TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer (NCT02988986), a na phase 2 study. The primary outcome is Ki67 Expression.

2. Clinical Question

In statistical terms, this is a question about the endpoint’s observed change over time in a single group receiving the combination. Such a result can describe what was observed among participants measured, but without a concurrent comparison group it cannot isolate the treatment combination’s effect from other explanations for change. The registry also lists participant counts meeting certain preoperative endocrine prognostic index criteria and participants with pathological complete response as secondary outcomes. Their numerical results are not reported in the registry record.

3. Trial Design

This was an open-label phase II trial of neoadjuvant TAK-228 plus tamoxifen. The registry lists the study model as single group, allocation as NA, and masking as none. It records enrollment of 28 and a completed status. The sponsor was The Methodist Hospital Research Institute. The study start date was 2017-04-24, and the primary completion date was 2019-02-01.

The intervention description specifies oral TAK-228 at 30 mg weekly for 16 weeks and oral tamoxifen at 20 mg daily for 16 weeks. Both drugs were part of the same regimen; the record does not describe separate randomized arms. Because the study was open label, participants and study personnel were not masked according to the registry entry. Further information about outcome assessment procedures is not reported in the registry record.

The primary endpoint was Ki67 expression change from baseline to 6 weeks. Its stated unit is the percentage of cells with Ki67 expression, with the measure summarized as a median and inter-quartile range. The registry also names two secondary outcomes: the number of participants meeting certain preoperative endocrine prognostic index criteria and the number with pathological complete response. Seven outcome measures and one analysis are recorded, but the specific analysis details beyond the primary endpoint summary type are not reported in the registry record.

The study’s single-group design is central to interpretation. It can describe outcomes observed during the regimen, but it does not provide a randomized or concurrent control contrast. The record’s separate planning illustration assumes equal allocation between two arms and a normal approximation; it is explicitly not the trial’s own design. Those assumptions should not be mistaken for the actual single-group study structure.

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: Change in baseline Ki67 expression at 6 weeks

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 Ki67 Expression, measured over Baseline to 6 weeks.

The primary endpoint is change in Ki67 expression from baseline to 6 weeks. The registry defines the unit as the percentage of cells with Ki67 expression and specifies the median and inter-quartile range as the summary measures. The numerical endpoint values are not reported in the registry record. Consequently, the amount and direction of change, and the spread of the observed values, cannot be stated from the information recorded.

As a general statistical explanation, a median describes the central position of a distribution without requiring the mean to represent a typical observation. The inter-quartile range describes the spread of the central part of that distribution. These summaries can be useful when observations are not well represented by a mean or when a distribution is asymmetric. They do not, by themselves, show how precisely an estimate has been obtained; that requires additional information such as a confidence interval or other uncertainty measure.

Assessing a measure at baseline and again at 6 weeks allows the study to frame the endpoint as change over time. That makes the endpoint a short-term measure of a biological feature rather than a direct count of a clinical event such as pathological complete response. The registry lists pathological complete response separately as a secondary outcome. It does not report the method used to calculate or analyze individual changes, the number of observations available at each time point, or uncertainty around the primary endpoint estimate.

The registry identifies Ki67 expression as the primary outcome, but does not report numerical results in the record details. It is therefore not possible to assess whether the median changed, how variable the measurements were, or whether an observed change was compatible with little or no change. The endpoint’s role is clear; its result and precision are not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The trial’s design and endpoint summary determine which statistical questions can be answered. The study is described as single group, open label, with allocation listed as NA and masking as none. Its primary endpoint is a change in Ki67 expression between baseline and 6 weeks, summarized using a median and inter-quartile range. The registry record does not report a numerical primary result, confidence interval, or p-value, so the statistical methods can be explained only in relation to the stated design and summaries.

What does a single-group design estimate?

