Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer

Woolf, David; Beresford, Mark; Li, S. P.; Dowsett, Mitchell; Sanghera, Bal; Wong, Wai Lup; Sonoda, Luke; Detre, Simone; Amin, Vivek; Ah-See, Mei-Lin; Miles, D. W.; Makris, Andreas

doi:10.1038/bjc.2014.207

Cited by 37 publications

(32 citation statements)

References 38 publications

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“…Small, single-center preliminary studies indicated good predictive value for response (11–14), whereas others did not (12,15–17). Our multicenter study suggested some utility for 18 F-FLT as an early predictor of response, but preliminary reports of other multicenter trials did not find a predictive value for 18 F-FLT (25).…”

Section: Discussionmentioning

confidence: 96%

A Phase II Study of 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688

et al. 2015

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Our objective was to determine whether early change in standardized uptake values (SUVs) of 3′deoxy-3′-18F-fluorothymidine (18F-FLT) using PET with CT could predict pathologic complete response (pCR) of primary breast cancer to neoadjuvant chemotherapy (NAC). The key secondary objective was to correlate SUV with the proliferation marker Ki-67 at baseline and after NAC. Methods This prospective, multicenter phase II study did not specify the therapeutic regimen, thus, NAC varied among centers. All evaluable patients underwent 18F-FLT PET/CT at baseline (FLT1) and after 1 cycle of NAC (FLT2); 43 patients were imaged at FLT1, FLT2, and after NAC completion (FLT3). The percentage change in maximum SUV (%ΔSUVmax) between FLT1 and FLT2 and FLT3 was calculated for the primary tumors. The predictive value of ΔSUVmax for pCR was determined using receiver-operating-characteristic curve analysis. The correlation between SUVmax and Ki-67 was also assessed. Results Fifty-one of 90 recruited patients (median age, 54 y; stage IIA–IIIC) met the eligibility criteria for the primary objective analysis, with an additional 22 patients totaling 73 patients for secondary analyses. A pCR in the primary breast cancer was achieved in 9 of 51 patients. NAC resulted in a significant reduction in %SUVmax (mean Δ, 39%; 95% confidence interval, 31–46). There was a marginal difference in %ΔSUVmax_FLT1-FLT2 between pCR and no-pCR patient groups (Wilcoxon 1-sided P = 0.050). The area under the curve for ΔSUVmax in the prediction of pCR was 0.68 (90% confidence interval, 0.50–0.83; Delong 1-sided P = 0.05), with slightly better predictive value for percentage mean SUV (P = 0.02) and similar prediction for peak SUV (P = 0.04). There was a weak correlation with pretherapy SUVmax and Ki-67 (r = 0.29, P = 0.04), but the correlation between SUVmax and Ki-67 after completion of NAC was stronger (r = 0.68, P < 0.0001). Conclusion 18F-FLT PET imaging of breast cancer after 1 cycle of NAC weakly predicted pCR in the setting of variable NAC regimens. Posttherapy 18F-FLT uptake correlated with Ki-67 on surgical specimens. These results suggest some efficacy of 18F-FLT as an indicator of early therapeutic response of breast cancer to NAC and support future multicenter studies to test 18F-FLT PET in a more uniformly treated patient population.

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Section: Discussionmentioning

confidence: 96%

A Phase II Study of 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688

et al. 2015

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“…In the neoadjuvant setting, the few studies are contradictory. A recent study including 20 women has reported disappointing results: FLT breast tumor uptake at [95]. In contrast, preliminary results of the ACRIN 6688 multicentric trials, presented at the 2014 ASCO meeting, found that FLT-PET after the first cycle of NAC was marginally predictive of pCR in 51 women [96].…”

Section: Changes In Tumor Cell Proliferationmentioning

confidence: 99%

Role of Positron Emission Tomography for the Monitoring of Response to Therapy in Breast Cancer

