recurrence. The prospectively defined secondary outcome was 10-year death due to any cause (i.e., overall survival). All additional outcomes such as risk of locoregional recurrence or disease-free survival (DFS) were not prospectively determined for this review but were reported as presented in included trials; these outcomes are referenced as tertiary outcomes in this review. Outcomes for other Key Questions (i.e., Key Questions #1, #4 and #5) were not prospectively defined due to the variability in endpoints relevant for these questions.
Summary of Findings
A total of 26 studies were included. Of these 26 studies, only five studies were relevant to the primary questions of this review (Key Questions #2 and #3). The following conclusions were drawn from the entire body of evidence:
There is a lack of external validation to support the reliability of Oncotype-DX; however, the current available evidence derived from internal industry validation studies suggests that Oncotype-DX is reliable (i.e., Oncotype-DX is repeatable and reproducible).
Current available evidence suggests a moderate failure rate of Oncotype-DX testing; however, the failure rate observed across clinical trials included in this review is likely inflated; the current Ontario experience suggests an acceptably lower rate of test failure.
In women with newly diagnosed early breast cancer (stage I–II) that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node negative:
There is low quality evidence that Oncotype-DX has prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole (the latter for postmenopausal women only),
There is very low quality evidence that Oncotype-DX can predict which women will benefit from adjuvant CMF/MF chemotherapy in women being treated with adjuvant tamoxifen.
In postmenopausal women with newly diagnosed early breast cancer that is estrogen-receptor positive and/or progesterone-receptor positive and lymph-node positive:
There is low quality evidence that Oncotype-DX has limited prognostic value in women who are being treated with adjuvant tamoxifen or anastrozole,
There is very low quality evidence that Oncotype-DX has limited predictive value for predicting which women will benefit from adjuvant CAF chemotherapy in women who are being treated with adjuvant tamoxifen.
There are methodological and statistical limitations that affect both the generalizability of the current available evidence, as well as the magnitude and statistical strength of the observed effect sizes; in particular:
Of the major predictive trials, Oncotype-DX scores were only produced for a small subset of women (<40% of the original randomized population) potentially disabling the effects of treatment randomization and opening the possibility of selection bias;
Data is not specific to HER-2/neu-negative women;
There were limitations with multivariate statistical analyses.
Additional trials of observational design may provide further validation of the prognostic and predictive value of Oncotype-DX; however, it is unlikely that prospective or randomized data will become available in the near future due to ethical, time and resource considerations.
There is currently insufficient evidence investigating how Oncoytpe-DX compares to other known prognostic estimators of risk, such as Adjuvant! Online, and there is insufficient evidence investigating how Oncotype-DX would impact clinician/patient decision-making in a setting generalizable to Ontario.
PMCID: PMC3382301  PMID: 23074401
2.  Role of Age and Health in Treatment Recommendations for Older Adults With Breast Cancer: The Perspective of Oncologists and Primary Care Providers 
Journal of Clinical Oncology  2008;26(33):5386-5392.
Purpose
To determine the impact of age and health status on adjuvant treatment recommendations for older patients with breast cancer from the perspective of medical oncologists and primary care physicians with geriatric expertise.
Patients and Methods
One hundred fifty-one oncologists and 158 primary care physicians with geriatric expertise participated in an online survey. The survey described hypothetical patients of varying ages (70, 75, 80, and 85 years) and health status (good, average, and poor) who had node-positive, hormone receptor–positive, human epidermal growth factor receptor 2 (HER-2)/neu–negative; and hormone receptor–negative, HER-2/neu–positive breast cancers. The effects of patient age and health status on the survey participants’ adjuvant treatment recommendations were examined using generalized estimation equation methods.
Results
The majority of both oncologists and primary care physicians recommended some form of adjuvant therapy for patients of all ages (70, 75, 80, and 85 years) and health status. Both oncologists and primary care providers were less likely to recommend adjuvant treatment as a patient's age increased or health status declined (P < .0001). There were no significant differences in treatment recommendations among primary care physicians and oncologists for patients with hormone receptor–negative, HER-2/neu–positive tumors (P = .54). However, primary care providers were more likely than oncologists to recommend no adjuvant treatment for patients age 75 years or older with hormone receptor–positive, HER-2/neu–negative tumors (P < .01).
Conclusion
Age and health status influence oncologists’ and primary care providers’ adjuvant treatment recommendations. Evidence-based guidelines for breast cancer treatment in older adults taking into account age and health status are needed.
doi:10.1200/JCO.2008.17.6891
PMCID: PMC2651077  PMID: 18955446
3.  Predictive and Prognostic Value of the 21-Gene Recurrence Score in Hormone Receptor–positive, Node-positive Breast Cancer 
The addition of adjuvant chemotherapy to hormonal therapy is recommended for patients with estrogen receptor–positive (ER+), node-positive (N+) early breast cancer (EBC). Some of these patients, however, are not likely to benefit from treatment and may, therefore, be overtreated while also incurring unnecessary treatment-related adverse events and health care costs. The 21-gene Recurrence Score assay has been clinically validated and recommended for use in patients with ER+, node-negative (N0) EBC to assess the 10-year risk of distant disease recurrence and predict the likelihood of response to adjuvant chemotherapy. A growing body of evidence from several large phase III clinical trials reports similar findings in patients with ER+, N+ EBC. A systematic review of published literature from key clinical trials that have used the 21-gene breast cancer assay in patients with ER+, N+ EBC was performed. The Recurrence Score has been shown to be an independent predictor of disease-free survival, overall survival, and distant recurrence-free interval in patients with ER+, N+ EBC. Outcomes from decision impact and health economics studies further indicate that the Recurrence Score affects physician treatment recommendations equally in patients with N+ or N0 disease. It also indicates that a reduction in Recurrence Score–directed chemotherapy is cost-effective. There is a large body of evidence to support the use of the 21-gene assay Recurrence Score in patients with N+ EBC. Use of this assay could help guide treatment decisions for patients who are most likely to receive benefit from chemotherapy.
doi:10.1097/COC.0000000000000086
PMCID: PMC4162320  PMID: 24853663
gene expression profiling; prognosis; breast cancer; cost-effectiveness; 21-gene recurrence score
4.  Impact of a Commercial Reference Laboratory Test Recurrence Score on Decision Making in Early-Stage Breast Cancer 
Journal of Oncology Practice  2007;3(4):182-186.
Purpose
To investigate whether recurrence score (RS) as determined using a commercial reference laboratory test influences clinicians' treatment recommendations and eventual treatment in patients with early-stage breast cancer.
