Predicting response to primary chemotherapy: gene expression profiling of paraffin-embedded core biopsy tissue.
ABSTRACT Primary chemotherapy provides an ideal opportunity to correlate gene expression with response to treatment. We used paraffin-embedded core biopsies from a completed phase II trial to identify genes that correlate with response to primary chemotherapy.
Patients with newly diagnosed stage II or III breast cancer were treated with sequential doxorubicin 75 mg/M2 q2 wks x 3 and docetaxel 40 mg/M2 weekly x 6; treatment order was randomly assigned. Pretreatment core biopsy samples were interrogated for genes that might correlate with pathologic complete response (pCR). In addition to the individual genes, the correlation of the Oncotype DX Recurrence Score with pCR was examined.
Of 70 patients enrolled in the parent trial, core biopsies samples with sufficient RNA for gene analyses were available from 45 patients; 9 (20%) had inflammatory breast cancer (IBC). Six (14%) patients achieved a pCR. Twenty-two of the 274 candidate genes assessed correlated with pCR (p < 0.05). Genes correlating with pCR could be grouped into three large clusters: angiogenesis-related genes, proliferation related genes, and invasion-related genes. Expression of estrogen receptor (ER)-related genes and Recurrence Score did not correlate with pCR. In an exploratory analysis we compared gene expression in IBC to non-inflammatory breast cancer; twenty-four (9%) of the genes were differentially expressed (p < 0.05), 5 were upregulated and 19 were downregulated in IBC.
Gene expression analysis on core biopsy samples is feasible and identifies candidate genes that correlate with pCR to primary chemotherapy. Gene expression in IBC differs significantly from noninflammatory breast cancer.
SourceAvailable from: Linda Rozmovits[Show abstract] [Hide abstract]
ABSTRACT: Determining the likely benefit of adjuvant chemotherapy for early-stage breast cancer patients depends on estimating baseline recurrence risk. Gene expression profile (gep) testing of tumours informs risk prediction, but evidence of its clinical utility is limited. We explored patient perceptions of gep testing and the impact of those perceptions on chemotherapy decisions. We conducted one focus group (n = 4) and individual interviews (n = 24) with patients who used gep testing, recruited through clinics at two hospitals in Ontario. Data were analyzed using content analysis and constant comparison techniques. Patients' understanding of gep testing was variable, and misapprehensions were common. Patients valued the test because it provided them with certainty amidst confusion, with options and a sense of empowerment, and with personalized, authoritative information. They commonly believed that the test was better and fundamentally different from other clinical tests, attributing to it unique power and truth-value. This kind of "magical thinking" was derived from an amplified perception of the test's validity and patients' need for reassurance about their treatment choices. Despite misperceptions or magical thinking, gep was widely considered to be the deciding factor in treatment decisions. Patients tend to overestimate the truth-value of gep testing based on misperceptions of its validity. Our results identify a need to better support patient understanding of the test and its limitations. Findings illustrate the deep emotional investment patients make in gep test results and the impact of that investment on their treatment decisions.Current Oncology 04/2014; 21(2):e203-11. DOI:10.3747/co.21.1524 · 1.64 Impact Factor
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ABSTRACT: Genomic information is increasingly being used to personalize health care. One example is gene expression profiling (GEP) tests, which estimate recurrence risk to inform chemotherapy decisions in breast cancer. Recently, GEP tests were publicly funded in Ontario. We explored the perceived utility of GEP tests, focusing on the factors influencing their use and value in treatment decision-making by patients and oncologists. Methods We conducted interviews with oncologists (n = 14) and interviews and a focus group with early-stage breast cancer patients (n = 28) who underwent GEP testing. Both groups were recruited through oncology clinics in Ontario. Data were analyzed using the content analysis and constant comparison techniques. Results Narratives from patients and oncologists provided insights into various factors facilitating and restricting access to GEP. First, oncologists are positioned as gatekeepers of GEP, providing access in medically appropriate cases. However, varying perceptions of appropriateness led to perceived inequities in access and negative impacts on the doctor-patient relationship. Second, media attention facilitated patient awareness of GEP, but also complicated gatekeeping. Third, the dedicated administration attached to GEP was burdensome and led to long waits for results and also to increased patient anxiety and delayed treatment. Collectively, because of barriers to access, those factors inadvertently heightened the perceived value of GEP for patients relative to other prognostic indicators. Conclusions Our study delineates the factors facilitating and restricting access to GEP, and highlights the roles of media and organization of services in the perceived value and utilization of GEP. The results identify a need for administrative changes and practice guidelines to support streamlined and standardized use of GEP tests.06/2014; 21(3):e426-33. DOI:10.3747/co.21.1782
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ABSTRACT: Background: The Biomarker Strategy Design has been proposed for trials assessing the value of a biomarker in guiding treatment in oncology. In such trials, patients are randomised to either receive the standard chemotherapy treatment or a biomarker-directed treatment arm, in which biomarker status is used to guide treatment. Methods: Motivated by a current trial, we consider an adaptive design in which two biomarkers are assessed. The trial is conducted in two stages. In the first stage, patients in the biomarker-guided arm are assessed using a standard and an alternative cheaper biomarker, with the standard biomarker guiding treatment. An analysis comparing biomarker results is then used to choose the biomarker to use for the remainder of the trial. The new biomarker is used if the results for the two biomarkers are sufficiently similar. Results: We show that in practical situations the first-stage results can be used to adapt the trial without type I error rate inflation. We also show that there can be considerable cost gains with only a small loss in power in the case where the alternative biomarker is highly concordant with the standard one. Conclusions: Adaptive designs have an important role in reducing the cost and increasing the clinical utility of trials evaluating biomarker-guided treatment strategies.British Journal of Cancer 03/2014; 110(8). DOI:10.1038/bjc.2014.156 · 4.82 Impact Factor