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Introduction: Carcinogenesis is driven by an array of complex genomic patterns; these patterns can render an individual resistant or sensitive to certain chemotherapy agents. The Personalized Oncogenomics (POG) project at BC Cancer has performed integrative genomic analysis of whole tumour genomes and transcriptomes for over 700 patients with advanced cancers, with an aim to predict therapeutic sensitivities. The aim of this study was to utilize the POG genomic data to evaluate a discrete set of biomarkers associated with chemo-sensitivity or-resistance in advanced stage breast and colorectal cancer POG patients. Methods: This was a retrospective multi-centre analysis across all BC CANCER sites. All breast and colorectal cancer patients enrolled in the POG program between July 1, 2012 and November 30, 2016 were eligible for inclusion. Within the breast cancer population, those treated with capecitabine, paclitaxel, and everolimus were analyzed, and for the colorectal cancer patients, those treated with capecitabine, bevacizumab, irinotecan, and oxaliplatin were analyzed. The expression levels of the selected biomarkers of interest (EPHB4, FIGF, CD133, DICER1, DPYD, TYMP, TYMS, TAP1, TOP1, CKDN1A, ERCC1, GSTP1, BRCA1, PTEN, ABCB1, TLE3, and TXNDC17) were reported as mRNA percentiles. Results: For the breast cancer population, there were 32 patients in the capecitabine cohort, 15 in the everolimus cohort, and 12 in the paclitaxel cohort. For the colorectal cancer population, there were 29 patients in the bevacizumab cohort, 12 in the oxaliplatin cohort, 29 in the irinotecan cohort, and 6 in the capecitabine cohort. Of the biomarkers evaluated, the strongest associations were found between Bevacizumab-based therapy and DICER1 (P = 0.0445); and between capecitabine therapy and TYMP (P = 0.0553). Conclusions: Among breast cancer patients, higher TYMP expression was associated with sensitivity to capecitabine. Among colorectal cancer patients, higher DICER1 expression was associated with sensitivity to bevacizumab-based therapy. This study supports further assessment of the potential predictive value of mRNA expression of these genomic biomarkers. [ABSTRACT FROM AUTHOR]

Objective To help facilitate economic evaluations of oncology treatments, we mapped responses on cancer-specific instrument to generic preference-based measures. Methods Cancer patients (n = 367) completed one cancer-specific instrument, the FACT-G, and two preference-based measures, the EQ-5D and SF-6D. Responses were randomly divided to form development (n = 184) and cross-validation (n = 183) samples. Relationships between the instruments were estimated using ordinary least squares (OLS), generalized linear models (GLM), and censored least absolute deviations (CLAD) regression approaches. The performance of each model was assessed in terms of how well the responses to the cancerspecific instrument predicted EQ-5D and SF-6D utilities using mean absolute error (MAE) and root mean squared error (RMSE). Results Physical, functional, and emotional well-being domain scores of the FACT-G best explained the EQ-5D and SF-6D. In terms of accuracy of prediction as measured in RMSE, the CLAD model performed best for the EQ-5D (RMSE = 0.095) whereas the GLM model performed best for the SF-6D (RMSE = 0.061). The GLM predicted SF-6D scores matched the observed values more closely than the CLAD and OLS. Conclusion Our results demonstrate that the estimation of both EQ-5D and SF-6D utility indices using the FACT-G responses can be achieved. The CLAD model for the EQ-5D and the GLM model for the SF-6D are recommended. Thus, it is possible to estimate quality-adjusted life years for economic evaluation from studies where only cancer-specific instrument have been administered. [ABSTRACT FROM AUTHOR]

The article presents a study which assessed the impact on survival of population-based access to new agents for the treatment of metastatic breast cancer (MBC). In the study, all patients with a first diagnosis of distant metastases in each of the time cohorts were identified and characterized, and their survival was compared. The results showed that survival in Cohort 1 and Cohort 2 was similar but survival was longer in Cohort 3.