Methods
A retrospective analysis was performed on 74 patients from a community-based oncology practice with estrogen receptor (ER) –positive, lymph node (LN) –negative stage I or II breast cancer for which RS was obtained. Demographic and pathology information was extracted from medical records. Ten-year relapse-free survival was calculated using Adjuvant! Online. Treatment recommendations before the RS knowledge were compared with treatment recommendations after RS knowledge and to the treatment eventually administered.
Results and Conclusion
A weak correlation was found between RS and both patient age and tumor size, modest correlation between RS and tumor grade, and modest correlation between RS and 10-year recurrence as determined by Adjuvant! Online. For 21% and 25% of patients, knowledge of the RS changed the clinicians' treatment recommendations and eventual treatment, respectively. The decision to change from hormone therapy to chemotherapy (with or without hormone therapy) was generally associated with high RS (high distant recurrence risk as determined by the commercial reference laboratory test), whereas the decision to change from chemotherapy to hormone therapy was generally associated with low RS (low distant recurrence risk as determined by the commercial reference laboratory test). Knowledge of the RS changed treatment recommendations and eventual treatment in patients with ER-positive/LN-negative early-stage breast cancer. Use of genomic-based prognosis may result in more accurate estimates of true recurrence risk than currently possible with commonly used prognostic factors (such as patient age, tumor size, and tumor grade) alone and thus lead to an increase in appropriate adjuvant therapy decision making.
doi:10.1200/JOP.0742001
PMCID: PMC2793805  PMID: 20859407
5.  Breast Medical Oncologists' Use of Standard Prognostic Factors to Predict a 21-Gene Recurrence Score 
The Oncologist  2011;16(10):1359-1366.
The ability of oncologists to predict the Oncotype DX® recurrence score using standard prognostic criteria is examined.
Background.
Half of all breast cancers are early stage, lymph node negative, and hormone receptor positive. A 21-gene (Oncotype DX®; Genomic Health, Inc., Redwood City, CA) recurrence score (RS) is prognostic for recurrence and predictive of chemotherapy benefit. We explored the ability of oncologists to predict the RS using standard prognostic criteria.
Methods.
Standard demographic and tumor prognostic criteria were obtained from patients with an available RS. Two academic pathologists provided tumor grade, histologic type, and hormone receptor status. Six academic oncologists predicted the RS category (low, intermediate, or high) and provided a recommendation for therapy. The oncologists were then given the actual RS and provided recommendations for therapy. Analysis for agreement was performed.
Results.
Thirty-one cases, including nine additional cases with variant pathology reads, were presented. There was substantial agreement in oncologists' ability to discriminate between true low or true intermediate and true high (κ = 0.75; p < .0001). Predictions between low and intermediate were not consistent. The most common discrepancies were predictions of a low RS risk when cases were true intermediate and predictions of an intermediate RS risk when cases were true low. The actual RS resulted in a change in the treatment recommendations in 19% of cases. Of the 186 scenarios and six oncologists in aggregate, five fewer chemotherapy recommendations resulted with the actual RS.
Conclusions.
Oncologists are able to differentiate between a low or intermediate RS and a high RS using standard prognostic criteria. However, provision of the actual RS changed the treatment recommendations in nearly 20% of cases, suggesting that the RS may reduce chemotherapy use. This effect was observed in particular in intermediate-risk cases. Prospective clinical trials are necessary to determine whether decisions based on the RS change outcomes.
doi:10.1634/theoncologist.2011-0048
PMCID: PMC3228065  PMID: 21934103
Breast cancer; recurrence disease management
6.  The Effect of Oncotype DX Recurrence Score on Treatment Recommendations for Patients with Estrogen Receptor–Positive Early Stage Breast Cancer and Correlation with Estimation of Recurrence Risk by Breast Cancer Specialists 
The Oncologist  2011;16(11):1520-1526.
The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor–positive early stage breast cancer. Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with recurrence scores. Recurrence scores provide useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.
Purpose.
The Oncotype DX assay predicts likelihood of distant recurrence and improves patient selection for adjuvant chemotherapy in estrogen receptor–positive (ER-positive) early stage breast cancer. This study has two primary endpoints: to evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations and to compare the estimated recurrence risk predicted by breast oncology specialists to RS.
Methods.
One hundred fifty-four patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested.
Results.
Ninety-five (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively. RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations. There was no significant difference in recommendations between groups of participants.
Conclusions.
Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. RS provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.
doi:10.1634/theoncologist.2011-0045
PMCID: PMC3233285  PMID: 22016474
Breast cancer; Risk assessment; Adjuvant chemotherapy; Gene expression profiling
7.  Oncologists’ recommendations for adjuvant endocrine therapy in older adults of varying health states 
Clinical breast cancer  2010;10(2):136-143.
Introduction
Currently, evidence supports the use of adjuvant endocrine therapy with aromatase inhibitors in postmenopausal patients with hormone-receptor positive breast cancer. The goal of the current study is to understand the impact of patient age and health status on the decision of the oncologist to recommend adjuvant endocrine therapy (with or without chemotherapy) in older women with hormone-receptor positive breast cancer.
Methods
An on-line survey was conducted, with questions related to treatment of a hypothetical patient of varying age and health status with a T2N2 hormone-receptor positive, HER2-negative breast cancer. Treatment options included chemotherapy and endocrine therapy, endocrine therapy alone, or no therapy. With recommendation of endocrine therapy, respondents were further asked to specify use of either tamoxifen or aromatase inhibitors. A generalized linear mixed-effects model was used to determine the impact of age and health status on treatment recommendations.
Results
As the hypothetical patient’s age increased or health status deteriorated, oncologists were less likely to recommend a combination of chemotherapy and endocrine therapy (P<0.0001 for both). In contrast, oncologists were more likely to recommend endocrine therapy alone with advanced age (P<0.0001) and deteriorating health status (P<0.0001). With respect to the type of endocrine therapy selected, oncologists were more likely to choose treatment with aromatase inhibitors as opposed to tamoxifen (P<0.01), irrespective of age or health status. No therapy was infrequently recommended, constituting 2% of responses on average.
Conclusions
With increasing age and declining health status, oncologists were more likely to recommend treatment with endocrine therapy alone as opposed to the combination of chemotherapy with endocrine therapy. Oncologists were most likely to recommend use of aromatase inhibitors, irrespective of age or health status.
doi:10.3816/CBC.2010.n.018
PMCID: PMC4011553  PMID: 20353934
8.  Breast cancer (non-metastatic) 
Clinical Evidence  2007;2007:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage IIIB)? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/ fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole breast radiotherapy plus breast conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ, radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery, but may not improve survival.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation or trastuzumab (in women who overexpress HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours, but adverse effects begin to outweigh benefit after 5 years of treatment. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4-6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality, but may increase mortality in node-negative women. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear.Adjuvant taxoid regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.Chemotherapy alone, while widely used, does not improve survival in women with locally advanced breast cancer.
