I-SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy

Barker, AD; Sigman, C. C.; Gj, Kelloff; Hylton, NM; Berry, DA; Esserman, LJ

doi:10.1038/clpt.2009.68

Cited by 672 publications

(478 citation statements)

References 11 publications

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“…CA 15-3, CA 27.29, and CEA are biomarkers for monitoring; ER, PR and HER-2 are biomarkers for treatment planning; and uPA and PAI-1 are biomarkers for recurrent risk prediction [19]. While these are the only markers ASCO approved for clinical use, ASCO does not discourage the use of other novel or innovative approaches in the context of clinical trials (e.g., I-SPY 2 trial [156]). For future advancement in clinically useful biomarkers, well-designed, collaborative studies involving the inclusion of specimens-procured, processed, and analyzed using standard operating procedures-from large cohorts of consenting patients and healthy volunteers (for example, in Ireland such studies are possible, as facilitated by the All Ireland Irish Clinical Oncology Research Group (ICORG), as well as through international collaborations) should help in identifying and validating biomarkers panels which can be translated to the clinic, in the interest of cancer patients.…”

Section: Limitations Of Blood-based Biomarkers and Future Directionsmentioning

confidence: 99%

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

Friel

Corcoran

Crown

et al. 2010

Breast Cancer Res Treat

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Early detection of cancer is vital to improved overall survival rates. At present, evidence is accumulating for the clinical value of detecting occult tumor cells in peripheral blood, plasma, and serum specimens from cancer patients. Both molecular and cellular approaches, which differ in sensitivity and specificity, have been used for such means. Circulating tumor cells and extracellular nucleic acids have been detected within blood, plasma, and sera of cancer patients. As the presence of malignant tumors are clinically determined and/or confirmed upon biopsy procurement-which in itself may have detrimental effects in terms of stimulating cancer progression/metastases-minimally invasive methods would be highly advantageous to the diagnosis and prognosis of breast cancer and the subsequent tailoring of targeted treatments for individuals, if reliable panels of biomarkers suitable for such an approach exist. Herein, we review the current advances made in the detection of such circulating tumor cells and nucleic acids, with particular emphasis on extracellular nucleic acids, specifically extracellular mRNAs and discuss their clinical relevance.

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Section: Limitations Of Blood-based Biomarkers and Future Directionsmentioning

confidence: 99%

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

Friel

Corcoran

Crown

et al. 2010

Breast Cancer Res Treat

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“…All candidates are screened for biomarker status, including estrogen receptor, ESR1(ER) and progesterone receptor, PGR(PR) expression (+/−), HER2 expression/amplification (+/−) and MammaPrint® 70 gene expression prognostic signature (MP high, MP low) 14 . The focus of the study is on disease at an early, potentially curable state.…”

Section: Novel Trial Designmentioning

confidence: 99%

“…Biopsy samples are collected at 4 points during the treatment cycle. The endpoint of the study is defined as pathologic complete response (pCR), based upon tumor tissue collected at surgery 14 . The FDA has recently released a draft guidance outlining the terms under which pCR is an appropriate endpoint for accelerated approval of antineoplastic agents for breast cancer when used in the neoadjuvant setting 16 .…”

Section: Novel Trial Designmentioning

confidence: 99%

“…Other efficiencies are accomplished by the multidrug trial using a single control arm for multiple experimental therapies. The fact that it is more likely for a patient to be assigned to a therapy, particularly a therapy that is statistically more likely to work with the individual biology of that patient’s tumor could also increase patient satisfaction and lead to increased trial participation 14,24–28 .…”

Section: Benefits To Adaptive Platform Design Illustrated By I-spy2mentioning

confidence: 99%

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NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Venook¹,

Arcila²,

Benson³

et al. 2014

J Natl Compr Canc Netw

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Defining treatment susceptible or resistant populations of cancer patients through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents both opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies because potential patient populations are divided into ever-smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists and information developers.

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“…[1][2][3] Adaptive clinical trials such as the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial and the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2 (I-SPY2) trial in breast cancer are recent examples of the use of biopsies to evaluate the molecular composition of evolving tumors and to detect biomarkers for patient stratification. 4,5 There is no universal method for biospecimen processing since this differs depending on the demands of the analytical platforms. Some journals now require key preanalytical variables to be reported, according to the framework provided by the Biospecimen Reporting for Improved Study Quality (BRISQ) guidelines.…”

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confidence: 99%

Next-generation biobanking of metastases to enable multidimensional molecular profiling in personalized medicine

et al. 2013

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Great advances in analytical technology coupled with accelerated new drug development and growing understanding of biological challenges, such as tumor heterogeneity, have required a change in the focus for biobanking. Most current banks contain samples of primary tumors, but linking molecular signatures to therapeutic questions requires serial biopsies in the setting of metastatic disease, next-generation of biobanking. Furthermore, an integration of multidimensional analysis of various molecular components, that is, RNA, DNA, methylome, microRNAome and post-translational modifications of the proteome, is necessary for a comprehensive view of a tumor's biology. While data using such biopsies are now regularly presented, the preanalytical variables in tissue procurement and processing in multicenter studies are seldom detailed and therefore are difficult to duplicate or standardize across sites and across studies. In the context of a biopsydriven clinical trial, we generated a detailed protocol that includes morphological evaluation and isolation of high-quality nucleic acids from small needle core biopsies obtained from liver metastases. The protocol supports stable shipping of samples to a central laboratory, where biopsies are subsequently embedded in support media. Designated pathologists must evaluate all biopsies for tumor content and macrodissection can be performed if necessary to meet our criteria of 460% neoplastic cells and o20% necrosis for genomic isolation. We validated our protocol in 40 patients who participated in a biopsy-driven study of therapeutic resistance in metastatic colorectal cancer. To ensure that our protocol was compatible with multiplex discovery platforms and that no component of the processing interfered with downstream enzymatic reactions, we performed array comparative genomic hybridization, methylation profiling, microRNA profiling, splicing variant analysis and gene expression profiling using genomic material isolated from liver biopsy cores. Our standard

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I-SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy

Cited by 672 publications

References 11 publications

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer

NCCN Working Group Report: Designing Clinical Trials in the Era of Multiple Biomarkers and Targeted Therapies

Next-generation biobanking of metastases to enable multidimensional molecular profiling in personalized medicine

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