Protocol for Women at Increased Risk of Developing Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Protocol for Women at Increased Risk of Developing Breast Cancer (NCT00291135), a na phase 2 study. The primary outcome is Change in Proliferation of Breast Epithelial Cells Obtained by Random Periareolar Fine Needle Aspiration..

2. Clinical Question

The clinical question is therefore about a measured tissue marker during a defined period of letrozole use in a particular high-risk population. It is not a direct comparison of letrozole with another treatment, no treatment, or continued hormone replacement therapy alone. Without a control group, observed changes over time cannot by themselves distinguish changes associated with letrozole from changes related to time, measurement variability, or other influences.

The outcome is a biomarker rather than breast cancer incidence. The registry description identifies Ki-67 staining as the means of assessing breast epithelial cell proliferation. It does not report whether the marker increased, decreased, or stayed similar, nor does it report the size or precision of any change. The posted record therefore establishes the population, treatment, follow-up interval, and intended primary measurement, but does not provide a numerical answer to the primary clinical question.

3. Trial Design

The registry describes a completed Phase 2, single-group study with 42 participants enrolled. The study is titled as a protocol for women at increased risk of developing breast cancer, and its official title describes examination of letrozole’s effect on breast biomarkers in high-risk postmenopausal women receiving hormone replacement therapy. The brief summary calls it a pilot study assessing breast-tissue risk markers during six months of letrozole.

Participants received oral letrozole 2.5 mg daily for six months. The primary outcome specifies measurements at baseline and six months. This is a within-participant time comparison in the sense that the same study population is assessed at both stated time points; it is not a comparison between independently assigned treatment groups. The registered model is single group, allocation is listed as not applicable, and masking is listed as none. A separate control arm and random assignment are not part of the registered design.

The registry lists the study as completed, with a start date of 2003-01 and primary completion date of 2008-10. These dates describe the record’s study timeline; they do not establish how long each participant was followed beyond the six-month endpoint timeframe. The registry states that all subjects completed the study and were used for analysis. It does not provide a detailed account of recruitment, adherence, protocol deviations, or the timing and handling of individual measurements.

The registered endpoint is change in proliferation of breast epithelial cells obtained by random periareolar fine needle aspiration. The result is defined in terms of the change in the percentage of cells positive for Ki-67, with the median and full range specified as the summary format. Although the endpoint and summary format are described, the numerical findings are not reported in the registry record. The record also does not report the statistical analysis used to compare baseline and six-month values.

The record’s sample-size planning assumptions describe an illustrative two-arm calculation with equal allocation, a two-sided significance level of 0.05, a normal approximation, and an effect defined as a fraction of the observed effect. Those assumptions are not the registered single-group design. The numerical planning outputs and a sample-size justification for the study’s actual design are not reported in the registry record.

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

Analysis population for the primary outcome, as defined in the registry: All subjects completed study and were used for analysis

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 Change in Proliferation of Breast Epithelial Cells Obtained by Random Periareolar Fine Needle Aspiration., measured over Baseline, 6 months.

The primary endpoint concerns proliferation of breast epithelial cells, assessed using Ki-67 staining in tissue obtained by random periareolar fine needle aspiration. The outcome is expressed as the change in the percentage of cells positive for Ki-67 between baseline and six months. The registry specifies the median and full range as the summary statistics, and describes immunocytochemistry as the method used to assess Ki-67.

Ki-67 is a marker used to identify cells engaged in proliferation. In general, measuring a tissue marker can provide information about a biological process in the sampled tissue. It is not the same as measuring a clinical event such as a breast cancer diagnosis. A change in a biomarker should therefore be interpreted as a change in that measured marker, not automatically as a change in future cancer risk or clinical outcomes.

The median describes the middle observation when values are ordered. The full range describes the lowest and highest observed values. In general, these summaries can be useful when individual values are unevenly distributed or when extreme observations make a mean less representative of a typical value. The registry does not report the actual median change or range, so neither the direction nor the magnitude of the observed endpoint can be assessed from the posted record.