A single-group study can describe measurements and outcomes among participants who received the study regimen. When an endpoint is defined as change from baseline, the target description concerns change observed over time in that group. It is not a randomized treatment contrast. A concurrent control group would supply a comparison under a different condition; no such group is recorded for this trial.

This distinction is important for causal interpretation. A before-and-after change can be associated with the period during which treatment was given, but the design alone cannot separate treatment effects from other causes of change. General examples include natural change over time, measurement variation, and influences not controlled by the study design. These are general methodological possibilities, not findings reported for this trial. The registry entries do not provide enough information to determine which explanations, if any, affected the observed measurements.

Why report the median and inter-quartile range?

The median is a measure of the center of a set of observations. The inter-quartile range describes the spread of the central portion of those observations. As a general statistical point, these summaries are often used when the distribution may be asymmetric or when extreme observations could make a mean less representative of the center. They describe location and spread, but do not alone quantify uncertainty in the estimated change.

The record specifies these summaries for the primary outcome, but gives no values. Without them, it is not possible to characterize the observed distribution. An inter-quartile range is not a confidence interval: the former describes spread among observations, while the latter, as a general concept, expresses uncertainty about an estimate. The registry does not report an uncertainty interval for the primary result in the registry record.

What does the baseline-to-follow-up framing add?

Measuring an endpoint at baseline and at a later time can make change over time the focus of analysis. In general, analysis of repeated measurements should account for the relationship between measurements from the same participant. The registry’s description identifies the time frame and the endpoint as change, but does not report the calculation method, the statistical test, or whether participant-level measurements were analyzed in a particular way. No specific paired test or model should therefore be attributed to the study.

The time frame is baseline to 6 weeks, while the intervention description gives a 16-week regimen. These are distinct time references in the registry: the primary endpoint is defined at the earlier follow-up, and the treatment course is described as lasting 16 weeks. The registry entries do not explain why that primary endpoint time point was selected or whether other Ki67 measurements were collected.

How should uncertainty and significance be read?

A confidence interval is, in general, a range of values compatible with an estimate under a specified statistical procedure. Its width provides information about precision, while its location helps readers assess which values are plausible. A p-value, as a general concept, measures how incompatible data are with a specified null model, subject to the model’s assumptions; it is not the probability that a treatment works or that a result is due to chance. Neither a confidence interval nor a p-value for the primary endpoint is reported in the registry record.

Even when a statistical test is reported, its interpretation depends on the design, endpoint definition, analysis population, and assumptions. In a single-group study, statistical evidence that a within-group measure changed would not supply the missing randomized comparison. Statistical significance and causal evidence are not interchangeable. The record details do not identify a primary endpoint test or its assumptions.

What do the planning illustrations represent?

The record describes planning illustrations 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 planning assumptions, not a description of the actual single-group trial. The stated illustrations are not the trial’s own design and should not be interpreted as observed power. No illustration values are included in the registry entries, and the primary endpoint result needed to understand an effect-based planning calculation is not reported.

The two-arm assumption also differs from the recorded single-group model. A hypothetical planning calculation for a future comparison can be useful for exploring design requirements, but it does not create a control group in the completed study or convert a within-group change into a comparative estimate. The record says time-to-event illustrations use total events and other illustrations use participants per arm; no time-to-event primary endpoint is identified in the registry record.

What does over-dispersion mean in general?

For count outcomes, over-dispersion means that observed variability exceeds what a chosen statistical model expects. If not addressed, standard errors and uncertainty estimates can be misleading. This is a general statistical issue; the registry entries do not state that over-dispersion was assessed or that a count model was used. The primary endpoint is described as a percentage measure summarized by a median and inter-quartile range, and the analysis method is not reported in the registry record.

In short, the available design and endpoint details support an explanation of the target measurement and the limitations of a single-group comparison. They do not permit reconstruction of the analysis, assessment of its assumptions, or judgment about the estimated primary effect’s magnitude or precision.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures and one analysis. It names participant counts meeting certain preoperative endocrine prognostic index criteria and participants with pathological complete response as secondary outcomes. The primary outcome is Ki67 expression change from baseline to 6 weeks. The registry entries do not list all seven measures individually, describe how the single analysis relates to each outcome, or report results for the named secondary outcomes.

