Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer (NCT00853996), a na phase 2 study. The primary outcome is Change in the Percentage of Breast Epithelial Cells Expressing Ki-67, From Baseline to 6 Months.

2. Clinical Question

The study concerns a biological measure of cell proliferation, not a direct count of breast cancers prevented. Breast epithelial cells were obtained by random periareolar fine needle aspiration at baseline and at 6 months, and Ki-67 expression was assessed by immunocytochemistry. The registered primary endpoint is the change in the percentage of cells expressing Ki-67.

The registry describes a phase II trial intended to study acolbifene in premenopausal women at high risk of breast cancer. It does not provide results for the primary endpoint, so the direction and magnitude of the observed change cannot be assessed from the registry record. It also does not report a control-group result. Consequently, the record cannot establish how any change compares with what would have happened without acolbifene.

Other registered outcomes concern mammographic breast density, hormone concentrations, hot flashes, and muscle or joint complaints. These measures address biological responses and reported symptoms, but their results are also not reported in the registry record. The central statistical question is therefore clear, while the posted information does not show its answer.

3. Trial Design

This is a phase II, single-group study of acolbifene hydrochloride in premenopausal women at high risk of breast cancer. The registry lists enrollment of 25, allocation as not applicable, and masking as none. No randomized or concurrent control group is described. The study status is completed; the recorded start is 2009-02 and primary completion is 2010-12.

Participants in the registered prevention group were to receive oral acolbifene hydrochloride once daily for 6 months in the absence of unacceptable toxicity. The registry describes this planned regimen, but does not report the duration actually received by participants, adherence, dose interruptions, or how many participants completed treatment. Those details are not reported in the registry record.

The primary outcome is change in the percentage of breast epithelial cells expressing Ki-67 from baseline to 6 months. Cells were obtained by random periareolar fine needle aspiration and assessed for Ki-67 immunocytochemical expression. Secondary outcomes include changes in mammographic breast density and serum estradiol, bioavailable estradiol, and testosterone concentrations, as well as reports of hot flashes and muscle or joint complaints.

A single-group baseline-to-follow-up design can describe change over time among participants with measurements, but it does not provide a like-for-like control comparison. Changes may reflect treatment, natural variation, measurement variation, or other influences over the study period. The registry record does not report a protocol-level statistical analysis plan, details of participant selection, or methods for handling incomplete follow-up. The rationale for the enrollment target is 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

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 the Percentage of Breast Epithelial Cells Expressing Ki-67, From Baseline to 6 Months, measured over Baseline to 6 months.

The primary endpoint is change from baseline to 6 months in the percentage of breast epithelial cells expressing Ki-67. Ki-67 expression was assessed by immunocytochemistry in cells collected through random periareolar fine needle aspiration. The registry describes Ki-67 as a measure of proliferation in breast epithelial cells.

In general, a proliferation measure describes the extent to which cells are in an active growth cycle. Measuring the proportion of cells expressing a proliferation marker can therefore provide a biological outcome that differs from a clinical outcome such as the occurrence of breast cancer. A change in this marker should not be treated as a count of cancers prevented, nor does it alone establish a change in future cancer risk.

The registered summary statistic is the median change, with inter-quartile range as the stated measure of dispersion. In general, the median describes the middle of the observed distribution, while the inter-quartile range describes the spread of its central portion. These summaries can be useful when individual changes are skewed or affected by extreme observations. The registry record does not report the actual median change, its inter-quartile range, the number with evaluable paired samples, or a confidence interval.

The baseline-to-6-month framing makes the endpoint a within-participant change when measurements are available at both time points. A valid interpretation of such a change depends on how missing samples and differences in measurement are handled; those procedures are not reported in the registry record. Without the endpoint result and its uncertainty, the direction, size, and precision of the observed change cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is defined as a change in Ki-67 expression between baseline and 6 months. In general, a change outcome compares measurements from different times. If the same participant contributes measurements at both times, the observations are paired: each participant's follow-up value is interpreted in relation to that participant's own baseline value. This can account for stable differences between participants, but it does not remove time-related influences or provide a control comparison. The registry record does not report the exact calculation used to define each participant's change or the analysis method used to summarize those changes.

Why report a median and inter-quartile range?

The registry specifies the median and inter-quartile range for the primary endpoint. In general, the median is the central value after observations are ordered. The inter-quartile range describes the interval between the lower and upper quartiles and gives a sense of how variable the central observations are. These summaries are less sensitive to unusually large or small observations than the mean and standard deviation. They may be appropriate when change scores are asymmetric or include outliers, but the registry record does not report the shape of the observed data or the rationale for choosing these summaries.

A median and inter-quartile range do not by themselves quantify the precision of an estimated treatment effect. A confidence interval, when reported, describes uncertainty around an estimate under the assumptions of the analysis. It is not a guarantee that the true value lies within the interval, nor does it correct for bias from a weak design or incomplete data. No confidence interval for the primary endpoint is reported in the registry record.