PMCID: PMC2943780  PMID: 19450345
9.  The 21-gene recurrence score assay impacts adjuvant therapy recommendations for ER-positive, node-negative and node-positive early breast cancer resulting in a risk-adapted change in chemotherapy use 
Annals of Oncology  2012;24(3):618-624.
Background
We carried out a prospective clinical study to evaluate the impact of the Recurrence Score (RS) on treatment decisions in early breast cancer (EBC).
Patients and methods
A total of 379 eligible women with estrogen receptor positive (ER+), HER2-negative EBC and 0–3 positive lymph nodes were enrolled. Treatment recommendations, patients' decisional conflict, physicians' confidence before and after knowledge of the RS and actual treatment data were recorded.
Results
Of the 366 assessable patients 244 were node negative (N0) and 122 node positive (N+). Treatment recommendations changed in 33% of all patients (N0 30%, N+ 39%). In 38% of all patients (N0 39%, N+ 37%) with an initial recommendation for chemoendocrine therapy, the post-RS recommendation changed to endocrine therapy, in 25% (N0 22%, N+ 39%) with an initial recommendation for endocrine therapy only to combined chemoendocrine therapy, respectively. A patients' decisional conflict score improved by 6% (P = 0.028) and physicians' confidence increased in 45% (P < 0.001) of all cases. Overall, 33% (N0 29%, N+ 38%) of fewer patients actually received chemotherapy as compared with patients recommended chemotherapy pre-test. Using the test was cost-saving versus current clinical practice.
Conclusion
RS-guided chemotherapy decision-making resulted in a substantial modification of adjuvant chemotherapy usage in node-negative and node-positive ER+ EBC.
doi:10.1093/annonc/mds512
PMCID: PMC3574549  PMID: 23136233
adjuvant; breast cancer; chemotherapy; node negative; node positive; recurrence score
10.  Breast cancer (non-metastatic) 
Clinical Evidence  2011;2011:0102.
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage 3B)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole-breast radiotherapy plus breast-conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ (DCIS), radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery. The role of tamoxifen added to radiotherapy for DCIS remains unclear because of conflicting results.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation, or trastuzumab (in women who over-express HER2/neu oncogene). Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results. Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema. Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance. Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours. Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4 to 6 months.Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality. Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear. Adjuvant taxane-based regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control. Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.We don't know if chemotherapy alone improves survival in women with locally advanced breast cancer as we found few trials.
PMCID: PMC3217212  PMID: 21718560
11.  Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer 
Objective
To define the optimal treatment for women with stage III or locally advanced breast cancer (LABC).
Evidence
Systematic review of English-language literature retrieved from MEDLINE (1984 to June 2002) and CANCERLIT (1983 to June 2002). A nonsystematic review of the literature was continued through December 2003.
Recommendations
· The management of LABC requires a combined modality treatment approach involving surgery, radiotherapy and systemic therapy.
Systemic therapy: chemotherapy
Operable tumours
· Patients with operable stage IIIA disease should be offered chemotherapy. They should receive adjuvant chemotherapy following surgery, or primary chemotherapy followed by locoregional management.
· Chemotherapy should contain an anthracycline. Acceptable regimens are 6 cycles of FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
Inoperable tumours
· Patients with stage IIIB or IIIC disease, including those with inflammatory breast cancer and those with isolated ipsilateral internal mammary or supraclavicular lymph-node involvement, should be treated with primary anthracycline-based chemotherapy.
· Acceptable chemotherapy regimens are FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
· Patients with stage IIIB or IIIC disease who respond to primary chemotherapy should be treated until the response plateaus or to a maximum of 6 cycles (minimum 4 cycles). Patients with stage IIIB disease should then undergo definitive surgery and irradiation. The locoregional management of patients with stage IIIC disease who respond to chemotherapy should be individualized. In patients with stage IIIB or IIIC disease who achieve maximum response with fewer than 6 cycles, further adjuvant chemotherapy can be given following surgery and irradiation. Patients whose tumours do not respond to primary chemotherapy can be treated with taxane chemotherapy or can proceed directly to irradiation followed by modified radical mastectomy, if feasible.
Systemic therapy: hormonal therapy
Operable and inoperable tumours
· Tamoxifen for 5 years should be recommended to pre- and postmenopausal women whose tumours are hormone responsive.
Locoregional management
Operable tumours
· Patients with stage IIIA disease should receive both modified radical mastectomy (MRM) and locoregional radiotherapy if feasible. They may be managed with MRM followed by chemotherapy and locoregional radiotherapy, or chemotherapy first followed by MRM and locoregional radiotherapy. Breast-conserving surgery is currently not a standard approach.
· Locoregional radiotherapy should be delivered to the chest wall and to the supraclavicular and axillary nodes. The role of internal mammary irradiation is unclear.
Inoperable tumours
· Patients with stage IIIB disease who respond to chemotherapy should receive surgery plus locoregional radiotherapy.
· The locoregional management of patients with stage IIIC disease who respond to chemotherapy is unclear and should be individualized.
· Patients whose disease remains inoperable following chemotherapy should receive locoregional radiotherapy with subsequent surgery, if feasible.
Validation
The authors' original text was revised by members of the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Subsequently, feedback was provided by 9 oncologists from across Canada. The final document was approved by the steering committee.
Sponsor
The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada.
Completion date
December 2003.
doi:10.1503/cmaj.1030944
PMCID: PMC359433  PMID: 15023926
12.  Review of the Clinical Studies Using the 21-Gene Assay 
The Oncologist  2010;15(5):447-456.
The literature supporting the prognostic and predictive ability of the 21-gene assay in hormone receptor–positive, node-negative and node-positive breast cancer patients in chemotherapy- and endocrine-treated and untreated populations is reviewed.
Purpose.
A major challenge in treating early-stage hormone receptor (HR)+ breast cancer is selecting women who, after initial surgery, do not require chemotherapy. Better prognostic and predictive tests are needed. The 21-gene assay is the only widely commercially available gene signature that can be performed on formalin-fixed paraffin-embedded tissue.
Methods.
We conducted a review of the literature supporting the prognostic and predictive ability of the 21-gene assay in HR+ node-negative and node-positive breast cancer patients in chemotherapy-/endocrine-treated and untreated populations.