The stated timeframe is baseline and six months. The registry identifies the analysis population as all subjects who completed the study and says they were used for analysis. It does not state whether the change was calculated for each participant and then summarized, nor does it give details of missing or unevaluable tissue samples. The endpoint definition is consequently clear about the marker and time points, while the reported numerical result and analysis details are absent.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry presents this as a single-group study with a baseline and six-month assessment. The primary outcome is a change in the percentage of cells positive for Ki-67, summarized using the median and full range. The record does not report an inferential analysis, a confidence interval, a p-value, or the numerical endpoint values. The methods that can be explained from the record are therefore limited to the outcome definition, the stated summary format, and the design characteristics. Any additional statistical explanation below is general context rather than a claim about the analysis actually used.

What does the median describe?

The median is the middle value in an ordered set of observations. General statistical context: unlike the arithmetic mean, it is not strongly pulled toward an unusually high or low observation. For a study that summarizes change using a median, the statistic describes the center of the observed changes, not necessarily the change experienced by every participant. A median alone does not describe how tightly observations cluster around that center. The registry’s use of the full range would give the minimum-to-maximum span, but the actual median and range are not reported.

The record does not explain precisely how the change values were formed or whether the median was calculated from participant-level changes. That distinction matters in a repeated-measures study: one approach is to calculate each participant’s change and summarize those changes, while another is to summarize measurements at each time point and compare the summaries. These approaches answer different statistical questions. The analysis method used for the registered endpoint is not reported in the registry record.

Why does a single-group design matter?

General statistical context: a baseline-to-follow-up comparison uses information from participants measured at more than one time. The observations from the same person are related, so methods for paired data generally account for that relationship. The registry identifies two time points but does not name the test or model used. It would therefore be inappropriate to attribute a particular paired procedure, model, or adjustment to this study.

A single-group comparison can describe the change observed during the study interval. It does not, on its own, supply the counterfactual comparison needed to estimate what would have happened to the same participants without the intervention. General statistical context: a concurrent control group can help distinguish treatment-associated change from background changes over time, although design and analysis choices still matter. This study has no separate control group according to the registry record.

What would a confidence interval add?

General statistical context: a confidence interval expresses the uncertainty around an estimate under a stated statistical procedure and its assumptions. It helps readers assess how compatible the data are with a range of possible underlying values. A point estimate without an uncertainty measure can give an incomplete picture, especially in a pilot study. No confidence interval is reported for the primary endpoint, so the precision of any estimated change cannot be assessed from the registry record.

A p-value, if reported, would address how unusual data at least as extreme as those observed would be under a specified null model. It would not, by itself, convey the size or clinical importance of a change. No p-value or statistical test for the primary endpoint is reported. General explanation of these concepts should not be mistaken for evidence that the study used a particular test or model.

How should the planning assumptions be read?

The registry describes a planning illustration based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The target effect is described as a stated fraction of the observed effect. These are assumptions for a hypothetical planning calculation; they do not describe the registered trial design, which is single group. Numerical planning results are not reported in the registry record, and the numerical observed effect needed to evaluate those illustrations is also absent.

General statistical context: sample-size calculations depend on assumptions about the effect to detect, variability, error rates, allocation, and the analysis method. A planning illustration is not a measure of the probability that a completed study found a statistically significant result. It is not observed power. The registry does not report a sample-size justification for the actual single-group study, so the planning assumptions should not be presented as the study’s original design rationale.

What can be concluded from the named analysis population?

The registry states that all subjects completed the study and were used for analysis. This identifies the intended analysis population at a broad level, but it does not specify the exact number with evaluable Ki-67 measurements at each time point, the treatment of any missing assay values, or whether all enrolled participants contributed to the primary endpoint. The statistical analysis plan and handling rules are not reported. Without those details and without the numerical endpoint result, the registered summaries do not allow an independent assessment of the analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary outcome measure: change in the percentage of breast epithelial cells positive for Ki-67 between baseline and six months. It does not report the numerical result or any statistical test for that outcome. The registry record does not describe a multiplicity strategy, such as a hierarchy of outcomes, an adjustment for multiple tests, or a distinction between confirmatory and exploratory analyses.