Rearrangements of the neuregulin (NRG1) gene have been implicated in breast carcinoma oncogenesis. To determine the frequency and clinical significance of NRG1 aberrations in clinical breast tumors, a breast cancer tissue microarray was screened for NRG1 aberrations by fluorescent in situ hybridization (FISH) using a two-color split-apart probe combination flanking the NRG1 gene. Rearrangements of NRG1 were identified in 17/382 cases by FISH, and bacterial artificial chromosome array comparative genomic hybridization was applied to five of these cases to further map the chromosome 8p abnormalities. In all five cases, there was a novel amplicon centromeric to NRG1 with a minimum common region of amplification encompassing two genes, SPFH2 and FLJ14299. Subsequent FISH analysis for the novel amplicon revealed that it was present in 63/262 cases. Abnormalities of NRG1 did not correlate with patient outcome, but the novel amplicon was associated with poor prognosis in univariate analysis, and in multivariate analysis was of prognostic significance independent of nodal status, tumor grade, estrogen receptor status, and human epidermal growth factor receptor (HER)2 overexpression. Of the two genes in the novel amplicon, expression of SPFH2 correlated most significantly with amplification. This amplicon may emerge as a result of breakpoints and chromosomal rearrangements within the NRG1 locus.Oncogene (2005) 24, 7281–7289. doi:10.1038/sj.onc.1208892; published online 18 July 2005 [ABSTRACT FROM AUTHOR]

The authors explore the significance of neoadjuvant trials in the search for new therapeutic strategies with the ability to assess response to systemic treatment. They discuss and offer comments on several studies, with an emphasis on the NeOAdjuvant Herceptin study of trastuzumab by Luca Gianni et al conducted among women with a locally advanced or inflammatory breast cancer. They discuss the clinical goals of neoadjuvant therapy, as well as the need to further exploit neoadjuvant trials in the search for new therapeutic strategies.

Thymidine kinase 1 (TK1) plays a critical role in DNA synthesis and cell proliferation. Recent studies have shown potential for serum TK1 activity (sTKa) as a prognostic marker and indicator of early response to endocrine therapy in advanced breast cancer. The aim of this study is to assess the correlation between sTKa and patient outcome. The Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) was a double-blind, double-dummy, randomised trial of fulvestrant versus exemestane after progression on non-steroidal aromatase inhibitor therapy, in postmenopausal women with advanced breast cancer. Retrospective analyses of serum archived from EFECT were conducted. sTKa was assessed using the DiviTum® assay on samples collected at baseline, after three and six months of endocrine therapy, and at disease progression. The median time to progression (mTTP) for patients with low baseline sTKa levels was 5.03 months (95% confidence interval [CI]: 3.91–5.89) versus 2.57 months (95% CI: 2.04–3.52) in patients with high sTKa baseline levels (P < 0.0001). On treatment, patients whose sTKa increased from baseline had a significantly shorter mTTP (3.39 months, 95% CI: 2.14–4.11) than those without an sTKa increase (5.39 months, 95% CI: 4.01–6.68) (P = 0.0045). Similar results were observed in the separate EFECT treatment arms. After adjusting for major prognostic factors, sTKa remained an independent marker. sTKa is a potential circulating prognostic marker in patients with advanced breast cancer treated with endocrine therapy. It may also represent a tool for upfront identification of endocrine therapy resistance and early positive response to therapy. Independent validation of these results is warranted. • Retrospective analyses of sera from the Evaluation of Faslodex versus Exemestane Clinical Trial to assess the association between serum thymidine kinase 1 activity (sTKa) and outcome. • Low baseline sTKa correlated with longer median time to progression (mTTP). • Stable or decreased sTKa while on endocrine treatment correlated with longer mTTP. • After adjusting for prognostic factors, sTKa remained an independent marker. • sTKa may identify early endocrine resistance and monitor response in sensitive disease. [ABSTRACT FROM AUTHOR]