F-18 16 Alpha-Fluoroestradiol-Labeled Positron Emission Tomography in Predicting Response to First-Line Hormone Therapy in Patients With Stage IV Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for F-18 16 Alpha-Fluoroestradiol-Labeled Positron Emission Tomography in Predicting Response to First-Line Hormone Therapy in Patients With Stage IV Breast Cancer (NCT00602043), a na phase 2 study. The primary outcome is Best Overall Response.

2. Clinical Question

In practical terms, the study asked whether an imaging measure of estrogen-receptor activity could help identify hormone sensitivity in metastatic disease. Participants were expected to begin endocrine therapy within 2 weeks of the FES PET scan, and response assessment was specified at 3 and 6 months. FES PET was the diagnostic marker under study; endocrine therapy was the clinical treatment context in which response was assessed. The registry record does not report which endocrine therapies participants actually received or whether every participant began treatment as expected.

The study enrolled 20 participants and is listed as completed. Its design can describe observations within the enrolled group, but it does not establish how outcomes compare with an untreated group or with a different imaging strategy. Since no outcome analyses are posted in the registry record, the central association between baseline FES uptake and clinical benefit cannot be estimated from the recorded results.

3. Trial Design

This was a phase 2, single-group diagnostic-imaging study sponsored by the National Cancer Institute. The registry record lists an enrollment of 20 and a completed status. The recorded start was 2008-09, and primary completion was 2011-08. Allocation is listed as not applicable, and masking as none.

Participants in the diagnostic group underwent an FES PET scan. They also underwent standard clinical FDG-PET or FDG-PET/CT up to 14 days before the FES PET scan. The listed interventions include F-18 16 alpha-fluoroestradiol, fludeoxyglucose F 18, PET, computed tomography, and laboratory biomarker analysis. These are diagnostic procedures and imaging agents in the registry description, not randomized treatment assignments.

The clinical outcome was assessed after endocrine therapy. The record says participants were expected to start therapy within 2 weeks of FES imaging, with response assessment at 3 and 6 months. It describes size-based criteria for participants with measurable disease under RECIST version 1.1, and FDG PET changes for participants whose disease was not evaluable by RECIST 1.1, largely those with bone-dominant metastatic breast cancer.

A single-group design is suited to recording imaging and clinical observations in the enrolled cohort. Without a randomized comparator, the study does not isolate the effect of an imaging strategy against an alternative strategy. The registry record does not report further details of the protocol, the statistical analysis plan, or how participants were selected for the different response-assessment approaches. These omissions limit the conclusions that can be drawn about design choices and analysis procedures.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Best Overall Response, measured over Up to 6 months.

The primary outcome is titled Best Overall Response, with the recorded unit described as patients with progressive disease and a timeframe of up to 6 months. The outcome description focuses the primary question on whether baseline FES uptake differed between participants with progressive disease and those with another outcome at 6 months. The registry record does not report a numerical result for this outcome.

Response assessment depended on whether disease was measurable by RECIST version 1.1. In participants with at least one measurable site, size-based response criteria were used. For participants without disease evaluable by RECIST 1.1, largely those with bone-dominant metastatic breast cancer, serial FDG PET was used. A decline in FDG PET SUV of 30% or more was considered a response, while an increase of 20% or more was considered progressive disease.

These criteria provide a way to classify clinical course for the intended comparison with baseline FES uptake. Combining response approaches accommodates the different ways disease may be evaluated in this population, but it also means that response classification was not described as relying on one measure for every participant. The registry record does not report the number classified in each response category, the distribution of FES uptake, or an estimate of the relationship between uptake and response. Thus the endpoint definition is available, but its observed result is not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study’s stated primary question involves a diagnostic measurement and a later clinical classification. Baseline FES uptake is the imaging measure of interest, while the clinical outcome is progressive disease versus another outcome at 6 months. The registry record describes this planned comparison but lists no analyses and reports no numerical outcome results. The methods below explain how such data are generally interpreted; they do not imply that any particular analysis was performed in this trial.

What does an association measure?

In general, an association describes how an outcome varies with a measured factor. For this study, that would mean comparing clinical outcome across levels or categories of baseline FES uptake. An association is not automatically causal. In a single-group study without randomized allocation, other characteristics may also relate to uptake and outcome. The registry record does not report an adjusted association, a prespecified uptake cut point, or the covariates considered in an analysis.

What does a binary outcome show?

The recorded primary outcome is a count-based endpoint: participants with progressive disease. A binary outcome classifies each assessed participant into a defined category, such as progressive disease or another outcome. Counts and proportions can describe how often each category occurred, while an estimate comparing categories of an imaging marker can quantify an association. Here, the record contains no primary outcome counts or estimate. No proportions, effect estimates, confidence intervals, or p-values for the primary endpoint are reported.