General statistical context: multiplicity arises when several outcomes, time points, subgroups, or statistical tests are examined. If many tests are conducted, the chance of at least one apparently notable result can increase unless the analysis plan accounts for that testing structure. The number and nature of all analyses conducted are not reported in the registry record, so the scope of any multiplicity issue cannot be assessed. The fact that one primary outcome measure is listed does not establish that no other outcomes or analyses were examined.

The record states that all subjects completed the study and were used for analysis. It does not give a participant flow account or detailed information about missing data, unavailable samples, exclusions, or deviations. The exact number with usable Ki-67 measurements at both time points is not reported in the registry record. It is also not reported whether the analysis population was defined before results were examined or how any incomplete measurements would have been handled.

General statistical context: missing-data methods rely on assumptions about why measurements are absent, and different methods can produce different estimates. A statement that participants completed a study does not, by itself, establish that every planned measurement was obtained or that no outcome data were missing. Since the registry does not describe missing-data handling, no particular imputation, complete-case, or other approach should be attributed to this trial.

The statistical analysis plan, including any prespecified modeling choices or sensitivity analyses, is not reported in the registry record. Consequently, the available description does not establish which analyses were prespecified, how multiple outcomes were handled, or how incomplete outcome data affected the primary analysis.

11. 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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists 42 participants at risk for serious adverse events and 0 with a serious adverse event in the Letrozole group. It lists 42 participants at risk for other adverse events and 42 affected in that category. These counts refer to the registry’s serious and other adverse-event categories; they do not report the types, severity grades, timing, or duration of the non-serious events. The top serious-event terms are not listed.

The entry for deaths is null, which means deaths are not reported in the registry record; it should not be interpreted as a reported count of zero. Similarly, the serious adverse-event count of 0 is a reported value for the listed group and category. The other-adverse-event count indicates that all 42 participants in the at-risk count were recorded as affected in that category, but the registry does not identify which events occurred or whether any participant had more than one event.

General statistical context: event counts describe what was recorded in the study population over the reported period. In a single-group study, they do not provide a comparative estimate of excess risk attributable to treatment. The safety figures should therefore be read as descriptive registry counts, not as a comparison with an untreated or alternative-treatment group. The record does not provide further details needed to characterize the adverse events.

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

The registry record documents a completed Phase 2 pilot study of oral letrozole 2.5 mg daily for six months in postmenopausal women at increased risk of breast cancer who were receiving hormone replacement therapy. Its primary endpoint concerns the change in the percentage of breast epithelial cells positive for Ki-67, assessed in samples obtained by random periareolar fine needle aspiration at baseline and six months. The record specifies the median and full range as the summary format and states that all subjects completed the study and were used for analysis.

The record does not report the numerical endpoint result. It therefore does not establish the direction, magnitude, or precision of the observed Ki-67 change. No conclusion that the marker increased, decreased, or remained stable can be drawn from the posted results. The study’s completion status and endpoint description do not replace the missing estimate.

The design also does not support a randomized treatment comparison: it is registered as single group, with allocation not applicable and no masking. General statistical context: an observed change from baseline to follow-up in a single group can describe what happened over time among participants, but it cannot isolate the effect of treatment from other possible explanations for change. There is no concurrent control group in the registered design.

The endpoint measures a breast-tissue biomarker. It is not a direct measure of breast cancer incidence, survival, or another clinical outcome. General clinical and statistical context: a biomarker result cannot automatically be translated into a clinical benefit or a change in future disease risk. The registry does not report a clinical cancer outcome or a demonstrated relationship between the measured Ki-67 changes and such outcomes in this study.

The safety record lists 0 participants with serious adverse events among 42 at risk and 42 affected by other adverse events among 42 at risk. The types of other events are not described, and the death entry is not reported. These counts are descriptive and, without a comparison group or further event details, do not answer comparative safety questions.

In short, the record is informative about the population, regimen, design, endpoint, and stated completion of the study. It does not provide the primary numerical result, an estimate of its precision, or a controlled comparison. Its scope should remain a pilot assessment of a tissue marker rather than evidence about a clinical outcome.