What can a single-group comparison tell us?

A before-and-after summary can describe how measured values changed among participants with relevant observations. It cannot, by itself, distinguish an intervention-related change from other changes over the same period. A randomized comparator can help address this by showing how outcomes change under a different assigned condition, subject to the quality of the trial and its analysis. No comparator group is registered for this study. The registry lists allocation as not applicable and masking as none.

In general, measurement variability matters when the endpoint is derived from biological samples and laboratory assessment. Differences may arise from sample collection, processing, or assessment as well as from underlying biology. Consistent procedures and clear analysis methods help readers understand how such variation was addressed. The record describes the sampling method and immunocytochemical assessment, but procedures for quality control, repeat measurements, or blinded assessment are not reported in the registry record.

How should planning illustrations be understood?

The record's planning assumptions describe illustrative calculations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. These are not the registered trial design: the study is single-group and has no registered control arm. Planning calculations ask what sample size could be needed under stated assumptions; they do not show what this study achieved. In particular, such calculations are not observed power. The endpoint estimate used to generate the illustrations is not reported in the registry record, so the illustrations cannot be independently interpreted as evidence of an outcome.

In general, a planning calculation depends on the effect size chosen, the variability assumed, the significance level, allocation, and the statistical model. A different effect or variability assumption can change the calculated sample size. The registry does not report the protocol's sample-size justification or establish that the planning assumptions were used to design this study. The stated two-arm, equal-allocation assumptions should therefore not be mistaken for a feature of the actual study.

What analysis details remain unclear?

The record does not report the statistical test or model for the primary endpoint, whether an estimate was adjusted for any covariates, how missing observations were treated, or which analysis population was used. These details affect both the estimate and the uncertainty attached to it. A reader would also need the number of participants with measurements at each time point, and the way incomplete pairs were handled, to assess how representative the endpoint analysis may be. These details are not reported in the registry record.

General statistical interpretation should distinguish the registered endpoint, the analysis actually performed, and the result posted. The endpoint definition is available, but the analysis method and result are not. Consequently, no significance test, confidence interval, or effect estimate should be inferred from the study description or from the planning assumptions.

10. Multiplicity, Missing Data and Analysis Populations

The record lists 7 outcome measures and 5 analyses. The primary outcome concerns change in Ki-67 expression; secondary outcomes concern mammographic breast density, serum hormone concentrations, hot flashes, and muscle or joint complaints. Because several outcomes are registered, there may be multiple opportunities to examine results. In general, repeated testing can make chance findings more likely across a collection of analyses, which is why prespecified priorities and multiplicity methods can matter.

The registry record does not report whether any adjustment for multiple comparisons was planned or used, how the 5 analyses relate to the listed outcomes, or which analyses were considered primary for statistical inference. It does not report a statistical analysis plan or clarify whether all registered outcomes were analyzed. The presence of several outcomes alone does not establish that a multiplicity adjustment was necessary or absent in the actual analysis; that information is not reported in the registry record.

Missing-data methods and analysis populations are also not reported in the registry record. The primary outcome requires baseline and 6-month measurements to characterize within-participant change, but the record does not state how participants without measurements at both time points were handled. It does not report the number with evaluable samples, whether analyses included all enrolled participants or a subset, or whether any imputation was used.

These omissions limit assessment of selection and precision. If follow-up is incomplete, the participants with observed measurements may differ from those without them; the direction and size of any resulting bias cannot be determined from the registry record. Without analysis-population definitions, missing-data methods, and outcome results, neither the extent of missingness nor its influence on the findings can be evaluated.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports 0 participants with serious adverse events among 25 at risk in the acolbifene group. It reports 20 participants with other adverse events among 25 at risk. These are the recorded affected-participant counts for separate categories; they are not a treatment-versus-control comparison. No control group is registered.

The record lists no top serious adverse-event terms. This means specific serious-event terms are not listed in the registry record; it does not provide event descriptions or further detail about the serious-event field. The deaths entry is not reported in the registry record, so it should not be interpreted as a reported count of zero.

These figures do not describe event timing, duration, severity grading, relationship to treatment, or whether multiple events occurred in an individual. The record also does not report how adverse events were collected or the length of safety follow-up. The counts therefore provide limited descriptive information and cannot establish comparative safety or quantify risk relative to another treatment or no treatment.

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

The study's registered primary question concerns change in a biological marker: the percentage of breast epithelial cells expressing Ki-67 from baseline to 6 months. The registry record describes how the cells were collected and the marker assessed, but does not report the endpoint result. It is therefore not possible to characterize the direction, magnitude, or precision of the observed change from this record.

