American Society of Clinical Oncology/College ofAmerican Pathologists guideline recommendations forimmunohistochemical testing of estrogen andprogesterone receptors in breast cancer

Purpose: To develop a guideline to improve theaccuracy of immunohistochemical (IHC) estrogen receptor(ER) and progesterone receptor (PgR) testing in breastcancer and the utility of these receptors as predictivemarkers.Methods: The American Society of Clinical Oncologyand the College of American Pathologists convened aninternational Expert Panel that conducted a systematicreview and evaluation of the literature in partnership withCancer Care Ontario and developed recommendations foroptimal IHC ER/PgR testing performance.Results: Up to 20% of current IHC determinations ofER and PgR testing worldwide may be inaccurate (falsenegative or false positive). Most of the issues with testinghave occurred because of variation in preanalyticvariables, thresholds for positivity, and interpretationcriteria.Recommendations: The Panel recommends that ER andPgR status be determined on all invasive breast cancers andbreast cancer recurrences. A testing algorithm that relieson accurate, reproducible assay performance is proposed.Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be consideredpositive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.(Arch Pathol Lab Med. 2010;134:907–922

Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration

The REMARK “elaboration and explanation” guideline, by Doug Altman and colleagues, provides a detailed reference for authors on important issues to consider when designing, conducting, and analyzing tumor marker prognostic studies

Prognostic and Predictive Markers in Cancer

The elucidation of the human genome and advances in knowledge about molecular abnormalities, signaling pathways, influence of the local tissue milieu and the relevance of genetic polymorphisms offer hope of designing more effective, individualized cancer treatment plans. Although the scientific and medical literature is replete with reports of putative prognostic or predictive markers for cancer, few new diagnostics have been incorporated into routine clinical practice. Criteria are needed to a) identify markers that have the promise to be clinically useful; b) assess the best methodology for clinical evaluation of the markers in question and c) confirm or validate that using the marker adds useful information compared to using standard prognostic factors alone. This review presents a methodology for the clinical evaluation of putative prognostic and predictive markers in cancer, with considerations of pitfalls in the early evaluation, rationale for development and optimization of assay methodology, and examples of possible clinical trials for assessing the clinical utility of putative markers

A Perspective On Challenges And Issues In Biomarker Development And Drug And Biomarker Codevelopment

A workshop sponsored by the National Cancer Institute and the US Food and Drug Administration addressed past lessons learned and ongoing challenges faced in biomarker development and drug and biomarker codevelopment. Participants agreed that critical decision points in the product life cycle depend on the level of understanding of the biology of the target and its interaction with the drug, the preanalytical and analytical factors affecting biomarker assay performance, and the clinical disease process. The more known about the biology and the greater the strength of association between an analytical signal and clinical result, the more efficient and less risky the development process will be. Rapid entry into clinical practice will only be achieved by using a rigorous scientific approach, including careful specimen collection and standardized and quality-controlled data collection. Early interaction with appropriate regulatory bodies will ensure studies are appropriately designed and biomarker test performance is well characterized

Kaplan-Meier plot for disease-free survival comparing patients with HU177 concentrations above and below the median value.

<p> <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001216#pmed.1001216-Hamilton1" target="_blank">[178]</a></p

Multivariable Cox regression analysis of relapse-free survival in patients with primary breast cancer showing the impact of adding the marker (PMN-E) to a base model of recognized prognostic variables [59].

a<p>Age in decades for pre- and postmenopausal patients;</p>b<p>Positive, ≥10 fmol/mg protein; negative <10 ng/mg protein;</p>c<p>High, >36.4 ng/mg protein; low, ≤36.4 ng/mg protein;</p>d<p>Log-transformed variable.</p><p>CI: confidence interval; ER: estrogen receptor; PgR: progesterone receptor.</p

Example of the REMARK profile illustrated using data from a study of ploidy in patients with advanced ovarian cancer [157] (from [20]).

a<p>Not considered for survival outcome as these factors are not considered as ‘standard’ factors and/or number of missing values was relatively large;</p>b<p>values not given in the paper.</p

Relation between marker (serum chromogranin A) and patient characteristics [181] (note that missing data were not indicated).

<p>CgA: chromogranin A; ECOG PS: Eastern Cooperative Oncology Group performance status; NSCLC: non-small cell lung cancer; Q1 to Q3: interquartile range.</p