13. Why This Trial Matters Statistically

This trial is statistically notable because it places a within-group biomarker question in a population and treatment context that are clearly described, while leaving the numerical outcome result unavailable in the registry record. The endpoint definition is specific: change in the percentage of breast epithelial cells positive for Ki-67 from baseline to six months, summarized by median and full range. Those details make clear what the study intended to measure, but without the estimate and its spread the central statistical finding cannot be assessed.

The single-group structure also illustrates an important distinction between measurement over time and causal comparison. Repeated measures can describe how a marker changes among participants during follow-up. General statistical context: a change observed after treatment is not automatically an estimate of the treatment’s causal effect, because there is no concurrent control group to represent what would have happened over the same period in the absence of the intervention. The registry’s allocation and model entries make that design limitation explicit.

The biomarker endpoint further highlights the difference between an intermediate biological measure and a clinical outcome. Ki-67 staining is used to assess proliferation in sampled breast tissue. General statistical context: a biomarker can be useful for studying biological activity, but it does not by itself establish a change in disease incidence or another patient-level outcome. Careful interpretation requires keeping the measured construct distinct from broader claims.

The record also distinguishes descriptive safety counts from comparative estimates. It reports serious and other adverse-event categories for the single treatment group, but does not provide detailed event descriptions or a control-group rate. The counts can be stated as registry observations; they cannot establish comparative safety.

Finally, the planning assumptions described in the record refer to a hypothetical two-arm calculation, whereas the registered trial is single group. General statistical context: planning calculations depend on design and assumptions and should not be treated as outcomes from the completed study. The numerical planning outputs and actual primary endpoint estimate are not reported. This makes the record a useful example of why design, endpoint reporting, and the availability of numerical results all matter when interpreting clinical statistics.

14. 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 main trial-specific limitation is the absence of the numerical primary endpoint result in the registry record. Although the endpoint is defined and the summary format is named, the median change and full range are not reported. The direction, magnitude, and dispersion of the observed Ki-67 changes are consequently unknown from the posted results. No confidence interval, p-value, or other precision measure is reported.

The registered design is single group, with allocation listed as not applicable and masking as none. There is no separate control group described. This means the design is not a randomized comparison and cannot distinguish an observed time change from other influences on the marker. Any interpretation must also remain specific to the enrolled population: postmenopausal women at increased risk of breast cancer who were receiving hormone replacement therapy.

The endpoint is a tissue biomarker rather than a clinical cancer outcome. The registry does not report breast cancer incidence or another clinical endpoint that would connect the biomarker measurement to a clinical event. The record therefore cannot establish from this endpoint whether later disease outcomes changed.

Although the registry states that all subjects completed and were used for analysis, it does not describe the number of evaluable samples at each time point, missing assay values, adherence, protocol deviations, or how any incomplete data were handled. The statistical method used to derive and compare the endpoint is not reported. Nor does the record describe a multiplicity plan, sensitivity analyses, or a detailed prespecified analysis plan.

The safety data are also limited in detail. The registry reports serious adverse events and other adverse events as counts, but does not list the types of other events or provide further characterization. The death count is not reported. These limitations restrict interpretation to the specific registry entries rather than a broader evaluation of safety or comparative effects.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Protocol for Women at Increased Risk of Developing Breast Cancer — NCT00291135.
• Registry record last updated 2016-06-15; status last verified 2016-05.
• Results first posted 2014-02-07.
• 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.

18. Record Summary

NCT00291135 is listed as a completed Phase 2, single-group pilot study of letrozole in postmenopausal women at increased risk of breast cancer who were receiving hormone replacement therapy. The registry lists 42 participants enrolled. The regimen was oral letrozole 2.5 mg daily for six months, with the primary assessment at baseline and six months.

The primary endpoint was change in the percentage of breast epithelial cells positive for Ki-67, assessed by immunocytochemistry in tissue obtained by random periareolar fine needle aspiration. The median and full range were specified as summary statistics. The registry states that all subjects completed the study and were used for analysis, but does not report the numerical endpoint result, its precision, or the statistical test used.

The study has no registered control group and is not a randomized comparison. Serious adverse events were recorded for 0 of 42 participants at risk; other adverse events were recorded for 42 of 42 at risk. The event types are not detailed, and deaths are not reported in the registry record.