We considered: (a) How accurate is the recurrence score (RS) as a prognostic factor for distant recurrence? (b) How accurate is the RS as a predictive factor for benefit from systemic therapy? (c) How does the RS compare with other prognostic/predictive factors such as tumor size, tumor grade, patient age, and integrated decision aids such as Adjuvant! Online? (d) How do patients and physicians view the 21-gene assay? (e) What are the cost implications of the 21-gene assay?
Results.
The 21-gene assay: (a) provided accurate risk information; (b) predicted response to cyclophosphamide, methotrexate, and 5-fluorouracil and to cyclophosphamide, doxorubicin, and 5-fluorouracil chemotherapy; (c) added additional information to traditional biomarkers; (d) was viewed positively by both physicians and patients; and (e) fell within the cost-effectiveness values in North America.
Conclusion.
This assay may be offered to patients with node-negative HR+ breast cancer to assist in adjuvant treatment decisions. Data are accumulating to support the use of the 21-gene assay in HR+ node-positive patients.
doi:10.1634/theoncologist.2009-0277
PMCID: PMC3227976  PMID: 20421266
Recurrence score; Prognostic test; Breast cancer; Adjuvant chemotherapy
13.  Paclitaxel-resistant advanced recurrent breast cancer: a case of partial response due to addition of bevacizumab to paclitaxel therapy: a case report 
BMC Research Notes  2013;6:254.
Background
Paclitaxel plus bevacizumab have shown a high response rate and prolonged progression-free survival in metastatic breast cancer patients. However, overall survival was not prolonged. Thus, no conclusion has been made on the effectiveness of bevacizumab. In our report, taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained.
Case presentation
The patient was a 68-year-old woman with a non-contributory history. In September 2004, she underwent a pectoral muscle-conserving mastectomy with axillary dissection for right-sided breast cancer (pT3N0M0-stage IIB, estrogen receptor positive, progesterone receptor negative, and human epidermal growth factor receptor type 2 negative). Adjuvant therapy consisted of 6 cycles of cyclophosphamide, epirubicin and fluorouracil, and subsequent oral anastrozole. In August 2007, the patient developed a recurrence in the left axillary lymph node. The chemotherapy was changed to high-dose toremifene, and radiation therapy was also performed. The patient achieved a complete response. In April 2009, CT showed left axillary lymph node enlargement once again and multiple lung metastases. Hormone therapy was changed to exemestane and long-term stable disease was achieved. In March 2011, the lung and left axillary lymph node metastases were enlarged and progressive disease was noted. Thus, the tumors were determined to be resistant to hormone therapy, and weekly paclitaxel was begun in May. Since partial response was achieved, this therapy was continued. In December, CT showed that lung and axillary lymph node metastases were enlarged and progressive disease was observed. Therefore, the tumors were determined to be resistant to paclitaxel. In January 2012, bevacizumab and weekly paclitaxel were begun. In April, lung and axillary lymph node metastases were reduced in size, and partial response was achieved. Thereafter the same treatment has been continued, and the patient has been followed up without clinical exacerbation as of January 2013.
Conclusion
Taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained. This result is considered important in increasing treatment options for patients with taxane resistance or patients using adjuvant taxane-based therapy and in examining the effectiveness of bevacizumab in metastatic breast cancer patients.
doi:10.1186/1756-0500-6-254
PMCID: PMC3707777  PMID: 23830415
Breast cancer; Bevacizumab; Paclitaxel
14.  Quantitative Measurement of Melanoma Spread in Sentinel Lymph Nodes and Survival 
PLoS Medicine  2014;11(2):e1001604.
In this study, Klein and colleagues investigated the impact of minimal cancer sentinel lymph node spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival. The authors found that cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death and the best predictor of outcome was a model based on combined quantitative effects of DCCD, tumor thickness, and ulceration.
Please see later in the article for the Editors' Summary
Background
Sentinel lymph node spread is a crucial factor in melanoma outcome. We aimed to define the impact of minimal cancer spread and of increasing numbers of disseminated cancer cells on melanoma-specific survival.
Methods and Findings
We analyzed 1,834 sentinel nodes from 1,027 patients with ultrasound node-negative melanoma who underwent sentinel node biopsy between February 8, 2000, and June 19, 2008, by histopathology including immunohistochemistry and quantitative immunocytology. For immunocytology we recorded the number of disseminated cancer cells (DCCs) per million lymph node cells (DCC density [DCCD]) after disaggregation and immunostaining for the melanocytic marker gp100. None of the control lymph nodes from non-melanoma patients (n = 52) harbored gp100-positive cells. We analyzed gp100-positive cells from melanoma patients by comparative genomic hybridization and found, in 45 of 46 patients tested, gp100-positive cells displaying genomic alterations. At a median follow-up of 49 mo (range 3–123 mo), 138 patients (13.4%) had died from melanoma. Increased DCCD was associated with increased risk for death due to melanoma (univariable analysis; p<0.001; hazard ratio 1.81, 95% CI 1.61–2.01, for a 10-fold increase in DCCD + 1). Even patients with a positive DCCD ≤3 had an increased risk of dying from melanoma compared to patients with DCCD = 0 (p = 0.04; hazard ratio 1.63, 95% CI 1.02–2.58). Upon multivariable testing DCCD was a stronger predictor of death than histopathology. The final model included thickness, DCCD, and ulceration (all p<0.001) as the most relevant prognostic factors, was internally validated by bootstrapping, and provided superior survival prediction compared to the current American Joint Committee on Cancer staging categories.
Conclusions
Cancer cell dissemination to the sentinel node is a quantitative risk factor for melanoma death. A model based on the combined quantitative effects of DCCD, tumor thickness, and ulceration predicted outcome best, particularly at longer follow-up. If these results are validated in an independent study, establishing quantitative immunocytology in histopathological laboratories may be useful clinically.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Because the skin contains many different cell types, there are many types of skin cancer. The most dangerous type—melanoma—develops when mutations occur in melanocytes, the cells that produce the pigment melanin. Less than 5% of skin cancers are melanomas, but melanoma causes most skin cancer deaths. Early signs of melanoma are a change in the appearance of a mole (a pigmented skin blemish) or the development of a new and unusual pigmented lesion. If these signs are noticed and the melanoma is diagnosed before it has spread from the skin into nearby lymph nodes and other tissues, surgery often provides a cure. For advanced melanomas, the outlook is generally poor, although novel therapies may prolong a patient's life.
Why Was This Study Done?
