CONTEXT: Gene expression-based prognostic assays for breast cancer are now available as commercial reference laboratory tests covered by insurance. OBJECTIVE: To provide practicing pathologists with information about the nature of these assays, differences among them, and their use by clinical oncologists in the management of patients diagnosed with breast cancer. DATA SOURCES: Review of literature and unpublished data from the National Surgical Adjuvant Breast and Bowel Project. This review focused on a general conceptual description of the technology behind these assays and differences among them to aid understanding by pathologists in practice. CONCLUSIONS: While these assays are clinically useful, they are still evolving. The future development of gene expression-based markers will need to be more clinical-context-specific to be clinically useful.
Gene Expression–Based Prognostic and Predictive Markers for Breast Cancer A Primer for Practicing Pathologists Chungyeul Kim, MD; Yusuke Taniyama, MD; Soonmyung Paik, MD ● Context.—Gene expression–based prognostic assays for Project. This review focused on a general conceptual de- breast cancer are now available as commercial reference scription of the technology behind these assays and differ- laboratory tests covered by insurance. ences among them to aid understanding by pathologists in Objective.—To provide practicing pathologists with in- practice. formation about the nature of these assays, differences Conclusions.—While these assays are clinically useful, among them, and their use by clinical oncologists in the they are still evolving. The future development of gene ex- management of patients diagnosed with breast cancer. pression–based markers will need to be more clinical-con- Data Sources.—Review of literature and unpublished text–speciﬁc to be clinically useful. data from the National Surgical Adjuvant Breast and Bowel (Arch Pathol Lab Med. 2009;133:855–859) CLINICAL BACKGROUND ment can consist of surgery alone, surgery plus antihor- The identiﬁcation of molecular markers with prognostic monal therapy, or surgery plus chemohormonal therapy, signiﬁcance may help cancer patients avoid treatment that depending on the stage and hormone receptor status of is unlikely to be successful. In breast cancer, for example, the tumor. This varying clinical context dictates that most clinical studies have shown that adding adjuvant chemo- clinically useful prognostic and predictive markers are therapy to tamoxifen in the treatment of node-negative, those developed with a speciﬁc clinical context in mind hormone receptor (HR)–positive breast cancer improves and tested and validated within that clinical context. Clin- disease outcome.1 However, treatment with tamoxifen ical tests can provide either prognostic or predictive in- alone is associated with a 15% likelihood of distant recur- formation or both. rence at 10 years in this population, suggesting that 85% In the past there was no distinction made between of these patients would do well without the addition of ‘‘prognostic’’ and ‘‘predictive’’ markers when investigators cytotoxic chemotherapy and could avoid the adverse conducted studies and such practice was a source of great events inherent to such treatment.1 Nevertheless, the cur- confusion in the ﬁeld. More recently, a distinction between rent National Comprehensive Cancer Network (NCCN)2 the two has become the norm rather than the exception. and St. Gallen3 clinical practice guidelines, using classical However, it also has become clear that for most chemo- histopathology and immunohistochemical prognostic therapy regimens in use today, general prognosticators markers, categorize less than 10% of patients with node- end up as predictive markers of the degree of beneﬁt from negative, HR-positive disease at low enough risk of recur- chemotherapy. For example, estrogen receptor status is not rence to forgo adjuvant chemotherapy. These treatment only prognostic and predictive of response to antihor- guidelines assume that patients will derive the same de- mone therapy, but also predictive of response to chemo- gree of beneﬁt from chemotherapy regardless of their therapy (the presence of the estrogen receptor is associ- baseline risk. ated with less beneﬁt from chemotherapy). Another ex- Clinical oncologists need 2 basic pieces of information ample is uPA/PAI-1 (urokinase-type plasminogen activa- to make treatment decisions for individual patients: (1) a tor/plasminogen activator inhibitor type 1). Harbeck and patient’s baseline risk after legacy treatment and (2) the colleagues4 analyzed samples from more than 8000 wom- expected degree of additional beneﬁt she will receive from en with node-negative breast cancer. Intratumoral concen- systemic therapy added to legacy treatment. Legacy treat- tration of uPA and its inhibitor, PAI-1, were found to cor- relate directly with risk of disease recurrence. Despite the fact that these markers have no suspected direct role in Accepted for publication November 10, 2008. chemotherapy response, patients categorized as high-risk, From the Division of Pathology, National Surgical Adjuvant Breast based on uPA/PAI-1 levels, derived signiﬁcant beneﬁt and Bowel Project Foundation, Pittsburgh, Pennsylvania. from chemotherapy, whereas low-risk patients gained lit- The authors have no relevant ﬁnancial interest in the products or
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