In general, a confidence interval expresses the uncertainty around an estimated quantity under the assumptions of the analysis. A wider interval indicates less precision, while a narrower interval indicates greater precision. Without an estimate and interval, the precision of the intended FES-outcome relationship cannot be evaluated. This is especially important when interpreting a small enrolled cohort: a result can be uncertain even when an estimate is available, and the enrollment alone does not tell readers how precise a result would be.

Why are response definitions important?

The registry uses different assessment approaches according to whether disease was measurable by RECIST version 1.1. Participants with at least one measurable site were assessed using size-based criteria. For those without disease evaluable by RECIST 1.1, largely participants with bone-dominant metastatic breast cancer, serial FDG PET was used. The specified FDG PET rules treat a decline in SUV of 30% or more as response and an increase of 20% or more as progressive disease. These rules define how certain observations enter outcome categories. The registry record does not report how many participants were assessed by each approach or how the outcome categories were distributed.

In general, when outcome measurement differs across participants, interpretation depends on whether the approaches classify clinical status comparably and are applied consistently. The record describes the rules but does not report information that would establish consistency, such as reviewer procedures or handling of ambiguous assessments. It would be inappropriate to infer those details.

What is the role of the comparator?

The study is recorded as single-group, with allocation not applicable and no masking. There is no randomized control arm. The primary comparison is within the cohort: FES uptake in relation to subsequent clinical outcome. In general, this can help describe whether a marker tracks with an outcome, but it does not establish that the marker-guided strategy performs better than another strategy. It also does not separate the influence of the marker from other factors that may be related to clinical response.

How should planning calculations be read?

The stated sample-size framework is a planning illustration, not the design justification reported by the investigators. It uses a two-sided significance level of 0.05, equal allocation between two hypothetical arms, and a normal approximation, with the target effect expressed as a fraction of an observed effect. For time-to-event settings, the framework describes total events; for other settings, it describes participants per arm. Those assumptions do not match the recorded single-group diagnostic design as a randomized two-arm comparison. Any resulting sample-size values are planning illustrations, not observed power and not evidence that the trial was designed to detect a particular effect. The registry record does not report the investigators’ sample-size justification or the observed primary effect needed to interpret such a calculation as specific to this endpoint.

More generally, power is a design property calculated under assumptions about the effect, variability, and analysis. It is not a measure of how convincing an observed result is. No observed primary analysis is posted, so no trial-specific conclusion about statistical significance, power, or precision can be drawn. The record also does not report an interim-analysis plan or the statistical model, if any, used for the intended association.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Diagnostic FES: Average FES SUVmean >1.5, no Negat", "Diagnostic FES: Patients With FES Negative Sites o")
n      <- c(13, 3)
events <- c(5, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Diagnostic FES: Average FES SUVmean >1.5, no Negat  13  5  38.5  13.9  68.4  17.7  64.5  17.7  64.9
ARM  Diagnostic FES: Patients With FES Negative Sites o  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists the primary outcome, Best Overall Response, and three secondary outcome types: number of participants with clinical benefit, time to progression, and correlation of FES uptake with ER assays. Four outcome measures are recorded overall. No analyses are listed, and no results are posted for these outcomes.

Multiplicity arises when several outcomes, time points, or statistical comparisons are examined. In general, conducting multiple tests can increase the chance of finding an apparently notable result by chance. A prespecified analysis plan and an approach to multiplicity can help readers understand which results were confirmatory and how results should be interpreted. The registry record does not report a multiplicity plan, a hierarchy among outcomes, or whether adjustments were intended.

Missing-data handling and analysis populations are also not reported in the registry record. The enrollment of 20 does not establish how many participants completed imaging, began endocrine therapy, had follow-up assessments, or were evaluable for the primary endpoint. The record does not state how missing assessments, withdrawals, or unevaluable scans were handled. It is not possible to determine whether the analysis used all enrolled participants or a subset.

These omissions matter because outcome counts and their uncertainty depend on who was included and how incomplete assessments were treated. They also prevent assessment of whether the primary and secondary outcomes were analyzed as planned. No particular missing-data method, analysis population, or multiplicity correction should be assumed.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The safety record lists 20 participants at risk for serious adverse events and zero participants affected. It also lists 20 participants at risk for other adverse events and zero affected. These are the posted counts for the diagnostic FES group. They should be read as recorded event counts, not as a comparative safety analysis, since the study had no randomized control arm.

The number of participants at risk is the denominator recorded for each category. The registry record does not provide event details for serious adverse events, and no serious adverse-event terms are listed. The deaths entry is not populated with a count, so deaths are not reported in the registry record; it should not be interpreted as a reported zero.

Zero affected participants in the posted counts means that no events are recorded in those categories in this record. It does not, by itself, establish that no events occurred outside the recorded reporting window or that safety information is complete. The registry record does not report additional details about safety monitoring or follow-up. These counts also do not address the primary question about FES uptake and clinical response.