Multiplicity arises when several outcomes or statistical tests are considered. As a general statistical principle, examining multiple results can increase the chance of at least one apparently notable finding, depending on the analyses and decision process. Methods such as adjusting significance thresholds or defining a hierarchy can address particular multiplicity concerns, but the registry record does not report whether any adjustment, hierarchy, or other multiplicity strategy was used. The number of analyses recorded does not, on its own, establish how many tests were performed or whether multiplicity was addressed.

Missing-data handling is not reported in the registry record. The registry entries do not state how many participants contributed baseline or 6-week Ki67 measurements, how absent measurements were treated, or whether any imputation or sensitivity analysis was used. Enrollment of 28 is not the same as a reported analysis population, and the number included in each endpoint analysis is not stated.

The analysis populations are also not reported in the registry record. There is no description of whether results were intended for all enrolled participants, participants who started treatment, participants with measurements at both time points, or another defined group. Without these details, readers cannot determine how exclusions or missing observations might affect the endpoint summary. The registry also does not report a statistical analysis plan, interim analyses, or sample-size justification. These aspects should be treated as unreported, not inferred from the phase, enrollment, or completed status.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hyperglycemia (3.6%).

The registry lists a group titled TAK-228 and Tamoxifen, with 28 participants at risk for serious adverse events and 1 affected. It also lists 28 at risk for other adverse events and 28 affected. The recorded number of deaths is 0. These are separate safety entries, and the counts should be read according to their labels rather than combined into a new total.

Hyperglycemia is listed among the top serious terms at 3.6%. The registry entries do not provide further event-level details, the event’s timing, severity grading, or the method used to determine whether an event was related to treatment. The listed term and percentage therefore describe the registry entry; they do not establish causation. An adverse event occurring during a trial is not, by itself, proof that the intervention caused it.

As a general statistical point, safety counts are easier to interpret when the population at risk, observation period, event definitions, and handling of repeated events are clear. The record provides at-risk and affected counts for the two categories, but the duration of safety follow-up and whether the counts refer to participants or event episodes beyond the labels are not further described in the registry record. These limitations matter when comparing safety results across studies, especially where designs and follow-up differ.

The figures are descriptive registry entries. They do not provide a controlled estimate of excess risk, and no concurrent comparator group is recorded for this study. The record also does not report enough information to assess the full range of adverse events or the completeness of safety reporting.

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

The trial asks about Ki67 expression change from baseline to 6 weeks during treatment with TAK-228 plus tamoxifen. The registry identifies this as the primary endpoint and specifies the median and inter-quartile range as summaries. However, numerical results for that endpoint are not reported in the registry record. The meaning of the observed result cannot be characterized without the result itself and information about its uncertainty.

Even if a within-group change were reported, its interpretation would be bounded by the design. A single-group study has no concurrent control group to estimate what would have occurred under another condition. A change over time can be described, but it cannot by itself establish that the regimen caused that change. The open-label design and the absence of reported details about outcome assessment also need to be considered.

The registry names preoperative endocrine prognostic index criteria and pathological complete response as secondary outcomes. Their numerical results are not reported in the registry record. It is therefore not possible to use those outcomes to corroborate, qualify, or contrast with the primary endpoint from these registry entries. The number of outcome measures is recorded as seven, but the registry entries do not identify the results for the full set.

The safety entries report 1 participant affected by a serious adverse event, 28 affected by other adverse events, and 0 deaths, with 28 at risk in each listed category. Hyperglycemia appears among the top serious terms at 3.6%. Those figures describe recorded safety information; they are not a controlled comparison and do not, on their own, establish treatment causation.