Even a reported change would need careful interpretation. This study has a single-group design, with no registered control group, so a before-and-after difference would not alone show that acolbifene caused the difference. General influences such as natural variation and measurement variation can affect repeated measurements. The record also does not report the analysis method, missing-data handling, or analysis population, all of which are relevant to understanding the estimate.

Ki-67 expression is not the same outcome as breast cancer incidence. The endpoint can describe a cellular proliferation measure, but it does not directly state how many cancers developed or were prevented. No cancer-incidence outcome result is reported in the registry record. The study's prevention framing should therefore be distinguished from the specific endpoint for which the registry provides a definition.

The registry also records secondary outcomes and adverse-event counts, but does not provide their detailed results. The safety counts are descriptive and lack a comparison group. The deaths field is not reported, and no top serious adverse-event terms are listed. None of these entries should be expanded into conclusions beyond what is recorded.

Overall, the record documents a completed phase II, single-group study with enrollment of 25 and a planned 6-month oral regimen. It supplies a defined primary biological endpoint and limited adverse-event counts, but does not report the outcome estimates or the statistical details needed to judge their uncertainty. The record alone therefore supports description of the study question and design, not a conclusion about clinical benefit or comparative safety.

13. Why This Trial Matters Statistically

This study illustrates why the outcome definition and the design need to be read together. The primary endpoint is a within-participant change in Ki-67 expression, a measure of cellular proliferation. Such a measure can describe biological change, but it is not itself a clinical event such as breast cancer incidence. Keeping that distinction clear prevents a biomarker outcome from being interpreted as direct evidence about cancer prevention.

The single-group design also matters. Baseline and follow-up measurements can describe change over time, but without a control group there is no direct comparison that separates treatment-associated change from other influences. This is a design limitation, not a judgment about the direction or size of an unreported result.

The record also shows why numerical results and analysis details are essential to statistical interpretation. It defines a median change and inter-quartile range as the primary summary, but does not report the estimate, its spread, a confidence interval, or the method of analysis. Without those details, readers cannot evaluate precision or determine how the observed data relate to the study question.

Finally, planning assumptions must be kept separate from the trial that was conducted. The registry's illustrative calculations assume equal allocation between two arms, while the registered study is single-group. Such calculations are not observed power and cannot replace outcome reporting. This distinction is useful when evaluating registry records that include hypothetical sample-size illustrations alongside a design that does not match their assumptions.

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 limitation for interpretation is that the registry record does not report the primary endpoint result. It gives no median change in Ki-67, inter-quartile range, confidence interval, or analysis test. The direction and precision of the endpoint therefore cannot be assessed. Results for the registered secondary outcomes are also not reported in the registry record.

The single-group design has no registered comparator, so any observed baseline-to-6-month change would not, on its own, establish that acolbifene caused it. The record lists allocation as not applicable and masking as none. It does not report details that would allow assessment of laboratory blinding or measurement quality control.

The registry does not report the criteria used to define high risk, detailed eligibility criteria, actual treatment exposure, adherence, or the number of participants with complete endpoint measurements. Missing-data methods and analysis populations are not reported. These omissions make it difficult to assess who contributed to the outcome analysis and whether incomplete follow-up could have affected interpretation.

The sample-size illustrations use assumptions for a two-arm, equal-allocation comparison, unlike the registered single-group design. The protocol's sample-size justification and the observed effect underlying those illustrations are not reported in the registry record. The illustrations should not be taken as a description of the study's actual design or as evidence of observed power.

For safety, the record gives counts of affected participants but not event descriptions, timing, severity details, or a control comparison. Deaths are not reported in the registry record. These limits apply specifically to interpreting the posted record and do not establish that the underlying study collected no further information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Acolbifene in Preventing Cancer in Premenopausal Women at High Risk of Breast Cancer — NCT00853996.
• Registry record last updated 2018-01-17; status last verified 2018-01.
• Results first posted 2017-03-13.
• 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

The registry record describes a completed phase II, single-group study of oral acolbifene hydrochloride in premenopausal women at high risk of breast cancer. Enrollment is listed as 25. The recorded study start is 2009-02, and primary completion is 2010-12. The registered regimen was once-daily treatment for 6 months in the absence of unacceptable toxicity.

The primary endpoint is change from baseline to 6 months in the percentage of breast epithelial cells expressing Ki-67, measured by immunocytochemical assessment of cells collected through random periareolar fine needle aspiration. The registry specifies a median and inter-quartile range, but does not report the endpoint result.

Secondary outcomes cover mammographic breast density, hormone concentrations, hot flashes, and muscle or joint complaints. Their results are not reported in the registry record. The safety entries report 0 participants with serious adverse events and 20 with other adverse events, each among 25 at risk. Deaths are not reported. The record does not describe a comparator group or provide the analysis and missing-data details needed to assess the outcome estimates.