Selecting Breast Cancer Patients for Chemotherapy: The Opening of the UK OPTIMA Trial

Bartlett, John M.S.; Canney, Peter; Campbell, A. I.; Cameron, David; Donovan, Jenny; Dunn, Janet A.; Earl, Helena; Francis, Adele; Hall, Peter; Harmer, Victoria; Higgins, Helen; Hillier, Loretta M.; Hulme, Claire; Hughes-Davies, Luke; Makris, Andreas; Morgan, Adrienne; McCabe, Chris; Pinder, Sarah; Poole, Christopher; Rea, Daniel; Stallard, Nigel; Stein, Robert

doi:10.1016/j.clon.2012.10.005

Cited by 37 publications

(24 citation statements)

References 46 publications

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“…4 Most prognostic tests provide an estimate of relapse risk following the treatment for ER+ breast cancer, but still lack predictive value for novel targeted treatment options. 2, 4 These multiparametric tests, which include OncotypeDx® (Genomic Health Inc.), 5, 6 Prosigna ™ (NanoString Technologies, Inc.), 7–9 MammaPrint® (Agendia Inc.), 10, 11 Breast Cancer Index (BioTheranostics Inc.), 12, 13 and EndoPredict (Sividon Diagnostics GmbH), 14 all provide broadly similar clinical utility. 15, 16 Although each is derived from RNA abundance studies, there are surprisingly few overlapping genes between different RNA signatures.…”

Section: Introductionmentioning

confidence: 99%

Molecular stratification of early breast cancer identifies drug targets to drive stratified medicine

et al. 2017

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Many women with hormone receptor-positive early breast cancer can be managed effectively with endocrine therapies alone. However, additional systemic chemotherapy treatment is necessary for others. The clinical challenges in managing high-risk women are to identify existing and novel druggable targets, and to identify those who would benefit from these therapies. Therefore, we performed mRNA abundance analysis using the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial pathology cohort to identify a signature of residual risk following endocrine therapy and pathways that are potentially druggable. A panel of genes compiled from academic and commercial multiparametric tests as well as genes of importance to breast cancer pathogenesis was used to profile 3825 patients. A signature of 95 genes, including nodal status, was validated to stratify endocrine-treated patients into high-risk and low-risk groups based on distant relapse-free survival (DRFS; Hazard Ratio = 5.05, 95% CI 3.53–7.22, p = 7.51 × 10−19). This risk signature was also found to perform better than current multiparametric tests. When the 95-gene prognostic signature was applied to all patients in the validation cohort, including patients who received adjuvant chemotherapy, the signature remained prognostic (HR = 4.76, 95% CI 3.61-6.28, p = 2.53× 10−28). Functional gene interaction analyses identified six significant modules representing pathways involved in cell cycle control, mitosis and receptor tyrosine signaling; containing a number of genes with existing targeted therapies for use in breast or other malignancies. Thus the identification of high-risk patients using this prognostic signature has the potential to also prioritize patients for treatment with these targeted therapies.

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Section: Introductionmentioning

confidence: 99%

Molecular stratification of early breast cancer identifies drug targets to drive stratified medicine

et al. 2017

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“…While breast oncologists are eagerly awaiting the results from three ongoing randomized clinical trials (Rxponder [36], MINDACT [37], OPTIMA [38]) to address this question, Ki67 IHC is intended to guide clinicians to weigh risk-benefit ratio of adjuvant chemotherapy as this is widely available and financially acceptable in most laboratories. Our study revealed that low Ki67 alone may not provide enough prognostic information for clinicians to abort adjuvant chemotherapy in node negative or node positive (LN=1-3) ES-HPBC.…”

Section: Discussionmentioning

confidence: 99%

Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer

Feng

Kornaga²,

Dean³

et al. 2016

Oncotarget

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IntroductionThis study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes.Methods532 formalin-fixed paraffin-embedded specimens of resected primary breast tumors were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome.ResultsRemarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02).ConclusionsThese data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.

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“…Moreover, threshold values for these multiparameter molecular markers are still controversial, there is no specific data on their performance in young women, and the majority of the world has no access to this technology for logistic or financial reasons. Prospective data from the ongoing trials evaluating the performance of gene-expression assays are awaited to reassess the prognosis and benefit of adjuvant treatment according to age and tumor biology in the modern era and to better identify those patients that may be safely spared adjuvant chemotherapy [88][89][90][91].…”

Section: Expert Opinionmentioning

confidence: 99%

News on the medical treatment of young women with early-stage HER2-negative breast cancer

Lambertini

Poggio

Vaglica

et al. 2016

Expert Opinion on Pharmacotherapy

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For women candidates to receive (neo)adjuvant chemotherapy, anthracycline- and taxane-based regimens are standard of care. In high-risk patients, dose-dense regimens should be preferred; in women with triple-negative breast cancer and BRCA mutations, the addition of platinum compounds may also be considered. Several adjuvant endocrine therapy options have become available for the treatment of premenopausal women with early-stage luminal breast cancer. Specifically, young patients at low risk of relapse may be safely spared chemotherapy: endocrine therapy alone with tamoxifen for 5 years is the most appropriate treatment. In women at higher risk of relapse, ovarian function suppression is therapeutic: in this scenario, luteinizing hormone-releasing hormone agonists (LHRHa) should be considered in addition to tamoxifen or aromatase inhibitors. To women concerned about the possible risk of chemotherapy-induced premature ovarian failure, the use of temporary ovarian suppression with LHRHa should be proposed as a valid strategy to potentially preserve ovarian function and fertility.

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Selecting Breast Cancer Patients for Chemotherapy: The Opening of the UK OPTIMA Trial

Cited by 37 publications

References 46 publications

Molecular stratification of early breast cancer identifies drug targets to drive stratified medicine

Molecular stratification of early breast cancer identifies drug targets to drive stratified medicine

Low Ki67/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer

News on the medical treatment of young women with early-stage HER2-negative breast cancer

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