When a person is diagnosed with melanoma, it is important to “stage” the tumor. Knowing the extent and severity of the melanoma helps oncologists plan treatments and estimate their patients' likely outcomes. The detection of isolated melanoma cells in sentinel lymph nodes (the nodes to which cancer cells are most likely to spread from a primary tumor) is included in melanoma staging recommendations. However, finding rare tumor cells in sentinel lymph node biopsies by examining the tissue requires the analysis of many slides from each node removed from the patient and is extremely time-consuming. In this study, the researchers investigate the predictive value of a quantitative immunocytological assay that involves disaggregation of the sentinel node and detection of disseminated cancer cells (DCCs) by immunostaining for gp100 (a marker for melanoma cells). They also use this new assay to examine the effect of increasing numbers of DCCs on melanoma-specific survival.
What Did the Researchers Do and Find?
The researchers used routine histopathology and immunocytology to analyze 1,834 sentinel lymph nodes from 1,027 patients with melanoma who underwent sentinel lymph node biopsy at one German hospital. For immunocytology, the researchers recorded the number of gp100-positive cells per million lymph node cells (the DCC density). During follow-up, 138 patients (13.4%) died from melanoma. The results indicated that increased DCC density was associated with an increased risk of death due to melanoma. Specifically, every 10-fold increase in DCC density + 1 was associated with a near doubling of the risk of death from melanoma (a hazard ratio of 1.81). Even patients with three or fewer gp100-positive cells per million lymph node cells had an increased risk of dying from melanoma compared to patients with no gp100-positive cells (hazard ratio 1.63). When other predictors of outcome such as age and primary tumor location were taken into account, DCC density was a stronger predictor of death than histopathology. Finally, a survival model that included tumor thickness, tumor ulceration, and DCC density provided survival prediction superior to that of a model based on the current standard staging recommendations.
What Do These Findings Mean?
These findings show that quantification of cancer cell dissemination from melanomas to sentinel lymph nodes is feasible and can be combined with other characteristics of the primary tumor to provide an accurate prediction of outcomes for individual patients with melanoma. Notably, the new prediction model identifies a group of patients at high risk of progression for whom the current clinical standard underestimates the risk of death. These patients may benefit from adjuvant therapies, so the new analysis presented in this study may help to stratify patients for clinical trials. Importantly, quantitative immunocytology and the new model, although internally validated in this study, need to be validated in an independent group of patients before they can be considered for routine clinical use. If external validation is successful, quantitative immunocytology, which is much less labor-intensive than histopathology, has the potential to change the routine clinical care of patients with melanoma and probably with other solid tumors, conclude the researchers.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001604.
The US National Cancer Institute provides information for patients and professionals on melanoma, cancer staging, and sentinel lymph node biopsy (in English and Spanish)
The nonprofit organization American Cancer Society provides information in several languages on cancer and how it develops and specific information on melanoma, including the AJCC system for staging and personal stories
The UK National Health Service Choices website includes an introduction to cancer and a page on melanoma that includes personal stories
The nonprofit organization Cancer Research UK provides basic information about cancer and detailed information on melanoma
doi:10.1371/journal.pmed.1001604
PMCID: PMC3928050  PMID: 24558354
15.  Surgical management of early stage invasive breast cancer: a practice guideline 
Canadian Journal of Surgery  2005;48(3):185-194.
Objectives
To assess the available evidence on sentinel lymph-node biopsy, and to examine the long-term follow-up data from large randomized phase III trials comparing breast-conserving therapy with mastectomy in order to make recommendations on the surgical management of early invasive breast cancer (stages I and II), including the optimum management of the axillary nodes: for the breast — modified radical mastectomy or breast-conserving therapy; for the axilla — complete axillary node dissection, axillary dissection of levels I and II lymph nodes, sentinel lymph-node biopsy or no axillary node surgery.
Outcomes
Overall survival, disease-free survival, local recurrence, distant recurrence and quality of life.
Evidence
MEDLINE, EMBASE, the Cochrane Library databases and relevant conference proceedings were searched to identify randomized trials and meta-analyses. Two members of the Practice Guidelines Initiative, Breast Cancer Disease Site Group (BCDSG) selected and reviewed studies that met the inclusion criteria. The systematic literature review was combined with a consensus process for interpretation of the evidence to develop evidence-based recommendations. This practice guideline has been reviewed and approved by the BCDSG, comprising surgeons, medical oncologists, radiation oncologists, pathologists, a medical sociologist, a nurse representative and a community representative.
Benefits, harms and costs
Breast-conserving therapy (lumpectomy with levels I and II axillary node dissection, plus radiotherapy) provides comparable overall and disease-free survival to modified radical mastectomy. Levels I and II axillary dissection accurately stages the axilla and minimizes the morbidity of axillary recurrence but is associated with lymphedema in approximately 20% of patients and arm pain in approximately 33%. Currently, there is insufficient data regarding locoregional recurrence and long-term morbidity associated with sentinel-node biopsy to advocate it as the standard of care. Breast-conserving therapy may offer an advantage over mastectomy in terms of body image, psychological and social adjustment but appears equivalent with regard to marital adjustment, global adjustment and fear of recurrence.
Recommendations
Women who are eligible for breast-conserving surgery should be offered the choice of either breast-conserving therapy with axillary dissection or modified radical mastectomy. Removal and pathological examination of levels I and II axillary lymph nodes should be the standard practice in most cases of stages I and II breast carcinoma. There is promising but limited evidence to support recommendations regarding sentinel lymph-node biopsy alone. Patients should be encouraged to participate in clinical trials investigating this procedure.
Validation
A draft version of this practice guideline and a 21-item feedback questionnaire was circulated to 201 practitioners in Ontario. Of the 131 practitioners who returned the questionnaire, 98 (75%) completed the survey and indicated that the report was relevant to their clinical practice. Eighty (82%) of these practitioners agreed that the draft document should be approved as a practice guideline.
Sponsors
The Practice Guidelines Initiative is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.
Completion date
Jan. 21, 2003.
PMCID: PMC3211547  PMID: 16013621
16.  Societal cost-effectiveness analysis of the 21-gene assay in estrogen-receptor–positive, lymph-node–negative early-stage breast cancer in Japan 
Background
Breast-cancer incidence and mortality have been increasing in Japan. Japanese-specific clinical validity and utility data for the 21-gene assay (Oncotype DX® Breast Cancer Assay; Genomic Health, Inc., Redwood City, USA) are now available. The objective of this study was to evaluate the cost-effectiveness of the 21-gene assay for the guidance of adjuvant chemotherapy decisions in estrogen-receptor–positive, lymph-node–negative, early-stage breast cancer patients, from the Japanese societal perspective.