et al. 2015

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This review considers the potential utility of positron emission tomography (PET) tracers in the setting of response monitoring in breast cancer, with a special emphasis on glucose metabolic changes assessed with 18 F-fluorodeoxyglucose (FDG). In the neoadjuvant setting of breast cancer, the metabolic response can predict the final complete pathologic response after the first cycles of chemotherapy. Because tumor metabolic behavior highly depends on cancer subtype, studies are ongoing to define the optimal metabolic criteria of tumor response in each subtype.The recent multicentric randomized AVATAXHER trial has suggested, in the human epidermal growth factor 2-positive subtype, a clinical benefit of early tailoring the neoadjuvant treatment in women with poor metabolic response after the first course of treatment. In the bone-dominant metastatic setting, there is increasing clinical evidence that FDG-PET/computed tomography (CT) is the most accurate imaging modality for assessment of the tumor response to treatment when both metabolic information and morphologic information are considered. Nevertheless, there is a need to define standardized metabolic criteria of response, including the heterogeneity of response among metastases, and to evaluate the costs and health outcome of FDG-PET/CT compared with conventional imaging. New non-FDG radiotracers highlighting specific molecular hallmarks of breast cancer cells have recently emerged in preclinical and clinical studies. These biomarkers can take into account the heterogeneity of tumor biology in metastatic lesions. They may provide valuable clinical information for physicians to select and monitor the effectiveness of novel therapeutics targeting the same molecular pathways of breast tumor. The Oncologist 2015;20:94-104 Implications for Practice:18 F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is a molecular imaging exam. It can monitor breast cancer response to therapy earlier than the tumor shrinking observed with conventional imaging. This review focuses on the advantages and limits of FDG-PET for early determination of response, both in the neoadjuvant and metastatic settings. It discusses the different PET timing and metabolic criteria to define response that have been evaluated in previous studies. The development of new radiotracers of specific molecular pathways of breast cancer cells is also a challenging and promising research area to monitor the effectiveness of the new target treatments emerging in breast cancer.

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“…Correlation with immunohistochemistry measures of proliferation such as Ki-67 has been shown for several tumor types including breast cancer (18)(19)(20). The limitations of 18 F-FLT PET are in imaging the liver and the bone marrow because 18 F-FLT undergoes glucuronidation in the liver, leading to a high background uptake level, and in the bone marrow there is high uptake of 18 F-FLT, which is attributed to physiologic proliferation.…”

Section: Breast Cancer Proliferation Probesmentioning

confidence: 99%

The Use of Novel PET Tracers to Image Breast Cancer Biologic Processes Such as Proliferation, DNA Damage and Repair, and Angiogenesis

Kenny

2016

J Nucl Med

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The balance between proliferation and cell death is pivotal to breast tumor growth. Because of a combination of environmental and genetic factors leading to activation of oncogenes or inactivation of tumor suppressor genes, these processes become deregulated in cancer. PET imaging of proliferation, angiogenesis, and DNA damage and repair offers the opportunity to monitor therapeutic efficacy to detect changes in tumor biology that may precede physical size reduction and simultaneously allows the study of intratumoral and intertumoral heterogeneity.This review examines recent developments in breast cancer imaging using novel probes. The probes discussed here are not licensed for routine use and are at various stages of development ranging from preclinical development (e.g., the DNA repair marker γH2AX) to clinical validation in larger studies (such as the proliferation probe 3′-deoxy-3′-18 F-fluorothymidine [ 18 F-FLT]). In breast cancer, most studies have focused on proliferation imaging mainly based on 18 F-labeled thymidine analogs. Initial studies have been promising; however, the results of larger validation studies are necessary before being incorporated into routine clinical use. Although there are distinct advantages in using process-specific probes, properties such as metabolism need careful consideration, because high background uptake in the liver due to glucuronidation in the case of 18 F-FLT may limit utility for imaging of liver metastases.Targeting angiogenesis has had some success in tumors such as renal cell carcinoma; however, angiogenesis inhibitors have not been particularly successful in the clinical treatment of breast cancer. This could be potentially attributed to patient selection due to the lack of validated predictive and responsive biomarkers; the quest for a successful noninvasive biomarker for angiogenesis could solve this challenge. Finally, we look at cell death including apoptosis and DNA damage and repair probes, the most well-studied example being 18 F-annexin V; more recently, probes that target caspase endoproteases have been developed and are undergoing early clinical validation studies.Further clinical studies including analysis of test-retest variability are essential to determine sensitivity and future utility of these probes in breast cancer.

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Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer

Cited by 37 publications

References 38 publications

A Phase II Study of 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688

A Phase II Study of 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688

Role of Positron Emission Tomography for the Monitoring of Response to Therapy in Breast Cancer

The Use of Novel PET Tracers to Image Breast Cancer Biologic Processes Such as Proliferation, DNA Damage and Repair, and Angiogenesis

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Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast cancer

Cited by 37 publications

References 38 publications

A Phase II Study of 3′-Deoxy-3′-18F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688

A Phase II Study of 3′-Deoxy-3′-18F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688

Role of Positron Emission Tomography for the Monitoring of Response to Therapy in Breast Cancer

The Use of Novel PET Tracers to Image Breast Cancer Biologic Processes Such as Proliferation, DNA Damage and Repair, and Angiogenesis

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A Phase II Study of 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688

A Phase II Study of 3′-Deoxy-3′-¹⁸F-Fluorothymidine PET in the Assessment of Early Response of Breast Cancer to Neoadjuvant Chemotherapy: Results from ACRIN 6688