13. What the Result Does, and Does Not, Mean

The registry record documents a phase 2 study designed to examine FES PET as a marker of hormone sensitivity in metastatic breast cancer. It gives a defined primary clinical question, an imaging procedure, response-assessment rules, an enrollment of 20, and a completed status. These details explain what the study set out to evaluate.

What the record does not provide is the observed primary outcome or the analysis connecting FES uptake with progressive disease versus other outcomes at 6 months. There is no posted count of participants with progressive disease, no association estimate, no confidence interval, and no p-value. Therefore, the available registry results do not show the direction or magnitude of any predictive relationship, or how precisely such a relationship was estimated.

Even if an association were reported, a single-group study would not establish that using FES imaging improves clinical decisions or outcomes. There is no randomized comparison of an FES-guided approach with an alternative approach. The distinction is important: a marker may be associated with an outcome without evidence that acting on the marker changes that outcome.

The registry’s response criteria indicate how clinical outcomes were intended to be classified, including the use of RECIST version 1.1 for measurable disease and FDG PET for disease not evaluable by RECIST. They are operational definitions, not evidence about the participants’ actual responses. Similarly, the zero adverse-event counts are safety entries and do not provide evidence about the imaging marker’s predictive performance.

The study can therefore be described by its design and stated aims, but the registry record does not support a conclusion about whether baseline FES uptake predicted clinical benefit. That question remains unanswered by the posted outcome results.

14. Why This Trial Matters Statistically

This trial is statistically notable for asking a marker-validation question in a setting where the outcome and the marker are measured in different ways: FES PET characterizes baseline uptake, while later clinical course is classified using RECIST-based size criteria or FDG PET. Such a design raises useful questions about how diagnostic measurements relate to outcomes and how consistently outcomes can be defined across different patterns of metastatic disease.

The study also illustrates the distinction between a planned question and a reported analysis. The registry contains an outcome definition and names several secondary outcome types, but records no analyses and no numerical outcome results. Without those results, readers cannot assess effect direction, magnitude, or precision. A complete protocol description is not a substitute for the actual endpoint data and analysis.

The single-group design is another important statistical feature. It can support descriptive study of imaging and clinical outcomes in a cohort, but it does not provide a randomized comparison of diagnostic strategies. Associations in such a cohort are not the same as evidence that decisions based on the imaging test improve outcomes. The design determines which inferences can be made, regardless of the clinical interest of the question.

Finally, the study underscores why safety counts, enrollment, and endpoint results answer different questions. The safety record lists zero affected participants in the serious and other adverse-event categories, and enrollment is 20. Neither fact supplies the missing analysis of whether FES uptake was associated with response. Statistical interpretation depends on matching the available evidence to the specific question being asked.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most immediate limitation of the registry record is that it contains no posted primary outcome analysis. The key relationship between baseline FES uptake and clinical benefit at 6 months cannot be evaluated without the outcome counts or an association estimate. The record also gives no confidence interval or other measure of precision.

The single-group design has no randomized comparator. As a result, it cannot directly compare an FES-based diagnostic strategy with another strategy or establish the effect of using imaging to guide care. Any observed association within the cohort would also need to be interpreted in light of other participant characteristics, but the registry record does not report an adjusted analysis.

The endpoint description allows different assessment approaches depending on whether disease was measurable by RECIST version 1.1. The record does not report the number assessed by each approach, how ambiguous assessments were handled, or whether outcome ascertainment was reviewed consistently. That limits evaluation of how comparable the classifications were across participants.

Although enrollment is recorded as 20, the registry does not report the size of the primary analysis population, the completeness of follow-up, or the handling of missing imaging and clinical assessments. The statistical analysis plan, sample-size justification, and multiplicity approach are also not reported in the registry record. The safety entries give counts but do not provide further event descriptions, and deaths are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: F-18 16 Alpha-Fluoroestradiol-Labeled Positron Emission Tomography in Predicting Response to First-Line Hormone Therapy in Patients With Stage IV Breast Cancer — NCT00602043.
• Registry record last updated 2020-02-19; status last verified 2020-02.
• Results first posted 2014-12-25.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT00602043 is a completed phase 2, single-group study sponsored by the National Cancer Institute. It enrolled 20 participants and evaluated F-18 16 alpha-fluoroestradiol PET imaging as a marker of hormone sensitivity in metastatic breast cancer. The registry lists a start of 2008-09 and primary completion of 2011-08. Allocation is not applicable, and masking is none.

The primary outcome concerns Best Overall Response and the relationship between baseline FES uptake and progressive disease versus another outcome at 6 months. Response assessment was described using RECIST version 1.1 for measurable disease and serial FDG PET for disease not evaluable by RECIST. The registry record lists no analyses and reports no primary outcome results, so the predictive association and its precision cannot be assessed from the posted data.

The safety record lists 20 participants at risk and zero affected for both serious and other adverse-event categories. Deaths are not reported in the registry record. The statistical analysis plan, analysis populations, missing-data methods, and sample-size justification are not reported.