Methods
The recurrence risk group distribution by the 21-gene assay result and the assay’s influence on adjuvant chemotherapy recommendations were obtained from a study of 104 patients. A state-transition cohort (Markov) model tracked time from surgery until distant recurrence and from distant recurrence to death. Adjuvant chemotherapy benefit by 21-gene assay risk group was based on published clinical validation studies. Direct and indirect medical costs were obtained from the referral centers. Utilities associated with progression and chemotherapy-related adverse events were extracted from literature. Sensitivity analyses assessed the key drivers and robustness of the primary outcomes.
Results
The 21-gene assay identified 48% of patients as low-risk, 36% as intermediate-risk, and 16% as high-risk. Total acute chemotherapy-related costs decreased by ¥154,066 due to less adjuvant chemotherapy usage. In the high-risk group, adjuvant chemotherapy use increased 18%, leading to survival benefits. Chemotherapy use overall decreased by 19%. Monitoring costs increased by ¥3,744 but recurrence costs declined by ¥46,113 per patient. Use of the 21-gene assay increased quality-adjusted–life-years (QALYs) by 0.241 per patient on average; the net cost per QALY gained was ¥636,752 ($6,368).
Conclusions
The 21-gene assay for women with estrogen-receptor–positive, lymph-node–negative, early-stage breast cancer is projected to be cost-effective in Japan.
doi:10.1186/1472-6963-14-372
PMCID: PMC4165904  PMID: 25190451
Breast cancer; Cost-effectiveness; Cost-benefit; Molecular diagnostic testing; Genetic testing
17.  A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients 
Breast Cancer Research  2006;8(3):R25.
Introduction
The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting.
Methods
A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score.
Results
After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values.
Conclusion
In this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients.
doi:10.1186/bcr1412
PMCID: PMC1557737  PMID: 16737553
18.  How Does Older Age Influence Oncologists' Cancer Management? 
The Oncologist  2010;15(6):584-592.
The study used a vignette-type survey to assess preferences and influential factors in geriatric cancer management of U.S. practicing oncologists. Advanced patient age was found to deter oncologists from choosing intensive cancer therapy, even if the patient was highly functional and lacked comorbidities.
Background.
Over half of new cancer cases occur in patients aged ≥65 years. Many older patients can benefit from intensive cancer therapies, yet evidence suggests that this population is undertreated.
Methods.
To assess preferences and influential factors in geriatric cancer management, practicing U.S. medical oncologists completed a survey containing four detailed vignettes exploring colon, breast, lung, and prostate cancer treatment. Participants were randomly assigned one of two surveys with vignettes that were identical except for patient age (<65 years or >70 years).
Results.
Physicians in each survey group (n = 200) were demographically similar. Intensive therapy was significantly less likely to be recommended for an older than for a younger, but otherwise identical, patient in two of the scenarios. For a woman with metastatic colon cancer (Eastern Cooperative Oncology Group [ECOG] score, 1) for whom chemotherapy was recommended, nearly all oncologists chose an intensive regimen if the patient's age was 63; but if her age was 85, one fourth of the oncologists chose a less intensive treatment. Likewise, for stage IIA breast cancer (ECOG score, 0), 93% recommended intensive adjuvant treatment for a previously healthy patient aged 63; but only 66% said they would do so if the patient's age was 75. Oncologists commonly identified patient age as an influence on treatment choice, but were even more likely to cite performance status as a determining factor.
Conclusions.
Advanced age can deter oncologists from choosing intensive cancer therapy, even if patients are highly functional and lack comorbidities. Education on tailoring cancer treatment and a greater use of comprehensive geriatric assessment may reduce cancer undertreatment in the geriatric population.
doi:10.1634/theoncologist.2009-0198
PMCID: PMC3227998  PMID: 20495217
Age factors; Antineoplastic agents/therapeutic use; Geriatric assessment; Health care disparities; Quality of health care
19.  Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM 9906 trial 
Introduction
EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2− BC patients in the GEICAM 9906 trial.
Methods
The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor–positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression.
Results
The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2− cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant.
Conclusions
EP is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone.
doi:10.1186/bcr3642
PMCID: PMC4076639  PMID: 24725534
20.  Breast Cancer and Autism 
Case Study
Amy is a 44-year-old woman with severe autism. She lives with her sister Susan, who is her caregiver and guardian. Amy is ambulatory and able to dress and feed herself. She is a healthy individual with no other significant comorbidities. She walks daily and enjoys her sister’s company. Amy’s life expectancy is greater than 10 years. However, she is difficult to care for medically, as she will not allow a physical examination and strikes out when strangers try to touch her. She is nonverbal and unable to participate in decision-making.
INITIAL DIAGNOSIS
Amy has a history of breast cancer diagnosed 2 years ago, originally presenting as a stage I lesion (T2N0) that was palpated by her caregiver while bathing. She underwent right simple mastectomy with sentinel lymph node resection. Susan recalls that the mastectomy was a very challenging ordeal, as Amy kept pulling out IV lines, drains, and dressings. Susan felt that Amy withdrew from her after the procedure as she most likely associated Susan with the cause of the pain, making her role as caregiver more difficult.
Pathology confirmed an invasive ductal carcinoma, moderately differentiated, 2.4 cm, estrogen/progesterone receptor negative, HER2/neu negative, with negative surgical margins. Two right axillary sentinel lymph nodes were negative for disease. The standard of care for a patient with these tumor features is surgery plus adjuvant chemotherapy (National Comprehensive Cancer Network [NCCN], 2012). According to the Adjuvant Online! database (2012), Amy’s risk for relapse was approximately 40% without adjuvant treatment; her risk for mortality was approximately 29%. After meeting with a medical oncologist, Amy did not receive adjuvant chemotherapy. According to Susan, she was not offered the choice, and the decision was not explained to them. She was simply told that it was not necessary. Aside from pathology, previous records were unavailable for review.
Medical assessment of Amy’s level of autism reveals marked impairments in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body posture, and gestures to regulate social interaction. She exhibits a total lack of development of spoken language, with no attempt to compensate through alternative modes of communication such as gesture. During the visit, she occupies herself with repetitive motor mannerisms. Susan believes that Amy struggles with overstimulation from tactile input. Therefore, she is combative with health-care providers and intolerant of invasive devices. Susan has an intimate understanding of Amy’s ability to communicate her needs and wants through nonverbal changes.