Thus, the registry entries support a description of the study’s regimen, design, endpoint definition, and selected safety entries. They do not support a conclusion that the treatment works or does not work, nor do they establish how large or precise any primary endpoint effect was. A treatment conclusion would require results and an appropriate basis for comparison, neither of which can be posted by the endpoint definition alone.

13. Why This Trial Matters Statistically

This study illustrates why design and endpoint reporting must be read together. The primary endpoint is a short-term change in a biological measure, summarized with a median and inter-quartile range. That definition identifies what the investigators intended to measure, but without the numerical result it does not show what happened or how precisely it was estimated.

The single-group structure is equally important. A baseline-to-follow-up measure can describe change within the group receiving the regimen, but it does not provide the counterfactual comparison needed to separate treatment-associated change from other explanations. The open-label design is another feature of the evidence context. These are not technical footnotes: they define the claims that the study can support.

The record also provides an example of why planning calculations must be kept distinct from the completed trial design. Its planning illustration assumes equal allocation between two arms and a normal approximation, whereas the trial is recorded as single group. Such an illustration may address hypothetical future planning, but it does not change the design or provide a comparison for this study. It is not observed power.

Finally, safety counts and secondary outcome definitions should not be mistaken for a complete efficacy or safety assessment. The registry names secondary outcomes and records selected adverse-event information, but the numerical secondary results and fuller analysis details are not reported in the registry record. The study therefore matters statistically as a case in separating endpoint definition, observed evidence, uncertainty, and causal interpretation.

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 principal limitation for interpreting the primary outcome is that its numerical result is not reported in the registry record. Although the endpoint, time frame, unit, and summary type are specified, the observed median, inter-quartile range, and any uncertainty estimate are absent in the registry record. The direction, magnitude, and precision of change therefore cannot be assessed.

The single-group design has no concurrent control group, and the study is open label. Consequently, the design does not support a direct treatment comparison within the trial. The registry entries do not describe outcome assessor masking, measurement procedures, adherence, or other details that could help assess possible sources of bias. These details are not reported in the registry record.

The registry lists enrollment of 28, but the number contributing data to the primary endpoint analysis is not reported. The registry entries do not state whether all enrolled participants started treatment, completed the regimen, or had measurements at both time points. Missing-data methods and the analysis population are also not reported in the registry record. The enrollment count should not be treated as the endpoint denominator.

Two secondary outcomes are named, but their numerical results are not reported. The record notes seven outcome measures and one analysis without describing the complete outcome set, the analysis method, multiplicity handling, or a statistical analysis plan. A sample-size justification and interim analyses are not reported in the registry record.

Finally, the safety entries lack further detail about event timing, attribution, follow-up duration, and repeated events. The reported safety counts are descriptive and there is no concurrent control group for comparison. These limitations restrict what can be concluded about both endpoint effects and safety from the registry entries alone.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer — NCT02988986.
• Registry record last updated 2021-09-22; status last verified 2021-08.
• Results first posted 2021-07-27.
• 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, open-label phase II trial of neoadjuvant TAK-228 plus tamoxifen in newly diagnosed ER-positive, HER2-negative breast cancer. The design is single group, with allocation listed as NA and masking as none. Enrollment was 28. TAK-228 was administered orally at 30 mg weekly for 16 weeks, and tamoxifen orally at 20 mg daily for 16 weeks.

The primary outcome was change in Ki67 expression from baseline to 6 weeks, measured as the percentage of cells with Ki67 expression and summarized by median and inter-quartile range. Its numerical result is not reported in the registry record. Named secondary outcomes are participant counts meeting certain preoperative endocrine prognostic index criteria and participants with pathological complete response; their results are also not reported in the registry record.

Safety entries list 1 participant affected by a serious adverse event, 28 affected by other adverse events, and 0 deaths, with 28 at risk in each category. Hyperglycemia is listed among top serious terms at 3.6%. Analysis populations, missing-data handling, multiplicity methods, and further analysis details are not reported in the registry record.