RECURRENCE
Approximately 2 months ago, Amy began favoring her right arm and appeared to be in pain when participating in various activities. Susan became aware of Amy’s pain issues by noticing that her posture was slightly altered and she was carrying herself differently. Further investigation with a CT scan showed concern for local disease recurrence involving the axillary lymph nodes. No distant metastases were seen. The standard of care for this diagnosis is surgical resection and consideration of radiation therapy, followed by adjuvant chemotherapy (NCCN, 2012). Susan does not want Amy to undergo further surgery and believes radiation would be too difficult to maneuver. The next best option would be a medical approach with chemotherapy as the main modality.
DIFFICULT DECISIONS
If treatment is pursued, the advanced practitioner will need to perform regular examinations and prescribe and monitor chemotherapy. The delivery of therapy, requiring frequent blood draws and IV access, will be a challenge for the health-care staff. The APN is apprehensive about the ability to accomplish these tasks safely given Amy’s limited capacity to participate. The APN is also concerned with how treatment will affect Amy’s life. The APN may have her own individual conflict of morals to contend with, given the limited understanding of the patient vs. nontreatment of a potentially curative malignancy.
Chemotherapy is not an easy task for any patient to undertake, especially for a patient with challenges such as Amy has. Although Susan can give legal consent for her sister, Amy is unable to participate in this decision-making. Susan strongly believes that Amy’s quality of life is much more important than the quantity. Withholding treatment may shorten the natural course of Amy’s life, yet administering chemotherapy will alter the quality of life that she now enjoys without her understanding or consent. Should Amy receive chemotherapy or should Susan refuse treatment on her behalf?
PMCID: PMC4093416  PMID: 25031990
21.  Prognostic Utility of the 21-Gene Assay in Hormone Receptor–Positive Operable Breast Cancer Compared With Classical Clinicopathologic Features 
Journal of Clinical Oncology  2008;26(25):4063-4071.
Purpose
Adjuvant! is a standardized validated decision aid that projects outcomes in operable breast cancer based on classical clinicopathologic features and therapy. Genomic classifiers offer the potential to more accurately identify individuals who benefit from chemotherapy than clinicopathologic features.
Patients and Methods
A sample of 465 patients with hormone receptor (HR) –positive breast cancer with zero to three positive axillary nodes who did (n = 99) or did not have recurrence after chemohormonal therapy had tumor tissue evaluated using a 21-gene assay. Histologic grade and HR expression were evaluated locally and in a central laboratory.
Results
Recurrence Score (RS) was a highly significant predictor of recurrence, including node-negative and node-positive disease (P < .001 for both) and when adjusted for other clinical variables. RS also predicted recurrence more accurately than clinical variables when integrated by an algorithm modeled after Adjuvant! that was adjusted to 5-year outcomes. The 5-year recurrence rate was only 5% or less for the estimated 46% of patients who have a low RS (< 18).
Conclusion
The 21-gene assay was a more accurate predictor of relapse than standard clinical features for individual patients with HR-positive operable breast cancer treated with chemohormonal therapy and provides information that is complementary to features typically used in anatomic staging, such as tumor size and lymph node involvement. The 21-gene assay may be used to select low-risk patients for abbreviated chemotherapy regimens similar to those used in our study or high-risk patients for more aggressive regimens or clinical trials evaluating novel treatments.
doi:10.1200/JCO.2007.14.4501
PMCID: PMC2654377  PMID: 18678838
22.  US Insurance Program's Experience With a Multigene Assay for Early-Stage Breast Cancer 
Journal of Oncology Practice  2011;7(3 Suppl):e38s-e45s.
This study presents Humana's experience with a multigene breast cancer assay and provides an analysis of the clinical utility and economics of this technology.
Purpose:
National guidelines recommend a 21-gene recurrence score (RS) to aid in adjuvant treatment decision in patients with estrogen receptor (ER) –positive, lymph node (LN) –negative early-stage breast cancer (ESBC). This study was performed to assess the economic implication of the assay in community practices from the perspective of a US payer.
Methods:
The study analyzed 952 women with ESBC enrolled with Humana (Louisville, KY) who were tested with the 21-gene RS between June 2006 and June 2010. The proportion of women classified by the assay according to RS risk category, use, and costs of chemotherapy regimens and supportive care, and costs of adverse events were obtained from Humana. We adopted a validated Markov model to compute the cost implications of RS for a representative patient. The probability of risk of recurrence, the chemotherapy benefit, and the decision impact of RS were derived from published studies.
Results:
Two hundred fifty-five patients within the tested population received adjuvant chemotherapy. Adjuvant chemotherapy was administered to 10% of women at low risk, 36% of women at intermediate risk, and 72% of women at high risk of recurrence. On the basis of a meta-analysis in the reduction of chemotherapy after RS, the model estimated an average test saving of $1,160 per patient. The immediate direct savings for chemotherapy drugs, supportive care, and management of adverse events were $1,885, $2,578, and $472, respectively. Prevention of recurrence through appropriate treatment of patients at high risk resulted in additional savings of $199.
Conclusion:
The adoption of the 21-gene RS led to targeted management of women with ER-positive, LN-negative ESBC and consequently directed savings to the payer.
doi:10.1200/JOP.2011.000303
PMCID: PMC3092466  PMID: 21886510
23.  Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy 
Objective
To provide information and recommendations to assist women with breast cancer and their physicians in making decisions regarding the use of locoregional post-mastectomy radiotherapy (PMRT).
Outcomes
Locoregional control, disease-free survival, overall survival and treatment-related toxicities.
Evidence
This guideline is based on a review of all meta-analyses, consensus statements and other guidelines published between 1966 and November 2002. Searches of MEDLINE and CANCERLIT for English-language randomized controlled trials published between 1995 and November 2002 were also conducted to supplement the literature previously reviewed by the American Society of Clinical Oncology (ASCO) Health Services Research Committee panel in its published guideline. A nonsystematic review of the literature was continued through June 2003.
RecommendationsLocoregional PMRT is recommended for women with an advanced primary tumour (tumour size 5 cm or greater, or tumour invasion of the skin, pectoral muscle or chest wall).Locoregional PMRT is recommended for women with 4 or more positive axillary lymph nodes.The role of PMRT in women with 1 to 3 positive axillary lymph nodes is unclear. These women should be offered the opportunity to participate in clinical trials of PMRT.Locoregional PMRT is generally not recommended for women who have tumours that are less than 5 cm in diameter and who have negative axillary nodes.Other patient, tumour and treatment characteristics, including age, histologic grade, lymphovascular invasion, hormone receptor status, number of axillary nodes removed, axillary extracapsular extension and surgical margin status, may affect locoregional control, but their use in specifying additional indications for PMRT is currently unclear.PMRT should encompass the chest wall and the supraclavicular, infraclavicular and axillary apical lymph node areas.To reduce the risk of lymphedema, radiation of the entire axilla should not be used routinely after complete axillary dissection of level I and II lymph nodes.A definite recommendation regarding the inclusion of the internal mammary lymph nodes in PMRT cannot be made because of limited and inconsistent data.The use of modern techniques in radiotherapy planning is recommended to minimize excessive normal tissue exposure, particularly to the cardiac and pulmonary structures.Common short-term side effects of PMRT, including fatigue and skin erythema, are generally tolerable and not dose-limiting. Severe long-term side effects, including lymphedema, cardiac and pulmonary toxicities, brachial plexopathy, rib fractures and secondary neoplasms, are relatively rare.The optimal sequencing of PMRT and systemic therapy is currently unclear. Regimens containing anthracyclines or taxanes should not be administered concurrently with radiotherapy because of the potential for increased toxicity.
Validation
The authors' original text was submitted for review, revision and approval by the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Subsequently, feedback was provided by 11 oncologists from across Canada. The final document was approved by the steering committee.
Sponsor
The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada.
Completion date
November 2003.
doi:10.1503/cmaj.1031000
PMCID: PMC385392  PMID: 15078851
24.  Cost-Effectiveness of the 21-Gene Recurrence Score Assay in the Context of Multifactorial Decision Making to Guide Chemotherapy for Early-Stage Breast Cancer 
Purpose
New evidence is available regarding the utility of the 21-gene Recurrence Score (RS) assay in guiding chemotherapy use for node-negative, estrogen receptor–positive breast cancer. We applied this evidence in a decision-analytic model to reevaluate the cost-effectiveness of the assay.
Methods
We cross-classified patients by clinicopathologic characteristics from the Adjuvant! risk index and by RS risk group. For non–RS-guided treatment, we assumed patients receiving hormonal therapy alone had low-risk characteristics and patients receiving chemotherapy and hormonal therapy had higher-risk characteristics. For RS-guided treatment, we assigned chemotherapy probabilities conditional on RS risk group and clinicopathologic characteristics.
Results
An estimated 40.4% of patients in the RS-guided strategy and 47.3% in the non–RS-guided strategy were expected to receive chemotherapy. The incremental gain in quality-adjusted life-years (QALYs) was 0.16 (95% CI, 0.08 to 0.28) with the RS-guided strategy. Lifetime medical costs to the health system were $2692 ($1546 to $3821) higher with the RS-guided strategy, for an incremental cost-effectiveness ratio of $16,677/QALY ($7613 to $37,219). From a societal perspective, the incremental cost-effectiveness was $10,788/QALY ($6840 to $30,265).
Conclusion
The findings provide supportive evidence for the economic value of the 21-gene RS assay in node-negative, estrogen receptor–positive breast cancer.
doi:10.1038/gim.2012.119
PMCID: PMC3743447  PMID: 22975761
Breast Neoplasms; Chemotherapy; Adjuvant; Cost-Benefit Analysis; Gene Expression; Health Care Costs; Prognosis
25.  Neoadjuvant or adjuvant therapy for resectable gastric cancer? A practice guideline 
Canadian Journal of Surgery  2002;45(6):438-446.
Objective
To make recommendations on the use of neoadjuvant or adjuvant therapy in addition to surgery in patients with resectable gastric cancer (T1–4, N1–2, M0).
Options
Neoadjuvant or adjuvant treatments compared with “curative” surgery alone.
Outcomes
Overall survival, disease-free survival, and adverse effects.
Evidence
The MEDLINE, CANCERLIT and Cochrane Library databases and relevant conference proceedings were searched to identify randomized trials.
Values
Evidence was selected and reviewed by one member of the Cancer Care Ontario Practice Guidelines Initiative (CCOPGI) Gastrointestinal Cancer Disease Site Group and methodologists. A systematic review of the published literature was combined with a consensus process around the interpretation of the evidence in the context of conventional practice, to develop an evidence-based practice guideline. This report has been reviewed and approved by the Gastrointestinal Cancer Disease Site Group, comprising medical oncologists, radiation oncologists, surgeons, a pathologist and 2 community representatives.
Benefits, harms and costs
When compared with surgery alone, at 3 years adjuvant chemoradiotherapy has been shown to increase overall survival by 9% (50% v. 41%, p = 0.005) and to improve relapse-free survival from 31% to 48% (p = 0.001). At 5 years, it has been shown to increase overall survival by 11.6% (40% v. 28.4%) and to improve relapse-free survival from 25% to 38% (p < 0.001). Treatment has been associated with toxic deaths in 1% of patients. The most frequent adverse effects (> grade 3 [Southwest Oncology Group toxicity scale] are hematologic (54%), gastrointestinal (33%), influenza-like (9%), infectious (6%) and neurologic (4%). The radiation fields used can possibly damage the left kidney, resulting in hypertension and other renal problems. Furthermore, this therapy could increase the demand on radiation resources. Physicians and patients should understand the tradeoffs between survival benefit and toxicity and cost before making treatment decisions.
Recommendations
After surgical resection, patients whose tumours have penetrated the muscularis propria or involve regional lymph nodes should be considered for adjuvant combined chemoradiotherapy. The current standard protocol consists of 1 cycle of 5-fluorouracil (5-FU) (425 mg/m2 daily) and leucovorin (20 mg/m2 daily) administered daily for 5 days, followed 1 month later by 45 Gy (1.8 Gy/d) of radiation given with 5-FU (400 mg/m2 daily) and leucovorin (20 mg/m2 daily) on days 1 through 4 and the last 3 days of radiation. One month after completion of radiation, 2 cycles of 5-FU (425 mg/m2 daily) and leucovorin (20 mg/m2 daily) in a daily regimen for 5 days are given at monthly intervals. There is no evidence on which to make a recommendation for patients with node-negative tumours that have not penetrated the muscularis propria. For patients unable to undergo radiation, adjuvant chemotherapy alone may be of benefit, particularly for those with lymph-node metastases. The optimal regimen remains to be defined. There is insufficient evidence from randomized trials to recommend neoadjuvant chemotherapy, or neoadjuvant or adjuvant radiotherapy or immunotherapy, either alone or in combination, outside a clinical trial.
Validation
A draft version of this document was circulated to 166 clinicians using a 21-item feedback questionnaire. Ninety-nine (63%) returned the questionnaire, and 74 of these indicated that the guideline was relevant to their clinical practice and completed the survey. Of the 74 clinicians, 52 (70%) agreed that the document should be approved as a practice guideline.
Sponsors
The CCOPGI is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.
PMCID: PMC3684659  PMID: 12500920

Results 1-25 (1267244)